A combined analysis of genomewide linkage scans for body mass index from the National Heart, Lung, and Blood Institute Family Blood Pressure Program

Abstract

A combined analysis of genome scans for obesity was undertaken using the interim results from the National Heart, Lung, and Blood Institute Family Blood Pressure Program. In this research project, four multicenter networks of investigators conducted eight individual studies. Data were available on 6,849 individuals from four ethnic groups (white, black, Mexican American, and Asian). The sample represents the largest single collection of genomewide scan data that has been analyzed for obesity and provides a test of the reproducibility of linkage analysis for a complex phenotype. Body mass index (BMI) was used as the measure of adiposity. Genomewide linkage analyses were first performed separately in each of the eight ethnic groups in the four networks, through use of the variance-component method. Only one region in the analyses of the individual studies showed significant linkage with BMI: 3q22.1 (LOD 3.45, for the GENOA network black sample). Six additional regions were found with an associated LOD >2, including 3p24.1, 7p15.2, 7q22.3, 14q24.3, 16q12.2, and 17p11.2. Among these findings, the linkage at 7p15.2, 7q22.3, and 17p11.2 has been reported elsewhere. A modified Fisher's omnibus procedure was then used to combine the P values from each of the eight genome scans. A complimentary approach to the meta-analysis was undertaken, combining the average allele-sharing identity by descent (pi) for whites, blacks, and Mexican Americans. Using this approach, we found strong linkage evidence for a quantitative-trait locus at 3q27 (marker D3S2427; LOD 3.40, P=.03). The same location has been shown to be linked with obesity-related traits and diabetes in at least two other studies. These results (1) confirm the previously reported obesity-susceptibility locus on chromosomes 3, 7, and 17 and (2) demonstrate that combining samples from different studies can increase the power to detect common genes with a small-to-moderate effect, so long as the same gene has an effect in all samples considered.

Figure 1

Multipoint VC LOD scores for linkage to BMI in each of the eight groups. 1 = GenNet white; 2 = GenNet black; 3 = GENOA white; 4 = GENOA black; 5 = GENOA Mexican American; 6 = HyperGEN white; 7 = HyperGEN black; and 8 = SAPPHIRe Asian. The X-axis is the chromosome location. Each chromosome is scaled according to its length from the genetic map and is separated from the others by vertical dotted lines.

Figure 2

Results from combining P values by means of the modified Fisher’s method. 1 = combined white; 2 = combined black; and 3 = all groups combined. Scaling and separation of each chromosome are as described in figure 1.

Figure 3

Results from combining IBD-sharing method. 1 = combined white; 2 = combined black; 3 = combined white, black, and Mexican American. Scaling and separation of each chromosome are as described in figure 1.