Abstract
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 × 10−3) and enrichment of functional annotations (P < 3.3 × 10−3) 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.
Highlights
In our rapidly evolving era of genomic medicine, designing genetically-based interventions for a disease in early life, for instance through genome editing approaches[1], demands a comprehensive understanding of its downstream consequences in later life[2]
Tests for genetic pleiotropy were performed between birthweight and each of the individual cardiometabolic disease traits (CMD) using a unified statistical approach implemented in Genetic analysis incorporating Pleiotropy and Annotation (GPA)[18]
In order to test whether genetic loci with known biological function are more likely to be associated with both birthweight and CMD compared to genetic loci that are not functional, tests of functional enrichment were performed between birthweight each of the 15 CMD using GPA
Summary
In our rapidly evolving era of genomic medicine, designing genetically-based interventions for a disease in early life, for instance through genome editing approaches[1], demands a comprehensive understanding of its downstream consequences in later life[2]. Recent genome-wide association studies (GWAS) have revealed that genetic factors that influence multiple phenotypes contribute to a substantial proportion of the correlations between birthweight and adulthood traits such as waist circumference, body mass index (BMI), type 2 diabetes, and coronary artery disease[14,15]. Scientific understanding of genetic pleiotropy among early and later life traits will help unravel common mechanisms that underlie fetal growth aberrations and adult chronic diseases. It may help elucidate molecular functions of genetic variants in www.nature.com/scientificreports/. Large scale GWASs conducted on several traits measured at birth and during adulthood have provided summary statistics data, paving the way for newly developed statistical approaches to test for genetic pleiotropy[17]
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