ABSTRACT
To date, no gene variants predisposing to common forms of migraine have been convincingly identified. Recently, significant linkage to a cluster of gamma-amino butyric acid (GABA)-A receptors on Chr 15q11-q13 was reported. We performed an extensive association study using 898 MA cases and 900 matched controls by covering the same gene cluster with 34 single nucleotide polymorphisms (SNPs). No association to MA was detected, suggesting that common variants of the GABA cluster are unlikely to be major contributors of MA susceptibility.
Subject(s)
Chromosomes, Human, Pair 15 , Migraine with Aura/genetics , Receptors, GABA-A/genetics , Case-Control Studies , Cohort Studies , Female , Genetic Predisposition to Disease , Genetic Variation , Genotype , Humans , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
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.
Subject(s)
Genetic Predisposition to Disease , Migraine Disorders/genetics , Chromosome Mapping , Female , Genetic Heterogeneity , Humans , Lod Score , MaleSubject(s)
Chromosomes, Artificial, Yeast , Genetic Vectors , Mice/genetics , Animals , Base Sequence , DNA/genetics , DNA/metabolism , DNA Primers , Deoxyribonuclease EcoRI/metabolism , Deoxyribonucleases, Type II Site-Specific/metabolism , Molecular Sequence Data , Polymerase Chain Reaction , RatsABSTRACT
The fatty liver dystrophy (fld) mutation is manifested in abnormalities of lipid and glucose metabolism and peripheral neuropathy. To identify the gene affected by this mutation, we generated a genetic map of the fld region on chromosome 12 by the analysis of F2 offspring from an intersubspecific cross between strains BALB/cByJ-fld and CAST/EiJ. The results localize fld to the 0.42-cM interval between the microsatellite markers D12Mit170 and D12Mit184. A contig of YACs and BACs covering the nonrecombinant genomic region has been constructed and used for the identification of genes. Expressed sequence tag mapping and exon trapping identified three transcripts within the critical interval: Ctla2b, which encodes a cysteine protease inhibitor, and mouse homologs of KIAA0188 and KIAA0575, two long human transcripts of unknown function. Expression analysis revealed that Kiaa0188 is expressed in wildtype but not in fld liver, implicating this gene as a candidate for harboring the fld mutation.
