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Comparative Study
. 2005 Sep;77(3):500-12.
doi: 10.1086/444510. Epub 2005 Jul 28.

Genomewide Significant Linkage to Migrainous Headache on Chromosome 5q21

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Free PMC article
Comparative Study

Genomewide Significant Linkage to Migrainous Headache on Chromosome 5q21

Dale R Nyholt et al. Am J Hum Genet. .
Free PMC article

Abstract

Familial 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.

Figures

Figure  1
Figure 1
Profile plot for the three symptomatic classes (CL1, CL2, and CL3) under the four-class model. Endorsement probabilities indicate the proportion of individuals in each class presenting with each symptom. All endorsement probabilities for CL0 were <0.005 (data not shown). Descriptions of symptom abbreviations are given in table 2.
Figure  2
Figure 2
Results of SOLAR genomewide multipoint linkage analysis for LCA migraine, showing thresholds for nominal P=.01 (dash-dot-dot line) and P=.05 (dotted line).
Figure  3
Figure 3
Results of MERLIN-regress genomewide multipoint linkage analysis for LCA migraine, showing thresholds obtained via simulation for significant linkage (dashed line) and suggestive linkage (dash-dot line). Thresholds estimated via linear regression for nominal P=.01 (dash-dot-dot line) and P=.05 (dotted line) are also displayed.
Figure  4
Figure 4
Results of MERLIN-regress chromosome-specific multipoint linkage analysis for LCA migraine and subphenotypes reaching nominal P⩽.05.

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