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

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.

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

“…Among the 38 migraine loci only two harbor known ion channels (KCNK5 23 and TRPM8 24 ), while three additional loci (SLC24A3 26 , ITPK1 27 , and GJA1 28 ) can be linked to ion homeostasis. This further supports the findings of previous studies that in common forms of migraine, ion channel dysfunction is not the major pathophysiological mechanism 20 . However, more generally, genes involved in ion homeostasis could be a component of the genetic susceptibility.…”

“…In familial hemiplegic migraine (FHM), a rare Mendelian form of the disease, three ion transport-related genes (CACNA1A, ATP1A2 and SCN1A) have been implicated [17][18][19] . These findings suggest that mechanisms that regulate neuronal ion homeostasis might also be involved in MO and MA, however, no genes related to ion transport have yet been identified for these more prevalent forms of migraine 20 .…”

Advances in the basic and clinical science of migraine

“…However, a recent extensive screen of a European population concluded that common variants in ion transport genes do not play a major role in susceptibility to common migraine. 28 The search for genes for common migraine continues.…”

Migraine: Molecular Basis and Herbal Medicine

“…Like other complex genetic traits, finding responsible genes are much more difficult (de Vries et al, 2006). Despite these problems and absence of any evidence of association between genes encoding the ion channels and common migraine in previous studies (Nyholt et al, 2008), it has been reported recently that there is a strong genetic link to common forms of migraine (Lafrenière et al, 2010). Using a candidate gene approach and functional analysis, researchers have identified a mutation, F139wfsX24, in the gene encoding the two-pore domain potassium channel TRESK (TWIK-related spinal cord potassium channel) KCNK18 in the patients with migraine with aura.…”