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

Nyholt, Dale R., LaForge, K. Steven, Kallela, Mikko, Alakurtti, Kirsi, Anttila, Verneri, Farkkila, Markus, Hamalainen, Eija, Kaprio, Jaakko, Kaunisto, Mari A., Heath, Andrew C., Montgomery, Grant W., Goebel, 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 and Palotie, Aarno (2008) A high-density association screen of 155 ion transport genes for involvement with common migraine. Human Molecular Genetics, 17 21: 3318-3331. doi:10.1093/hmg/ddn227


Author Nyholt, Dale R.
LaForge, K. Steven
Kallela, Mikko
Alakurtti, Kirsi
Anttila, Verneri
Farkkila, Markus
Hamalainen, Eija
Kaprio, Jaakko
Kaunisto, Mari A.
Heath, Andrew C.
Montgomery, Grant W.
Goebel, 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
Title A high-density association screen of 155 ion transport genes for involvement with common migraine
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
1460-2083
Publication date 2008-11-01
Year available 2008
Sub-type Article (original research)
DOI 10.1093/hmg/ddn227
Open Access Status Not yet assessed
Volume 17
Issue 21
Start page 3318
End page 3331
Total pages 14
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
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 5 0.00002; global P 5 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.
Formatted 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.
Keyword Biochemistry & Molecular Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
GENETICS & HEREDITY
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 200923
LSHM-CT-2004-504837
QLG2-CT-2002-01254
RO1 NS37675
AA007535
941177
FOR423
903-52-291
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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