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

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    24 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)261-266
    Number of pages6
    JournalNeurogenetics
    Volume13
    Issue number3
    DOIs
    StatePublished - Aug 1 2012

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    Keywords

    • Association
    • Gene
    • Migraine

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)
    • Cellular and Molecular Neuroscience

    Cite this

    Cox, H. C., Lea, R. A., Bellis, C., Carless, M., Dyer, T. D., Curran, J., Charlesworth, J., MacGregor, S., Nyholt, D., Chasman, D., Ridker, P. M., Schürks, M., Blangero, J., & Griffiths, L. R. (2012). A genome-wide analysis of 'Bounty' descendants implicates several novel variants in migraine susceptibility. Neurogenetics, 13(3), 261-266. https://doi.org/10.1007/s10048-012-0325-x