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

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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.

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Acknowledgments

This research was supported by funding from the National Health and Medical Research Council (NHMRC) of Australia, from a Medical Bioinformatics Genomics Proteomics Program grant as well as an Australian DEST International Science Linkages grant. Hannah Cox was supported by a NHMRC Biomedical Postgraduate Scholarship and Rod Lea is partially supported by a Corbett Research Fellowship. The SOLAR statistical genetics computer package is supported by a grant from the US National Institute of Mental Health (MH059490). Lastly, we extend our appreciation to the Norfolk Islanders who volunteered for this study.

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Authors and Affiliations

  1. Genomics Research Centre, Griffith Health Institute, Griffith University, Queensland, 4222, Australia

    Hannah C. Cox, Rod A. Lea, Claire Bellis & Lyn R. Griffiths

  2. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 78245-0549, USA

    Claire Bellis, Melanie Carless, Thomas D. Dyer, Joanne Curran, Jac Charlesworth & John Blangero

  3. Menzies Research Institute, University of Tasmania, Hobart, Tasmania, 7000, Australia

    Jac Charlesworth

  4. Statistical Genetics Laboratory, Queensland Institute of Medical Research, The Bancroft Centre, Herston, Queensland, 4006, Australia

    Stuart Macgregor & Dale Nyholt

  5. Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA, 02215-1204, USA

    Daniel Chasman, Paul M. Ridker & Markus Schürks

  6. Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA, 02215-1204, USA

    Daniel Chasman & Paul M. Ridker

  7. Department of Neurology, University Hospital Essen, Essen, Germany

    Markus Schürks

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  1. Hannah C. Cox
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  2. Rod A. Lea
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  3. Claire Bellis
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Corresponding author

Correspondence to Lyn R. Griffiths.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary document 1. Methodology. (DOC 80 kb)

Supplementary Fig. 1

Manhattan Plot of autosomal genome-wide associations for migraine in the Norfolk Island pedigree. (DOC 73 kb)

Supplementary Fig. 2

(PPTX 142 kb)

Supplementary Table 1

Summary of the top 0.05 % of SNPs (n = 172) detected in the Norfolk study (DOC 322 kb) (DOC 322 kb)

Supplementary Table 2

Results of replication study in WGHS cohort. (DOCX 78 kb)

ESM 2

(DOCX 166 kb)

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Cox, H.C., Lea, R.A., Bellis, C. et al. A genome-wide analysis of 'Bounty' descendants implicates several novel variants in migraine susceptibility. Neurogenetics 13, 261–266 (2012). https://doi.org/10.1007/s10048-012-0325-x

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  • DOI: https://doi.org/10.1007/s10048-012-0325-x

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