Institut for Biomedicin

Ditte Demontis

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • F Lescai
  • T D Als
  • Q Li, BGI-Shenzhen, Shenzhen, China.
  • ,
  • M Nyegaard
  • Gudrid Andorsdottir, Genetic Biobank of the Faroe Islands, Torshavn, Faroe Islands
  • ,
  • Marjun Biskopstø, Genetic Biobank of the Faroe Islands, Torshavn, Faroe Islands
  • ,
  • A Hedemand, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • ,
  • A Fiorentino, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London
  • ,
  • Niamh L O'Brien, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London
  • ,
  • Alex Jarram, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London
  • ,
  • T J Liang, BGI-Shenzhen, Shenzhen, China.
  • ,
  • J Grove
  • J Pallesen
  • ,
  • E Eickhardt
  • ,
  • M Mattheisen
  • L Bolund
  • D Demontis
  • A G Wang, Mental Health Centre Amager, Copenhagen, Denmark.
  • ,
  • A. McQuillin, BGI-Shenzhen, Shenzhen, China.
  • ,
  • O Mors
  • J Wang, BGI-Shenzhen, Shenzhen, China.
  • ,
  • A D Børglum

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.

OriginalsprogEngelsk
TidsskriftTranslational Psychiatry
Vol/bind7
Nummer2
Sider (fra-til)e1034
ISSN2158-3188
DOI
StatusUdgivet - 14 feb. 2017

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