Identification of shared risk loci and pathways for bipolar disorder and schizophrenia

PLoS One. 2017 Feb 6;12(2):e0171595. doi: 10.1371/journal.pone.0171595. eCollection 2017.

Abstract

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.

MeSH terms

  • Bipolar Disorder / genetics*
  • Bipolar Disorder / metabolism*
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • Risk
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism*
  • Signal Transduction*

Grant support

The study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A to M.M.N. and S.C., grant 01ZX1314G to M.R.). M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. The study was supported by the German Research Foundation (DFG; grant FOR2107; RI908/11-1 to M.R.; NO246/10-1 to M.M.N.). The study was also supported by the Swiss National Science Foundation (SNSF, grant 156791 to S.C.). M.G.S. received grant no. 89/2012 from UEFISCDI, Romania. Canadian patients were genotyped within the ConLiGen project (www.ConLiGen.org), with the support of a grant from the DFG to M.R., M.B., and T.G.S. (RI 908/7-1). Controls for Germany II were drawn from the Heinz Nixdorf Recall Study (HNR) cohort, which was established with the support of the Heinz Nixdorf Foundation. Recruitment of the Australian sample was supported by an Australian NHMRC program grant (number 1037196). The recruitment of the Canadian patients was supported by a grant from the Canadian Institutes of Health Research #64410 to M.A. The study also used data generated by the GABRIEL consortium (controls for the sample Russia). Funding for the generation of these data was provided by the European Commission as part of GABRIEL contract number 018996 under the Integrated Program LSH-2004-1.2.5-1. Post genomic approaches to understand the molecular basis of asthma aiming at a preventive or therapeutic control and the Wellcome Trust under award 084703. Canadian controls were drawn from the French Canadian study (SLSJ), which was supported in part by the Canada Research Chair Environment and genetics of respiratory diseases and allergy, the Canadian Institutes of Health Research (Operating grant No. MOP-13506), and the Quebec Respiratory Network of the Fonds de rechercheen Santé du Québec (FRQS). Polish controls were recruited by the International Agency for Research on Cancer (IARC)/Centre National de Genotypage (CNG) GWAS Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.