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Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes

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Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates<0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P=0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P=5.00×10(-4); odds ratio 2.60, P=0.049).

Original languageEnglish
JournalHuman Molecular Genetics
Volume25
Issue number6
Pages (from-to)1247-1254
ISSN0964-6906
DOIs
Publication statusPublished - 10 Jan 2016

ID: 46199905