title: Integrated Post-GWAS Analysis Sheds New Light on the Disease Mechanisms of Schizophrenia.
abstract: Schizophrenia is a severe mental disorder with a large genetic component. Recent genome-wide association studies (GWAS) have identified many schizophrenia-associated common variants. For most of the reported associations, however, the underlying biological mechanisms are not clear. The critical first step for their elucidation is to identify the most likely disease genes as the source of the association signals. Here, we describe a general computational framework of post-GWAS analysis for complex disease gene prioritization. We identify 132 putative schizophrenia risk genes in 76 risk regions spanning 120 schizophrenia-associated common variants, 78 of which have not been recognized as schizophrenia disease genes by previous GWAS. Even more significantly, 29 of them are outside the risk regions, likely under regulation of transcriptional regulatory elements contained therein. These putative schizophrenia risk genes are transcriptionally active in both brain and the immune system, and highly enriched among cellular pathways, consistent with leading pathophysiological hypotheses about the pathogenesis of schizophrenia. With their involvement in distinct biological processes, these putative schizophrenia risk genes, with different association strengths, show distinctive temporal expression patterns, and play specific biological roles during brain development.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Jhih-Rong
authors.initials: JR
authors.lastname: Lin
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Quanwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogales-Cadenas
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461 zhengdong.zhang@einstein.yu.edu.
authors.forename: Zhengdong D
authors.initials: ZD
authors.lastname: Zhang
mesh_terms: D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*
keywords: GWAS; disease risk gene prioritization; schizophrenia