Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes
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Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes. / Pers, Tune H; Timshel, Pascal; Ripke, Stephan; Lent, Samantha; Sullivan, Patrick F; O'Donovan, Michael C; Franke, Lude; Hirschhorn, Joel N; Schizophrenia Working Group of the Psychiatric Genomics Consortium.
In: Human Molecular Genetics, Vol. 25, No. 6, 10.01.2016, p. 1247-1254.Research output: Contribution to journal › Journal article › Research › peer-review
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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: journals.permissions@oup.com.
PY - 2016/1/10
Y1 - 2016/1/10
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).
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).
U2 - 10.1093/hmg/ddw007
DO - 10.1093/hmg/ddw007
M3 - Journal article
C2 - 26755824
VL - 25
SP - 1247
EP - 1254
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 6
ER -
ID: 156085305