Journal Article

FZJ-2015-02100

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function

Luo, X.-J. (Corresponding Author) ; Mattheisen, M. ; Li, M. ; Huang, L. ; Rietschel, M. ; Børglum, A. D. ; Als, T. D. ; van den Oord, E. J. ; Aberg, K. A. ; Mors, O. ; Mortensen, P. B. ; Luo, Z. ; Degenhardt, F. ; Cichon, S.FZJ* ; Schulze, T. G. ; Nöthen, M. M. ; iPSYCH-GEMS SCZ, w. g. ; MooDS SCZ, C. ; Su, B. ; Zhao, Z. ; Gan, L. ; Yao, Y.-G.

2015
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/schbul/sbv017

Abstract: Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10(-6)). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10(-6); single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10(-10)). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10(-5) and P = 9.00×10(-5), respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool.

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Contributing Institute(s):

1. Strukturelle und funktionelle Organisation des Gehirns (INM-1)

Research Program(s):

1. 571 - Connectivity and Activity (POF3-571) (POF3-571)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Current Contents - Social and Behavioral Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Social Sciences Citation Index ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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