Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Sci Rep. 2019 Mar 11;9(1):4076. doi: 10.1038/s41598-019-40834-w.
Before implementing therapeutic genomic interventions for optimizing health in early life, comprehensive understanding of their effect on several traits across the life course is warranted. Abnorml birthweight is associated with cardiometabolic disease risk in adulthood; however, the extent of genetic pleiotropy in the association has not been comprehensively investigated. We tested for pleiotropy and enrichment of functional loci between birthweight and 15 cardiometabolic disease traits (CMD). We found significantly abundant genetic pleiotropy (P < 3.3 × 10) and enrichment of functional annotations (P < 3.3 × 10) in loci influencing both birthweight and CMD. We did not observe consistent effect directions of pleiotropic loci on the traits. A total of 67 genetic loci, of which 65 loci have been reported in previous genome-wide association studies, were associated with both birthweight and CMD at a false discovery rate of 5%. Two novel loci were associated with birthweight and adult coronary artery disease (rs2870463 in CTRB1) and with birthweight and adult waist circumference (rs12704673 in CALCR). Both loci are known to have regulatory effects on expression of nearby genes. In all, our findings revealed pervasive genetic pleiotropy in early growth and adulthood cardiometabolic diseases, implying the need for caution when considering genetic loci as therapeutic targets.
在实施治疗性基因组干预措施以优化生命早期的健康之前，有必要全面了解它们对生命过程中多种特征的影响。出生体重异常与成年人心血管代谢疾病风险相关；然而，这种关联中的遗传多效性的程度尚未得到全面研究。我们测试了出生体重与 15 种心血管代谢疾病特征（CMD）之间的多效性和功能位点富集。我们发现，影响出生体重和 CMD 的基因座之间存在显著丰富的遗传多效性（P < 3.3 × 10）和功能注释富集（P < 3.3 × 10）。我们没有观察到多效性基因座对这些特征的一致作用方向。共有 67 个遗传基因座，其中 65 个基因座在之前的全基因组关联研究中已有报道，与出生体重和 CMD 相关，假发现率为 5%。两个新的基因座与出生体重和成年冠心病（CTRB1 中的 rs2870463）和出生体重与成年腰围（CALCR 中的 rs12704673）相关。这两个基因座都已知对附近基因的表达具有调节作用。总之，我们的研究结果揭示了早期生长和成年心血管代谢疾病中普遍存在的遗传多效性，这表明在将遗传基因座视为治疗靶点时需要谨慎。
