Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1051-1063, 17 April 2008
doi:10.1016/j.ajhg.2008.03.003
Article
Consistently Replicating Locus Linked to Migraine on 10q22-q23
Verneri Anttila1, 2, 3, 13, 14, Dale R. Nyholt4, 14, Mikko Kallela5, Ville Artto5, Salli Vepsäläinen5, Eveliina Jakkula1, 2, 11, 12, Annika Wennerström1, 2, Päivi Tikka-Kleemola1, 2, Mari A. Kaunisto1, 2, 6, Eija Hämäläinen1, 2, Elisabeth Widén2, Joseph Terwilliger1, 7, Kathleen Merikangas8, Grant W. Montgomery4, Nicholas G. Martin4, Mark Daly12, Jaakko Kaprio9, 10, Leena Peltonen1, 11, 12, 13, Markus Färkkilä5, Maija Wessman1, 2, 3, 6 and Aarno Palotie1, 2, 3, 12, 13, 
, 
1 Biomedicum Helsinki, Research Program in Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland
2 The Finnish Genome Center, University of Helsinki, 00290 Helsinki, Finland
3 Department of Clinical Chemistry, Helsinki University Central Hospital, 00029 Helsinki, Finland
4 Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia
5 Department of Neurology, Helsinki University Central Hospital, 00029 Helsinki, Finland
6 Folkhälsan Research Center, 00290 Helsinki, Finland
7 Department of Psychiatry and Columbia Genome Center, Columbia University, New York, NY 10032, USA
8 Section on Developmental Genetic Epidemiology, National Institute of Mental Health, NIH, Bethesda, MD 10032, USA
9 Department of Public Health, University of Helsinki, 00014 Helsinki, Finland
10 Department of Mental Health and Alcohol Research, National Public Health Institute, 00300 Helsinki, Finland
11 Department of Molecular Medicine, National Public Health Institute, 00290 Helsinki, Finland
12 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
13 Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
Corresponding author14 These authors contributed equally to this work.
Abstract
Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95% of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants.
Article Information
PubMed
Related Articles
- A Simple Correction for Multiple Testing for Single-Nucleoti...A Simple Correction for Multiple Testing for Single-Nucleotide Polymorphisms in Linkage Disequilibrium with Each Other
The American Journal of Human Genetics, Volume 74, Issue 4, 1 April 2004, Pages 765-769
Dale R. Nyholt
AbstractIn this report, we describe a simple correction for multiple testing of single-nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) with each other, on the basis of the spectral decomposition (SpD) of matrices of pairwise LD between SNPs. This method provides a useful alternative to more computationally intensive permutation tests. A user-friendly interface (SNPSpD) for performing this correction is available online (http://genepi.qimr.edu.au/general/daleN/SNPSpD/). Additionally, output from SNPSpD includes eigenvalues, principal-component coefficients, and factor “loadings” after varimax rotation, enabling the selection of a subset of SNPs that optimize the information in a genomic region.
Abstract | | - Trait Components Provide Tools to Dissect the Genetic Suscep...Trait Components Provide Tools to Dissect the Genetic Susceptibility of Migraine
The American Journal of Human Genetics, Volume 79, Issue 1, 1 July 2006, Pages 85-99
V. Anttila, M. Kallela, G. Oswell, M.A. Kaunisto, D.R. Nyholt, E. Hämäläinen, H. Havanka, M. Ilmavirta, J. Terwilliger, E. Sobel, L. Peltonen, J. Kaprio, M. Färkkilä, M. Wessman and A. Palotie
AbstractThe commonly used “end diagnosis” phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components—individual clinical symptoms of migraine—to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.
Abstract | | - Genomewide Significant Linkage to Migrainous Headache on Chr...Genomewide Significant Linkage to Migrainous Headache on Chromosome 5q21
The American Journal of Human Genetics, Volume 77, Issue 3, 1 September 2005, Pages 500-512
Dale R. Nyholt, Katherine I. Morley, Manuel A.R. Ferreira, Sarah E. Medland, Dorret I. Boomsma, Andrew C. Heath, Kathleen R. Merikangas, Grant W. Montgomery and Nicholas G. Martin
AbstractFamilial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23–90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs (130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine.
Abstract | | - …more
