A high-density association screen of 155 ion transport genes for involvement with common migraine.
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.
Nyholt
Dale R
DR
Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane4029, Queensland, Australia. dale.nyholt@qimr.edu.au
LaForge
K Steven
KS
Kallela
Mikko
M
Alakurtti
Kirsi
K
Anttila
Verneri
V
Färkkilä
Markus
M
Hämaläinen
Eija
E
Kaprio
Jaakko
J
Kaunisto
Mari A
MA
Heath
Andrew C
AC
Montgomery
Grant W
GW
Göbel
Hartmut
H
Todt
Unda
U
Ferrari
Michel D
MD
Launer
Lenore J
LJ
Frants
Rune R
RR
Terwindt
Gisela M
GM
de Vries
Boukje
B
Verschuren
W M Monique
WM
Brand
Jan
J
Freilinger
Tobias
T
Pfaffenrath
Volker
V
Straube
Andreas
A
Ballinger
Dennis G
DG
Zhan
Yiping
Y
Daly
Mark J
MJ
Cox
David R
DR
Dichgans
Martin
M
van den Maagdenberg
Arn M J M
AM
Kubisch
Christian
C
Martin
Nicholas G
NG
Wessman
Maija
M
Peltonen
Leena
L
Palotie
Aarno
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D003710:Demography; D005260:Female; D005387:Finland; D005787:Gene Frequency; D005796:Genes / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017136:Ion Transport / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020326:Migraine without Aura / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D055815:Young Adult