BMI is associated with multiple variants in the 11q linked region in the Framingham Heart Study
Nancy <redacted>, Matthew G Phillips, Larry <redacted>
The 11q22-25 region has been linked to body mass index (BMI) by seven studies, including the Framingham Heart Study (FHS). The average lodscore in FHS across six exams was at least 2.0 between 118 and 128MB (maximum lodscore was 4.5). To search for variants associated with BMI, we genotyped analyzed 4442 SNPs in this 10MB region.
We performed measured genotype analysis on all SNPs for each of the six exams comprised of 293 families (894 individuals with phenotype). Sex, age, age^2 and cohort status were included as covariates. Significant association was determined by likelihood ratio test.
We set a conservative region wide significance level of 0.01 that was further reduced to 0.01/6 = 0.0017 to account for testing six exams. To determine the adjusted significance level for this region we constructed, on the –log(log (p) scale, an empirical null distribution by repeating the analysis 5000 times using a simulated null phenotype. The point on the empirical distribution that corresponds to a p-value of 0.0017 was 6.4 which we used as the adjusted region wide significance level.
Results across all six exams showed there were seven independent regions with –log(log (p) > 6.4. The most significant SNP in each region, along with the maximum –log(p), and any associated gene were: rs1177562, 7.90, VPS11; rs1143770515092, 7.1978, LOC399959BLID; rs10790522, 8.18, UBASH3B; rs7933163, 7.90, ASAM; rs733744, 7.01, PKNOX2; rs2464870, 6.67, inter-genic; rs3562656, 6.83, inter-genic. Note that ASAM is ‘adipocyte specific adhesion molecule’ which is an obvious candidate gene.