Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Drive, Room 3204, Bethesda, MD, 20892-7004, USA.
Laboratorio de Endocrinologia Molecular, Hospital Juárez de México, Mexico City, Mexico.
Hum Genomics. 2019 Apr 4;13(1):17. doi: 10.1186/s40246-019-0202-x.
Obesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic traits using a unified statistical approach that integrates pleiotropy and functional annotation data.
Pleiotropic genetic effects were significantly abundant in 13 out of 15 childhood BMI-adult cardiometabolic trait tests (P < 3.3 × 10). SNPs associated with both childhood BMI and adult traits were more likely to be functionally deleterious than SNPs associated with neither trait. Genetic variants associated with increased childhood obesity tend to increase risk of cardiometabolic diseases in adulthood. We replicated 39 genetic loci that are known to be associated with childhood BMI and adult traits (coronary artery disease, HDL cholesterol, myocardial infarction, triglycerides, total cholesterol, type 2 diabetes, BMI, waist circumference, and waist-to-hip ratio) in previous genome-wide association studies. We also found a novel association of rs12446632 near GPRC5B, which is highly expressed in adipose tissue and the central nervous system, with adult HDL cholesterol.
This study found significant pleiotropic genetic effects and enrichment of functional annotations in genetic variants that were jointly associated with childhood obesity and adult cardiometabolic diseases. The findings provide new avenues to disentangle the genetic basis of life course associations between childhood obesity and adult cardiometabolic diseases.
儿童肥胖会增加成年后患 2 型糖尿病和冠心病等不良心血管代谢疾病的风险。儿童和成人体重指数（BMI）之间存在较强的遗传相关性证据表明，存在共同的遗传效应。我们采用一种整合了遗传多效性和功能注释数据的统一统计方法，对与儿童 BMI 相关的单核苷酸多态性（SNP）和 15 种成年心血管代谢特征进行了多效性（遗传共享）和功能富集检验。
在 15 项儿童 BMI-成年心血管代谢特征测试中有 13 项存在显著的多效遗传效应（P < 3.3×10）。与儿童 BMI 和成年特征均相关的 SNP 比与两者均不相关的 SNP 更有可能具有功能破坏性。与儿童肥胖相关的遗传变异更有可能增加成年患心血管代谢疾病的风险。我们复制了 39 个已知与儿童 BMI 和成年特征（冠心病、高密度脂蛋白胆固醇、心肌梗死、甘油三酯、总胆固醇、2 型糖尿病、BMI、腰围和腰臀比）相关的遗传位点，这些位点先前在全基因组关联研究中已经被发现。我们还发现了一个位于 GPRC5B 附近的 rs12446632 的新关联，该基因在脂肪组织和中枢神经系统中高度表达，与成人高密度脂蛋白胆固醇有关。
本研究发现，与儿童肥胖和成年心血管代谢疾病相关的遗传变异存在显著的多效遗传效应和功能注释富集。这些发现为阐明儿童肥胖与成年心血管代谢疾病之间的遗传基础提供了新的途径。
