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.
Highlights
Obesity, a major global public health concern, is a deleterious factor associated with different diseases, including cardiovascular events, type 2 diabetes mellitus, sleep -breathing abnormalities, and some cancers [1,2]
Logarithm base 10 q-values are presented in Figure 1 for the association tests between candidate SNPs and longitudinal body mass index (BMI) adjusted for birth weight, age, and sex
Recent genome-wide association studies have identified several variants associated with BMI
Summary
A major global public health concern, is a deleterious factor associated with different diseases, including cardiovascular events, type 2 diabetes mellitus, sleep -breathing abnormalities, and some cancers [1,2]. The prevalence of obesity in children and adults has increased strikingly over the past decades, leading to an increased likelihood of serious obesity-related complications and decreased life expectancy [3]. Reducing obesity prevalence in adults and preventing overweight from early childhood is of great importance in terms of public health. The predisposition to obesity varies widely in the population and is partially genetically determined. Intrauterine growth, measured by birth weight, can influence the probability of suffering from obesity in future life [4,5]. Heritability of the underlying genetic components ranges from 25% to 40% according to family studies, and from 50% to 80% according to twin studies
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