Migraine is a common neurological disorder that shows evidence of a significant genetic contribution. However, the genes underlying the predisposition to develop migraine have remained elusive. Although the identification of mutations in a calcium channel gene in a rare, Mendelian form of migraine offered the first insight into potential mechanisms as a complex phenotype that is likely polygenic in origin, candidate gene approaches have not generally proven useful in the search for the genes involved in common migraine.
The aims of this proposal are directed toward the identification of major contributing loci involved in migraine susceptibility using the Finnish population. The search for genes predisposing to complex traits is a potentially arduous task, however, the genetically well-characterized population will afford a distinct advantage for initial locus identification that will make the search for the genes predisposing to migraine a more realistic task. It is hypothesized that the predisposition to migraine in a population like Finland is influenced by a subset of loci. The large study sample from this population will improve the ability to detect these loci. A genome-wide scan strategy will be employed to identify susceptibility loci using both a large sample of Finnish migraine families and affected sib-pairs. Statistical simulation studies of the proposed sample suggest that the study material is sufficient to detect major genes predisposing to migraine. Once suggestive evidence for a susceptibility locus has been detected, special statistical strategies including allelic association and shared haplotype analysis will be used in sub-isolates and in families with common ancestors to restrict and confirm the locus. High-resolution physical maps of the candidate regions will be made followed by search for positional candidate genes within the restricted region. Candidate genes will be scrutinized for sequence variations, potentially involved in migraine predisposition. The second hypothesis is that the loci contributing to migraine susceptibility within the isolate are also contributing in a more genetically heterogeneous population. This is supported by findings in other complex diseases, which indicate that the same predisposing loci are detected in genetic isolates as in more mixed populations. Thus, loci identified from the genome scan in the genetic isolate will be examined in multiplex migraine families from Southern California to determine whether the same loci are contributing in the broader population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037675-04
Application #
6650852
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Gwinn, Katrina
Project Start
2000-09-25
Project End
2004-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
4
Fiscal Year
2003
Total Cost
$308,622
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Nyholt, Dale R; LaForge, K Steven; Kallela, Mikko et al. (2008) A high-density association screen of 155 ion transport genes for involvement with common migraine. Hum Mol Genet 17:3318-31
Oswell, G; Kaunisto, M A; Kallela, M et al. (2008) No association of migraine to the GABA-A receptor complex on chromosome 15. Am J Med Genet B Neuropsychiatr Genet 147B:33-6
Keskitalo, Kaisu; Knaapila, Antti; Kallela, Mikko et al. (2007) Sweet taste preferences are partly genetically determined: identification of a trait locus on chromosome 16. Am J Clin Nutr 86:55-63
Tikka-Kleemola, Paivi; Hamalainen, Eija; Tuomainen, Kari et al. (2007) The enhancement of homogenous mass extension reaction: comparison of two enzymes. Mol Cell Probes 21:216-21
Knaapila, Antti; Keskitalo, Kaisu; Kallela, Mikko et al. (2007) Genetic component of identification, intensity and pleasantness of odours: a Finnish family study. Eur J Hum Genet 15:596-602
Wessman, Maija; Terwindt, Gisela M; Kaunisto, Mari A et al. (2007) Migraine: a complex genetic disorder. Lancet Neurol 6:521-32
Kaunisto, M A; Kallela, M; Hamalainen, E et al. (2006) Testing of variants of the MTHFR and ESR1 genes in 1798 Finnish individuals fails to confirm the association with migraine with aura. Cephalalgia 26:1462-72
Peltonen, Leena; Perola, Markus; Naukkarinen, Jussi et al. (2006) Lessons from studying monogenic disease for common disease. Hum Mol Genet 15 Spec No 1:R67-74

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