Department of Epidemiology, Tulane University, New Orleans, Louisiana, United States of America.
PLoS One. 2012;7(2):e31470. doi: 10.1371/journal.pone.0031470. Epub 2012 Feb 15.
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<510-8) 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<7.610-4). 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.
全基因组关联研究（GWAS）已经确定了多个与体重指数（BMI）相关的常见变异。在这项研究中，我们在 658 名受试者中测试了 23 个经过基因分型的 GWAS 显著 SNP（p 值<510-8）与儿童期（3-17 岁）和成年期（18-45 岁）BMI 的纵向关联。我们还提出了一种启发式正向搜索，以找到最佳的联合效应模型来解释 BMI 的纵向变化。在使用错误发现率（FDR）对多重检验进行调整后，发现儿童期和成年期 BMI 分别与 6 个 SNP 显著相关（q 值<0.05），其中一个 SNP 与两种 BMI 测量均相关：KCTD15 rs29941（q 值<7.610-4）。这 12 个 SNP 位于大脑中表达的基因（BDNF、KCTD15、TMEM18、MTCH2 和 FTO）或涉及细胞凋亡和增殖的基因（FAIM2、MAP2K5 和 TFAP2B）附近或附近。FAIM2 rs7138803 对儿童期 BMI 的纵向影响和 MAP2K5 rs2241423 对成年期 BMI 的纵向影响随着年龄的增长而降低（q 值<0.05）。FTO 候选 SNP，5'-末端的 rs6499640 和下游的 rs1121980 和 rs8050136，分别与儿童期和成年期 BMI 相关，rs6499640 和 rs1121980 的风险效应随着出生体重的降低而增加。儿童期和成年期 BMI 的最佳联合效应模型分别包含 14 个和 15 个 SNP，其中 11 个 SNP 相同，解释方差的百分比分别从 0.17%和 9.0*10(-6)%增加到 2.22%和 2.71%。总之，这项研究证明了基因对肥胖发展的长期主要影响的存在，这些基因涉及与神经发育和细胞代谢相关的途径，并且不同的基因集与儿童期和成年期 BMI 相关。基因效应可以随年龄而变化，并受到产前发育的影响。最佳的联合效应模型表明，尽管单独作用较弱或不存在的多个变体可以共同对 BMI 产生较大的纵向影响。
