Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies.
Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies.
复制标题
作者：
den Hoed M;Ekelund U;Brage S;Grontved A;Zhao JH;Sharp SJ;Ong KK;Wareham NJ;Loos RJ
迄今为止，大规模全基因组关联（GWA）研究已经确定了16个与成人肥胖相关特征无可争议的基因座。我们研究了这些基因座变异与儿童和青少年人体测量特征的关联。来自欧洲青年心脏研究（EYHS）的1252名儿童（平均±SD年龄9.7±0.4岁）和790名青少年（15.5±0.5岁）的17个变异代表了16个肥胖易感位点的基因分型。我们测试了个体变异和遗传易感性评分（GPS-17）的关联，通过将效应等位基因的数量与人体测量学特征相加来计算。对于13个变异，与BMI相关的汇总统计数据与先前报道的数据进行meta分析（Ntotal = 13071名儿童和青少年）。在EYHS中，15个变异显示出与人体测量特征的关联或趋势，与早期在成人中报道的方向一致。meta分析显示，所有13个变异与BMI的相关性方向一致，其中9个变异显著（0.033-0.098 SD/等位基因；P < 0.05）。近tmem18变异的影响最强（0.098 SD/等位基因P = 8.5 × 10−11）。与先前报道的成人相比，儿童和青少年中SEC16B、TMEM18和KCTD15或其附近的变异对BMI的影响更明显（0.028 - 0.035 SD/等位基因高），而BDNF中rs925946的影响不那么明显（0.028 SD/等位基因低）。GPS-17中每增加一个效应等位基因与BMI增加0.034 SD （P = 3.6 × 10−5）、皮肤褶增加0.039 SD （P = 1.7 × 10−7）和腰围增加0.022 SD （P = 1.7 × 10−4）相关，这与成人报告的结果相当（BMI增加0.039 SD/等位基因和腰围增加0.033 SD/等位基因）。成人GWA研究发现的大多数肥胖易感位点已经与儿童/青少年的人体测量特征相关。尽管某些变异的关联可能随年龄而不同，但累积效应大小是相似的。
Large-scale genome-wide association (GWA) studies have thus far identified 16 loci incontrovertibly associated with obesity-related traits in adults. We examined associations of variants in these loci with anthropometric traits in children and adolescents. Seventeen variants representing 16 obesity susceptibility loci were genotyped in 1,252 children (mean ± SD age 9.7 ± 0.4 years) and 790 adolescents (15.5 ± 0.5 years) from the European Youth Heart Study (EYHS). We tested for association of individual variants and a genetic predisposition score (GPS-17), calculated by summing the number of effect alleles, with anthropometric traits. For 13 variants, summary statistics for associations with BMI were meta-analyzed with previously reported data (Ntotal = 13,071 children and adolescents). In EYHS, 15 variants showed associations or trends with anthropometric traits that were directionally consistent with earlier reports in adults. The meta-analysis showed directionally consistent associations with BMI for all 13 variants, of which 9 were significant (0.033–0.098 SD/allele; P < 0.05). The near-TMEM18 variant had the strongest effect (0.098 SD/allele P = 8.5 × 10−11). Effect sizes for BMI tended to be more pronounced in children and adolescents than reported earlier in adults for variants in or near SEC16B, TMEM18, and KCTD15, (0.028–0.035 SD/allele higher) and less pronounced for rs925946 in BDNF (0.028 SD/allele lower). Each additional effect allele in the GPS-17 was associated with an increase of 0.034 SD in BMI (P = 3.6 × 10−5), 0.039 SD, in sum of skinfolds (P = 1.7 × 10−7), and 0.022 SD in waist circumference (P = 1.7 × 10−4), which is comparable with reported results in adults (0.039 SD/allele for BMI and 0.033 SD/allele for waist circumference). Most obesity susceptibility loci identified by GWA studies in adults are already associated with anthropometric traits in children/adolescents. Whereas the association of some variants may differ with age, the cumulative effect size is similar.