Shared Genetic Influence on Early Growth and Type 2 Diabetes in Adulthood

Abstract

Background: There is a strong evidence of association between birthweight (BW) and type 2 diabetes (T2D) in adulthood. Although shared genetics has been suggested to be a significant contributor to these associations, to date, we know very few shared genetic loci. We conducted a systematic genome-wide investigation of shared genetic effects (pleiotropy) and enrichment of biologically functional loci implicated in BW-T2D associations. Methods: We evaluated pleiotropy, enrichment of functional annotation, and association of single nucleotide polymorphisms (SNPs) using genome-wide summary statistics of 2,893,797 SNPs for BW from the Early Growth Genetics Consortium, and T2D from the DIAbetes Genetics Replication And Meta-analysis Consortium. Analyses were conducted using the Genetic analysis incorporating Pleiotropy and Annotation (GPA). Tests for enrichment of annotations from functional datasets were performed in loci associated with pairs of traits. Results: We found significant enrichment of genetic pleiotropy (P <10-30) and biologically functional loci jointly associated with BW and T2D (enrichment fold of shared vs. BW-specific vs. T2D-specific loci: 1.45 vs. 1.24 vs. 0.57; P=1.73x10-21). A total of 178 independent SNPs in genes NYAP2-IRS1, ADCY5, ST6GAL1, CDKAL1, ANK1, HHEX-ECOC6, FAT3-MTNR1B, and MPHOSPH9 were associated with both BW and T2D at a false discovery rate of 5%. The locus at NYAP2-IRS1 (rs1515098 C) associated with reduced BW and increased T2D risk was novel. Functional analysis showed that rs62188784, in strong LD with rs1515098 (r2=0.91), has potential regulatory (cis-eQTL) effect on expression of the IRS1 gene in adipose tissues. Conclusions: We found shared genetic loci that influence early growth and type 2 diabetes, including novel shared variant in the insulin receptor substrate 1 gene. Findings suggest that genetic regulation of insulin signaling in adipose tissue potentially influences the associations of early growth and type 2 diabetes later in life. Disclosure F. Tekola-Ayele: None. A. Lee: None. T. Workalemahu: None. D. Shrestha: None.