Identification of Putative Causal Relationships Between Type 2 Diabetes and Blood-Based Biomarkers in East Asians by Mendelian Randomization

Observational studies have revealed phenotypic associations between type 2 diabetes (T2D) and many biomarkers. However, causality between these conditions in East Asians is unclear. We leveraged genome-wide association study (GWAS) summary statistics on T2D (n = 77,418 cases; n = 356,122 controls) from the Asian Genetic Epidemiology Network (sample recruited during 2001-2011) and GWAS summary statistics on 42 biomarkers (n = 12,303-143,658) from BioBank Japan (sample recruited during 2003-2008) to investigate causal relationships between T2D and biomarkers. Applications of Mendelian randomization approaches consistently revealed genetically instrumented associations of T2D with increased serum potassium levels (liability-scale beta = 0.04-0.10; P = 6.41 x 10(-17)-9.85 x 10(-5)) and decreased serum chloride levels (liability-scale beta = -0.16 to -0.06; P = 5.22 x 10(-27)-3.14 x 10(-5)), whereas these 2 biomarkers showed no causal effects on T2D. Heritability Estimation Using Summary Statistics (rho-HESS) and summary-data-based Mendelian randomization highlighted 27 genomic regions and 3 genes (alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (MGAT1), transducing-like enhancer (TLE) family member 1, transcriptional corepressor (TLE1), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)) that interactively associated with the shared genetics underlying T2D and the 2 biomarkers. Thus, T2D may causally affect serum potassium and chloride levels among East Asians. In contrast, the relationships of potassium and chloride with T2D are not causal, suggesting the importance of monitoring electrolyte disorders for T2D patients.