Author： Nyholt Dale R. LaForge K. Steven Kallela Mikko Alakurtti Kirsi Anttila Verneri Frkkil Markus Hmalinen Eija Kaprio Jaakko Kaunisto Mari A. Heath Andrew C. Montgomery Grant W. Gbel Hartmut Todt Unda Ferrari Michel D. Launer Lenore J. Frants Rune R. Terwindt Gisela M. de Vries Boukje Verschuren W.M. Monique Brand Jan Freilinger Tobias Pfaffenrath Volker Straube Andreas Ballinger Dennis G. Zhan Yiping Daly Mark J. Cox David R. Dichgans Martin van den Maagdenberg Arn M.J.M. Kubisch Christian Martin Nicholas G. Wessman Maija Peltonen Leena Palotie Aarno
Publisher： Oxford University Press
ISSN： 1460-2083
Source： Human Molecular Genetics, Vol.17, Iss.21, 2008-11, pp. : 3318-3331
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Abstract
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 5257 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 casecontrol samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 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 casecontrol 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.
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