Sex-specific effects of weight-affecting gene variants in a life course perspective-The HUNT Study, Norway

OBJECTIVE: The impact of previously identified genetic variants directly or indirectly associated with obesity, were investigated at birth, adolescence and adulthood to provide knowledge concerning timing and mechanisms of obesity susceptibility with focus on sex differences. DESIGN: Twenty four previously identified obesity-and eating disorder susceptibility loci were tested for association with adiposity traits at birth (ponderal index (PI)), adolescence and young adulthood (body mass index (BMI), waist circumference (WC) and waist-hip ratio (WHR)) in 1782 individuals from the HUNT study. Single-nucleotide polymorphism (SNPs) were evaluated individually and by haplotype sliding-window approach for windows <= 50 kb (near-MC4R, FTO and near-BDNF). The analyses were performed on the total and sex stratified samples. RESULTS: The most substantial effect on BMI was observed for the near-MC4R variants at adolescence and adulthood (adjusted P-values in adolescence: 0.002 and 0.003 for rs17782313 and rs571312, respectively). The same variants showed inverse association with PI in males (adjusted P-values: 0.019-0.036). Furthermore, significant effects were observed at adolescence with BMI for the near-KCTD15 variant (rs11084753) (adjusted P = 0.038) in the combined sample. The near-INSIG2 (rs7566605) was significantly associated to WHR in males and near-BDNF (rs925946) in the combined sample (adjusted P = 0.027 and P = 0.033, respectively). The OPRD1 locus was associated to BMI and WC in males both at adolescence and adulthood with highest effect in adults (adjusted P = 0.058). Interaction with sex was identified for near-MC4R, OPRD1, COMT, near-BDNF and DRD2. CONCLUSIONS: Most obesity susceptibility variants show stronger effect at adolescence than at birth and adulthood with a clear sex-specific effect at some loci. The near-MC4R locus exhibit inverse effect on weight at birth in boys compared with findings at adolescence and adulthood. Some variants less known for obesity-susceptibility such as OPRD1 were found to be associated to weight with strongest effects in males.