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. 2008 Nov 1;17(21):3318-31.
doi: 10.1093/hmg/ddn227. Epub 2008 Aug 2.

A high-density association screen of 155 ion transport genes for involvement with common migraine

Dale R Nyholt  1 , K Steven LaForge, Mikko Kallela, Kirsi Alakurtti, Verneri Anttila, Markus Färkkilä, Eija Hämaläinen, Jaakko Kaprio, Mari A Kaunisto, Andrew C Heath, Grant W Montgomery, Hartmut Göbel, Unda Todt, Michel D Ferrari, Lenore J Launer, Rune R Frants, Gisela M Terwindt, Boukje de Vries, W M Monique Verschuren, Jan Brand, Tobias Freilinger, Volker Pfaffenrath, Andreas Straube, Dennis G Ballinger, Yiping Zhan, Mark J Daly, David R Cox, Martin Dichgans, Arn M J M van den Maagdenberg, Christian Kubisch, Nicholas G Martin, Maija Wessman, Leena Peltonen, Aarno Palotie
Affiliations

A high-density association screen of 155 ion transport genes for involvement with common migraine

Dale R Nyholt et al. Hum Mol Genet. .

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 case-control 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 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.

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Figures

Figure 1.
Figure 1.
Allelic association results for Finnish MA cases versus controls. Horizontal red line indicates the required global significance threshold [−log10(P) = 4.7286] to ensure an overall type I error rate of 5%.
Figure 2.
Figure 2.
QQ-plot of Finnish case–control allelic association results for clinical migraine with aura end-diagnosis (closed black circles). The solid red line represents the expected (reference) distribution under the null. The broken red lines indicate the point-wise 95% CI envelope based on the standard errors of order statistics for an independent sample from the reference distribution.
Figure 3.
Figure 3.
Overview of study design.
See this image and copyright information in PMC

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