Longitudinal replication studies of GWAS risk SNPs influencing body mass index over the course of childhood and adulthood

Abstract

Genome-wide association studies (GWAS) have identified multiple common variants associated with body mass index (BMI). In this study, we tested 23 genotyped GWAS-significant SNPs (p-value<5*10-8) for longitudinal associations with BMI during childhood (3-17 years) and adulthood (18-45 years) for 658 subjects. We also proposed a heuristic forward search for the best joint effect model to explain the longitudinal BMI variation. After using false discovery rate (FDR) to adjust for multiple tests, childhood and adulthood BMI were found to be significantly associated with six SNPs each (q-value<0.05), with one SNP associated with both BMI measurements: KCTD15 rs29941 (q-value<7.6*10-4). These 12 SNPs are located at or near genes either expressed in the brain (BDNF, KCTD15, TMEM18, MTCH2, and FTO) or implicated in cell apoptosis and proliferation (FAIM2, MAP2K5, and TFAP2B). The longitudinal effects of FAIM2 rs7138803 on childhood BMI and MAP2K5 rs2241423 on adulthood BMI decreased as age increased (q-value<0.05). The FTO candidate SNPs, rs6499640 at the 5 '-end and rs1121980 and rs8050136 downstream, were associated with childhood and adulthood BMI, respectively, and the risk effects of rs6499640 and rs1121980 increased as birth weight decreased. The best joint effect model for childhood and adulthood BMI contained 14 and 15 SNPs each, with 11 in common, and the percentage of explained variance increased from 0.17% and 9.0*10(-6)% to 2.22% and 2.71%, respectively. In summary, this study evidenced the presence of long-term major effects of genes on obesity development, implicated in pathways related to neural development and cell metabolism, and different sets of genes associated with childhood and adulthood BMI, respectively. The gene effects can vary with age and be modified by prenatal development. The best joint effect model indicated that multiple variants with effects that are weak or absent alone can nevertheless jointly exert a large longitudinal effect on BMI.

Figure 1. Association of candidate SNPs with repeated measures of body mass index (BMI), adjusted for sex, age, and birth weight.

(A) childhood BMI and (B) adulthood BMI.

Figure 2. FTO regional linkage disequilibrium (LD) and recombination rate.

The LD is from HapMap rel. 27 and the recombination rate is from HapMap rel. 22. SNP position is based on NCBI build 36 of the human genome.

Figure 3. Major effects of genotypes for candidate SNPs on repeated measures of (A) childhood BMI and (B) adulthood BMI, adjusted for age and birth weight.

Figure 4. Percentage of cumulative BMI variance explained by sequentially added SNPs, shown from left to right, for (A) childhood BMI and (B) adulthood BMI.

Solid line: percentage of cumulative explained BMI variance. Dashed line: percentage of single-variant explained BMI variance. The reference allele is indicated at the top of each column.