Increased identification of novel variants in type 2 diabetes, birth weight and their pleiotropic loci

Background: Clinical and epidemiological findings point to an association between type 2 diabetes (T2D) and low birth weight. However, the nature of the relationship is largely unknown. The aim of this study was to identify novel single nucleotide polymorphisms (SNPs) in T2D and birth weight, and their pleiotropic loci.

Methods: A pleiotropy-informed conditional false discovery rate (cFDR) method was applied to two independent genome-wide association studies (GWAS) summary statistics of T2D (n = 149 821) and birth weight (n = 26 836).

Results: A conditional Q-Q plot showed strong enrichment of genetic variants in T2D conditioned on different levels of association with birth weight. 133 T2D-associated SNPs, including 120 novel SNPs, were identified with a significance threshold of cFDR < 0.05; 13 significant birth weight-associated SNPs, including 12 novel SNPs (cFDR < 0.05) were identified. Conjunctional cFDR (ccFDR) analysis identified nine pleiotropic loci, including seven novel loci, shared by both T2D and birth weight (ccFDR < 0.05). Two novel SNPs located at the CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1; rs1012635; cFDR < 0.05) and adenylate cyclase 5 (ADCY5; rs4677887; cFDR < 0.05) genes are of note. These two genes increase the risk of T2D and low birth weight through the pathway of the "fetal insulin hypothesis."

Conclusion: Several pleiotropic loci were identified between T2D and birth weight by leveraging GWAS results. The results make it possible to explain a greater proportion of trait heritability and improve our understanding of the shared pathophysiology between T2D and birth weight.