The Global Now Project

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.

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Gene Function in Schizophrenia - Genetics

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Gene Mapping in Schizophrenia - Genetics

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Genetic Association in Schizophrenia - Genetics

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Genetic Expression in Schizophrenia - Genetics

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Genetic Expression Patterns in Schizophrenia - Genetics

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Genetic Linkaging for Schizophrenia - Genetics

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Genetic Susceptibility in Schizophrenia - Genetics

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Genetic Variants in Schizophrenia - Genetics

Genetic variation is the differences in the DNA of a given species, a key to fitness and survival as it increases the chance of adaptability.

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Genetics of Schizophrenia - Genetics

Studies

The Genetics of Schizophrenia

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

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The epidemiology of schizophrenia.	PLoS Med	2005	Saha S, Welham J, Chant D, McGrath J		2: e141
A selective review of recent North American long-term followup studies of schizophrenia	Schizophr Bull	1998	McGlashan TH		14: 515â€“542.
Medical comorbidity in schizophrenia	Schizophr Bull	1996	Jeste DV, Gladsjo JA, Lindamer LA, Lacro JP		22: 413â€“430.
Excess mortality of mental disorder.	Br J Psychiatry	1998	Harris EC, Barraclough BB		173: 11â€“53.
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Effects of family history and place and season of birth on the risk of schizophrenia	N Engl J Med	1999	Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, et al.		340: 603â€“608.
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Genetics	American Psychiatric Publishing. In press	2005	Sullivan PF, Owen MJ, ODonovan MC, Freedman RR
From QTL to gene: The harvest begins	Nat Genet	2002	Korstanje R, Paigen B		31: 235â€“ 236
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A genomewide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: Support for loci on chromosome 10p and 6	Mol Psychiatry	2000	Schwab SG, Hallmayer J, Albus M, Lerer B, Eckstein GN, et al.		5: 638â€“649
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A schizophreniasusceptibility locus at 6q25, in one of the worldâ€™s largest reported pedigrees	Am J Hum Genet	2001	Lindholm E, Ekholm B, Shaw S, Jalonen P, Johansson G, et al.		69: 96â€“105
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Genetic case-control association studies in neuropsychiatry	Arch Gen Psychiatry	2001	Sullivan PF, Eaves LJ, Kendler KS, Neale MC		58: 1015â€“1024.
Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: A large-scale association study plus meta-analysis	Biol Psychiatry	2005	Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, et al.		57: 139â€“144
A highly significant association between a COMT haplotype and schizophrenia.	Am J Hum Genet	2002	Shifman S, Bronstein M, Sternfeld M, PisanteShalom A, Lev-Lehman E, et al		71: 1296â€“1302
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Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration	Am J Hum Genet	2005	Zareparsi S, Branham KE, Li M, Shah S, Klein RJ, et al. (		77: 149â€“153.
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The Role of Genetics in the Etiology of Schizophrenia

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.

Recent Advances in the Genetics of Schizophrenia

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:

Large copy number variants
Rare coding inherited
De novο variants
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.

Research Questions

Studies

Studies

References

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