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The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

ABSTRACT: BACKGROUND:Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS:We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS:Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS:The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.

SUBMITTER: Blokland GAM

PROVIDER: S-EPMC5882601 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

Blokland Gabriëlla A M GAM Del Re Elisabetta C EC Mesholam-Gately Raquelle I RI Jovicich Jorge J Trampush Joey W JW Keshavan Matcheri S MS DeLisi Lynn E LE Walters James T R JTR Turner Jessica A JA Malhotra Anil K AK Lencz Todd T Shenton Martha E ME Voineskos Aristotle N AN Rujescu Dan D Giegling Ina I Kahn René S RS Roffman Joshua L JL Holt Daphne J DJ Ehrlich Stefan S Kikinis Zora Z Dazzan Paola P Murray Robin M RM Di Forti Marta M Lee Jimmy J Sim Kang K Lam Max M Wolthusen Rick P F RPF de Zwarte Sonja M C SMC Walton Esther E Cosgrove Donna D Kelly Sinead S Maleki Nasim N Osiecki Lisa L Picchioni Marco M MM Bramon Elvira E Russo Manuela M David Anthony S AS Mondelli Valeria V Reinders Antje A T S AATS Falcone M Aurora MA Hartmann Annette M AM Konte Bettina B Morris Derek W DW Gill Michael M Corvin Aiden P AP Cahn Wiepke W Ho New Fei NF Liu Jian Jun JJ Keefe Richard S E RSE Gollub Randy L RL Manoach Dara S DS Calhoun Vince D VD Schulz S Charles SC Sponheim Scott R SR Goff Donald C DC Buka Stephen L SL Cherkerzian Sara S Thermenos Heidi W HW Kubicki Marek M Nestor Paul G PG Dickie Erin W EW Vassos Evangelos E Ciufolini Simone S Reis Marques Tiago T Crossley Nicolas A NA Purcell Shaun M SM Smoller Jordan W JW van Haren Neeltje E M NEM Toulopoulou Timothea T Donohoe Gary G Goldstein Jill M JM Seidman Larry J LJ McCarley Robert W RW Petryshen Tracey L TL

Schizophrenia research 20171003

<h4>Background</h4>Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection.<h4>Methods</h4>We identified existing samples collected for schizophrenia studies consisting of pa ...[more]

PMID: 28982554

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Project description:ImportanceThe Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration.ObjectiveTo build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs).Design, setting, and participantsA total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018.Main outcomes and measuresA genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition.ResultsThe final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 × 10-8) and 2 nearly significant regions (P < 9 × 10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis.Conclusions and relevanceThese analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

Dataset Information

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

Publications

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

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