Human Molecular Genetics Advance Access published online on August 2, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn227
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A high-density association screen of 155 ion transport genes for involvement with common migraine
,31 Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia 2 Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA 3 Biomedicum Helsinki, Research Program in Molecular Medicine and Departments of Clinical Chemistry and Medical Genetics, University of Helsinki, Helsinki 00014, Finland 4 Department of Neurology, Helsinki University Central Hospital, Helsinki 00014, Finland 5 The Finnish Institute for Molecular Medicine, Finnish Genome Centre, Helsinki 00014, Finland 6 Department of Public Health, University of Helsinki, Helsinki 00014, Finland 7 Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki 00300, Finland 8 Folkhälsan Research Centrum, Helsinki 00014, Finland 9 Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA 10 Molecular Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia 11 Kiel Pain and Headache Centre, Kiel 24149, Germany 12 Institute of Human Genetics, Institute for Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne 50923, Germany 13 Department of Neurology, Leiden University Medical Centre, Leiden, 2300 RC, The Netherlands 14 Epidemiology, Demography and Biometry Program (EDBP) and National Institute of Aging (NIA) and National Institute of Health (NIH), Bethesda, MD 20892, USA 15 Department of Human Genetics, Leiden University Medical Centre, Leiden, 2300 RC, The Netherlands 16 National Institute for Public Health and the Environment, Centre for Prevention and Health Services Research, Bilthoven, BA 3720, The Netherlands 17 Migräne- und Kopfschmerz-Klinik Königstein, Ölmühlweg 31, 61462, Königstein im Taunus, Germany 18 Department of Neurology, Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Marchioninistr, Munich 81377, Germany 19 Neurologische Gemeinschaftspraxis Leopoldstraße, Munich 81377, Germany 20 Perlegen Sciences, Inc., Mountain View, CA 94043, USA 21 Current address Affymetrix, Inc., Santa Clara, CA 95051, USA 22 Broad Institute of MIT and Harvard, Cambridge, MA 02141-2023, USA 23 Department of Molecular Medicine, National Public Health Institute, The Finnish Institute for Molecular Medicine, and Department of Medical Genetics, University of Helsinki, Helsinki 00014, Finland 24 The Wellcome Trust Sanger Institute, Cambridge CB10 1HH, UK
* To whom correspondence should be addressed at: Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland, 4029, Australia. Tel: +61-7-33620258; Fax: +61-7-33620101; Email: Dale.Nyholt{at}qimr.edu.au
Received June 6, 2008; Revised July 21, 2008; Accepted July 31, 2008
The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5,257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2,835 unrelated migraine cases and 2,740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes KCNB2 and CACNB2. Multiple rare variants or trans regulatory elements of these genes are not ruled out.
Deceased