Dataset Information

Chromosome 19p13 loci in Finnish migraine with aura families.

ABSTRACT: Chromosomal area 19p13 contains two migraine associated genes: a Ca(v)2.1 (P/Q-type) calcium channel alpha(1) subunit gene, CACNA1A, and an insulin receptor gene, INSR. Missense mutations in CACNA1A cause a rare Mendelian form of migraine, familial hemiplegic migraine type 1 (FHM1). Contribution of CACNA1A locus has also been studied in the common forms of migraine, migraine with (MA) and without aura (MO), but the results have been contradictory. The role of INSR is less well established: A region on 19p13 separate from CACNA1A was recently reported to be a major locus for migraine and subsequently, the INSR gene was associated with MA and MO. Our aim was to clarify the role of these loci in MA families by analyzing 72 multigenerational Finnish MA families, the largest family sample so far. We hypothesized that the potential major contribution of the 19p13 loci should be detected in a family sample of this size, and this was confirmed by simulations. We genotyped eight polymorphic microsatellite markers surrounding the INSR and CACNA1A genes on 757 individuals. Using parametric and non-parametric linkage analysis, none of the studied markers showed any evidence of linkage to MA either under locus homogeneity or heterogeneity. However, marginally positive lod scores were observed in three families, and thus for these families the results remain inconclusive. The overall conclusion is that our study did not provide evidence of a major MA susceptibility region on 19p13 and thus we were not able to replicate the INSR locus finding.

SUBMITTER: Kaunisto MA

PROVIDER: S-EPMC6217809 | biostudies-literature | 2005 Jan

REPOSITORIES: biostudies-literature

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Chromosome 19p13 loci in Finnish migraine with aura families.

Kaunisto Mari A MA Tikka Päivi J PJ Kallela Mikko M Leal Suzanne M SM Papp Jeanette C JC Korhonen Arja A Hämäläinen Eija E Harno Hanna H Havanka Hannele H Nissilä Markku M Säkö Erkki E Ilmavirta Matti M Kaprio Jaakko J Färkkilä Markus M Ophoff Roel A RA Palotie Aarno A Wessman Maija M

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20050101 1

Chromosomal area 19p13 contains two migraine associated genes: a Ca(v)2.1 (P/Q-type) calcium channel alpha(1) subunit gene, CACNA1A, and an insulin receptor gene, INSR. Missense mutations in CACNA1A cause a rare Mendelian form of migraine, familial hemiplegic migraine type 1 (FHM1). Contribution of CACNA1A locus has also been studied in the common forms of migraine, migraine with (MA) and without aura (MO), but the results have been contradictory. The role of INSR is less well established: A reg ...[more]

PMID: 15449251

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Project description:IntroductionIt is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related.AimUsing a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO.MethodsGene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO.ResultsWe found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10(-4)). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue.ConclusionsOur results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine.

Dataset Information

Chromosome 19p13 loci in Finnish migraine with aura families.

Publications

Chromosome 19p13 loci in Finnish migraine with aura families.

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