Microsatellite linkage analysis, single-nucleotide polymorphisms, and haplotype associations with ECB21 in the COGA data

Abstract

This study, part of the Genetic Analysis Workshop 14 (GAW14), explored real Collaborative Study on the Genetics of Alcoholism data for linkage and association mapping between genetic polymorphisms (microsatellite and single-nucleotide polymorphisms (SNPs)) and beta (16.5-20 Hz) oscillations of the brain rhythms (ecb21). The ecb21 phenotype underwent the statistical adjustments for the age of participants, and for attaining a normal distribution. A total of 1,000 subjects' available phenotypes were included in linkage analysis with microsatellite markers. Linkage analysis was performed only for chromosome 4 where a quantitative trait locus with 5.01 LOD score had been previously reported. Previous findings related this location with the gamma-aminobutyric acid type A (GABAA) receptor. At the same location, our analysis showed a LOD score of 2.2. This decrease in the LOD score is the result of a drastic reduction (one-third) of the available GAW14 phenotypic data. We performed SNP and haplotype association analyses with the same phenotypic data under the linkage peak region on chromosome 4. Seven Affymetrix and two Illumina SNPs showed significant associations with ecb21 phenotype. A haplotype, a combination of SNPs TSC0044171 and TSC0551006 (the latter almost under the region of GABAA genes), showed a significant association with ecb21 (p = 0.015) and a relatively high frequency in the sample studied. Our results affirmed that the GABA region has potential of harboring genes that contribute quantitatively to the beta oscillation of the brain rhythms. The inclusion of the remaining 614 subjects, which in the GAW14 had missing data for the ecb21, can improve the strength of the associations as they have already shown that they contribute quite important information in the linkage analysis.

Figure 1

Linkage analysis of ecb21 (all data).

Figure 2

Significant associated haplotypes, significant SNP locations, and genes. Left, the names of 7 Affymetrix SNPs. They are followed by two vertical lines, ticks of one of them represent the physical map in Mb. The next column lists gene symbols. The GABA region is circled. Seven columns follow, which represent best haplotypes and their color-coded SNP states. The next column represents the cytogenetic locations, which are followed by gene function descriptions. At the bottom of the figure, the frequency, p-value of the association of the best haplotype to the ecb21, and the number of nuclear families a particular haplotype is present, are provided.