Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

F Lescai, T D Als, Q Li, M Nyegaard, G Andorsdottir, M Biskopstø, A Hedemand, A Fiorentino, N O'Brien, A Jarram, J Liang, J Grove, J Pallesen, E Eickhardt, M Mattheisen, L Bolund, D Demontis, August G. Wang, A McQuillin, O MorsJ Wang, A D Børglum

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)
1 Downloads (Pure)

Abstract

Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder.

Original languageEnglish
JournalTranslational psychiatry
Volume7
Issue number2
DOIs
Publication statusPublished - 14 Feb 2017

Keywords

  • bipolar disorders
  • calcium-binding proteins
  • case-control study
  • Denmark
  • gene regulatory networks
  • genetic predisposition ti disease
  • humans
  • membrane proteins
  • mutation
  • missense
  • nitric oxide synthase type 1
  • phosphatidylinositol 3-kinases
  • phosphoproteins
  • polymorphism
  • genetic
  • rna-binding proteins
  • sequence analysis
  • dna
  • united kingdom
  • journal article
  • research support
  • non-u.s gov't

Fingerprint

Dive into the research topics of 'Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder'. Together they form a unique fingerprint.

Cite this