Research Questions

Journal Published
Schizophrenia Bulletin, Volume 44, Issue 2, March 2018, Pages 398–408,

Year Published
2017

Full Article
SystemicZBiomarkersZofZAcceleratedZAgingZinZSchizophrenia.pdf

Hypothesis

This study aims to evaluate evidence for accelerated biological aging in schizophrenia using systemic markers of biological aging. 

• Are aging-related biomarkers abnormal in schizophrenia? 

• Which biomarkers are specifically involved in aging in schizophrenia? 

• What clinical characteristics in schizophrenia are risk vs protective factors for accelerated biological aging? 

• Are aging-related biomarkers abnormal in schizophrenia? 

• Which biomarkers are specifically involved in aging in schizophrenia?

Background

• Schizophrenia is associated with markedly increased physical comorbidity and mortality.

• Physiological changes seen throughout the body with normal aging occur at an earlier age in people with schizophrenia than in healthy comparison subjects (HCs).

• Younger adults with schizophrenia are prone to diseases associated with aging such as diabetes and cardiovascular disorders 

• The average life span of a person with schizophrenia is 15–20 years shorter than that of an unaffected person

• Patients with schizophrenia have 2–12 times higher mortality rate than age-comparable general population.

• Given that lifespans are generally increasing for the population as a whole, understanding alterations in the aging process within schizophrenia is clearly imperative

• Two-thirds of the excess deaths in schizophrenia are not from suicide, but due to “natural causes” such as cardiac and metabolic disorders.

• This has led to a provocative suggestion that schizophrenia is not only a brain disease but rather, a disease of the whole body.

• Prior attempts to address systemic biological defects in schizophrenia failed,at least in part, because of a lack of specific and sensitive systemic biomarkers of aging. 

• Several prior reviews have examined accelerated aging in schizophrenia from various perspectives (including metabolic disease cognition, brain structure, telomere length (TL),and oxidative stress, however, no publication, to our knowledge, has provided a comprehensive review of multiple biomarkers relevant to the hypothesis of accelerated biological aging in schizophrenia.

• Although many comparisons and similarities have been drawn between schizophrenia and normal aging, we have a limited understanding as to which biomarkers are most altered with age in schizophrenia.

• The identification of biological factors that underlie alterations in the aging process may permit identification of individuals at high risk for accelerated aging, and potentially open up consideration of new avenues for intervention.

• Though the recent literature has frequently used the term “accelerated biological aging,” no review has synthesized evidence for this claim at system level.

Journal Published
Am J Psychiatry

Year Published
2016

Full Article
AcceleratedZBrainZAgingZinZSchizophrenia.pdf

Hypothesis

Does the progressive brain loss in schizophrenia reflect accelerated aging of the brain, or is it caused by a fundamentally different process?

Background

• Cross-sectional MRI studies have convincingly shown that brain volumesin schizophrenia patients are smaller than those in healthy subjects.
• Some of these abnormalities (such as changes in white matter volume and structure) are present beforeillness onset and aremostlikely of a developmental, possibly genetic, nature and appear to be stable over time.
• In contrast, other brain changes (such as reductionsin gray matter volume) become more pronounced during the course of the illness.
• Although several studies suggest that gray matter volume reductions are related to outcome, psychosis, relapses, medication, cannabis use, and genetic liability, the cause and nature of the progressive loss of gray matter are still unclear.
• Indeed, despite the multitude of longitudinal neuroimaging studies, a basic question on the progressive brain loss in schizophrenia remains unaddressed.

Description

• Human aging is characterized by a chronic, low-grade inflammation, known as “inflammaging.
• Inflammaging is an important risk factor for both morbidity and mortality in older adults, which can be potentially prevented and even cured 
• A recent review concluded that the evidence on inflammation in schizophrenia is provocative.
• Elevated levels of pro-inflammatory cytokines and chemokines in schizophrenia including:

1. Interleukin (IL)-6
2. IL-1β
3. Tumor necrosis factor alpha (TNFα)
4. Eotaxin-1
5. Eotaxin-2
6. monocyte chemoattractant protein-1
7. macrophage inflammatory protein-1β
8. thymus- and activation-regulated chemokine
9. macrophage-derived chemokine

• Lower levels of the anti-inflammatory cytokine IL-2.
• For TNF-α and IL-6, group differences were reduced and in some cases nonsignificant after controlling for potential confounds.
• Elevations were observed for other biomarkers related to inflammation, including markers of astrocyte and microglial activation (eg, S100B, glial fibrillary acid protein, CD11b), which can further induce cytokine production as well as enzymes and transcription factors for the arachidonic acid and nuclear factor kappa B (NF-κB) signaling pathways.
• Of the 11 articles, 3 reported effect sizes ranging from small to medium in size, for elevated levels in schizophrenia.2
• Other studies found no differences for C-reactive protein (CRP) or intercellular adhesion molecule-1 (ICAM-1); however, a more inclusive review and meta-analysis of all studies of CRP (without the specific study inclusion criteria that we used) has shown consistent elevations in CRP in schizophrenia.
• Thirty-six percent of articles reported differential relationships between inflammation and age in schizophrenia and HCs. Three observed correlations between older age and increased IL-6, S100B, and scores on a chemokine index, which included MDC and Eotaxin-1, in schizophrenia but not in HCs.
• The strengths of correlation coefficients suggest medium effects; however, these investigations did not statistically compare the age-relationship between groups.
• Prostaglandin-related genes were different between older schizophrenia patients and age-comparable HCs, which were not observed between younger schizophrenia patients and their HCs, suggestive of differential aging trajectories between the groups.
• Only one study investigated an age × group interaction, and did not observe a group-specific age association for any chemokine.
• The remaining 64% of studies did not observe significant relationships between age and levels of cytokines (eg, IL-1β, IL-2, IL-6, TNFα), chemokines, CRP, ICAM-1, or brain mRNA levels of IL-1 receptor protein, markers of astrocyte and microglial activation, NF-κB transcription factor subunits, or arachidonic cascade enzymes.
• Illness duration was reportedly associated with inflammation in 3 studies, suggesting that elevated levels may be related to disease progression.
• Longer illness duration was associated with higher IL-6 levels and chemokine index; the strengths of these relationships were small to moderate in size, respectively.
• Additionally, Eotaxin-1 levels were significantly higher in chronic patients compared to HCs.
• No relationships were observed between IL-2, TNFα, IL-6, IL-1β, S100B, or ICAM-1 and illness duration, antipsychotic medication use or dose, or cigarette smoking.

Source
Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions

Journal
Schizophrenia Bulletin, Volume 44, Issue 2, March 2018, Pages 398–408,

Year
2017

Website
https://watermark.silverchair.com/sbx069.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAqUwggKhBgkqhkiG9w0BBwagggKSMIICjgIBADCCAocGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMr2JonSEDE9Uhdz3FAgEQgIICWHUJMABpViug7UF4FPpROHH6276K8MmLs1bsJpcg5P1pzxMb

Journal Published
Br J Psychiatry. Nov;179:403-8

Year Published
2001

Full Article
signs_of_asphyxia_at_birth_and_risk_of_schizophrenia.pdf

Hypothesis

To assess the role of different complications, and in particular to distinguish between disordered foetal development and hypoxia at birth.

Background

• It has been suggested that foetal or neonatal damage to the central nervous system (CNS) could increase the risk of schizophrenia as an adult
• Schizophrenia is twice as likely in those with any obstetric complication. 
• Previous research has found an association between obstetric complications and schizophrenia, but in many studies the sample size was limited, and no assessment of specific exposures was possible.

Journal Published
Frontiers in Psychiatry

Year Published
2019

Abstract
AutoimmuneZDiseasesZZPsychoticZDisorders.pdf

Background

• The association between immunological processes and mental disorders was observed by doctors centuries before the immune system was discovered.
• Psychosis arising either with the occurrence or disappearance of acute fever has been described by many scientists from Hippocrates around 400 BC to Kraepelin around 1900. In the 1930s it was first hypothesized by Hermann Lehmann-Facius that schizophrenia was the product of an autoimmune reaction with antibodies attacking brain tissue 
• In the 1950s and 1960s it was noticed that celiac disease seemed to occur more often within those suffering from schizophrenia than in the general population, and conversely, that schizophrenia occurred less frequently within patients with rheumatoid arthritis.
• Additionally, autoantibodies cross-reacting with brain antigens were found in patients with schizophrenia back in the 1960s, and interest in anti-neuronal antibodies in psychotic disorders has increased during the last couple of decades, with an increasing number of reports on previously unknown antibodies with brain reactivity in patients suffering from psychosis.
• The amount of evidence supporting the notion of a link between immunological processes and psychotic disorders has increased.
• Elevated levels of inflammatory markers have been found both in the blood and CSF of patients with psychosis, with even higher levels in patients in first episode psychosis or acute relapse.
• Furthermore, some have found association between higher levels of inflammation in childhood and adolescence and increased risk of psychotic disorders, elevated inflammatory biomarkers has been associated with lack of treatment response, and anti-inflammatory treatment has been found to have especially beneficial effect in an inflamed subgroup of patients.
• Moreover, it has been suggested that schizophrenia could be an autoimmune disease, based on similarities such as the remitting-relapsing phenotype of the illness, as well as the above-mentioned immunological processes.
• Research in the field of psychoneuroimmunology is still evolving, with many different aspects being investigated.
• The notion of a role of the immune system in psychotic disorders seems evident, and understanding the link between autoimmune diseases and mental disorders may shed light on possible etiological mechanisms herein.
• Understanding how the immune system and psychotic illness interact can improve our understanding of psychosis and give rise to a wide range of new treatment options in psychiatry; amongst other the possibility to identify subgroups of patients with psychotic disorders and ongoing inflammatory processes that could benefit from more targeted treatment.
• Additionally, it is very important for clinicians to be aware of somatic comorbidities, particularly in patients with psychotic disorders, in order to improve detection and treatment, and thus the course of illness.
• The notion of immunological pathways playing a role in the etiology of a subset of psychotic disorders has received increased interest in the last decades.
• There is an apparent link between autoimmune diseases and psychotic disorders.
• This is supported by genetic findings associating immune-related genetic markers with schizophrenia and clinical studies finding increased levels of inflammatory markers in patients with psychosis.
• Several large-scale epidemiologic studies have found positive associations between autoimmune diseases and psychosis. Particularly, autoimmune diseases as multiple sclerosis and lupus are known to have higher frequencies of neuropsychiatric symptoms, including psychosis, compared to healthy controls.
• Cross sectional studies have found higher prevalence of psychiatric diagnoses among those with autoimmune diseases, and longitudinal studies have shown bidirectional associations between several autoimmune diseases and increased risks associated with schizophrenia.
• Moreover, a family history of autoimmune diseases has been shown to be associated with an increased risk of psychotic disorders and vice versa. In this review we will summarize the epidemiologic evidence on associations between autoimmune diseases seases and psychosis.
• Possible mechanisms accountable for the association will be discussed, amongst others the probable role of shared genetic risk factors, the impact of infections on both autoimmunity and the development of psychotic disorders, and the potential role of the microbiome.

School, Department or Faculty
Schizophrenia Working Group of the Psychiatric Genomics Consortium

Journal Published
Schizophrenia Bulletin

Year Published
2016

Authors / Collaborators
Pouget JG1, Gonçalves VF2, Raychaudhuri S, Kennedy JL, Knight J5.

Hypothesis

The variation in immune genes contributes to schizophrenia

Background

• There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies.
• The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis.
• However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se.

Journal Published
Methods Find Exp Clin Pharmacol.

Year Published
1984

Authors / Collaborators
Knight JG.

Background

• Autoimmunity has been shown to be the basis of an ever-increasing number of human diseases.
• Schizophrenia shares a number of genetic features with these autoimmune diseases and therefore could be an autoimmune disease itself.
• Several lines of evidence suggest that overactivity of dopaminergic pathways in some areas of the brain are involved in schizophrenia, but the apparent absence of an increase in dopamine turnover suggests that this hyperactivity could be mediated by a dopamine agonist rather than by dopamine itself.
• Schizophrenia is reviewed in the light of precedents from the field of autoimmune diseases in which autoantibodies have been shown to be able to interact with, and sometimes stimulate hormone receptors, thereby causing disease.

Journal Published
British Journal of Medical Practitioners

Year Published
2015

Authors / Collaborators
James Paul Pandarakalam

Abstract
TheZAutoimmuneZZInfectious.pdf

Hypothesis

The author has reported on a review of the literature relating to the immunity- and viral-based aetiological models of schizophrenia to gain a detailed understanding of aetiological models of a subset of schizophrenia.

Background

• A clearer understanding of the aetio-pathogenesis of schizophrenia would ultimately lead to effective treatment strategies and provide the impetus for elucidation.
• The autoimmune hypothesis promulgates that it is the auto-antibodies that are responsible for schizophrenia and, according to the viral hypothesis, it may be the body’s abnormal response to a slow viral infection or the undefeated viral antigens causing the schizophrenia pathology.
• The autoimmune and viral hypotheses are interlinked, as autoimmune disorders can be triggered by microbial infection.
• Viral aetiology is less convincing than the autoimmune model, but from a treatment perspective, the former is more promising than the latter.

Journal Published
Journal of Neuroinflammation

Year Published
2018

Authors / Collaborators
Souhel Najja , Johann Steiner , Amanda Najjar and Karl Bechter

Abstract
AZclinicalZapproachZtoZnew-onsetZpsychosis.pdf

Description

• The associations with psychotic disorders have been found for a broad range of autoimmune diseases. 
• The world-wide prevalence of schizophrenia is known to be around 1% and the prevalence of autoimmune diseases have been found in a Danish nationwide study to be 4%.
• The vast majority of epidemiological studies have found a general association between autoimmunity and psychotic disorders.
• In large-scale register-based studies from Denmark, 6% of those diagnosed with schizophrenia also had a hospital contact related to an autoimmune disease during follow-up, and a Taiwanese study found that 3.4% of persons with a hospital contact for autoimmune diseases also had a hospital contact related to schizophrenia.
• A Danish study based on 7704 patients with schizophrenia, found an increased prevalence by about 45% of the occurrence of an autoimmune disease, which was later confirmed in a Taiwanese population-based study. Regarding the risk of psychosis after an autoimmune disease diagnosis, a Danish nationwide study found this to be increased by 45%, which diminished to a 29% increased risk when excluding the effect of infections, and a very recent meta-analysis by Cullen et al. found that a diagnosis of a non-neurological autoimmune disease increased the risk of later being diagnosed with a psychotic disorder by 43%.
• Additionally, being diagnosed with schizophrenia increases the lifetime prevalence of autoimmune diseases.
• Two Danish register-based studies found that individuals with psychotic disorders had a subsequently elevated risk for autoimmune diseases by around 50%. Supporting this, the recent meta-analysis found that the risk of having an autoimmune disease was 55% higher among those with a prior diagnosis of a psychotic disorder.
• Autoimmune diseases and psychosis are not only associated on an individual level. Having a first degree relative with schizophrenia has also been found to increase the risk of autoimmune diseases with 6%, and a family history of autoimmunity has been found to increase risk of both schizophrenia and non-affective psychoses with 10%.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2018

Website
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435494/#__ffn_sectitle

Description

• The original findings from the 1950s of an association between celiac disease and schizophrenia has since been explored further.
• During the next decades it was noticed that populations with lower consumption of wheat had lower incidence rates of schizophrenia, and small studies have since found beneficial effect on psychotic symptoms of a gluten-free diet in patients suffering from both celiac disease and schizophrenia.
• One epidemiological study found no significant correlation between celiac disease and psychosis however another large-scale study found a 2.11-times increased risk of schizophrenia. 
• The recent meta-analysis also found an association with an elevated risk of schizophrenia with 53%.
•  Additionally, it has been found in a Taiwanese population, that the risk of celiac disease is increased when suffering from schizophrenia.
• When discussing epidemiological studies using health records, it is important to note that celiac disease might be majorly underdiagnosed particularly within those who have already debuted with psychotic symptoms.
• In summary, most studies found a positive association between celiac disease and psychotic disorders.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435494/pdf/fpsyt-10-00131.pdf

Description

• Multiple sclerosis (MS) is an autoimmune disease associated with many neuropsychiatric symptoms, such as depression and anxiety.
• It has been found that 4% of patients with MS experiences psychosis, a prevalence much higher than that of the general population.
• Danish register-based studies have found that having MS increases the risk of schizophrenia with up to 44%, with an even further increase in risk when having both MS and a prior hospital contact due to infection. 
• Two studies found increased risk of schizophrenia with up to 30% in individuals with a family history of MS; however, they found no associations on an individual level.
• A study from Taiwan only found a trend toward an increased risk of schizophrenia in those with a diagnosis of MS.
• On the risk of a subsequent MS diagnosis in patients with schizophrenia, contradictory results have been found between a Danish and a Swedish nationwide study, finding the risk to be respectively increased by 57% and decreased by 40%.
• Current evidence of an association between MS and psychotic disorders is limited with studies showing conflicting results.
• Many, especially sensory, symptoms of multiple sclerosis might be misinterpreted as part of the patients' psychotic disorders, complicating the diagnostic process, and psychotic symptoms in people with MS might not be diagnosed since they are considered to be delirium in relation to acute MS exacerbations.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Systemic Lupus Erythematosus (SLE) is another autoimmune disease known to have a high degree of neuropsychiatric problems, such as depression and anxiety, occurring in between 21 and 95% of patients However, it has been estimated that only 13–38%, are directly attributable to SLE, whereas the remaining is suggested to be due to for example treatment complications.
• Regarding psychosis in SLE, the prevalence ranges from 2.3 to 11% in studies.
• A study from England comprising 458 patients with SLE, found that only 2.3% experienced psychosis, while a higher prevalence of psychosis have been found in a black Caribbean study population (366 patients, 7% with psychosis) and in a Brazilian population (520 patients, 11% with psychosis).
• In those experiencing psychosis, this was one of the initial symptoms of SLE in up to 60% of these patients.
• In population-based studies, a nationwide Taiwanese study found an increased risk of schizophrenia among those with SLE
• In one Danish study the presence of both SLE and a prior hospital contact with infection resulted in an increased risk of schizophrenia.
• None of the other epidemiological studies have found significant association between psychotic disorders and SLE
• The number of cases available was very small in all studies, limiting the significance of possible findings.
• In summary, large scale studies with a greater number of cases have been able to find positive associations between SLE and psychotic disorders, while smaller studies have failed to do so.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Graves' disease, the most common cause of hyperthyroidism, is also known to be linked to neuropsychiatric issues, and some even present with psychotic disorders.
• A German study found that in a cohort of 100 patients with a schizophreniform illness, 19 had increases antithyroid autoantibodies in sera, and 13 showed signs of intrathecal synthesis hereof. 
• In epidemiological studies, both Graves' disease and thyrotoxicosis have been linked with an increased risk of schizophrenia.
• Additionally, the prevalence hereof has been found to be increased among individuals with schizophrenia, though this finding has not been replicated in all studies.
• Hence, most studies indicate a positive association between Graves' disease/thyrotoxicosis and psychotic disorders.
• No studies has been able to show a significant association between autoimmune thyroiditis and schizophrenia on an individual level, but one Danish study found an increased incidence among parents and siblings of patients with schizophrenia.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Diabetes mellitus type 1 is a disease characterized by the presence of glutamic acid decarboxylase (GAD) antibodies.
• These autoantibodies have been linked with neurological problems, and thus have shown ability to cross the blood brain barrier, making them an interesting topic in the discussion of pathophysiological mechanisms.
• However, conflicting results have been found regarding the association of type 1 diabetes and psychotic disorders. Two Danish studies found an increased risk of schizophrenia when suffering from type 1 diabetes, and one found an increased risk of type 1 diabetes after having been diagnosed with schizophrenia.
• This, however, was not replicated neither in a Swedish cohort, a Taiwanese cohort nor in the recent meta-analysis, and a Finnish study even found a negative association.
• In summary, there does not seem to be a clear association between type 1 Diabetes and psychosis.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• A disease which has consistently been found to be negatively associated with schizophrenia is rheumatoid arthritis (RA).
• This apparent “protective” effect of schizophrenia on the development of rheumatoid arthritis was investigated as early as the 1950s.
• The negative association between the two has since been backed by epidemiological studies, finding decreased risk of schizophrenia in those with RA and vice versa.
• However, some studies did not find associations, and regarding the association on the risk of psychosis after a RA diagnosis, more controversy exist, with a Danish study finding that a combined history of a hospital contact due to infection and RA increased the risk of schizophrenia and a new Taiwanese study finding an increased risk of developing schizophrenia in individuals with a history of RA.
• Moreover, a Danish study found an increased prevalence of RA in the family of those with schizophrenia.
• One explanation of the consistent finding of negative association with subsequent RA diagnosis after a schizophrenia diagnosis could be that RA tends to be underdiagnosed in those suffering from psychotic disorder, and in concordance with this, both a Swedish and Danish nationwide study has shown that the same negative association can be found with other musculoskeletal diseases.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Something that really spiked the interest in autoimmunity as a player in mental illness, was the discovery of autoimmune encephalitis.

• As a group, these diseases are characterized by the presence of neuronal surface antibodies (NSAbs) and symptoms include:

1. Psychiatric and cognitive alterations

2. Seizures and movement disorders

3. With the most commonly affected part of the brain being the limbic system.

• The most discussed antibody in psychotic disorders at the moment is the N-methyl-D-aspartate receptor (NMDA-R) antibody.

• It has been reported that as many as 74% of patients suffering from NMDA-R encephalitis experience psychotic symptoms, and a recent smaller study found that 13% were initially admitted to the hospital with a psychiatric diagnosis.

• Multiple studies have investigated the frequency of NMDA-R antibodies in schizophrenia, but so far most have only had access to serum not CSF, most have had no healthy control group, and results have varied markedly.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Associations have been found between psychotic disorders and other autoimmune diseases as well.
• The incidence of psoriasis have been found to be significantly increased in individuals with schizophrenia, but not in all studies.
• Increased incidence of psoriasis have also been found in individuals with a family history of schizophrenia
• In addition, the risk of developing schizophrenia has been found in multiple studies to be increased in those with a history of psoriasis, with an additional increase when combined with a prior hospital contact due to an infection.
• The risk of developing Guillain-Barré syndrome, an autoimmune disease attacking peripheral nerves, has been found to be increased markedly in individuals with schizophrenia, and when having both a history of a hospital contact with an infection as wells as Guillain-Barré, the risk of developing schizophrenia has also been found to be increased.
• However, one other study found no association.
• Autoimmune hepatitis has been found to be greatly associated with psychotic disorders as well, with both individual history and family history hereof increasing the risk of schizophrenia, and schizophrenia increasing the risk of autoimmune hepatitis.
• Some evidence of an association between schizophrenia and Crohn's disease has also been found, though no significantly increased risk was shown in two other studies or the recent meta-analysis.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• One potential contributing factor to the link between some autoimmune diseases with mental illness, can be the presence of neuronal surface antibodies (NSAbs).
• GAD-antibodies have been linked with multiple neurological problems, and in neuropsychiatric lupus, an increased amount of antibodies was found both in serum and CSF compared to lupus with no neuropsychiatric manifestation.
• Furthermore, gliadin antibodies, associated with celiac disease, have been found to be increased in the serum of patients with recent onset schizophrenia.
• With the discovery of NMDA-receptor encephalitis, and its ability to mimic mental disorders, the interest spiked further, and with GAD-antibodies being able to induce limbic encephalitis and antibodies reacting with the NR2 subunit of NMDA being present in some cases of lupus, a possible link emerged.
• Many studies have sought to evaluate the presence of multiple different NSAbs in mental illness, but so far, consistency in methods and assays have limited the generalization of the findings.
• Many studies have lacked a healthy control group to compare their results with, and most studies have included serum but not CSF samples.
• The relevance of circulating NSAbs in serum is still unknown, and therefore comprehensive studies including healthy controls evaluating antibodies in both CSF and serum is needed to increase knowledge further.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• A dysregulated balance between regulatory T cells and Th17 cells have been described to be essential for immunological homeostasis and have been implicated in the development of several autoimmune disorders.
• Signs of a dysregulated immune system has also been found in mental illnesses and might play a role in the association found between the two.
• A meta-analysis found that levels of several lymphocytes differed when examining patients with schizophrenia compared to healthy controls.
• Studies have linked decreased regulatory T cells with negative symptoms and cognitive deficits, as well as increased levels of Th17 with psychopathology.
• In recent years, B cells have received increasing attention in the pathology of autoimmunity, and have been implicated to play a big role in for example MS, where it has also been found that anti B-cell antigen (anti-CD20) have great efficacy in the treatment hereof.
• It has been shown that oligoclonal bands (OCBs) in the CSF, something which is found in approximately 90% of patients with MS, is a sign of ongoing stimulation and maturation of antibody-expressing B-cells.
• A recent meta-analysis found that OCBs were found in the CSF of up to 12.5% of patients with schizophrenia.

Another frequent finding in patients with schizophrenia is increased levels of pro-inflammatory and decreased levels of anti-inflammatory cytokines in serum (10). Dysregulation of the anti-inflammatory cytokine IL-10 has been found to be linked with abnormal responses to common infections, and to increase the risk of developing autoimmune diseases (69).

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• It is thought that one of the most important triggers for developing autoimmune diseases is infection (70), and it is known that infectious encephalitis, specifically with herpes-simplex virus, markedly increases the risk of developing NMDA-receptor encephalitis.
• As it was shown in a large Danish nationwide study, prior infection increased the risk of developing schizophrenia in a dose-response fashion and this finding has been repeated in other large studies.
• The effect of infection on risk of schizophrenia was present regardless of autoimmune diseases, but additionally, a significant synergy was found in those with both a history of autoimmunity and infections.
• For many of the individual autoimmune diseases, it was seen that the effect on the risk of schizophrenia increased when a prior hospital contact due to infection was also present.
• Being exposed to viral or bacterial infection is known to increase the permeability of the blood-brain-barrier (BBB), which allows the entering into the central nervous system of immune cells and pro-inflammatory cytokines.
• This in itself might allow an inflammatory state in the brain, which has been theorized to play a role in the development of psychotic disorders. It may also explain the synergistic effect on risk of schizophrenia of having both an autoimmune disease and prior infections, as BBB disruption might also allow the entering of circulating antibodies.
• Supporting the role hereof, signs of a disrupted BBB has been found in patient with schizophrenia with evidence of increased albumin CSF:plasma ratio and increased levels of circulating s100-b.
• It has also been found that infections during pregnancy increases the risk of schizophrenia in the offspring.
• On the basis hereof, it has been considered whether infections during the prenatal phase might prime the immune system, making it more vulnerable and perhaps more likely to produce abnormal responses to later infections, resulting in increased inflammation
• A new study have shown that even maternal infections before and after pregnancy increases the risk of mental illness, which could also indicate a genetic susceptibility for infections associated with mental illness.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Both schizophrenia and autoimmune diseases are known to be highly hereditable.
• The most consistent finding in genetic studies of patients with schizophrenia, are differences in genes known to be linked to the immune system, and several genetic loci that increases the risk of autoimmune diseases has been located.
• As with schizophrenia, some of the discovered genetic loci in autoimmune diseases are located in the MHC region
• However, while one study found significant overlap in genes between MS and schizophrenia (but not MS and bipolar disorder), another study found no genetic association between 25 different autoimmune diseases and schizophrenia
• Genetic pleiotropy has also been hypothesized to account for the negative association found between RA and schizophrenia, with genes found to be associated with schizophrenia possibly decreasing the risk of RA.
• Another possible role of genetics in the association of autoimmune diseases and psychotic disorders could be a hereditary susceptibility for shared risk factors.
• It has been hypothesized that some of the genetic findings associated with schizophrenia might increase the risk of having infections, that then subsequently increase the risk of both autoimmune diseases and psychotic disorders.
• Additionally, it has been theorized whether some individuals with schizophrenia, might have a genetic predisposition for an abnormal immune response to common infections and foreign pathogens, for example via differences in the HLA region and complement system, which in turn could increase the risk of developing autoimmune reactions.
• The complement system has also been implicated to play a role in neurodevelopment and -maturation, and evidence of altered complement activity in patients with schizophrenia have been found.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• The gastro-intestinal tract of humans contains vast amounts of bacteria, phyla and other microorganisms, their genes collectively known as the microbiome, containing at least 100 times more genetic material than the human genome.
• This area has received great attention in the research of many different illnesses in the last years and have been implicated as a possible etiological factor in both neuropsychiatric illnesses and autoimmune diseases.
• As early as 1953, interest in gastro-intestinal inflammation in psychosis was raised, when a group of researchers found in an autopsy study that out of 82 patients with schizophrenia, 50% had gastritis, 88% enteritis and 92% colitis.
• This study has not since been replicated, but other signs of microbiome dysbiosis in this group of patients has been found with significant difference between cases and controls in the presence of both bacteria and fungi, and bacteriophages.
• Studies so far have mainly focused on the oropharyngeal microbiome due to practical limitations.
• One study however, has looked into fecal microbiome, finding no significant difference between healthy controls and patients, but showing associations between microbiome composition and symptom severity and outcome.
• The composition of the microbiome has been hypothesized to be very important in the development of both the central nervous system and the immune system. 
• Dysbiosis of the microbiome has been shown to affect both the Th1/Th2 balance and the ratio of T regulatory and Th17 cells, impacting the immune response to foreign pathogens.
• Dysbiosis have been found to influence the T-cell mediated inflammation in MS patients, and has also been suspected to play a part in the development of celiac disease, as well as non-gastro-intestinal autoimmune diseases.
• In rodents, disruption of the microbiome has been found to impair social functioning, behavior and cognition, and induce neurodevelopmental disorders.
• An important function of the microbiome, seems to be its effect on the epithelial cells in the GI wall, with evidence implicating that the composition of the microbiome is important for the tightness of the gut-blood barrier.
• Severance et al. found markers in the serum of patients with schizophrenia indicating increased permeability, also known as “leaky gut.”
• A leaky gut allows the entrance of foreign pathogens and antigens into the blood. It has been suspected to induce systemic inflammation, and in mice it has been found to even result in neuroinflammation, both of which might increase the risk of mental illness and autoimmune diseases.
• Interestingly, both infections and the treatment hereof with antibiotics can modulate the microbiome, linking the previously mentioned epidemiological findings of the influence of infections with the microbiome theory.
• Additionally, it has been theorized that maternal infection might alter both the maternal and fetal microbiome, possibly impacting the immune system and neuropsychiatric development of the offspring.
• A few studies have tried probiotic treatment in patients with schizophrenia, but no evidence of effect hereof on psychopathology has yet been found.
• However, further research on the actual composition of the microbiome in patients with mental illness as well as the possibility of using probiotics as treatment hereof is warranted.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Psychological stress such as sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying, both in childhood and later on, has been associated with increased risk of psychotic disorders in multiple studies.
• A Swedish register-based study found that stress-related disorders increased the risk of subsequent development of autoimmune disorders and, accordingly, in many other studies, stress have been found to be associated with disease onset and disease exacerbations in several autoimmune conditions.
• Stress can theoretically influence many of the above-mentioned possible etiological factors.
• Acute psychological stress, even in brief episodes, have been found in a meta-analysis to increase circulating proinflammatory cytokines such as IL-6, IL-1β, and TNF-α, possibly via the sympathetic nerve system and the HPA axis, and multiple adverse life events or stressful living conditions might therefore possibly contribute to a more chronic inflammatory state with dysregulation of immune response.
• Psychological stress have been thought to influence composition of the microbiome and vice versa, as well as the microbiome's effect on peripheral inflammation.
• Additionally, it has been hypothesized to increase susceptibility to infections, with one study finding that healthy subjects with higher scores on questionnaires on psychological stress were more prone to developing clinical cold and respiratory infections after exposure to respiratory viruses
• Acute stress, for example as a result of a psychiatric disorder or hospitalization, may also lead to exacerbation in symptoms of autoimmune diseases, leading to the discovery of a disease formerly undiagnosed.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• “Autoimmune psychosis” includes those autoimmune disorders presenting primarily with atypical psychotic features masquerading as drug-resistant primary psychosis. This term suggests that this subtype of psychosis has anatomical and immunological footprints in the brain. It also serves as a reminder not to overlook appropriate neurological workup, (such as neuroimaging, EEG testing, and CSF investigation), but rather to apply it more broadly to formulate accurate differential diagnostic considerations that entertain underlying autoimmune process among other organic etiologies. Examples of atypical psychotic presentations suggestive of organic causes are:

1. Ttypical age of onset
2. Predominance of particular symptoms such as confusion, disorientation, and language disintegration
3. Catatonia, given its diverse etiology
4. Predominance of visual or multi-modal hallucinations (visual and tactile)
5. Olfactory hallucinations suggestive of mesial temporal lobe pathology
6. Predominance of specific delusions such as those related to misidentifications (Capgras syndrome)
7. Antecedent or concurrent medical illness or systemic manifestations including significant weight loss; and
8. Lack of predisposing risk factors for primary psychosis such as a strong family history of schizophrenia, a premorbid schizoid personality, or precipitating stress for mental disorder

• Antibodies against neurotransmitter receptors and synaptic proteins in schizophrenia and newonset psychosis: the concept of autoimmune psychosis In individuals with schizophrenia suggests that autoimmunity plays a role in a subgroup of these patients, early identification of antibodies targeting neurotransmitter receptors such as: 

1. 5-hydroxytryptamine
2. 1A receptor
3. Muscarinic cholinergic receptor 1 as well as
4. Dopamine-2 receptor

• Notably, the recent discovery of antibodies against synaptic and neuronal cell membrane proteins such as antiN-methyl-D-aspartate receptor (NMDAR) and gammaaminobutyric acid beta receptor (GABAßR) provides more direct evidence etiologically linking autoimmunity-related dysregulation of glutamatergic and GABAergic neurotransmissions to subsequent hazard of psychosis 
• One meta-analysis showed that patient with psychiatric illnesses such as schizophrenia and schizoaffective disorders are about three times more likely to have NMDAR antibodies (mostly of IgA or IgM type against GluN1 (NR1) subunit), compared with healthy controls 
• Similarly, other studies reported higher, albeit variable, prevalence of IgG antibodies targeting GluN1 subunit of NMDAR in the sera of individuals with first-episode psychosis (ranging from 0 to 12%)
• Furthermore, NMDAR antibody immunofluorescence response in schizophrenia patients with past catatonia is shown to be greater than that in healthy controls.
• Additional studies revealed higher prevalence of other neuronal antibodies such as voltagegated potassium channel (VGKC)- complex antibodies in patients with schizophrenia
• On the contrary, the findings from other studies provide counterargument to the putative pathogenic significance of synaptic and neuronal antibodies in a subset of individuals with schizophrenia and new-onset psychosis.
• Several studies showed comparable prevalence of antibodies targeting synaptic and neuronal cell membrane protein among healthy and schizophrenia cohorts.
• Another recent study showed that the prevalence of these antibodies among individuals with first-episode psychosis was low and comparable to that of healthy controls.
• The mixed results and the variability in the estimates of synaptic and neuronal antibody seropositivity may in part be attributed to methodological heterogeneity (e.g., cell-based assay (CBA) using live as opposed to fixed cells) that might have influenced the sensitivity and specificity of immunostaining assays used across these studies.
• The growing human and experimental data supporting an association between autoimmunity and risk of developing psychosis have prompted some authors to use the term “autoimmune psychosis”

Source
A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis

Journal
Journal Of Neuroinflammation

Year
2018

Website
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1067-y

Journal Published
npj Schizophrenia volume 5, Article number: 5

Year Published
2019

Authors / Collaborators
Vanessa Kiyomi Ota, Patricia Natalia Moretti, Marcos Leite Santoro, Fernanda Talarico, Leticia Maria Spindola, Gabriela Xavier, Carolina Muniz Carvalho, Diogo Ferri Marques, Giovany Oliveira Costa, Renata Pellegrino, Simone de Jong, Quirino Cordeiro, Hakon Hakonarson, Gerome Breen, Cristiano Noto, Rodrigo Affonseca Bressan, Ary Gadelha, Jair de Jesus Mari & Sintia I. Belangero

Full Article
GeneZExpressionZOverZTheZCourseZofZSchizophrenia.pdf

Hypothesis

To find genes related to a prepsychotic stage (i.e., genes differentially expressed in CHR compared to other groups), to an acute psychotic stage (i.e., genes differentially expressed in FEP compared to other groups), to a long-term psychotic state, or following a long exposure to antipsychotics (i.e., genes differentially expressed in CSZ compared to the other groups). The aim of the study is to determine whether patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression.

They further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences. 

Background

• Schizophrenia (SZ) is a heterogenous disorder, with a wide array of clinical, functional, and cognitive outcomes.
• The different disease trajectories, in which a patient can present distinct clinical and biological features of disease progression, are a one major source of heterogeneity.
• Clinical staging models have been proposed, but relatively few studies compare biological measures in the distinct stages.
• Although the heritability of schizophrenia is very high (~80%), genetics still lack a major impact in clinical practice.
• Gene expression, the transcription of a gene’s DNA information into an RNA copy, is also influenced by a combination of environmental and genetic factors, such as expression quantitative trait loci (eQTLs), which are genomic loci that contribute to variation in expression levels.
• Schizophrenia risk loci have been noted as being enriched for eQTLs.
• Although many studies have investigated gene expression in the blood of patients with schizophrenia, most were performed in patients with a long time of treatment and disease.
• Our previous studies have shown that antipsychotics affect gene expression and DNA methylation, suggesting that gene expression may be influenced by the time of treatment and disease.
• Other studies have investigated prodromal or FEP patients, but no study has compared RNA expression between patients in different stages.

Journal Published
Research in Translation

Year Published
2017

Full Article
GeneticsZofZSchizophrenia.png

Hypothesis

The study will provide a high-level review of progress, its limitations, and the implications for clinical research and clinical practice.

Background

• There has been progress on research into the etiology of schizophrenia but particularly regarding the molecular genetics of this complex disorder of mind and brain.
• A number of critically important and unresolved issues remain that qualify the ultimate clinical and scientific validity of the results.

References

Full Article
TheZRoleZofZGeneticsZinZtheZEtiologyZofZSchizophrenia.pdf

Hypothesis

The aim of the study is to introduce the reader to the genetics of schizophrenia - its background, the status of a variety of genetic findings, new developments and current and future 

Background

• Genome-wide experiments  have discovered uncommon copy number variations (mainly deletions) associated with schizophrenia as well as common SNPs with alleles associated with schizophrenia.
• The aggregate data provide initial support for polygenic inheritance and for genetic overlap of schizophrenia with autism and with bipolar disorder.
• It is anticipated that  the application of a myriad of tools from systems biology will lead to a delineation of biological pathways involved in the pathophysiology of schizophrenia and eventually to new therapies as genetic discoveries accumulate challenges.

University or Organisation
Johns Hopkins University

School, Department or Faculty
Institute of Genetic Medicine & Department of Psychiatry

Journal Published
Molecular Neuropsychiatry

Year Published
2018

Authors / Collaborators
Dimitrios Avramopoulos

Full Article
RecentZAdvancesZinZtheZGeneticsZofZSchizophreniaZPDF.pdf

Hypothesis

• Focus on genetic variation showing robust associations with schizophrenia including high-penetrance rare variants and low penetrance common variants
• Describe transcriptomics work
• Provide an alternative approach to the genetics of the disease
• The use of alternative phenotypes termed endophenotypes, which is widening our understanding of the dimensionality of mental illness.
• Discuss how cutting-edge technologies are opening new directions in the ways we can experimentally model Schizophrenia

Background

• The last decade brought tremendous progress in the field of schizophrenia genetics.
• As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include:

1. Large copy number variants
2. Rare coding inherited 
3. De novο variants
4. Over 100 loci harboring common risk variants.

• While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory.
• Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups.
• Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes.
• The challenge is to apply this new knowledge to prevention and treatment and help patients.
• The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

Description

• Bipolar disorder, schizoaffective disorder and schizophrenia share some phenotypic aspects in common, both in terms of symptoms and also therapeutics with all responding to antipsychotic drugs.
• Emil Kraepelin defined dementia praecox as a group of psychotic conditions with a tendency toward poor prognosis. He grouped under the term manic-depressive psychoses a set of conditions that included periodic and circular insanity, simple mania, and melancholia which he thought did not result in deterioration. Kraepelin believed that dementia praecox and manic-depressive psychoses had specific and separate causes.
• However, reality proved to be more complex and in 1933 Jacob Kasanin coined the term schizoaffective psychosis to refer to a disorder with mixed features of schizophrenia and affective disorder.
• Compared to the general population, family studies show that the clinically intermediate diagnosis of schizoaffective disorder is more common in families ascertained from probands with schizophrenia as well as in families ascertained from probands with bipolar disorder.
• The diagnostic distinction between schizophrenia or bipolar disorder and schizoaffective disorder is not reliable.
• The specific time criterion for affective symptoms relative to the schizophrenic symptoms is not well defined and varies in different modern classifications.

Source
The Role of Genetics in the Etiology of Schizophrenia

Journal
Psychiatr Clin North Am

Year
2010

Website
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826121/pdf/nihms164007.pdf

Description

• Schizophrenia belongs to a group of pathologies known as complex genetic disorders.
• Our understanding of complex genetic disorders is still evolving as new experiments uncover novel mechanisms of disease.
• It is commonly thought that many genes are involved in each disorder with each gene conferring only a small effect on the phenotype.
• The individual risk variants are thus without diagnostic predictive value and any estimations of risk are probably going to change in the future as large epidemiological samples become available for analysis.
• Epistatic interactions between these genes and among their products and interactions with environmental risk factors are considered highly plausible, however the study of genetic interactions utilizing genome-wide data remains largely unexplored because of need to correct for an enormous number of statistical comparisons.
• Our knowledge is shifting from oligogenic models to a polygenic model of schizophrenia, but its genetic architecture still remains largely unknown.
• The current evidence strongly suggests that the mutation frequency spectrum comprises a mix of many common and rare mutations.
• The idea that complex disorders do not result from abnormal function of individual genes but from dysfunction of entire molecular networks, the concept of system disorder, is making strong inroads in the literature . Whether this applies to schizophrenia is still an empirical question that remains to be addressed.
• It has traditionally been assumed that changes in DNA sequence are solely responsible for the transmission of schizophrenia, however twin studies show that it is also conceivable that an epigenetic mechanism may contribute to the transmission of schizophrenia.
• The possibility of a role for epigenetics (i.e. changes in phenotype not explained by DNA sequence was raised first as an explanation of the incomplete concordance for schizophrenia in monozygotic twins, but still remains little tested due to methodological difficulties.

Source
The Role of Genetics in the Etiology of Schizophrenia

Journal
Psychiatr Clin North Am

Year
2010

Website
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826121/pdf/nihms164007.pdf

Description

• Ernst Rüdin conducted the first systematic family study for a psychiatric disorder.
• He realized that the data would not fit a model of simple monogenic Mendelian transmission but missed the evidence for additional complexity.
• Many family studies of schizophrenia were conducted since then, with the available evidence showing that the child of a parent with schizophrenia has an elevated empirical risk about tenfold over the general population risk
• The risk of a disease in a type of relative compared to that in the general population is often called λ (if the risk is conferred by an allelic variant, it is further specified as an allele specific λ).
• The relative risk to siblings resulting from having a proband with the illness is called λs 41.
• Common disorders have a smaller λs than rare disorders even with similar overall genetic effects (e.g. the respective λs for the autosomal dominant Huntington disease (assuming population prevalence 0.0001), the autosomal recessive cystic fibrosis (assuming population prevalence 0.0004) and autism are 5,000, 625, and 60–100, though the λs for major adult psychiatric disorders of the adult typically are under 10 (λs is ~10 for schizophrenia).
• The risk for schizophrenia to a relative of an affected proband decays much more rapidly than the proportion of genes shared between them. 
• Still most cases of schizophrenia in the general population are sporadic, which may seem surprising at first glance.
• Assuming polygenic inheritance (which explains the molecular findings of schizophrenia better than other models, for a disease with a prevalence of 1% and 90% heritability, more sporadic than familial cases are expected.

Source
The Role of Genetics in the Etiology of Schizophrenia

Journal
Psychiatr Clin North Am

Year
2010

Website
https://www.theglobalnowproject.com/dc/studies-full-article/TheZRoleZofZGeneticsZinZtheZEtiologyZofZSchizophrenia.pdf

Description

• Schizophrenia is a disease with remarkable phenotypic heterogeneity.  
• Each patient's symptoms lead to an overall highly heterogeneous phenotype.
• Heterogeneity also manifests in the patients’ response to medication, frequently resulting in multiple changes in treatment strategy during the course of the illness as patients navigate through ineffective treatments  
• It is clear that schizophrenic patients would benefit considerably from a robust prediction of their response through individualized medicine.
• A good understanding of the underlying genetics, the importance of environmental factors and the interaction of the two, along with careful clinical characterization may achieve that in the not so distant future.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
2018, Vol.4, No. 1 June 2018 Vol.4, No. 1 June 2018

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• In addition to the importance of genetics, the environment also plays a major role in the risk to develop schizophrenia.
• Environmental factors explain the significant non-heritable fraction of the disease variance
• Multiple studies have already implicated a diverse array of environmental factors that increase the risk to develop schizophrenia. These include social factors such as:

1. Migrant status
2. Urban environment
3. Re- and perinatal factors such as maternal malnutrition
4. Birth month (i.e. those born in winter or spring)

• There are many studies suggesting increased risk accompanying infections such as toxoplasmosis, rubella, influenza, herpes and others. 
• It appears from these associations that stress, whether in utero, at birth, or during life, is an important determinant of risk for schizophrenia.
• These environmental factors are also likely to interact with genetic variation, increasing the risk only in their presence.
• One such replicated example has been reported for CMV infection and common variants near the CTNNA3 gene.
• Knowing these relationships will become increasingly important as we learn more about the genetics of the disease, allowing us to achieve individualized prevention and treatment strategies and move precision medicine into psychiatry.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• Patients with schizophrenia have significantly fewer children compared to the general population

• In theory, this should be generating an enormous negative selective pressure quickly removing risk alleles from the population; however, the disease maintains a relatively high heritability and prevalence at ∼1%.

• The reasons for this paradox remain unclear and have sparked much debate and speculation.

• Among possible explanations are balancing selection favoring genotype diversity; advantage for those who carry the allele but do not get sick; changing environments that expose or protect cryptic variation; or quick replenishment by new mutations, in view of the possibility that disruption of thousands of different genes may be able to lead to disease

• The results of genome-wide association studies (GWAS) that we will discuss below support this highly polygenic architecture.

• In addition, GWAS results are consistent with theoretical predictions that common schizophrenia alleles can only show low odds ratios because of this negative selection. This observation, which has the consequence that GWAS variants explain very little genetic variance, has led some health scientists to challenge the value of GWAS. This, however, is a narrow view of the value of these results.

• Common variants that survive selection might have small effects on risk, but pharmacological interventions can be designed to have a larger effect on the gene regulation, its product or the related pathway, providing major benefits.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry 2018, Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• The polygenic nature of schizophrenia has been suspected and debated for a long time
• Hoping that at least some families might segregate a single disease-causing variant, or that the overall number of such variants is limited, numerous linkage studies have tested both parametric and non-parametric approaches.
• Starting as early as 1972 possible linkage of schizophrenia was reported with specific blood groups, and many other linkage studies followed.
• Unfortunately, most were met with disappointment, almost always showing weak results and often failing to replicate one another.
• The same was true for the first association studies that focused on candidate genes or followed up previous linkage results.
• At the time, we did not appreciate the large number of risk variants underlying schizophrenia and the small contribution these variants have on the risk.
• The studies of the era were vastly underpowered and often produced no or false positive results.
• Only now that we have succeeded in identifying true schizophrenia risk variants have we come to appreciate the serious limitations of earlier work.
• Very few of the early gene findings remain under investigation today, and those that do are not because of robust evidence for a role in the disease, but rather because of continuing interest in their function revealed by the work initially triggered by the associations.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• There is strong link between a deletion syndrome and schizophrenia

• A recurrent deletion in chromosomal band 22q11.2 causing a phenotype called velo-cardio-facial syndrome (VCFS) was noted to be often accompanied by psychosis

• Following the reports of this comorbidity, deletion screening of schizophrenia patients showed that some had the 22q deletion but were not diagnosed with VCFS because of their mild features

• Most recently, this deletion was determined to increase the risk of carriers 68-fold and to be present in 0.3% of individuals diagnosed with schizophrenia.

• The deleted region includes more than 50 genes including the highly cited catecholamine-degrading enzyme gene COMT.

• The deletion is recurrent and is due to flanking low copy repeats that mediate unequal meiotic crossing over

• There are multiple repeats in the 22q11.2 region so the deletion can vary in size, the most common (90%) being ∼3 Mb followed by ∼1.5 Mb deletions.

• Interestingly, the reciprocal duplication has been reported to be protective against schizophrenia.

• While the 22q11.2 deletion was the first to be discussed in schizophrenia, the ever-increasing use of microarrays, whether for CNV detection or for genotyping, provided data that allowed us to recognize more and smaller copy number variants (CNVs). As a result, many additional CNVs have now been reported to be associated with schizophrenia.

• The 16p11.2 region first received attention after an association of its deletion with autism Later, it was shown that the reciprocal duplication is associated with schizophrenia.

• Interestingly, the deletion and duplication show opposite effects on intracranial volume, brain size, compartmental measures of gray and white matter, subcortical structures, and the cerebellum also show reciprocal effects on head circumference [40] visual evoked potential amplitude and BMI phenotypes

• It has been suggested that the major driver of the neuroanatomical phenotypes may be the gene KCTD13 which has been implicated in long-term positioning and dendritic maturation of cerebral cortical neurons.

• A more distal and smaller region on 16p11.2 has also been implicated in schizophrenia when deleted, as well as in developmental delay and obesity  

• The 2p16.3 deletion was first identified by comparative genome hybridization and disrupts the NRXN1 gene encoding neurexin 1 a presynaptic cell adhesion molecule which interacts with neuroligins to induce synapse formation and maturation. The initial association with schizophrenia was confirmed soon after by a larger SNP array-based study.

• The deletion at 15q13.3 was reported to cause mental retardation and seizures before being associated with schizophrenia

• Two childhood-onset schizophrenia cases with duplications at this locus have also been reporte. It contains the CHRNA7 gene encoding the A7 nicotinic acetylcholine receptor, previously linked to many psychiatric phenotypes including schizophrenia.

• The 1q21.1 CNV was first reported by the International Schizophrenia Consortium to increase the risk when deleted and later the reciprocal duplication was also found in excess in schizophrenia patients.

• Like the 16p11.2 CNV, reciprocal phenotypes have been described for the 1q21.1 CNV.

• Deletion and duplication cause microcephaly and macrocephaly, respectively, and schizophrenia is only one of many associated neurodevelopmental phenotypes.

• The 3q29 deletion was first described to cause mental retardation, with slight dysmorphic facial features [55] and in some cases autism and was later linked to schizophrenia.

• The 7q11.23 duplication is reciprocal to the Williams-Beuren syndrome deletion and in addition to schizophrenia has been associated with autism, language delay, and mental retardation

•  Tyhe 15q11.2 is also associated with developmental and language delay, mild dysmorphic features, autism, and seizures in addition to schizophrenia.

• Many additional, perhaps more rare CNVs or CNVs with smaller odds ratios are likely to be below our current detection threshold and are not on this list. Their existence however is supported by the overall enrichment for CNVs in cases compared to controls, even after exclud ing those reaching significance.

• Additionally, it is thought, largely due to the likely negative selection of these high-risk variants, that CNV leading to schizophrenia often occur de novo and can be recurrent due to flanking low copy repeats, which has been directly demonstrated.

• An important observation is that these CNVs include both gains and losses of genetic material, and are often also associated with autism and/or intellectual disability.

• The associations are often with reciprocal alleles (22q, 16p) but sometimes they are with the same CNV allele. This not only supports the notion of genetic overlap between psychiatric disorders (see below) but also adds a level of complexity showing that for specific loci the allelic effects can be different.

• Overall, within CNV regions in schizophrenia there is excess of genes involved in axon guidance, nervous system development, genes coding for targets of the RNA-binding protein FMRP (responsible for Fragile X syndrome) and for proteins of the activity-regulated cytoskeletal (ARC) complex involved in learning and memory.

• A special case of chromosomal rearrangement that has been linked to schizophrenia is the DISC1 locus.

• A balanced 1q43: 11q14 translocation has been described in a large Scottish pedigree with multiple psychiatric phenotypes including schizophrenia.

• The pedigree showed significant genetic linkage between the disease and the translocation which disrupted two genes, DISC1 on chromosome 1 and DISC2 on chromosome 11. Of the two, DISC1 is the gene that appears most relevant.

• A later study also identified a frameshift mutation in DISC1 segregating in an American family with schizophrenia and schizoaffective disorder, and there has been a significant volume of research on the gene’s function supporting its importance in cortical development.

• The initial DISC1 report has also been followed by numerous association studies with mixed results and significant controversy regarding its role in schizophrenia.

• The gene also shows no association with schizophrenia in large GWAS, which suggests it contains no common alleles that increase the risk, but does not exclude its involvement in disease through rare highly penetrant variation like the 1q43: 11q14 translocation and the reported frameshift mutations.

• The strong linkage results, but most importantly the large volume of functional information that has now accumulated and linked the gene to brain development, certainly makes its study worthwhile.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• In the last decade, new technologies have made sequencing of the entire exome or genome much more affordable, having a significant impact on the strategies used to study complex diseases including schizophrenia.

• Hypothesizing the existence of rare or de novo variants that have a strong impact on the risk, many investigators have sought them by sequencing case/control cohorts or parent-patient trios. However, despite the recent price reduction, the cost of sequencing remains significant and the size of the sequenced cohorts lags behind those studied in GWAS. This, along with the low frequency of such variants, leads to insufficient power at the gene level.

• Investigators have worked around this limitation by exploring the burden of likely functional variants across schizophrenia-related gene groups.

• In addition to the limitations of the “candidate pathway” approach and the uncertainties regarding gene group membership, a number of arbitrary thresholds are typically set to filter the variants by allele frequency and evidence of function.

• Nevertheless, there have been interesting results that are consistent with the results of both CNV and GWAS studies.

• In one of the first exome sequencing studies, the exomes of 14 schizophrenia probands and their parents and reported an excess of exonic de novo mutations, the higher prevalence of gene-disruptive de novo mutations and reporting recurrent mutations in four genes (LAMA2, DPYD, TRRAP, and VPS39).

• Increased de novo mutation burden in select groups of genes, namely those encoding proteins closely associated with N-methyl-D-aspartate (NMDA) receptors and proteins that interact with the activity-regulated cytoskeleton-associated protein ARC, reiterating the results of CNV studies.

• They also reported recurrence for the TAF13 gene.

• De novo mutations in genes involved in chromatin remodeling and previously implicated in autism and intellectual disability, re-iterating the disease overlaps reported for CNVs.

• Synonymous variants that overlap brain-derived DNase hypersensitivity sites, genomic sites where chromatin is open, suggesting functional significance.

• One of the genes they identified, SETD1A, showed two loss-of-function and one synonymous de novo mutation.

• The mutated genes were mapped onto transcriptome profiles measured in normal human brains aged between the 13th week of gestation and adulthood.

• Mutated genes mapped on transcriptional coexpression and protein interaction networks involved in regulation of transcription, cellular transport, signaling, neuronal migration, and synaptic transmission.

• Rare variants are unlikely to be a major risk factor for schizophrenia.

• The contribution of recessive and compound heterozygous rare likely functional variants but neither was able to show a significant contribution; however, a number of possible limitations including sample size do not allow definite conclusions from these negative results.  

• Therev is a high polygenic burden of very rare disruptive mutations in schizophrenics.

• While no individual gene test achieved study-wide significance, they showed enrichment in genes related to voltage-gated calcium channels and the ARC-associated proteins, once again supporting the same enrichments observed with CNVs.

• There is highly significant excess of ultra-rare gene-disruptive variants, particularly in genes expressed in neurons.

• The corresponding RNAs included many known to interact with synaptic proteins, so they concluded that these rare genetic variants disrupt synaptic function.

• In schizophrenia, genes intolerant of loss-of-function variation and genes whose RNAs bind FMRP, similar to CNV results, carried an excess of rare alleles with minor allele frequency less than 0.1%.

• The only individual gene to show study-wide significant enrichment for rare loss-of-function variants is SETD1A, specifically suggesting a role for epigenetic dysregulation in the histone H3K4 methylation in schizophrenia

• Overall, the evidence of a role of rare and de novo mutations in schizophrenia is overwhelming, and involves some of the same functional categories with genes implicated by CNVs, although their overall contribution to disease is modest.

• The limited examples of recurrent hits of the same gene with de novo mutations, suggests that the number of genes involved in schizophrenia is quite large.

• The penetrance of these de novo variants and the extent to which their expression depends on the rest of the genome and the environment remains unknown, and requires large sample sizes to study.

• A limitation of current sequencing studies is that although they make a valid point on the involvement of rare or de novo variants, what they show is deviations from the expected number of such variants; they do not yet point to specific variants that increase the risk with enough certainty to warrant investing resources on follow-up. This however is likely to change as sample sizes increase.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• In complex disorders GWAS have far superior power than genome-wide linkage studies, which is the preferred way to map genes for diseases like schizophrenia.
• The first GWAS for schizophrenia to adequately cover the genome in a relatively large collaborative case/control sample was published in 2008. Following a two-step analysis to reduce genotyping cost, and including BD patients in an effort to increase power, this study reported a single association around the ZNF804A gene, a gene that has been replicated in subsequent studies.
• This was followed by a larger study combining data from multiple others to reach 13,000 cases and 35,000 controls and reporting three genomic loci including the Human Leukocyte Antigen (HLA) region on chromosome 6 and near the genes TCF4 and NRGN on chromosomes 18 and 11, respectively.
• At the same time, the International Schizophrenia Consortium also reported on the HLA association as well as significant genetic overlap with BD.
• After these studies, smaller groups began consolidating collected samples and genotypes of patients and controls into larger consortia.
• Efforts such as the Molecular Genetics of Schizophrenia collection and the Genetic Association Information Network (GAIN) were developed in order to achieve the statistical power necessary for robust discovery.
• The biggest collaborative consortium, the Psychiatric Genomics Consortium (PGC) with its schizophrenia group currently includes over 400 investigators from 40 countries.
• The PGC published its first GWAS in 2011 identifying five new loci for schizophrenia using a discovery sample of 21,856 Europeans and 29,839 independent subjects for replication.
• Many other important papers followed until most recently in 2014 they published on 36,989 cases and 113,075 controls, reporting 108 significant loci that represent 128 independent association signals, 83 of which had not been previously reported.
• The authors mapped the variants onto epigenetic marks characteristic of active enhancers in 56 tissues and cell lines.
• As expected, they found enrichment in brain tissue enhancers (highest in midfrontal and angular gyrus), but also in tissues with important roles in immunity (highest in CD19 and CD20 B cells).
• The same group also developed an analytical framework to use summary statistics data from this GWAS to identify and rank common gene/functional pathways between schizophrenia, BD, and major depressive disorder (MDD). They reported associations for the histone methylation pathway as well as for immune and neuronal signaling and postsynaptic density.
• Li et al. have recently added 30 new loci to the PGC results by adding a large Chinese sample of ∼36,000 individuals and combining them with the PGC data in meta-analysis. The PGC has also continued increasing their sample size and at the 2017 World Congress of Psychiatric Genetics, they reported the identification of 248 genome-wide significant loci, confirming the speculation that a large number of genes are likely involved in schizophrenia, and providing the basis for a tremendous amount of future work on the etiology of schizophrenia.
• While combining samples through consortia has tremendous value, there is also the limitation that it is hard to replicate every finding in an independent comparable sample. However, the persistence of signals constitutes equally strong validation to independent replication, suggesting it is highly unlikely to be a false positive. Each new sample increase brings new candidate associations forward while validating many of the previously reported.
• In addition to identifying multiple reliable associations, the advent of GWAS also has led to a novel approach in the study of the genetics of complex diseases, the development of polygenic risk scores (PRSs).
• The International Schizophrenia Consortium was the first to use PRSs.
• In a paper reporting an early schizophrenia GWAS that identified the HLA locus as mentioned above, the authors performed an additional analysis where they used the GWAS results as a reference dataset to calculate PRSs on other independent datasets.
• In a first step, the method selects variants from the GWAS at some significance threshold and assigns to their alleles the observed effect on risk.
• Then, based on the genotypes of the individuals in the target data set at these loci, it calculates a PRS for each individual. While most of the selected loci are not genome-wide significant, and many are false positives, those will have random effect size and direction; so, final score is mostly driven by true risk loci.
• In the original paper, the author used this method to formally demonstrate a long-suspected genetic overlap between schizophrenia and BD that is also supported by CNV and rare variant data. The polygenic scores also became a tool for other explorations in the genetic architecture of schizophrenia and its relationship to other phenotypes.
• Hamshere et al. showed an overlap of schizophrenia PRS with attention-deficit hyperactivity disorder (ADHD), while the Cross-Disorder Group of the PGC published on overlaps across five disorders, autism, ADHD, BP, MDD, and schizophrenia showing strongest overlaps between schizophrenia BP and MDD.
• Others have shown positive correlations of schizophrenia PRS with the risk for posttraumatic stress disorder, addiction, and cortical thinning in patients.
• In contrast, a large study from Iceland found that an increased score correlated with higher creativity, using membership in artistic societies and creative profession as a proxy.
• It is clear both from PRSs and from the results of CNV and rare variant analyses that the roles of some genes cut across multiple clinical diagnoses.
• It may be that subset variants confer risk for specific diseases while others affect general mental health robustness, while yet others do not increase the risk per se but only the outcome following loss of robustness.
• A recent study on a large sample (n ≈ 14,000) of BD patients and controls showed that only 22 of 107 leading schizophrenia SNPs reached nominal significance. While this is more than expected by chance, it clearly demonstrated that not all variants are important across diseases.
• As the reference GWAS and the target samples become larger, PRSs will gain power that may allow us to understand how behavioral and other phenotypes relate to each other at the level of the gene. 
• Having identified over 100 robust association signals for schizophrenia is a tremendous achievement and demonstrates the power of collaboration in science. However, the true benefits of these discoveries will only be realized once we begin to understand the disease mechanisms that underlie these associations.
• There are a number of obstacles in this path forward. First, most associated variants disrupt regulatory sequences as demonstrated by the lack of coding variation in linkage disequilibrium (LD).
• In contrast to coding sequences, we know very little about the rules governing regulatory sequences and the many association signals per locus due to LD; this makes it difficult to identify the biologically relevant variant.
• It is also often not clear which gene(s) and which isoform(s) are regulated by such variants and under what conditions or at what time during development the regulation is occurring.
• In the GTEx database for example, many of the GWAS variants are not identified as eQTLs in the included tissues, while many others are eQTLs for multiple genes across many tissues.
• Further, eQTLs that only affect splicing or are only active at specific times/conditions may be near invisible.
• Another obstacle is that the effect of GWAS variants on the risk is quite small, with most carriers of risk alleles being healthy.
• It is therefore unlikely to observe a phenotype even if one could imitate the exact same biological effect in a model organism.
• Applying more extreme disruptions such as gene knockouts might give a phenotype but reduces the credibility of the conclusions.
• Despite the obstacles, new disease biology is already emerging from the GWAS results.
• Beyond the group enrichments and network analyses described above, many studies have begun to link variants to specific genes as eQTLs and experimentally follow them up to understand the biological consequences of these variants. Examples include signals near ZNF804A, TCF4, and CACNA1C.
• The most detailed and well publicized such study has been that of Sekar et al.in the HLA region.
• The authors investigated the strongest signal from the PGC GWAS and found that the associated SNPs were proxies for the genomic structure of a nearby gene, C4A, which along with C4B show structurally diverse alleles. These alleles correspond to differences in the expression levels of the genes, which in turn lead to differences in synaptic pruning as the authors demonstrated by modeling in mice.
• A connection between schizophrenia and synaptic pruning was first made hypothetically 35 years ago and the involvement of the complement has also been reported.
• The work of Sekar et al., took advantage of the GWAS results to provide some of the strongest support for this hypothesis to date.
• With 108 loci to investigate and more than twice that expected as the PGC continues to expand their sample size, there is a lot of work to be done.
• The vision of biology-based psychiatry is becoming a reality.
• As we understand the basis of each genetic association, their common elements, the differences between them, and their interplay with the environment, we will likely soon make leaps in prevention, treatment, and management tailored to the individual patient.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• The study of the transcriptome has only been possible in the last two decades with the advent of microarray technologies, which have been replaced more recently by transcriptome sequencing.
• There have been numerous studies attempting to characterize the schizophrenia transcriptome, with the first study on postmortem brain tissue of schizophrenics appearing in 2000 and reporting abnormalities in presynaptic function.
• Subsequent studies have shown fairly consistent results incriminating mitochondrial function and energy metabolism , oligodendrocyte function, immunity-related genes and GABA neurotransmission
• A study by Cohen et al. implicated alternative splicing in schizophrenia by showing differential expression of particular exons and 3′ untranslated regions, a result that was supported by an independent study from Oldmeadow et al. and later another independent observation by Takata et al, who found enrichment of splicing QTLs among schizophrenia-associated loci.
• Also studying schizophrenia-associated loci, Birnbaum et al. showed that they were enriched for genes transcribed during fetal life, supporting a developmental origin of the disease.
• The same finding was independently reported a year later by Ohi et al. Jaffe et al. mapped DNA methylation across development and found 2,104 CpGs differing between schizophrenia patients and controls. These were enriched for brain development and neuronal differentiation genes, and were often located at GWAS schizophrenia risk loci.
• Ellis et al. studying both autism and schizophrenia brains found significant excess of shared sets of downregulated genes between them, adding to the evidence of etiological overlaps between psychiatric disorder.
• Finally, using data from the CommonMind Consortium, Fromer et al. showed that ∼20% of schizophrenia loci have variants that alter gene expression.
• In cases where a single gene was involved (FURIN, TSNARE1, CNTN4), they showed that altering its expression changed neurodevelopment in zebrafish.
• Using gene coexpression network analysis, they showed support for gene networks involved in neurobiological functions that had already been suggested by other studies like the ARC protein complex, targets of FMRP, neuronal markers, postsynaptic density proteins, and NMDA receptors.
• Most recently, Gandal et al. applied transcriptomic analysis to further explore the overlap between psychiatric disorders.
• They identified patterns of both shared and distinct gene expression perturbations and similar to reported polygenic overlaps, they found strong overlaps with BD autism and MDD in order of overlap strength and reported specific expression patterns.
• Three other studies have used the transcriptome as a readout to characterize the biological consequences of schizophrenia-associated genes.
• Chen et al.studied the ZNF804A gene by analyzing the effects of a gene knockdown in neurons derived from human induced pluripotent stem cells and reported enrichment of downregulated genes involved in interferon signaling.
• Pham et al., following up on their own linkage, association, and functional data, modified an isoform-specific promoter of the DPYSL2 gene by CRISPR/Cas9 and found a complementary effect to transcriptomic changes induced by antipsychotics, enrichment in immune system process genes, as well as a significant overlap with the results of Chen et al.
• This last point is of interest as it connects ZNF804A and DPYSL2, two genes that have no other known functional connection other than their associations with schizophrenia.
• Finally, Hill et al. knocked down the schizophrenia-associated gene TCF4 and reported that this resulted in RNA-level changes of genes involved in the cell cycle and the proliferation of human cortical progenitor cells.
• Across different study designs exploring CNVs, rare variants, de novo variants, common variants, or the disease transcriptome, it is clear that certain gene groups and pathways appear repeatedly. 

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Description

• Endophenotypes are a concept initially described by Gottesman and Shields as internal phenotypes discoverable by a “biochemical test or microscopic examination.”
• They are phenotypes that are not immediately observable, but can be related to a disease because they are present in patients and sometimes their non-affected relatives as a presumed consequence of higher penetrance of the endophenotype compared to the disease phenotype.
• The initial idea behind their study was that endophenotypes may be the result of a subset of the many disease genes and may have higher expressivity, making it easier to identify these genes.
• This approach has been successfully used in diseases other than schizophrenia.
• A prominent example is the identification of genes for long QT syndrome, an endophenotype for syncope, ventricle arrhythmias, and sudden death.
• Other terms that have been used in place of endophenotype include:

1. Intermediate phenotype
2. Biological marker
3. Subclinical trait and
4. Vulnerability marker.

• The concept is of particular interest for psychiatric diseases for the additional reason that it may provide an objectively measurable phenotype.
• It is closely related to the Research Domain Criteria (RDoC) in psychiatric research, an NIMH project to create a research framework for genomics and neuroscience aimed to eventually inform classification schemes.
• Some of the major endophenotypes that have been studied for schizophrenia are:

1. Sensory motor gating
2. Eye-tracking dysfunction
3. Working memory and
4. Executive cognition.

• There have been many studies looking for linkage and associations between schizophrenia endophenotypes and common genetic variation.
• The largest effort to investigate endophenotypes and identify linkage with schizophrenia has been the Consortium on the Genetics of Schizophrenia (COGS), a 7-site study funded by the National Institute of Mental Health. They have reported on the significant impairment of:

1. P50 inhibition
2. Prepulse inhibition
3. Verbal declarative memory and
4. Working memory in schizophrenic patients and relatives

• Positive but weaker results were also reported for the antisaccade task performance and reduced auditory P300 amplitude
• A linkage analysis of their 12 phenotypes identified a LOD score of 4.0 on chromosome 3p14 for the antisaccade task but no other genome-wide significant result,
• Heritability analysis in the COGS-1 family sample has shown comparable levels between endophenotypes and psychotic disorders
• More recently, the group has reported on new endophenotypes from measures derived from the original endophenotype tests finding nine to be significantly heritable and discriminate between schizophrenia patients and controls.
• As GWAS are currently the state-of-the-art and provide much more reliable results, we will not report on the multiple candidate gene association studies.
• Unfortunately, GWAS for schizophrenia endophenotypes have generally been limited in sample size.
• One of the first GWAS examined 11 cognitive phenotypes in 750 subjects but did not find genome-wide significant associations.
• Hatzimanolis et al  in a GWAS on multiple endophenotypes in young male adults that also did not show genome-wide significant results, reported that schizophrenia polygenic risk influences neurocognitive performance, a result recapitulated by a study in childhood
• Roussos et al also showed that in addition to reduced cognition, increased PRS for schizophrenia was associated with reduced PPI validating this additional endophenotype.
• More recently, a meta-analysis by the Cognitive Genomics Consortium (COGENT) reported on a sample of 35,298 healthy individuals of European ancestry.
• They found polygenic correlations between cognitive performance, educational attainment, several psychiatric disorders, birth length/weight, smoking behavior and the personality trait of openness. Importantly, they also reported on some specific loci significantly associated with general cognitive function.
• Finally, schizophrenia-derived polygenic scores have also been correlated with cortical gyrification, an additional potential schizophrenia endophenotype.
• While endophenotypes were initially considered a way to facilitate disease gene discovery, the results suggest that their genetics are similarly complex. However, these results also highlight the value of polygenic scores in the study of the genetics of schizophrenia and the underlying polygenic architecture.
• With larger samples, we might be able to better understand their relationships to schizophrenia and how it relates to the underlying genetics.
• This multifaceted approach to disease may prove to be key in achieving individualized medicine and extending precision medicine into psychiatry.

Source
Recent Advances in the Genetics of Schizophrenia

Journal
Molecular Neuropsychiatry Vol.4, No. 1

Year
2018

Website
https://www.karger.com/Article/FullText/488679

Full Article
s12888-020-02861-0.pdf

Background

Lived experience research is conducted by people who have experience of mental health issues and is therefore better placed than more traditional research to illuminate participants’ experiences. Findings that focus on identifying enablers of recovery from a lived experience perspective have the potential to assist people in their recovery process. However, this lived experience research is often difficult to find, access and interpret. We coproduced user-friendly and engaging resources to disseminate findings from six lived experience research studies. This paper seeks to answer the research questions: a) Did exposure to lived experience research increase hopefulness for participants?; and b) How else did interacting with lived experience research resources influence participants’ lives?

Journal Published
Neuron Volume 52, Issue 1, 5 October

Year Published
2006

Abstract
NeurobiologyZofZSchizophrenia.html.txt

Hypothesis

• The review provides a definitive study of the neurobiology of schizophrenia is now possible.
• The neurobiological study of schizophrenia may help illuminate the nature of normal thought, perception, and emotion.
• Understanding schizophrenia may help us better understand human nature itself.

Background

• Schizophrenia affects about 0.5 to 1.0 percent of the population worldwide with devastating consequences for affected individuals and their families, is the seventh most costly medical illness to our society
• The available symptomatic treatment is only partially successful, and therefore the development of rational therapeutics, based on an understanding of the etiology and pathogenesis of schizophrenia, is imperative.
• Until recently, progress in schizophrenia has been painfully slow and limited by a number of factors, including the heterogeneity of the schizophrenia phenotype and the lack of clear pathological lesions like those that have provided reference points in the study of Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders.
• Investigation into the mechanism of action of the drugs used to treat schizophrenia has not provided clear understanding of the pathogenesis of the disease.
• While schizophrenia is highly heritable (it has a heritability score of approximately 0.8), the genetics are complex and the interpretation of genetic data has proven difficult.
• Now, however, advances in phenotypic analysis, neuroimaging, genetics, and molecular pathology provide the basis for optimism. Schizophrenia can be understood, at least in part, as a subtle disorder of brain development
• Evidence now supports an etiologic role for mutations or polymorphisms in a number of genes  as well as obstetrical and premorbid abnormalities of development and cognition.

School, Department or Faculty
Laboratory of Cellular Neuropathology (McLean Hospital); Department of Psychiatry (Beth Israel Deaconess Medical Center); Department of Psychiatry (Harvard Medical School).

Journal Published
Current Top Behaviour Neuroscience

Year Published
Tsung-Ung W. Woo

Abstract
NeurobiologyZofZSchizophreniaZOnset.pdf

Hypothesis

This review discusses the possible pathophysiological mechanisms that may contribute to the dysfunction of PV neurons in schizophrenia, focusing on:

• Deficient glutamatergic innervation
• Oxidative stress and
• Impaired formation of ECM structures called perineuronal nets (PNNs).

Background

• Schizophrenia is a complex, prevalent, and extremely debilitating brain disorder affecting approximately 1% of the population worldwide.

• It is defined by a constellation of positive (i.e., delusions and hallucinations) and negative (i.e., affective flattening, avolition, alogia, anergia, and anhedonia) symptoms.

• In addition, patients exhibit prominent cognitive deficits (such as disturbances in executive functions), working memory, and attention.

• Together, these symptoms and cognitive deficits render the individuals inflicted with the illness a life-long course of intellectual, vocational, interpersonal and social impairment.

• At present, antipsychotic medications provide some symptomatic relief in some but not all patients, but they do not appear to impact the course or the long-term outcome of the illness in any meaningful fashion.

• The current lack of truly effective treatment, in no small part, is because after decades of research the pathophysiological basis of schizophrenia remains poorly understood.

• It has long been known that the onset of schizophrenia typically occurs during the period of late adolescence and early adulthood. In recent years, there has been growing emphasis in the field in identifying the clinical characteristics that immediately precede the onset of full-blown illness

• The clinical symptoms and cognitive and functional deficits of schizophrenia typically begin to gradually emerge during late adolescence and early adulthood. 

• The underlying concept is that timely intervention during this critical phase of the pathogenetic process could attenuate or perhaps even prevent the onset of overt symptoms and deficits.

• Although this line of research has evoked significant optimism and enormous excitement, reliable methods to faithfully predict who will ultimately develop symptoms and deficits do not yet exist.

• Perhaps more importantly, it is far from clear as to what preventative or early intervention strategies would be effective.

• The single most significant impediment is that the neurobiological mechanisms that mediate the onset of illness are at present virtually unknown.

• The period of adolescence is a time of profound changes, when the highest-order cognitive functions, such as reasoning, abstract thinking, and planning, gradually achieve maturation.

• This maturational process is thought to reflect the coming online of the executive brain system of the cerebral cortex, orchestrated in large part by the maturation of the prefrontal cortex (PFC) via extensive pruning of excitatory synapses, dendritic spines on pyramidal neurons on which these synapses form, and axon terminals of pyramidal neurons that are presynaptic to these synapses.

• This connectional pruning process is associated with the maturation of the capacity of PFC pyramidal neuronal networks to oscillate and synchronize, especially in the gamma (i.e., 30–80 Hz) frequency band

• In addition, gamma band oscillation appears to be an electrophysiological correlate of working memory, a core PFC function that is required for the integrity of executive functioning.

•  Interestingly, in patients with schizophrenia, working memory and executive functioning are compromised and gamma band oscillation has repeatedly been shown to be impaired.

• The fact that many of the symptoms and cognitive deficits of schizophrenia typically begin to emerge during late adolescence and early adulthood has long led to the hypothesis that disturbances of the synaptic pruning process that occurs in the PFC during this period may play a role in triggering the onset of illness, although the specific neurobiological mechanisms that underlie the presumed synaptic pruning disturbances have not been systematically formulated. T

• his is in large part due to the fact that, for a long time, the biological determinants of this synaptic pruning process were completely unknown. However, recent studies in rodents have identified the maturation of intracortical inhibition subserved by the parvalbumin (PV)-containing inhibitory neurons and the formation of extracellular matrix (ECM) environment as two important mechanisms that regulate the time course of the critical period for developmental synaptic plasticity in the cerebral cortex 

• Interpretation of these findings in the context of our current understanding of neuronal type-specific regulation of gamma band oscillation and PFC circuit dysfunction in schizophrenia allows us to begin to develop specific, experimentally testable hypotheses of the neurobiology of developmental synaptic pruning in the human PFC and the possible pathophysiological mechanisms of schizophrenia onset.

• Specifically, it is postulated that the inhibitory neurons that contain PV may play a central role in regulating the time course of PFC synaptic pruning during late adolescence and arly adulthood and that disturbances of PV neurons may lead to aberrant loss of synapses and thereby cortical circuitry instability, hence triggering the onset of schizophrenia 

School, Department or Faculty
Psychiatry Service (San Francisco VA Medical Center); Department of Psychiatry (University of California)

Journal Published
Frontiers in Human Neuroscience

Year Published
2012

Authors / Collaborators
Daniel H. Mathalon and Judith M. Ford

Abstract
NeurobiologyZofZSchizophreniaZZSearchZforZtheZElusiveZCorrelationZWithZSymptoms.pdf

Full Article
NeurobiologyZofZSchizophrenia_1.html.txt

Hypothesis

This paper provides an overview of the myriad conceptual and methodological obstacles that undermine efforts to link the severity of specific symptoms to specific neurobiological measures, obstacles that ultimately impede progress toward elucidating the neurobiological mechanisms underlying these symptoms.

Background

• Advances in neuroscience methods over the past 50 years have provided the means to study complex psychiatric disorders in vivo, firmly establishing that disorders once viewed as psychological reactions to stressful environments (particularly family environments) are associated with subtle abnormalities in brain structure and function.
• This historical transition toward reconceptualizing psychiatric disorders as brain disorders is exemplified by the paradigm shift that gave primacy to neurobiological and neurodevelopmental perspectives in understanding the etiopathology of schizophrenia.
• Despite the clinical heterogeneity of schizophrenia, a wide variety of neurobiological abnormalities have been replicated across clinical samples and research laboratories, providing some support for the neurobiological validity of the clinical criteria used to diagnose patients.
• Efforts to understand the neurobiological bases of the clinical heterogeneity that schizophrenia comprises, mainly by correlating neurobiological measures with specific symptoms, have been largely unsuccessful. 
• Inconsistency” has been the most consistent finding to emerge from such efforts.

Journal Published
Am J Psychiatry

Year Published
2002

Authors / Collaborators
Mary Cannon, Peter B. Jones, Robin M. Murray

Hypothesis

This paper reviews the literature on obstetric complications as a risk factor for schizophrenia. The authors trace the evolution of this literature through different methods and carry out a quantitative review of the results from prospective, population-based studies

Background

• The much-investigated association between obstetric complications and schizophrenia has provided crucial support for developmental and nongenetic etiological models of the disorder.  
• The first mention of an association between birth complications and schizophrenia occurred in the American Journal of Psychiatry in 1934.
• Rosanoff and colleagues published “The Etiology of So-Called Schizophrenic Psychoses” based on detailed case reports of 142 pairs of twins concordant and discordant for schizophrenia.
• The authors concluded that schizophrenia could be regarded (at least in part) as a “decerebration syndrome which may result from birth trauma.”
• Somewhat surprisingly, nothing further was published on this topic until 1956 when Pasamanick and colleagues proposed their now-classic thesis of a “continuum of reproductive casualty,” whereby pregnancy and birth complications can lead to a gradient of injury extending from fetal and neonatal death through cerebral palsy, epilepsy, mental deficiency, and behavior disorder.
• The paper by Pasamanick and colleagues initially had its greatest impact on the field of child psychiatry.
• In the early 1960s, there were reports of significant associations between pregnancy complications (particularly toxemia, bleeding, and severe maternal illness) and childhood psychosis. However, diagnostic uncertainty about the classification of childhood psychosis seems to have halted research in this area. Even though a review in 1966 concluded that “the need for further researces is strongly indicated by these findings”
• There was a gap of 10 years before a study by Torrey and colleagues reported an association between bleeding in pregnancy and childhood psychosis.

Description

• Bleeding and preeclampsia in pregnancy have been associated with psychosis since the earliest days of such research.
• Pasamanick and colleagues singled out the “anoxia-producing complications of pregnancy such as toxemia and bleeding” as most likely to be associated with behavior problems.
• Preeclampsia came to particular attention in 1996 when Kendell and colleagues reported a very strong association between preeclampsia and later schizophrenia, but, in their attempt to extend the study group and replicate this finding, a flaw in the original study design was uncovered, and a retraction was published.
• The revised analysis found no significant effect for preeclampsia.
• In the largest single population-based study to date, preeclampsia was the only obstetric risk factor that remained significant after the analysis controlled for all potentially confounding factors.
• The most popular theory at present involves the mechanism of abnormal fetal blood flow resulting in chronic fetal hypoxia or malnutrition.
• Bleeding during pregnancy has many causes. Implantation bleeding and abbreviated menses are common in the first month, and placenta praevia and premature separation of the placenta are frequent causes in the last month.
• The causes of mid-pregnancy bleeding are less well understood. In one study, two-thirds of the cases were found to be due to premature separation, placenta praevia, hydatiform moles, incompetent cervices, and other identifiable causes, while in one-third of the cases, the cause could not be determined.
• In severe cases of bleeding, the pathogenic effect on the fetus is thought to be anoxia, but, in many cases, the amount of bleeding may be slight and anoxic brain damage is unlikely.
• Another explanation is that bleeding can represent a threatened spontaneous abortion.
• The process of uterine rejection could have begun but been interrupted.
• Genetic or autoimmune factors may play a part in such a process.
• The association between diabetes in pregnancy and later schizophrenia, although strong, is based on only two studies in this analysis, neither of which provided information on the type of diabetes.
• Indirect support for the association comes from one report that high prepregnancy body mass increases the risk of schizophrenia in the offspring, since high maternal body mass index is associated with non-insulin-dependent diabetes and gestational diabetes.
• The effects on the developing brain of altered glucose metabolism are not well understood.
• Poorly controlled maternal diabetes is associated with an increased risk of congenital anomalies and impaired intellectual and psychomotor development in offspring.
• Insulin-dependent diabetes mellitus has been found to be more common among the firstdegree relatives of patients with schizophrenia than among comparison subjects, indicating that an autoimmune process might be involved.
• Autoimmune mechanisms could also be implicated in the association between rhesus incompatibility and later schizophrenia.
• Rhesus hemolytic disease of the newborn is an illness with neurological consequences secondary to effects of a maternal antibody.
• Hemolytic disease can lead to early spontaneous abortion, chronic fetal hypoxia, neonatal asphyxia and pulmonary edema, and neonatal hyperbilirubinemia and kernicterus.
• The association has independent support from a cohort study that found a twofold increase in relative risk of schizophrenia among men from rhesus-incompatible pregnancies and a report that neonatal hyperbilirubinemia is a risk factor for later mental illness.

Source
Obstetric Complications and Schizophrenia: Historical and Meta-Analytic Review

Journal
Am J Psychiatry

Year
2002

Website
https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.159.7.1080

Journal Published
Br J Psychiatry

Year Published
2006

Authors / Collaborators
Emma Robertson Blackmore 1, Ian Jones, Monica Doshi, Sayeed Haque, Roger Holder, Ian Brockington, Nick Craddock

Full Article
obstetric-variables-associated-with-bipolar-affective-puerperal-psychosis.pdf

Journal Published
British Journal of Psychiatry

Year Published
2005

Authors / Collaborators
EMMA ROBERTSON, IAN JONES, SAYEED HAQUE, ROGER HOLDER EMMA ROBERTSON, IAN JONES, SAYEED HAQUE, ROGER HOLDER and NICK CRADDOCK

Full Article
risk-of-puerperal-and-non-puerperal-recurrence-of-illness-following-bipolar-affective-puerperal-post-partum-psychosis.pdf