Article open access publication

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, Oxford University Press (OUP), ISSN 0586-7614

Volume 41, 6, 2015

DOI:10.1093/schbul/sbv017, Dimensions: pub.1060023928, PMC: PMC4601704, PMID: 25759474,

Affiliations

Organisations

  1. (1) Kunming Institute of Zoology, grid.419010.d
  2. (2) These authors contributed equally to this work
  3. (3) University of Bonn, grid.10388.32
  4. (4) Lundbeck Foundation, grid.452548.a
  5. (5) Aarhus University, grid.7048.b, AU
  6. (6) Lieber Institute for Brain Development, grid.429552.d
  7. (7) First Affiliated Hospital of Gannan Medical University, grid.452437.3
  8. (8) Central Institute of Mental Health, grid.413757.3
  9. (9) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  10. (10) Virginia Commonwealth University, grid.224260.0
  11. (11) Medical University of South Carolina, grid.259828.c
  12. (12) Forschungszentrum Jülich, grid.8385.6
  13. (13) University of Basel, grid.6612.3
  14. (14) Ludwig Maximilian University of Munich, grid.5252.0
  15. (15) University of Göttingen, grid.7450.6
  16. (16) Vanderbilt University, grid.152326.1
  17. (17) Chinese Academy of Sciences, grid.9227.e

Description

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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