Metabolic Drivers of Dysglycemia in Pregnancy: Ethnic-Specific GWAS of 146 Metabolites and 1-Sample Mendelian Randomisation Analyses in a UK Multi-Ethnic Birth Cohort

Abstract

Gestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and is associated with short- and long-term health implications for both mother and child. Prevalence of GDM varies between ethnicities, with South Asians (SAs) experiencing up to three times the risk compared to white Europeans (WEs). This study aimed to evaluate the causal role of metabolic characteristics in the ethnic-associated differences in gestational dysglycemia.A one-sample Mendelian Randomisation (MR) was performed separately on 3688 SA and 3354 WE women (<28thweek of pregnancy) from the Born in Bradford (BiB) cohort for 146 metabolites exposures for the outcomes of fasting glucose and 2-hr post glucose (P ≤ 1 × 10−5was considered significant). Additional GWAS and MR analyses on 22 composite measures of metabolite classes were also conducted.Through an extensive GWAS analysis this study identified 15 novel genome-wide significant (GWS) SNPs associated with tyrosine in theFOXNandSLC13A2genes and 1 novel GWS SNP (currently in no known gene) associated with acetate in SAs. Through the utilisation of a MR analysis. 14 metabolites were found to be associated with postprandial glucose in WEs, while in SAs a distinct panel of 11 metabolites were identified. In WEs cholesterols were most common metabolite class identified, whereas in SAs saturated fatty acids were most common. Furthermore, in SAs a composite measure of the fatty acid class was also found to associate with 2-hour post glucose.The presence of ethnic-specific causal relationships between a comprehensive set of metabolites and postprandial glucose measures (fasting glucose and 2-hour post glucose) in mid-pregnancy has been established in a UK SA and WE population. Future work should aim to investigate the biological mechanisms of metabolites on GDM risk in order to inform ethnically tailored GDM prevention strategies.