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

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, Bing Su, Zhongming Zhao, Lin Gan, Yong Gang Yao

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1294-1308
Number of pages15
JournalSchizophrenia Bulletin
Volume41
Issue number6
DOIs
StatePublished - Nov 2015
Externally publishedYes

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Genome-Wide Association Study
Schizophrenia
Lung
Brain
Genes
Gene Pool
Alleles
Gene Expression
Quantitative Trait Loci
Population Genetics
Frontal Lobe
Single Nucleotide Polymorphism
Meta-Analysis
Hippocampus
Down-Regulation
Genome

Keywords

  • Association
  • eQTL
  • Hippocampus
  • Positive selection
  • Schizophrenia
  • ZNF323

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

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, Xiong Jian; Mattheisen, Manuel; Li, Ming; Huang, Liang; Rietschel, Marcella; Børglum, Anders D.; Als, Thomas D.; Van Den Oord, Edwin J.; Aberg, Karolina A.; Mors, Ole; Mortensen, Preben Bo; Luo, Zhenwu; Degenhardt, Franziska; Cichon, Sven; Schulze, Thomas G.; Nöthen, Markus M.; Su, Bing; Zhao, Zhongming; Gan, Lin; Yao, Yong Gang.

In: Schizophrenia Bulletin, Vol. 41, No. 6, 11.2015, p. 1294-1308.

Research output: Contribution to journalArticle

Luo, XJ, Mattheisen, M, Li, M, Huang, L, Rietschel, M, Børglum, AD, Als, TD, Van Den Oord, EJ, Aberg, KA, Mors, O, Mortensen, PB, Luo, Z, Degenhardt, F, Cichon, S, Schulze, TG, Nöthen, MM, Su, B, Zhao, Z, Gan, L & Yao, YG 2015, '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', Schizophrenia Bulletin, vol. 41, no. 6, pp. 1294-1308. https://doi.org/10.1093/schbul/sbv017
Luo, Xiong Jian ; Mattheisen, Manuel ; Li, Ming ; Huang, Liang ; Rietschel, Marcella ; Børglum, Anders D. ; Als, Thomas D. ; Van Den Oord, Edwin J. ; Aberg, Karolina A. ; Mors, Ole ; Mortensen, Preben Bo ; Luo, Zhenwu ; Degenhardt, Franziska ; Cichon, Sven ; Schulze, Thomas G. ; Nöthen, Markus M. ; Su, Bing ; Zhao, Zhongming ; Gan, Lin ; Yao, Yong Gang. / 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. In: Schizophrenia Bulletin. 2015 ; Vol. 41, No. 6. pp. 1294-1308.
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AU - Mattheisen, Manuel

AU - Li, Ming

AU - Huang, Liang

AU - Rietschel, Marcella

AU - Børglum, Anders D.

AU - Als, Thomas D.

AU - Van Den Oord, Edwin J.

AU - Aberg, Karolina A.

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Luo, Zhenwu

AU - Degenhardt, Franziska

AU - Cichon, Sven

AU - Schulze, Thomas G.

AU - Nöthen, Markus M.

AU - Su, Bing

AU - Zhao, Zhongming

AU - Gan, Lin

AU - Yao, Yong Gang

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N2 - 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.

AB - 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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