Integrated post-GWAS analysis sheds new light on the disease mechanisms of schizophrenia

Jhih Rong Lin, Ying Cai, Quanwei Zhang, Wen Zhang, Rubén Nogales-Cadenas, Zhengdong D. Zhang

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1587-1600
Number of pages14
JournalGenetics
Volume204
Issue number4
DOIs
StatePublished - Dec 1 2016

Keywords

  • Disease risk gene prioritization
  • GWAS
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics

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