1 Large-scale genome-wide association studies (GWAS) using a case-control design have detected many common variants that collectively account for as much as 7% of risk for schizophrenia. Schizophrenia is a severe and persistent psychotic disorder with a prevalence of approximately 1% and a heritability of as much as 80%. 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. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. 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.Ĭonclusions and Relevance These analyses identified several genomic regions of interest that require further exploration and validation. 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. Results The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. Main Outcomes and Measures A 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. Data were analyzed from October 28, 2016, to May 4, 2018. Data for COGS-1 were collected from January 6, 2003, to Augdata for COGS-2, from June 30, 2010, to February 14, 2014. 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.

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. Objective To 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).ĭesign, Setting, and Participants A 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. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Importance The 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. Shared Decision Making and Communication.Scientific Discovery and the Future of Medicine.Health Care Economics, Insurance, Payment.Clinical Implications of Basic Neuroscience.Challenges in Clinical Electrocardiography.CTNNA2, CSMD1, and ZNF804A were prominent genes in these analyses with external support from studies of schizophrenia diagnosis but do not directly connect into the defined network.

C indicates genes identified as associated with a schizophrenia diagnosis through GWAS of common variants R, those identified by studies of rare and de novo variation. Genes with additional evidence of association in the genome-wide association study (GWAS) of the independent cases with schizophrenia and healthy comparison participants are indicated in green, with a solid box representing genes meeting the enrichment threshold of P < 1 × 10 −4 and a dashed box representing nominal significance ( P < .01).

Those with pleiotropic associations to at least 4 endophenotypes in the COGS families are shown in bold. Genes and interactions in black revealed association (blue box) or linkage (red box) with 1 or more endophenotypes, whereas those in gray represent other interacting genes. Genes are represented as nodes with solid lines representing direct protein-protein interactions and dashed arrows representing more indirect effects on expression, activation, or inhibition.

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