title: 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.
authors.affiliation: Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane4029, Queensland, Australia. dale.nyholt@qimr.edu.au
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: K Steven
authors.initials: KS
authors.lastname: LaForge
authors.forename: Mikko
authors.initials: M
authors.lastname: Kallela
authors.forename: Kirsi
authors.initials: K
authors.lastname: Alakurtti
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.forename: Markus
authors.initials: M
authors.lastname: Färkkilä
authors.forename: Eija
authors.initials: E
authors.lastname: Hämaläinen
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.forename: Mari A
authors.initials: MA
authors.lastname: Kaunisto
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Hartmut
authors.initials: H
authors.lastname: Göbel
authors.forename: Unda
authors.initials: U
authors.lastname: Todt
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.forename: Boukje
authors.initials: B
authors.lastname: de Vries
authors.forename: W M Monique
authors.initials: WM
authors.lastname: Verschuren
authors.forename: Jan
authors.initials: J
authors.lastname: Brand
authors.forename: Tobias
authors.initials: T
authors.lastname: Freilinger
authors.forename: Volker
authors.initials: V
authors.lastname: Pfaffenrath
authors.forename: Andreas
authors.initials: A
authors.lastname: Straube
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Ballinger
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: David R
authors.initials: DR
authors.lastname: Cox
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Maija
authors.initials: M
authors.lastname: Wessman
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
mesh_terms: 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