neurogenetics

, Volume 13, Issue 3, pp 261–266

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

Authors

  • Hannah C. Cox
    • Genomics Research Centre, Griffith Health Institute
  • Rod A. Lea
    • Genomics Research Centre, Griffith Health Institute
  • Claire Bellis
    • Genomics Research Centre, Griffith Health Institute
    • Department of GeneticsTexas Biomedical Research Institute
  • Melanie Carless
    • Department of GeneticsTexas Biomedical Research Institute
  • Thomas D. Dyer
    • Department of GeneticsTexas Biomedical Research Institute
  • Joanne Curran
    • Department of GeneticsTexas Biomedical Research Institute
  • Jac Charlesworth
    • Department of GeneticsTexas Biomedical Research Institute
    • Menzies Research InstituteUniversity of Tasmania
  • Stuart Macgregor
    • Statistical Genetics Laboratory, Queensland Institute of Medical ResearchThe Bancroft Centre
  • Dale Nyholt
    • Statistical Genetics Laboratory, Queensland Institute of Medical ResearchThe Bancroft Centre
  • Daniel Chasman
    • Division of Preventive Medicine, Department of Medicine, Brigham and Women’s HospitalHarvard Medical School
    • Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women’s HospitalHarvard Medical School
  • Paul M. Ridker
    • Division of Preventive Medicine, Department of Medicine, Brigham and Women’s HospitalHarvard Medical School
    • Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women’s HospitalHarvard Medical School
  • Markus Schürks
    • Division of Preventive Medicine, Department of Medicine, Brigham and Women’s HospitalHarvard Medical School
    • Department of NeurologyUniversity Hospital Essen
  • John Blangero
    • Department of GeneticsTexas Biomedical Research Institute
    • Genomics Research Centre, Griffith Health Institute
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