Our lab is interested in investigating the genetic background of diabetes 25and related metabolic traits that may help us better understand the un-derlying disease mechanisms. We have been focusing on the genetic contribu-tion to type 2 diabetes (T2D) susceptibility in the Japanese population by using the rich genetic resources generated by Biobank Japan (BBJ). By using the full BBJ collection, we conducted a single population genome-wide association study (GWAS) of T2D in 191,764 Japanese. In addition to the then established >150 T2D loci, we identified 28 novel loci. We joined this effort with our in-ternational collaborators in the Asian Genetic Epidemiology Network for T2D (AGEN-T2D) to include 433,540 East Asian individuals in the GWAS meta-analysis. We identified 301 distinct association signals at 183 loci. Previously undescribed associations included signals in or near genes and a microRNA cluster that affects the differentiation of muscle and adipose tissues, which are essential in the development of T2D. Interestingly, expression quantitative trait loci at two overlapping T2D signals affect two genes in different tissues (Figure). Association studies in diverse populations demonstrated the benefit of identify-ing additional loci and elucidating disease-associated genes, biology and path-ways. We are currently combining these results with those investigated in other ethnicities.Figure: Two distinct T2D-association signals at the ANK1-NKX6-3 locus are associated with ex-pression levels of two transcripts in two tissuesTop, Regional association plot for East Asian sex-combined BMI-unadjusted meta-analysis at the ANK1-NKX6-3 locus highlighting three distinct T2D-association signals (P<1x10-5): signal 1, rs33981001; signal 2, rs62508166; signal 3, rs144239281. Variants are colored red and blue according to the strength of East Asian linkage disequilibrium (LD) with the lead variants of first and second signals, respectively. Middle, Variant rs12549902, which is in high LD (EAS LD r2=0.80) with signal 1 rs33981001, shows the strongest association with the expression level of NKX6-3 in pancreatic islets (n=118). Bot-tom, Variant rs516946, which is in high LD (EAS LD r2=0.96) with signal 2 rs62508166, shows the strongest association with the expression level of ANK1 in subcutaneous adipose tissue (n=770).Recent Major PublicationsChen J*, Spracklen CN*, Marenne G*, Varshney A*, Corbin LJ*, Luan J, Willems SM, Wu Y, Zhang X, Horikoshi M, Boutin TS, Mägi R, Waage J, Li-Gao R, Chan KHK, Yao J, Anasanti MD, Chu AY, Claringbould A, Heikkinen J, Hong J, Hottenga JJ, Huo S, Kaakinen MA, Louie T, März W, Moreno-Macias H, Ndungu A, Nelson SC, Nolte IM, North KE, Raulerson CK, Ray D, Rohde R, Rybin D, Schurmann C, Sim X, Southam L, Stewart ID, Wang CA, Wang Y, Wu P, Zhang W, Ahluwalia TS, Appel EVR, Bielak LF, Brody JA, Burtt NP, Cabrera CP, Cade BE, Chai JF et al. The trans-ancestral genomic architecture of glycemic traits. Nat Genet 53, 840-860 (2021)Imamura M, Takahashi A, Matsunami M, Horikoshi M, Iwata M, Araki SI, Toyoda M, Susarla G, Ahn J, Park KH, Kong J, Moon S, Sobrin L; International Diabetic Retinopathy and Genetics CONsortium (iDRAGON), Yamauchi T, Tobe K, Maegawa H, Kad-owaki T, Maeda S. Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. Hum Mol Genet 30, 716-726 (2021)Spracklen CN*, Horikoshi M*, Kim YJ*, Lin K*, Bragg F, Moon S, Suzuki K, Tam CHT, Tabara Y, Kwak SH, Takeuchi F, Long J, Lim VJY, Chai JF, Chen CH, Nakatochi M, Yao J, Choi HS, Iyengar AK, Perrin HJ, Brotman SM, van de Bunt M, Gloyn AL, Below JE, Boehnke M, Bowden DW, Chambers JC, Mahajan A, McCarthy MI, Ng MCY, Petty LE, Zhang W, Morris AP, Adair LS, Akiyama M, Bian Z, Chan JCN, Chang LC, Chee ML, Chen YI, Chen YT, Chen Z, Chuang LM, Du S, Gordon-Larsen P, Gross M, Guo X, Guo Y, Han S, Howard AG et al. Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature 582, 240-245 (2020)*These authors jointly contributed to the workInvited presentationsHorikoshi M. “Large-scale genome-wide association study of type 2 diabetes” The 64th Annual Meeting of the Japan Diabe-tes Society (Toyama, Japan/Online) May 2021Horikoshi M. “Large-scale genome-wide association study of type 2 diabetes” The 11th Annual Meeting of Obesity and Digestive disease (Tokyo, Japan/Online) April 2021Horikoshi M. “Large-scale genome-wide association study of type 2 diabetes” The 94th Annual Meeting of the Japan Endo-crinology Society (Online) April 2021Laboratory for Genomics of Diabetes and MetabolismTeam Leader: Momoko Horikoshi
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