We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Recent results of genome wide association study (GWAS) for diabetes genes, while reaching impressive technical milestones and implicating new findings for research, have been uniformly disappointing in terms of immediate clinical utility. The relative risk associated with any of the newly reported genetic loci, or even considering all of them together, is far less than simply that which can be obtained by taking a history and a physical exam. For type 2 diabetes (T2D), GWAS have implicated novel pathways, supported previously known associations, and highlighted the importance of the beta cell and insulin secretion. Monogenic forms of diabetes, on the other hand, continue to yield interesting insights into genes controlling human beta cell function but most cases of monogenic diabetes are simply not diagnosed. Here, we briefly review recent results related to type 1, type 2 and maturity onset diabetes of youth (MODY) diabetes and suggest that future studies emphasizing quantitative traits are likely to yield even more insights.

14To understand the mechanistic underpinnings of type 2 diabetes (T2D) loci mapped through GWAS, we 15 performed a tissue-specific gene association study in a cohort of over 100K individuals (n cases ⇡ 26K, 16 n controls ⇡ 84K) across 44 human tissues using MetaXcan, a summary statistics extension of PrediXcan. 17We found that 90 genes significantly (FDR < 0.05) associated with T2D, of which 24 are previously 18 reported T2D genes, 29 are novel in established T2D loci, and 37 are novel genes in novel loci. Of these, 1913 reported genes, 15 novel genes in known loci, and 6 genes in novel loci replicated (FDR rep < 0.05) in an 20 independent study (n cases ⇡ 10K, n controls ⇡ 62K). We also found enrichment of significant associations 21 in expected tissues such as liver, pancreas, adipose, and muscle but also in tibial nerve, fibroblasts, and 22 breast. Finally, we found that monogenic diabetes genes are enriched in T2D genes from our analysis 23 suggesting that moderate alterations in monogenic (severe) diabetes genes may promote milder and later 24 onset type 2 diabetes. 25. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/108134 doi: bioRxiv preprint first posted online Feb. 13, 2017; 2 Introduction 26Type 2 diabetes (T2D) is a complex disease characterized by impaired glucose homeostasis resulting from 27 dysfunction in insulin-secreting pancreatic islets and decreased insulin sensitivity in peripheral tissues 28 [1]. In addition to environmental factors such as a sedentary lifestyle and poor diet, genetic susceptibility 29 is an important contributor to the development of T2D [2]. Genome-wide association studies (GWAS) 30 have uncovered more than 100 loci that significantly associate with either T2D or glucose-related traits 31 [3, 4, 2]. However, the majority of single nucleotide polymorphisms (SNPs) significantly associated with 32 T2D reside in intronic and intergenic regions rather than protein-encoding regions [5, 6]. The results from 33GWAS suggest an important role for genetic variation that regulates gene expression rather than altering 34 codon sequence [7] and have motivated e↵orts to map the regulatory landscape of the genome [8, 9, 10]. 35Indeed, sets of trait-associated SNPs are enriched for variants that associate with gene expression (i.e. 36expression quantitative trait loci or eQTLs) [11] and that occupy DNAse hypersensitivity sites (DHS) [12] 37 -regions overrepresented for eQTLs per se [13]. Moreover, DHS explain a disproportionately high share 38 of SNP heritability [14] across 11 complex traits [15] and eQTLs mapped in insulin-responsive peripheral 39 tissues similarly "concentrate" SNP heritability estimates for T2D [16]. human hepatocytes [17]. Moreover, Sort1 knockdown and overexpression studies in mice altered LDL-C 46 and very low density lipoprotein (VLDL) levels [17]. In a study of the FTO locus harboring the strongest 47 associati...

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