Identification of type 2 diabetes loci in 433,540 East Asian individuals

Abstract

SUMMARY Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D) 1 , 2 , however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1 , PTF1A , SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation 3 . At another locus, eQTLs at two overlapping T2D signals affect two genes, NKX6-3 and ANK1 , in different tissues 4 – 6 . Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.

Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

“…The DIAMANTE (DIAbetes Meta-ANalysis of Trans-Ethnic association studies) Consortium was established to assemble T2D GWAS across diverse populations and develop methodological blueprints for intra-and inter-ancestry meta-analyses relevant to any complex trait. Analyses of the European and East Asian ancestry-specific components of DIAMANTE have previously been reported (4,6). Here, we describe the results of our transancestry meta-analysis of T2D GWAS, which partially overlaps with these ancestry-specific efforts, focussing on genetic variation shared across population groups at loci robustly associated with the disease.…”

“…Genome-wide association studies (GWAS) have been extremely successful in identifying T2D susceptibility loci but have mostly focused on populations of European ancestry (1)(2)(3)(4). To address this population bias, more recent largescale T2D GWAS have expanded into East Asian ancestry populations (5,6) and multiancestry biobanks (7,8). The DIAMANTE (DIAbetes Meta-ANalysis of Trans-Ethnic association studies) Consortium was established to assemble T2D GWAS across diverse populations and develop methodological blueprints for intra-and inter-ancestry meta-analyses relevant to any complex trait.…”

NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

“… - Nkx6.1 suppresses Gcg expression by targeting PAX6 [ 52 ]. - ARX and GCG genes are completely absent in hiPSC-derived β cells that express NKX6.1 [ 76 ]. Role in β cell proliferation - Nkx6.1 controls the expression of Nr4a1, Nr4a3, and c-Fos, which are crucial for β cell proliferation [ 59 , 60 ].…”

“…Mounting evidence suggests that NKX6.1, the β cell-enriched TF, may have a prominent role in the development of T2D. Three genome-wide association studies (GWAS) reports have identified NKX6.1 variants that are associated with T2D in East Asian individuals [ 76 , 78 , 79 ]. Also, decreased expression of NKX6.1 has been shown to be involved in the development of T2D in humans and rodents [ 47 , 80 ].…”

Synergistic Effects of Vitamin D and Mindfulness Training in Pain Severity, Pain-Related Disability and Neuropathy-Specific Quality of Life Dimensions in Painful Diabetic Neuropathy: A Randomized Clinical Trial with Placebo-controlled

“…Today's, more than 500 million type-2 diabetic patients living in all around the world and this prevalence steadily increasing (1). Painful diabetic neuropathy (PDN) with 60% prevalence is the main complication of diabetic patients, speci ed by feet cramps, burning, numbness and tingling.…”