Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study

This genome-wide association study reports 11 schizophrenia-related endophenotypes in an independent cohort of patients with schizophrenia and healthy comparison participants within the Consortium on the Genetics of Schizophrenia study population. 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. 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. 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). Design, 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. 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 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. Results The 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 x 10(-8)) and 2 nearly significant regions (P < 9 x 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 Relevance These 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. Question Can a genome-wide association study of neurophysiological and neurocognitive endophenotypes identify genes related to the underlying molecular dysfunctions in schizophrenia? Findings A total of 7 regions exceeding a conventional genome-wide significance threshold (P < 5 x 10(-8)) were associated with various endophenotype deficits, and the genes within these regions largely implicate glutamate and axonal dysfunctions as well as other neurobiologically salient targets. Many regions of interest were identified, including 39 previously associated with a schizophrenia diagnosis. Meaning These results suggest that the use of quantitative endophenotypes in genomic studies may provide an important, strong inference-based strategy for understanding the molecular basis of schizophrenia and may suggest novel treatment targets.