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

Abstract

<jats:title>SUMMARY</jats:title><jats:p>Meta-analyses of genome-wide association studies (GWAS) have identified &gt;240 loci associated with type 2 diabetes (T2D), 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 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 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 <jats:italic>GDAP1</jats:italic>, <jats:italic>PTF1A</jats:italic>, <jats:italic>SIX3, ALDH2,</jats:italic> a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, <jats:italic>NKX6-3</jats:italic> and <jats:italic>ANK1</jats:italic>, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.</jats:p><jats:p>Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues<jats:sup>1</jats:sup>. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified &gt;240 loci influencing the risk of T2D<jats:sup>2</jats:sup>. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another<jats:sup>3,4</jats:sup>. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci<jats:sup>4</jats:sup>. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference<jats:sup>5</jats:sup>. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.</jats:p>

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

“…Genome-wide association studies (GWAS) have been extremely successful in identifying T2D susceptibility loci but have mostly focused on populations of European ancestry ( 1-4 ). To address this population bias, more recent large-scale T2D GWAS have expanded into East Asian ancestry populations ( 5,6 ) and multi-ancestry 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.…”

“…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 trans-ancestry 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.…”

“…Consequently, after genomic control correction, we observed stronger signals of association at lead SNVs at most loci in the meta-regression than in the fixed- or random-effects meta-analyses ( Figure S4 ). Eleven of the 277 loci have not been reported in recently published T2D GWAS meta-analyses ( 4,6,8 ), which together contributed 78.6% of the total effective sample size of this trans-ancestry meta-regression ( Figure S3 ). Supplementary Note 1 summarises the loci reported across investigations incorporating DIAMANTE GWAS.…”

The Population-Specific Impact of Neandertal Introgression on Human Disease

“…It has been noted that analyzing different ancestries can yield new insights into phenotypes ( SIGMA Type 2 Diabetes Consortium et al 2014 ; Wojcik et al. 2019 ; Spracklen et al. 2020 ).…”

A common East Asian-specific ALDH2 mutation causes obesity and insulin resistance: therapeutic effect of reducing toxic aldehydes by ALDH2 activation

“…Epidemiological studies suggest a correlation between this inactivating mutation and several diseases including oral cancer, esophageal cancers, and blood and solid tumors associated with Fanconi anemia 7,8 . Importantly, several large-scale meta-analyses of genome-wide association studies revealed that this inactivating mutation is strongly associated with type 2 diabetes 9 , body mass index 10 , and serum lipids 11 in East Asians. A validation study further con rmed a close association of ALDH2*2 with visceral fat distribution in 2,958 Chinese subjects 12 .…”