Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.(Nature Publishing Group, 2019) Bentley, A.R.; Chasman, D. I.; Schwander, K.; Ntalla, I.; Kraja, A.T.; Winkler, T.W.; Brown, M. R.; Sung, Y. J.; Lim, E.; Huffman, J.E.; Vojinovic, D.; Sim, X.; Cheng, C.Y.; Lu, Y.; Liu, J.; Guo, X.; Deng, X.; Musani, S.K.; Li, C.; Feitosa, M.F.; Richard, M.A.; Noordam, R.; Baker, J.; Chen, G.; Aschard, H.; Bartz, T.M.; Ding, J.; Dorajoo, R.; Manning, A.K.; Rankinen, T.; Smith, A. V.; Tajuddin, S.M.; Zhao, W.; Graff, M.; Alver, M.; Boissel, M.; Chai, J. F.; Chen, X.; Divers, J.; Evangelou, E.; Gao, C.; Goel, A.; Hagemeijer, Y.; Harris, S. E.; Hartwig, F. P.; He, M.; Horimoto, A.R.V. R.; Hsu, F.C.; Hung, Y. J.; Jackson, A. U.; Kasturiratne, A.; Komulainen, P.; Kühnel, B.; Leander, K.; Lin, K. H.; Luan, J.; Lyytikäinen, L.P.; Matoba, N.; Nolte, I. M.; Pietzner, M.; Prins, B.; Riaz, M.; Robino, A.; Said, M. A.; Schupf, N.; Scott, R. A.; Sofer, T.; Stancáková, A.; Takeuchi, F.; Tayo, B. O.; van der Most, P. J.; Varga, T. V.; Wang, T. D.; Wang, Y.; Ware, E. B.; Wen, W.; Xiang, Y. B.; Yanek, L. R.; Zhang, W.; Zhao, J. H.; Adeyemo, A.; Afaq, S.; Amin, N.; Amini, M.; Arking, D.E.; Arzumanyan, Z.; Aung, T.; Ballantyne, C.; Barr, R. G.; Bielak, L. F.; Boerwinkle, E.; Bottinger, E.P.; Broeckel, U.; Chen, Y. I.; Charumathi, S.; Canouil, M.; Campbell, A.; Cade, B. E.; Brown, M.; Christensen, K.; de Las Fuentes, L.; Connell, J. M.; Concas, M. P.; COGENT-Kidney Consortium; de Silva, H.J.; de Vries, P. S.; Doumatey, A.; Duan, Q.; Eaton, C. B.; Eppinga, R.N.; Faul, J. D.; Floyd, J.S.; Gigante, B.; Gharib, S. A.; Forouhi, N.G.; Ghanbari, M.; Gao, H.; Gandin, I.; Friedlander, Y.; Forrester, T.; Hixson, J. E.; Hirata, M.; Justice, A. E.; Jonas, J. B.; Johnson, C.; Joehanes, R.; Jia, Y.; EPIC-InterAct Consortium; Ikram, M.A.; Katsuya, T.; Khor, C.C.; Kilpeläinen, T.O.; Koh, W. P.; Kolcic, I.; Kooperberg, C.; Krieger, J.E.; Kritchevsky, S.B.; Kubo, M.; Kuusisto, J.; Lakka, T. A.; Langefeld, C.D.; Langenberg, C.; Launer, L. J.; Lehne, B.; Lewis, C. E.; Li, Y.; Liang, J.; Lin, S.; Liu, C.T.; Liu, J.; Liu, K.; Loh, M.; Lohman, K.K.; Louie, T.; Luzzi, A.; Mägi, R.; Mahajan, A.; Manichaikul, A.W.; McKenzie, C.A.; Meitinger, T.; Metspalu, A.; Milaneschi, Y.; Milani, L.; Mohlke, K. L.; Momozawa, Y.; Morris, A. P.; Murray, A. D.; Nalls, M. A.; Nauck, M.; Nelson, C. P.; North, K. E.; O'Connell, J.R.; Palmer, N.D.; Papanicolau, G.J.; Pedersen, N. L.; Peters, A.; Peyser, P. A.; Polasek, O.; Poulter, N.; Raitakari, O.T.; Reiner, A. P.; Renström, F.; Rice, T.K.; Rich, S.S.; Robinson, J.G.; Rose, L. M.; Rosendaal, F. R.; Rudan, I.; Schmidt, C.O.; Schreiner, P. J.; Scott, W.R.; Sever, P.; Shi, Y.; Sidney, S.; Sims, M.; Smith, J. A.; Snieder, H.; Starr, J. M.; Strauch, K.; Stringham, H. M.; Tan, N. Y. Q.; Tang, H.; Taylor, K. D.; Teo, Y. Y.; Tham, Y. C.; Tiemeier, H.; Turner, S. T.; Uitterlinden, A. G.; Understanding Society Scientific Group; van Heemst, D.; Waldenberger, M.; Wang, H.; Wang, L.; Wang, L.; Wei, W. B.; Williams, C. A.; Wilson, G. Sr.; Wojczynski, M. K.; Yao, J.; Young, K.; Yu, C.; Yuan, J. M.; Zhou, J.; Zonderman, A. B.; Becker, D. M.; Boehnke, M.; Bowden, D. W.; Chambers, J. C.; Cooper, R. S.; de Faire, U.; Deary, I. J.; Elliott, P.; Esko, T.; Farrall, M.; Franks, P. W.; Freedman, B. I.; Froguel, P.; Gasparini, P.; Gieger, C.; Horta, B. L.; Juang, J. J.; Kamatani, Y.; Kammerer, C. M.; Kato, N.; Kooner, J. S.; Laakso, M.; Laurie, C. C.; Lee, I. T.; Lehtimäki, T.; Lifelines Cohort; Magnusson, P. K. E.; Oldehinkel, A. J.; Penninx, B. W. J. H.; Pereira, A. C.; Rauramaa, R.; Redline, S.; Samani, N. J.; Scott, J.; Shu, X. O.; van der Harst, P.; Wagenknecht, L. E.; Wang, J. S.; Wang, Y. X.; Wareham, N. J.; Watkins, H.; Weir, D. R.; Wickremasinghe, A.R.; Wu, T.; Zeggini, E.; Zheng, W.; Bouchard, C.; Evans, M. K.; Gudnason, V.; Kardia, S. L. R.; Liu, Y.; Psaty, B. M.; Ridker, P. M.; van Dam, R. M.; Mook-Kanamori, D. O.; Fornage, M.; Province, M. A.; Kelly, T. N.; Fox, E. R.; Hayward, C.; van Duijn, C. M.; Tai, E. S.; Wong, T. Y.; Loos, R. J. F.; Franceschini, N.; Rotter, J. I.; Zhu, X.; Bierut, L. J.; Gauderman, W. J.; Rice, K.; Munroe, P. B.; Morrison, A. C.; Rao, D. C.; Cupples, L. A.; Rotimi, C. N.The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.Item Genetic drivers of heterogeneity in type 2 diabetes pathophysiology(Nature Publishing Group, 2024) Suzuki, K.; Hatzikotoulas, K.; Southam, L.; Taylor, H.J.; Yin, X.; Lorenz, K.M.; Mandla, R.; Huerta-Chagoya, A.; Melloni, G.E.M.; Kanoni, S.; Rayner, N.W.; Bocher, O.; Arruda, A.L.; Sonehara, K.; Namba, S.; Namba, S.S.K.; Preuss, M.H.; Petty, L.E.; Schroeder, P.; Vanderwerff, B.; Kals, M.; Bragg. F.; Lin, K.; Guo, X.; Zhang, W.; Yao, J.; Kim, Y.J.; Graff, M.; Takeuchi, F.; Nano, J.; Lamri, A.; Nakatochi, M.; Moon, S.; Scott, R.A.; Cook, J.P.; Lee, J.J.; Pan, I.; Taliun, D.; Parra, E.J.; Chai. J.F.; Bielak, L.F.; Tabara, Y.; Hai, Y.; Thorleifsson, G.; Grarup, N.; Sofer, T.; Wuttke, M.; Sarnowski, C.; Gieger, C.; Nousome, D.; Trompet, S.; Kwak, S.H.; Long, J.; Sun, M.; Tong, L.; Chen, W.M.; Nongmaithem, S.S.; Noordam, R.; Lim, V.J.Y.; Tam, C.H.T.; Joo, Y.Y.; Chen, C.H.; Raffield, L.M.; Prins, B.P.; Nicolas, A.; Yanek, L.R.; Chen, G.; Brody, J.A.; Kabagambe, E.; An, P.; Xiang, A.H.; Choi, H.S.; Cade, B.E.; Tan, J.; Broadaway, K.A.; Williamson, A.; Kamali, Z.; Cui, J.; Thangam, M.; Adair, L.S.; Adeyemo, A.; Aguilar-Salinas, C.A.; Ahluwalia, T.S.; Anand, S.S.; Bertoni, A.; Bork-Jensen, J.; Brandslund, I.; Buchanan, T.A.; Burant, C.F.; Butterworth, A.S.; Canouil, M.; Chan, J.C.N.; Chang, L.C.; Chee, M.L.; Chen, J.; Chen, S.H.; Chen, Y.T.; Chen, Z.; Chuang, L.M.; Cushman, M.; Danesh, J.; Das, S.K.; de Silva, H.J.; Dedoussis, G.; Dimitrov, L.; Doumatey, A.P.; Du, S.; Duan, Q.; Eckardt, K.U.; Emery, L.S.; Evans, D.S.; Evans, M.K.; Fischer, K.; Floyd, J.S.; Ford, I.; Franco, O.H.; Frayling, T.M.; Freedman, B.I.; Genter, P.; Gerstein, H.C.; Giedraitis, V.; González-Villalpando, C.; González-Villalpando, M.E.; Gordon-Larsen, P.; Gross, M.; Guare, L.A.; Hackinger, S.; Hakaste, L.; Han, S.; Hattersley, A.T.; Herder, C.; Horikoshi, M.; Howard, A.; Hsueh, W.; Huang, M.; Huang, W.; Hung, Y.; Hwang, M.Y.; Hwu, C.; Ichihara, S.; Ikram, M.A.; Ingelsson, M.; Islam, M.T.; Isono, M.; Jang, H.; Jasmine, F.; Jiang, G.; Jonas, J.B.; Jørgensen, T.; Kamanu, F.K.; Kandeel, F.R.; Kasturiratne, A.; Katsuya, T.; Kaur, V.; Kawaguchi,T.; Keaton, J.M.; Kho, A.N.; Khor, C.; Kibriya, M.G.; Kim, D.; Kronenberg, F.; Kuusisto , J.; Läll, K.; Lange, L.A.; Lee, K.M.; Lee, M.; Lee, N.R.; Leong, A.; Li, L.; Li, Y.; Li-Gao, R.; Ligthart, S.; Lindgren, C.M.; Linneberg, A.; Liu, C.; Liu, J.; Locke, A.E.; Louie, T.; Luan, J.; Luk, A.O.; Luo, X.; Lv, J.; Lynch, J.A.; Lyssenko, V.; Maeda, S.; Mamakou, V.; Mansuri, S.R.; Matsuda, K.; Meitinger, T.; Melander, O.; Metspalu, A.; Mo, H.; Morris, A.D.; Moura, F.A.; Nadler, J.L.; Nalls, M.A.; Nayak, U.; Ntalla, I.; Okada, Y.; Orozco, L.; Patel, S.R.; Patil, S.; Pei, P.; Pereira, M.A.; Peters, A.; Pirie, F.J.; Polikowsky, H.G.; Porneala, B.; Prasad, G.; Rasmussen-Torvik, L.J.; Reiner, A.P.; Roden, M.; Rohde, R.; Roll, K.; Sabanayagam, C.; Sandow, K.; Sankareswaran , A.; Sattar,N.; Schönherr, S.; Shahriar, M.; Shen , B.; Shi, J.; Shin, D.M.; Shojima, N.; Smith, J.A.; So, W.Y.; Stančáková, A.; Steinthorsdottir, V.; Stilp, A.M.; Strauch, K.; Taylor, K.D.; Thorand, B.; Thorsteinsdottir, U.; Tomlinson, B.; Tran, T.C.; Tsai, F.; Tuomilehto, J.; Tusie-Luna, T.; Udler , M.S.; Valladares-Salgado, A.; Dam, R.M.V.; Klinken, J.B.V.; Varma, R.; Wacher-Rodarte, N.; Wheeler,E.; Wickremasinghe, A.R.; Dijk, K.W.V.; Witte, D.R.; Yajnik, C.S.; Yamamoto, K.; Yamamoto, K.; Yoon, K.; Yu, C.; Yuan, J.; Yusuf, S.; Zawistowski, M.; Zhang, L.; Zheng, W.; Raffel, L.J.; Igase, M.; Ipp, E.; Redline, S.; Cho, Y.S.; Lind, L.; Province, M.A.; Fornage, .M.; Hanis, C.L.; Ingelsson, E.; Zonderman, A.B.; Psaty, B.M.; Wang, Y.; Rotimi, C.N.; Becker,D.M.; Matsuda,F.; Liu, Y.; Yokota,M.; Kardia, S.L.R.; Peyser, P.A.; Pankow, J.S.; Engert, J.C.; Bonnefond, A.; Froguel, P.; Wilson, J.G.; Sheu, W.H.H.; Wu, J.; Hayes, M.G.; Ma, R.C.W.; Wong, T.; Mook-Kanamori, D.O.; Tuomi, T.; Chandak, G.R.; Collins, F.S.; Bharadwaj, D.; Paré, G.; Sale, M.M.; Ahsan, H.; Motala, A.A.; Shu , X.; Park, K.; Jukema, J.W.; Cruz, M.; Chen, Y.I.; Rich, S.S.; McKean-Cowdin, R.; Grallert, H.; Cheng, C.; Ghanbari,M.; Tai , E.; Dupuis, J.; Kato, N.; Laakso, M.; Köttgen, A.; Koh, W.; Bowden, D.W.; Palmer, C.N.A.; Kooner, J.S.; Kooperberg, C.; Liu, S.; North, K.E.; Saleheen, D.; Hansen, T.; Pedersen, O.; Wareham, N.J.; Lee, J.; Kim, B.; Millwood , I.Y.; Walters, R.G.; Stefansson, K.; Ahlqvist, E.; Goodarzi, M.O.; Mohlke, K.L.; Langenberg, C.; Haiman, C.A.; Loos, R.J.F.; Florez, J.C.; Rader, D.J.; Ritchie, M.D.; Zöllner, S.; Mägi, R.; Marston, N.A.; Ruff, C.T.; Heel , D.A.V.; Finer, S.; Denny, J.C.; Yamauchi, T.; Kadowaki, T.; Chambers, J.C.; Ng, M.C.Y.; Sim, X.; Below, J.E.; Tsao, P.S.; Chang, K.; McCarthy, M.I.; Meigs, J.B.; Mahajan, A.; Spracklen, C.N.; Mercader, J.M.; Boehnke, M.; Rotter, J.I.; Vujkovic, M.; Voight, B.F.; Morris, A.P.; Zeggini, E.Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.