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

TY - JOUR

T1 - Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes

AU - Pers, Tune H

AU - Timshel, Pascal

AU - Ripke, Stephan

AU - Lent, Samantha

AU - Sullivan, Patrick F

AU - O'Donovan, Michael C

AU - Franke, Lude

AU - Hirschhorn, Joel N

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

N1 - © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

PY - 2015/8/17

Y1 - 2015/8/17

N2 - 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).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author.

AB - 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).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author.

U2 - 10.1093/hmg/ddw007

DO - 10.1093/hmg/ddw007

M3 - Journal article

C2 - 26755824

SN - 0964-6906

VL - 25

SP - 1247

EP - 1254

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 6

ER -