neurogenetics

, Volume 13, Issue 3, pp 261–266

A genome-wide analysis of 'Bounty' descendants implicates several novel variants in migraine susceptibility

  • Hannah C. Cox
  • Rod A. Lea
  • Claire Bellis
  • Melanie Carless
  • Thomas D. Dyer
  • Joanne Curran
  • Jac Charlesworth
  • Stuart Macgregor
  • Dale Nyholt
  • Daniel Chasman
  • Paul M. Ridker
  • Markus Schürks
  • John Blangero
  • Lyn R. Griffiths
Original Article

DOI: 10.1007/s10048-012-0325-x

Cite this article as:
Cox, H.C., Lea, R.A., Bellis, C. et al. Neurogenetics (2012) 13: 261. doi:10.1007/s10048-012-0325-x

Abstract

Migraine is a common neurological disease with a complex genetic aetiology. The disease affects ~12 % of the Caucasian population and females are three times more likely than males to be diagnosed. In an effort to identify loci involved in migraine susceptibility, we performed a pedigree-based genome-wide association study of the isolated population of Norfolk Island, which has a high prevalence of migraine. This unique population originates from a small number of British and Polynesian founders who are descendents of the Bounty mutiny and forms a very large multigenerational pedigree (Bellis et al.; Human Genetics, 124(5):543–5542, 2008). These population genetic features may facilitate disease gene mapping strategies (Peltonen et al.; Nat Rev Genet, 1(3):182–90, 2000. In this study, we identified a high heritability of migraine in the Norfolk Island population (h2 = 0.53, P = 0.016). We performed a pedigree-based GWAS and utilised a statistical and pathological prioritisation approach to implicate a number of variants in migraine. An SNP located in the zinc finger protein 555 (ZNF555) gene (rs4807347) showed evidence of statistical association in our Norfolk Island pedigree (P = 9.6 × 10−6) as well as replication in a large independent and unrelated cohort with >500 migraineurs. In addition, we utilised a biological prioritisation to implicate four SNPs, in within the ADARB2 gene, two SNPs within the GRM7 gene and a single SNP in close proximity to a HTR7 gene. Association of SNPs within these neurotransmitter-related genes suggests a disrupted serotoninergic system that is perhaps specific to the Norfolk Island pedigree, but that might provide clues to understanding migraine more generally.

Keywords

MigraineAssociationGene

Supplementary material

10048_2012_325_MOESM1_ESM.doc (80 kb)
Supplementary document 1. Methodology. (DOC 80 kb)
10048_2012_325_MOESM2_ESM.doc (74 kb)
Supplementary Fig. 1Manhattan Plot of autosomal genome-wide associations for migraine in the Norfolk Island pedigree. (DOC 73 kb)
10048_2012_325_MOESM3_ESM.pptx (142 kb)
Supplementary Fig. 2(PPTX 142 kb)
10048_2012_325_MOESM4_ESM.doc (322 kb)
Supplementary Table 1Summary of the top 0.05 % of SNPs (n = 172) detected in the Norfolk study (DOC 322 kb) (DOC 322 kb)
10048_2012_325_MOESM5_ESM.docx (78 kb)
Supplementary Table 2Results of replication study in WGHS cohort. (DOCX 78 kb)
10048_2012_325_MOESM6_ESM.docx (166 kb)
ESM 2(DOCX 166 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Hannah C. Cox
    • 1
  • Rod A. Lea
    • 1
  • Claire Bellis
    • 1
    • 2
  • Melanie Carless
    • 2
  • Thomas D. Dyer
    • 2
  • Joanne Curran
    • 2
  • Jac Charlesworth
    • 2
    • 3
  • Stuart Macgregor
    • 4
  • Dale Nyholt
    • 4
  • Daniel Chasman
    • 5
    • 6
  • Paul M. Ridker
    • 5
    • 6
  • Markus Schürks
    • 5
    • 7
  • John Blangero
    • 2
  • Lyn R. Griffiths
    • 1
  1. 1.Genomics Research Centre, Griffith Health InstituteGriffith UniversityAustralia
  2. 2.Department of GeneticsTexas Biomedical Research InstituteSan AntonioUSA
  3. 3.Menzies Research InstituteUniversity of TasmaniaHobartAustralia
  4. 4.Statistical Genetics Laboratory, Queensland Institute of Medical ResearchThe Bancroft CentreHerstonAustralia
  5. 5.Division of Preventive Medicine, Department of Medicine, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  6. 6.Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  7. 7.Department of NeurologyUniversity Hospital EssenEssenGermany