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Nat Commun. 2019 Feb 8;10(1):670. doi: 10.1038/s41467-019-08666-4.

Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk.

Huo Y1, Li S1,2, Liu J1, Li X1,2, Luo XJ3,4,5,6.

Author information

1
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
2
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.
3
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China. luoxiongjian@mail.kiz.ac.cn.
4
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China. luoxiongjian@mail.kiz.ac.cn.
5
Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China. luoxiongjian@mail.kiz.ac.cn.
6
KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. luoxiongjian@mail.kiz.ac.cn.

Abstract

Genome-wide association studies (GWASs) have identified over 180 independent schizophrenia risk loci. Nevertheless, how the risk variants in the reported loci confer schizophrenia susceptibility remains largely unknown. Here we systematically investigate the gene regulatory mechanisms underpinning schizophrenia risk through integrating data from functional genomics (including 30 ChIP-Seq experiments) and position weight matrix (PWM). We identify 132 risk single nucleotide polymorphisms (SNPs) that disrupt transcription factor binding and we find that 97 of the 132 TF binding-disrupting SNPs are associated with gene expression in human brain tissues. We validate the regulatory effect of some TF binding-disrupting SNPs with reporter gene assays (9 SNPs) and allele-specific expression analysis (10 SNPs). Our study reveals gene regulatory mechanisms affected by schizophrenia risk SNPs (including widespread disruption of POLR2A and CTCF binding) and identifies target genes for mechanistic studies and drug development. Our results can be accessed and visualized at SZDB database ( http://www.szdb.org/ ).

PMID:
30737407
PMCID:
PMC6368563
DOI:
10.1038/s41467-019-08666-4
[Indexed for MEDLINE]
Free PMC Article

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