The trans-ancestral genomic architecture of glycemic traits

Abstract

Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P <5x10 -8 ), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

Telomere length and metabolic syndrome traits: A Mendelian randomisation study

“…Secondly, our findings are based on data from GWAS conducted in subjects of European ancestry. Hence, our results and conclusions might not extend to other ethnic populations although, evidence from a recent, large, ancestrally diverse GWAS meta‐analysis of glycaemic traits suggests that similar results might also be expected (Chen et al, 2021 ). Thirdly, two‐sample MR studies assume that the SNP‐exposure (in this case LTL) associations are also present in the outcome dataset(s).…”

Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course

“…However, due to advances in GWAS methods, populations with mixed genetic backgrounds can now be included in GWAS to obtain accurate estimates of SNP effects, boost power, and improve fine-mapping of effects by leveraging linkage disequilibrium differences (Asimit et al 2016 ; Atkinson et al 2020 ). Beside the general benefits to gene discovery studies, the inclusion of diverse genetic backgrounds will improve our understanding of genetic liability across diverse populations, as demonstrated for example in a study of glycemic traits (Chen et al 2021 ), where 30% of the participants were of non-European ancestry.…”

The importance of increasing population diversity in genetic studies of type 2 diabetes and related glycaemic traits

“…Recently, efforts to jointly analyse different genetic datasets from populations of diverse ancestry have become more widespread [5,6]. These multi-ancestry genetic analyses boost power for new locus discovery, provide the opportunity to test for widespread replication of signals across independent populations and allow exploration of the genetic architecture of phenotypes across ancestries.…”

“…Often the variant identified from combined multi-ancestry analysis does not meet stringent genome-wide significance thresholds in individual contributing ancestries but there is still evidence that it captures a proportion of the heritability of that trait in that ancestry (Fig. 2) [2,[4][5][6]. Specifically, a recent study by the Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC), which included 30% non-European ancestry participants, showed that including lead variants identified from the meta-analysis across ancestries in a genetic score captured more of the trait variance than the more limited set of variants that met stringent genome-wide significant thresholds in that population (Fig.…”

“…glucose, insulin, HbA 1c levels) has surged. To date, more than 270 loci (with >400 signals) associated with type 2 diabetes risk and/or glycaemic traits have been identified mostly through meta-analysis of existing GWAS [2][3][4][5][6]. Despite this success, most type 2 diabetes GWAS do not represent the diversity of affected individuals as they have focused on individuals of European ancestry [7,8] and, more recently, East Asian ancestry [2,3].…”