Original Article

neurogenetics

, Volume 13, Issue 3, pp 261-266

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

  • Hannah C. CoxAffiliated withGenomics Research Centre, Griffith Health Institute
  • , Rod A. LeaAffiliated withGenomics Research Centre, Griffith Health Institute
  • , Claire BellisAffiliated withGenomics Research Centre, Griffith Health InstituteDepartment of Genetics, Texas Biomedical Research Institute
  • , Melanie CarlessAffiliated withDepartment of Genetics, Texas Biomedical Research Institute
  • , Thomas D. DyerAffiliated withDepartment of Genetics, Texas Biomedical Research Institute
  • , Joanne CurranAffiliated withDepartment of Genetics, Texas Biomedical Research Institute
  • , Jac CharlesworthAffiliated withDepartment of Genetics, Texas Biomedical Research InstituteMenzies Research Institute, University of Tasmania
  • , Stuart MacgregorAffiliated withStatistical Genetics Laboratory, Queensland Institute of Medical Research, The Bancroft Centre
  • , Dale NyholtAffiliated withStatistical Genetics Laboratory, Queensland Institute of Medical Research, The Bancroft Centre
    • , Daniel ChasmanAffiliated withDivision of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolDonald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School
    • , Paul M. RidkerAffiliated withDivision of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolDonald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School
    • , Markus SchürksAffiliated withDivision of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurology, University Hospital Essen
    • , John BlangeroAffiliated withDepartment of Genetics, Texas Biomedical Research Institute
    • , Lyn R. GriffithsAffiliated withGenomics Research Centre, Griffith Health Institute Email author 

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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 (h 2 = 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

Migraine Association Gene