Significant Linkage of BMI to Chromosome 10p in the U.K. Population and Evaluation of GAD2 as a Positional Candidate
Article Figures & Tables
Figures
- FIG. 1.
A: A genome-wide quantitative trait multipoint linkage analysis of BMI in 573 pedigrees. The vertical broken lines indicate chromosome boundaries. The analysis was carried out using MERLIN-REGRESS, as described in the text. B: Chromosome 10 quantitative trait multipoint linkage analysis of BMI. The microsatellite markers used in the analysis are shown along the top. The position of the centromere is indicated on the x-axis. The linkage results from nine previous studies of BMI and obesity are shown below the x-axis by diamonds. The sizes of diamonds are proportional to −log(P value) of the maximum LOD (or nonparametric linkage) scores reported in the respective articles, the positions of which represent the locations of the linkage peaks, converted where appropriate into Haldane centimorgan units [cM(H)], from the respective reports. Locus boundaries (indicated by horizontal lines) were either undefined (15), author defined (7,11,14), or estimated as a 1-LOD support interval (8–10,12,13).
- FIG. 2.
Genomic structure and LD relationships of the GAD2 gene. A: Top to bottom: Base pair position (National Center for Biotechnology Information build 35), genomic structure of GAD2, sequence coverage of the gene by Environmental Genome Project (EGP), SNPs discovered by EGP, and haplotype block structure based on EGP SNP data. The eight SNPs in the present study are shown in full and condensed. B: Genomic positions, minor allele frequencies, and pairwise LD relationships (r2 measures above the diagonal and D′ measures below) for the eight SNPs typed in the present study.
Tables
- TABLE 1
Tests of total association of individual GAD2 SNPs with BMI
GAD2 SNP(s) Total association (P value) Trait means (Z scores)* QTDT QPDTPHASE Common allele Minor allele Initial three SNPs rs2236418 0.025 0.051 0.28 0.13 rs992990 0.092 0.055 0.29 0.19 rs928197 0.011 0.017 0.29 0.12 Subsequent five SNPs rs2839669 0.036 0.038 0.29 0.15 rs7071922 0.031 0.029 0.30 0.17 rs3781117 >0.1 0.996 0.27 0.25 rs7908975 >0.1 0.555 0.27 0.25 rs3781107 >0.1 0.432 0.28 0.22 - *
* Mean trait values from QPDTPHASE. The trait values are Z scores (i.e., log-transformed BMI adjusted for the effects of age and sex and standardized against the U.K. population [3]).
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- TABLE 2
Tests of association of block-tagging GAD2 SNP combinations with BMI
Block tagging GAD2 SNP combination Global QPDTPHASE (P value)* Significant haplotypes {frequency} (trait mean) [P value]† rs2839669, rs2236418 0.049 11 {0.901} (0.29) [0.051] 22 {0.097} (0.14) [0.038] rs7071922, rs3781117, rs7908975 0.044 111 {0.639} (0.31) [0.048] 211 {0.166} (0.14) [0.010] rs992990, rs928197, rs3781107 0.032 111 {0.629} (0.31) [0.025] 221 {0.119} (0.13) [0.014] - *
* Haplotypes of these SNPs are examined in a global (or omnibus) test, with rare (<1% frequency) haplotypes pooled.
- †
† Significant haplotypes from the haplotype-specific comparisons from QPDTPHASE. 1, common allele; 2, rare allele. For all three GAD2 SNP combinations, only two haplotypes were significant in the haplotype-specific comparisons. The frequency and mean trait values (Z scores) for each haplotype are shown. P values (all uncorrected for multiple testing) are for the haplotype in question tested against all others pooled.
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- TABLE 3
Tests of multipoint linkage and association of GAD2 with BMI
Associated GAD2 SNP(s) Analyses assuming one SNP cluster Analyses assuming three SNP clusters Linkage alone (LOD) Linkage given association (LOD) Linkage alone (LOD) Linkage given association (LOD) rs2839669 3.88 3.54 4.32 3.94 rs2236418 4.08 3.58 4.62 4.09 rs2839669, rs2236418 4.19 3.79 4.77 4.31 rs7071922 2.88 2.79 3.25 3.12 rs7071922, rs3781117, rs7908975 2.80 2.55 3.18 3.00 rs928197 3.63 3.14 4.19 3.63 rs992990, rs928197, rs3781107 3.28 2.88 3.84 3.47 -
Linkage alone: baseline multipoint LOD score for linkage to BMI calculated only in those individuals who have genotypes for the GAD2 SNP in question. Linkage given association: multipoint LOD score for linkage to BMI after the GAD2 association has been accounted for, by adjustment on the GAD2 covariate.
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