Shared Genetics between Age at Menarche and Type 2 Diabetes Mellitus: Genome-Wide Genetic Correlation Study

Abstract

Background: Age at menarche (AAM) has been associated with type 2 diabetes mellitus (T2DM). However, little is known about their shared heritability. Methods: Our data comes from the Taiwan Biobank. Genome-wide association studies (GWASs) were conducted to identify single-nucleotide polymorphisms (SNPs) related to AAM-, T2DM-, and T2DM-related phenotypes, such as body fat percentage (BFP), fasting blood glucose (FBG), and hemoglobin A1C (HbA1C). Further, the conditional false discovery rate (cFDR) method was applied to examine the shared genetic signals. Results: Conditioning on AAM, Quantile-quantile plots showed an earlier departure from the diagonal line among SNPs associated with BFP and FBG, indicating pleiotropic enrichments among AAM and these traits. Further, the cFDR analysis found 39 independent pleiotropic loci that may underlie the AAM-T2DM association. Among them, FN3KRP rs1046896 (cFDR = 6.84 × 10−49), CDKAL1 rs2206734 (cFDR = 6.48 × 10−10), B3GNTL1 rs58431774 (cFDR = 2.95 × 10−10), G6PC2 rs1402837 (cFDR = 1.82 × 10−8), and KCNQ1 rs60808706 (cFDR = 9.49 × 10−8) were highlighted for their significant genetic enrichment. The protein–protein interaction analysis revealed a significantly enriched network among novel discovered genes that were mostly found to be involved in the insulin and glucagon signaling pathways. Conclusions: Our study highlights potential pleiotropic effects across AAM and T2DM. This may shed light on identifying the genetic causes of T2DM.

Keywords

• age at menarche
• type 2 diabetes mellitus
• genome-wide association study
• conditional false discovery rate
• Taiwan Biobank