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

• Verfasst von: Luo, Xiong-Jian [VerfasserIn]
• Verfasst von: Mattheisen, Manuel [VerfasserIn]
• Verfasst von: Li, Ming [VerfasserIn]
• Verfasst von: Huang, Liang [VerfasserIn]
• Verfasst von: Rietschel, Marcella [VerfasserIn]
• Verfasst von: Børglum, Anders D. [VerfasserIn]
• Verfasst von: Als, Thomas D. [VerfasserIn]
• Verfasst von: van den Oord, Edwin J. [VerfasserIn]
• Verfasst von: Aberg, Karolina A. [VerfasserIn]
• Verfasst von: Mors, Ole [VerfasserIn]
• Verfasst von: Mortensen, Preben Bo [VerfasserIn]
• Verfasst von: Luo, Zhenwu [VerfasserIn]
• Verfasst von: Degenhardt, Franziska [VerfasserIn]
• Verfasst von: Cichon, Sven [VerfasserIn]
• Verfasst von: Schulze, Thomas G. [VerfasserIn]
• Verfasst von: Nöthen, Markus M. [VerfasserIn]
• Verfasst von: Su, Bing [VerfasserIn]
• Verfasst von: Zhao, Zhongming [VerfasserIn]
• Verfasst von: Gan, Lin [VerfasserIn]
• Verfasst von: Yao, Yong-Gang [VerfasserIn]
• Titel: 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
• Verf.angabe: Xiong-Jian Luo, Manuel Mattheisen, Ming Li, Liang Huang, Marcella Rietschel, Anders D. Børglum, Thomas D. Als, Edwin J. van den Oord, Karolina A. Aberg, Ole Mors, Preben Bo Mortensen, Zhenwu Luo, Franziska Degenhardt, Sven Cichon, Thomas G. Schulze, Markus M. Nöthen, iPSYCH-GEMS SCZ working group, MooDS SCZ Consortium, Bing Su, Zhongming Zhao, Lin Gan, and Yong-Gang Yao
• E-Jahr: 2015
• Jahr: 10 March 2015
• Umfang: 15 S.
• Illustrationen: Illustration$aDiagramme
• Fussnoten: Gesehen am 03.01.2018
• Titel Quelle: Enthalten in: Schizophrenia bulletin
• Ort Quelle: Oxford : Oxford Univ. Press, 1969
• Jahr Quelle: 2015
• Band/Heft Quelle: 41(2015), 6, Seite 1294-1308
• ISSN Quelle: 1745-1701
• DOI: doi:10.1093/schbul/sbv017
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 866084940

Abstract

ZNF323; association; eQTL; hippocampus; positive selection; schizophrenia. 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.