Copyright © 2006 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 79, Issue 1, 85-99, 1 July 2006
doi:10.1086/504814
Article
Trait Components Provide Tools to Dissect the Genetic Susceptibility of Migraine
V. Anttilaa, b, M. Kallelaf, G. Oswella, j, k, M.A. Kaunistob, c, D.R. Nyholtl, E. Hämäläinenb, H. Havankam, M. Ilmavirtan, J. Terwilligera, o, E. Sobelk, L. Peltonend, g, p, J. Kaprioe, h, M. Färkkiläf, M. Wessmanb, c, i and A. Palotiea, b, c, p, 
, 
a From the Finnish Genome Center, Helsinki
b Biomedicum Helsinki, Research Program in Molecular Medicine, Helsinki
c Department of Clinical Chemistry, University of Helsinki, Helsinki
d Department of Medical Genetics, University of Helsinki, Helsinki
e Department of Public Health, University of Helsinki, Helsinki
f Department of Neurology, Helsinki University Central Hospital, Helsinki
g Department of Human Molecular Genetics, Helsinki
h Department of Mental Health and Alcohol Research, Helsinki
i National Public Health Institute, and Folkhälsan Research Center, Helsinki
j Department of Pathology, David Geffen School of Medicine at University of California–Los Angeles, Los Angeles
k Department of Human Genetics, David Geffen School of Medicine at University of California–Los Angeles, Los Angeles
l Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia
m Department of Neurology, Länsi-Pohja Central Hospital, Kemi, Finland
n Department of Neurology, Central Hospital of Central Finland, Jyväskylä
o Department of Psychiatry and Columbia Genome Center, Columbia University, New York
p The Broad Institute of MIT and Harvard, Cambridge, MA
Address for correspondence and reprints: Dr. Aarno Palotie, Finnish Genome Center, Haartmaninkatu 8, Helsinki, FinlandAbstract
The 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.
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