Journal/Magazine Articles
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This collection contains original research articles, review articles and case reports published in local and international peer reviewed journals by the staff members of the Faculty of Medicine
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Item GDF15 linked to maternal risk of nausea and vomiting during pregnancy(Nature Pub. Group, 2024) Fejzo, M.; Rocha, N.; Cimino, I.; Lockhart, S.M.; Petry, C.J.; Kay, R.G.; Burling, K.; Barker, P.; George, A.L.; Yasara, N.; Premawardhena, A.; Gong, S.; Cook, E.; Rimmington, D.; Rainbow, K.; Withers, D.J.; Cortessis, V.; Mullin, P.M.; MacGibbon, K.W.; Jin, E.; Kam, A.; Campbell, A.; Polasek, O.; Tzoneva, G.; Gribble, F.M.; Yeo, G.S.H.; Lam, B.Y.H.; Saudek, V.; Hughes, I.A.; Ong, K.K.; Perry, J.R.B.; Sutton, C.A.; Baumgarten, M.; Welsh, P.; Sattar, N.; Smith, G.C.S.; Charnock- Jones, D.S.; Coll, A.P.; Meek, C.L.; Mettananda, S.; Hayward, C.; Mancuso, N.; O'Rahilly, S.GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy (NVP) including its most severe form, Hyperemesis Gravidarum (HG), but a full mechanistic understanding is lacking [1-4]. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally-labelled GDF15 variant we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with beta-thalassemia, a condition where GDF15 levels are chronically high [5], report very low levels of NVP. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally-derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.Item Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci(Frontiers Research Foundation, 2023) de Las, F.L.; Schwande, K.L.; Brown, M.R.; Bentley, A.R.; Winkler, T.W.; Sung, Y.J.; Munroe, P.B.; Miller, C.L.; Aschard, H.; Aslibekyan, S.; Bartz, T.M.; Bielak, L.F.; Chai, J.F.; Cheng, C.Y.; Dorajoo, R.; Feitosa, M.F.; Guo, X.; Hartwig, F.P.; Horimoto, A.; Kolčić, I.; Lim, E.; Liu, Y.; Manning, A.K.; Marten, J.; Musani, S.K.; Noordam, R.; Padmanabhan, S.; Rankinen, T.; Richard, M.A.; Ridker, P.M.; Smith, A.V.; Vojinovic, D.; Zonderman, A.B.; Alver, M.; Boissel, M.; Christensen, K.; Freedman, B.I.; Gao, C.; Giulianini, F.; Harris, S.E.; He, M.; Hsu, F.C.; Kühnel, B.; Laguzzi, F.; Li, X.; Lyytikäinen, L.P.; Nolte, I.M.; Poveda, A.; Rauramaa, R.; Riaz, M.; Robino, A.; Sofer, T.; Takeuchi, F.; Tayo, B.O.; van der, M.P.J.; Verweij, N.; Ware, E.B.; Weiss, S.; Wen, W.; Yanek, L.R.; Zhan, Y.; Amin, N.; Arking, D.E.; Ballantyne, C.; Boerwinkle, E.; Brody, J.A.; Broeckel, U.; Campbell, A.; Canouil, M.; Chai, X.; Chen, Y.I.; Chen, X.; Chitrala, K.N.; Concas, M.P.; de Faire, U.; de Mutsert, R.; de Silva, H.J.; de Vries, P.S.; Do, A.; Faul, J.D.; Fisher, V.; Floyd, J.S.; Forrester, T.; Friedlander, Y.; Girotto, G.; Gu, C.C.; Hallmans, G.; Heikkinen, S.; Heng, C.K.; Homuth, G.; Hunt, S.; Ikram, M.A.; Jacobs, D.R.J.R.; Kavousi, M.; Khor, C.C.; Kilpeläinen, T.O.; Koh, W.P.; Komulainen, P.; Langefeld, C.D.; Liang, J.; Liu, K.; Liu, J.; Lohman, K.; Mägi, R.; Manichaikul, A.W.; McKenzie, C.A.; Meitinger, T.; Milaneschi, Y.; Nauck, M.; Nelson, C.P.; O'Connell, J.R.; Palmer, N.D.; Pereira, A.C.; Perls, T.; Peters, A.; Polašek, O.; Raitakari, O.T.; Rice, K.; Rice, T.K.; Rich, S.S.; Sabanayagam, C.; Schreiner, P.J.; Shu, X.; Sidney, S.; Sims, M.; Smith, J.A.; Starr, J.M.; Strauch, K.; Tai, E.S.; Taylor, K.D.; Tsai, M.Y.; Uitterlinden, A.G.; Heemst, D.V.; Waldenberger, M.; Wang, Y.; Wei, W.; Wilson, G.; Xuan, D.; Yao, J.; Yu, C.; Yuan, J.; Zhao, W.; Becker, D.M.; Bonnefond, A.; Bowden, D.W.; Cooper, R.S.; Deary, I.J.; Divers, J.; Esko, T.; Franks, P.W.; Froguel, P.; Gieger, C.; Jonas, J.B.; Kato, N.; Lakka, T.A.; Leander, K.; Lehtimäki, T.; Magnusson, P.K.E.; North, K.E.; Ntalla, I.; Penninx, B.; Samani, N.J.; Snieder, H.; Spedicati, B.; Harst, P.V.D.; Völzke, H.; Wagenknecht, L.E.; Weir, D.R.; Wojczynski, M.K.; Wu, T.; Zheng, W.; Zhu, X.; Bouchard, C.; Chasman, D.I.; Evans, M.K.; Fox, E.R.; Gudnason, V.; Hayward, C.; Horta, B.L.; Kardia, S.L.R.; Krieger, J.E.; Mook-Kanamori, D.O.; Peyser, P.A.; Province, M.M.; Psaty, B.M.; Rudan, I.; Sim, X.; Smith, B.H.; Dam, R.M.V.; Duijn, C.M.V.; Wong, T.Y.; Arnett, D.K.; Rao, D.C.; Gauderman, J.; Liu, C.; Morrison, A.C.; Rotter, J.I.; Fornage, M.INTRODUCTION: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. METHODS: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). RESULTS: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. DISCUSSION: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.Item Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis(BioMed Central Ltd, 2022) Kanoni, S.; Graham, S.E.; Wang, Y.; Surakka, I.; Ramdas, S.; Zhu, X.; Clarke, S.L.; Bhatti, K.F.; Vedantam, S.; Winkler, T.W.; Locke, A.E.; Marouli, E.; Zajac, G.J.M.; Wu, K.H.; Ntalla, I.; Hui, Q.; Klarin, D.; Hilliard, A.T.; Wang, Z.; Xue, C.; Thorleifsson, G.; Helgadottir, A.; Gudbjartsson, D.F.; Holm, H.; Olafsson, I.; Hwang, M.Y.; Han, S.; Akiyama, M.; Sakaue, S.; Terao, C.; Kanai, M.; Zhou, W.; Brumpton, B.M.; Rasheed, H.; Havulinna, A.S.; Veturi, Y.; Pacheco, J.A.; Rosenthal, E.A.; Lingren, T.; Feng, Q.; Kullo, I.J.; Narita, A.; Takayama, J.; Martin, H.C.; Hunt, K.A.; Trivedi, B.; Haessler, J.; Giulianini, F.; Bradford, Y.; Miller, J.E.; Campbell, A.; Lin, K.; Lin, K.; Millwood, I.Y.; Rasheed, A.; Hindy, G.; Faul, J.D.; Zhao, W.; Weir, D.R.; Turman, C.; Huang, H.; Graff, M.; Choudhury, A.; Sengupta, D.; Mahajan, A.; Brown, M.R.; Zhang, W.; Yu, K.; Schmidt, E.M.; Pandit, A.; Gustafsson, S.; Yin, X.; Luan, J.; Zhao, J.H.; Matsuda, F.; Jang, H.M.; Yoon, K.; Medina-Gomez, C.; Pitsillides, A.; Hottenga, J.J.; Wood, A.R.; Ji, Y.; Gao, Z.; Haworth, S.; Yousri, N.A.; Mitchell, R.E.; Chai, J.F.; Aadahl, M.; Bjerregaard, A.A.; Yao, J.; Manichaikul, A.; Hwu, C.M.; Hung, Y.J.; Warren, H.R.; Ramirez, J.; Bork-Jensen, J.; Kårhus, L.L.; Goel, A.; Sabater-Lleal, M.; Noordam, R.; Mauro, P.; Matteo, F.; McDaid, A.F.; Marques-Vidal, P.; Wielscher, M.; Trompet, S.; Sattar, N.; Møllehave, L.T.; Munz, M.; Zeng, L.; Huang, J.; Yang, B.; Poveda, A.; Kurbasic, A.; Lamina, C.; Forer, L.; Scholz, M.; Galesloot, T.E.; Bradfield, J.P.; Ruotsalainen, S.E.; Daw, E.; Zmuda, J.M.; Mitchell, J.S.; Fuchsberger, C.; Christensen, H.; Brody, J.A.; Vazquez-Moreno, M.; Feitosa, M.F.; Wojczynski, M.K.; Wang, Z.; Preuss, M.H.; Mangino, M.; Christofidou, P.; Verweij, N.; Benjamins, J.W.; Engmann, J.; Tsao, N.L.; Verma, A.; Slieker, R.C.; Lo, K.S.; Zilhao, N.R.; Le, P.; Kleber, M.E.; Delgado, G.E.; Huo, S.; Ikeda, D.D.; Iha, H.; Yang, J.; Liu, J.; Demirkan, A.; Leonard, H.L.; Marten, J.; Frank, M.; Schmidt, B.; Smyth, L.J.; Cañadas-Garre, M.; Wang, C.; Nakatochi, M.; Wong, A.; Hutri-Kähönen, N.; Lyssenko, V.; Fernandez-Lopez, J.C.; Huerta-Chagoya, A.; Xia, R.; Sim, X.; Nongmaithem, S.S.; Bayyana, S.; Stringham, H.M.; Irvin, M.R.; Oldmeadow, C.; Kim, H.N.; Ryu, S.; Timmers, P,R,H,J,; Arbeeva, L.; Dorajoo, R.; Lange, L.A.; Prasad, G.; Lorés-Motta, L.; Pauper, M.; Long, J.; Li, X.; Theusch, E.; Takeuchi, F.; Spracklen, C.N.; Loukola, A.; Bollepalli, S.; Warner, S.C.; Wang, Y.X.; Wei, W.B.; Nutile, T.; Ruggiero, D.; Sung, Y.J.; Chen, S.; Liu, F.; Yang, J.; Kentistou, K.A.; Banas, B.; Nardone, G.G.; Meidtner, K.; Bielak, L.F.; Smith, J.A.; Hebbar, P.; Farmaki, A.E.; Hofer, E.; Lin, M.; Concas, M.P.; Vaccargiu, S.; van der Most, P.J.; Pitkänen, N.; Cade, B.E.; van der Laan, S.W.; Chitrala, K.N.; Weiss, S.; Bentley, A.R.; Doumatey, A.P.; Adeyemo, A.A.; Lee, J.Y.; Petersen, E.R.B.; Nielsen, A.A.; Choi, H.S.; Nethander, M.; Freitag-Wolf, S.; Southam, L.; Rayner, N.W.; Wang, C.A.; Lin, S.Y.; Wang, J.S.; Couture, C.; Lyytikäinen, L.P.; Nikus, K.; Cuellar-Partida, G.; Vestergaard, H.; Hidalgo, B.; Giannakopoulou, O.; Cai, Q.; Obura, M.O.; van Setten, J.; Li, X.; Liang, J.; Tang, H.; Terzikhan, N.; Shin, J.H.; Jackson, R.D.; Reiner, A.P.; Martin, L.W.; Chen, Z.; Li, L.; Kawaguchi, T.; Thiery, J.; Bis, J.C.; Launer, L.J.; Li, H.; Nalls, M.A.; Raitakari, O.T.; Ichihara, S.; Wild, S.H.; Nelson, C.P.; Campbell, H.; Jäger, S.; Nabika, T.; Al-Mulla, F.; Niinikoski, H.; Braund, P.S.; Kolcic, I.; Kovacs, P.; Giardoglou, T.; Katsuya, T.; de Kleijn, D.; de Borst, G.J.; Kim, E.K.; Adams, H.H.H.; Ikram, M.A.; Zhu, X.; Asselbergs, F.W.; Kraaijeveld, A.O.; Beulens, J.W.J.; Shu, X.O.; Rallidis, L.S.; Pedersen, O.; Hansen, T.; Mitchell, P.; Hewitt, A.W.; Kähönen, M.; Pérusse, L.; Bouchard, C.; Tönjes, A.; Chen, Y.I.; Pennell, C.E.; Mori, T.A.; Lieb, W.; Franke, A.; Ohlsson, C.; Mellström, D.; Cho, Y.S.; Lee, H.; Yuan, J.M.; Koh, W.P.; Rhee, S.Y.; Woo, J.T.; Heid, I.M.; Stark, K.J.; Zimmermann, M.E.; Völzke, H.; Homuth, G.; Evans, M.K.; Zonderman, A.B.; Polasek, O.; Pasterkamp, G.; Hoefer, I.E.; Redline, S.; Pahkala, K.; Oldehinkel, A.J.; Snieder, H.; Biino, G.; Schmidt, R.; Schmidt, H.; Bandinelli, S.; Dedoussis, G.; Thanaraj, T.A.; Kardia, S.L.R.; Peyser, P.A.; Kato, N.; Schulze, M.B.; Girotto, G.; Böger, C.A.; Jung, B.; Joshi, P.K.; Bennett, D.A.; de Jager, P.L.; Lu, X.; Mamakou, V.; Brown, M.; Caulfield, M.J.; Munroe, P.B.; Guo, X.; Ciullo, M.; Jonas, J.B.; Samani, N.J.; Kaprio, J.; Pajukanta, P.; Tusié-Luna, T.; Aguilar-Salinas, C.A.; Adair, L.S.; Bechayda, S.A.; de Silva, H.J.; Wickremasinghe, A.R.; Krauss, R.M.; Wu, J.Y.; Zheng, W.; Hollander, A.I.; Bharadwaj, D.; Correa, A.; Wilson, J.G.; Lind, L.; Heng, C.K.; Nelson, A.E.; Golightly, Y.M.; Wilson, J.F.; Penninx, B.; Kim, H.L.; Attia, J.; Scott, R.J.; Rao, D.C.; Arnett, D.K.; Hunt, S.C.; Walker, M.; Koistinen, H.A.; Chandak, G.R.; Mercader, J.M.; Costanzo, M.C.; Jang, D.; Burtt, N.P.; Villalpando, C.G.; Orozco, L.; Fornage, M.; Tai, E.; van Dam, R.M.; Lehtimäki, T.; Chaturvedi, N.; Yokota, M.; Liu, J.; Reilly, D.F.; McKnight, A.J.; Kee, F.; Jöckel, K.H.; McCarthy, M.I.; Palmer, C.N.A.; Vitart, V.; Hayward, C.; Simonsick, E.; van Duijn, C.M.; Jin, Z.B.; Qu, J.; Hishigaki, H.; Lin, X.; März, W.; Gudnason, V.; Tardif, J.C.; Lettre, G.; Hart, L.M.; Elders, P.J.M.; Damrauer, S.M.; Kumari, M.; Kivimaki, M.; van der Harst, P.; Spector, T.D.; Loos, R.J.F.; Province, M.A.; Parra, E.J.; Cruz, M.; Psaty, B.M.; Brandslund, I.; Pramstaller, P.P.; Rotimi, C.N.; Christensen, K.; Ripatti, S.; Widén, E.; Hakonarson, H.; Grant, S.F.A.; Kiemeney, L.A.L.M.; de Graaf, J.; Loeffler, M.; Kronenberg, F.; Gu, D.; Erdmann, J.; Schunkert, H.; Franks, P.W.; Linneberg, A.; Jukema, J.W.; Khera, A.V.; Männikkö, M.; Jarvelin, M.R.; Kutalik, Z.; Francesco, C.; Mook-Kanamori, D.O.; van Dijk, K.W.; Watkins, H.; Strachan, D.P.; Grarup, N.; Sever, P.; Poulter, N.; Chuang, L.M.; Rotter, J.I.; Dantoft, T.M.; Karpe, F.; Neville, M.J.; Timpson, N.J.; Cheng, C.Y.; Wong, T.Y.; Khor, C.C.; Li, H.; Sabanayagam, C.; Sabanayagam, C.; Peters, A.; Gieger, C.; Hattersley, A.T.; Pedersen, N.L.; Magnusson, P.K.E.; Boomsma, D.I.; Willemsen, A.H.M.; Cupples, L.; van Meurs, J.B.J.; Ghanbari, M.; Gordon-Larsen, P.; Huang, W.; Kim, Y.J.; Tabara, Y.; Wareham, N.J.; Langenberg, C.; Zeggini, E.; Kuusisto, J.; Laakso, M.; Ingelsson, E.; Abecasis, G.; Chambers, J.C.; Kooner, J.S.; de Vries, P.S.; Morrison, A.C.; Hazelhurst, S.; Ramsay, M.; North, K.E.; Daviglus, M.; Kraft, P.; Martin, N.G.; Whitfield, J.B.; Abbas, S.; Saleheen, D.; Walters, R.G.; Holmes, M.V.; Black, C.; Smith, B.H.; Baras, A.; Justice, A.E.; Buring, J.E.; Ridker, P.M.; Chasman, D.I.; Kooperberg, C.; Tamiya, G.; Yamamoto, M.; van Heel, D.A.; Trembath, R.C.; Wei, W.Q.; Jarvik, G.P.; Namjou, B.; Hayes, M.G.; Ritchie, M.D.; Jousilahti, P.; Salomaa, V.; Hveem, K.; Åsvold, B.O.; Kubo, M.; Kamatani, Y.; Okada, Y.; Murakami, Y.; Kim, B.J.; Thorsteinsdottir, U.; Stefansson, K.; Zhang, J.; Chen, Y.; Ho, Y.L.; Lynch, J.A.; Rader, D.J.; Tsao, P.S.; Chang, K.M.; Cho, K.; O'Donnell, C.J.; Gaziano, J.M.; Wilson P.W.F.; Frayling, T.M.; Hirschhorn, J.N.; Kathiresan, S.; Mohlke, K.L.; Sun, Y.V.; Morris, A.P.; Boehnke, M.; Brown, C.D.; Natarajan, P.; Deloukas, P.; Willer, C.J.; Assimes, T.L.; Peloso, G.M.BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Item A saturated map of common genetic variants associated with human height(Nature Publishing Group, 2022) Vedantam, S.; Marouli, E.; Sidorenko, J.; Bartell, E.; Sakaue, S.; Graff, M.; Eliasen, A.U.; Jiang, Y.; Raghavan, S.; Miao, J.; Arias, J.D.; Graham, S.E.; Mukamel, R.E.; Spracklen, C.N.; Yin, X.; Chen, S.H.; Ferreira, T.; Highland, H.H.; Ji, Y.; Karaderi. T,; Lin, K.; Lüll, K.; Malden, D.E.; Medina-Gomez, C.; Machado, M.; Moore, A.; Rüeger, S.; Sim. X,; Vrieze, S.; Ahluwalia, T.S.; Akiyama, M.; Allison, M.A.; Alvarez, M.; Andersen, M.K.; Ani, A.; Appadurai, V.; Arbeeva, L.; Bhaskar, S.; Bielak, L.F.; Bollepalli, S.; Bonnycastle, L.L.; Bork-Jensen, J.; Bradfield, J.P.; Bradford, Y.; Braund, P.S.; Brody, J.A.; Burgdorf, K.S.; Cade, B.E.; Cai, H.; Cai, Q.; Campbell, A.; Cañadas-Garre, M.; Catamo, E.; Chai, J.F.; Chai, X.; Chang, L.C.; Chen, C.H.; Chesi, A.; Choi, S.H.; Chung, R.H.; Cocca, M.; Concas, M.P.; Couture, C.; Cuellar-Partida, G.; Danning, R.; Daw, E.W.; Degenhard, F.; Delgado, G.E.; Delitala, A.; Demirkan, A.; Deng, X.; Devineni, P.; Dietl, A.; Dimitriou, M.; Dimitrov, L.; Dorajoo, R.; Ekici, A.B.; Engmann, J.E.; Fairhurst-Hunter, Z.; Farmaki, A.E.; Faul, J.D.; Fernandez-Lopez, J.C.; Forer, L.; Francescatto, M.; Freitag-Wolf, S.; Fuchsberger, C.; Galesloot, T.E.; Gao, Y.; Gao, Z.; Geller, F.; Giannakopoulou, O.; Giulianini,F.; Gjesing, A.P.; Goel, A.; Gordon, S.D.; Gorski, M.; Grove, J.; Guo, X.; Gustafsson, S.; Haessler, J.; Hansen, T.F.; Havulinna, A.S.; Haworth, S.J.; He, J.; Heard-Costa, N.; Hebbar, P.; Hindy, G.; Ho, Y.A.; Hofer, E.; Holliday, E.; Horn, K.; Hornsby, W.E.; Hottenga, J.J.; Huang, H.; Huang, J.; Huerta-Chagoya, A.; Huffman, J.E.; Hung, Y.J.; Huo, S.; Hwang, M.Y.; Ha, H.; Ikeda, D.D.; Isono, M.; Jackson, A.U.; Jäger, S.; Jansen, I.E.; Johansson, I.; Jonas, J.B.; Jonsson, A.; Jørgensen, T.; Kalafati, I.P.; Kanai, M.; Kanoni, S.; Kårhus, L.L.; Kasturiratne, A.; Katsuya, T.; Kawaguchi, T.; Kember, R.L.; Kentistou, K.A.; Kim, H.N.; Kim, Y.J.; Kleber, M.E.; Knol, M.J.; Kurbasic, A.; Lauzon, M.; Le, P.; Lea, R.; Lee, J.Y.; Leonard, H.L.; Li, S.A.; Li, X.; Li, X.; Liang, J.; Lin, H.; Lin, S.Y.; Liu, J.; Liu, X.; Lo, K.S.; Long, J.; Lores-Motta, L.; Luan, J.; Lyssenko, V.; Lyytikäinen, L.P.; Mahajan, A.; Mamakou, V.; Mangino, M.; Manichaikul, A.; Marten, J.,; Mattheisen, M.; Mavarani, L.; McDaid, A.F.; Meidtner, K.; Melendez, T.L.; Mercader, J.M.; Milaneschi, Y.; Miller, J.E.; Millwood, I.Y.; Mishra, P.P.; Mitchell, R.E.; Møllehave, L.T.; Morgan, A.; Mucha, S.; Munz, M.; Nakatochi, M.; Nelson, C.P.; Nethander, M.; Nho, C.W.; Nielsen, A.A.; Nolte, I.M.; Nongmaithem, S.S.; Noordam, R.; Ntalla, I.; Nutile, T.; Pandit, A.; Christofidou, P.; Pärna, K.; Pauper, M.; Petersen, E.R.B.; Petersen, L.V.; Pitkänen, N.; Polašek, O.; Poveda, A.; Preuss, M.H.; Pyarajan, S.; Raffield, L.M.; Rakugi, H.; Ramirez, J.; Rasheed, A.; Raven, D.; Rayner, N.W.; Riveros, C.; Rohde, R.; Ruggiero, D.; Ruotsalainen, S.E.; Ryan, K.A.; Sabater-Lleal, M.; Saxena, R.; Scholz, M.; Sendamarai, A.; Shen, B.; Shi, J.; Shin, J.H.; Sidore, C.; Sitlani, C.M.; Slieker, R.C.; Smit, R.A.J.; Smith, A.V.; Smith, J.A.; Smyth, L.J.; Southam, L.; Steinthorsdottir, V.; Sun, L.; Takeuchi, F.; Tallapragada, D.S.P.; Taylor, K.D.; Tayo, B.O.; Tcheandjieu, C.; Terzikhan, N.; Tesolin, P.; Teumer, A.; Theusch, E.; Thompson, D.J.; Thorleifsson, G.; Timmers, P.R.H.J.; Trompet, S.; Turman, C.; Vaccargiu, S.; van der Laan, S.W.; van der Most, P.J.; van Klinken, J.B.; van Setten, J.; Verma, S.S.; Verweij, N.; Veturi, Y.; Wang, C.A.; Wang, C.; Wang, L.; Wang, Z.; Warren, H.R.; Bin Wei, W.; Wickremasinghe, A.R.; Wielscher, M.; Wiggins, K.L.; Winsvold, B.S.; Wong, A.; Wu, Y.; Wuttke, M.; Xia, R.; Xie, T.; Yamamoto, K.; Yang, J.; Yao, J.; Young, H.; Yousri, N.A.; Yu, L.; Zeng, L.; Zhang, W.; Zhang, X.; Zhao, J.H.; Zhao. W.; Zhou, W.; Zimmermann, M.E.; Zoledziewska, M.; Adair, L.S.; Adams, H.H.H.; Aguilar-Salinas, C.A.; Al-Mulla, F.; Arnett, D.K.; Arnett, D.K.; Asselbergs, F.W.; Åsvold, B.O.; Attia, J.; Banas, B.; Bandinelli, S.; Bennett D.A.; Bergler, T.; Bharadwaj, D.; Biino, G.; Bisgaard, H.; Boerwinkle, E.; Böger, C.A.; Bønnelykke, K.; Boomsma, D.I.; Børglum, A.D.; Borja, J.B.; Bouchard, C.; Bowden, D.W.; Brandslund, I.; Brumpton, B.; Buring, J.E.; Caulfield, M.J.; Chambers, J.C.; Chandak, G.R.; Chanock, S.J.; Chaturvedi, N.; Chen, Y.I.; Chen, Z.; Cheng, C.Y.; Christophersen, I.E.; Ciullo, M.; Cole, J.W.; Collins, F.S.; Cooper, R.S.; Cruz, M.; Cucca, F.; Cupples, L.A.; Cutler, M.J.; Damrauer, S.M.; Dantoft, T.M.; de Borst, G.J.; de Groot, L.C.P.G.M.; de Jager, P.L.; de Kleijn, D.P.V.; de Silva, H.J.; Dedoussis, G.V.; den Hollander, A.I.; Du, S.; Easton, D.F.; Elders, P.J.M.; Eliassen, A.H.; Ellinor, P.T.; Elmståhl, S.; Erdmann, J.; Evans, M.K.; Fatkin, D.; Feenstra, B.; Feitosa, M.F.; Ferrucci, L.; Ford, I.; Fornage, M.; Franke, A.; Franks, P.W.; Freedman, B.I.; Gasparini, P.; Gieger, C.; Girotto, G.; Goddard, M.E.; Golightly, Y.M.; Gonzalez-Villalpando. C.; Gordon-Larsen, P.; Grallert, H.; Grant, S.F.A.; Grarup, N.; Griffiths, L.; Gudnason, V.; Haiman, C.; Hakonarson, H.; Hansen, T.; Hartman, C.A.; Hattersley, A.T.; Hayward, C.; Heckbert, S.R.; Heng, C.K.; Hengstenberg, C.; Hewitt, A.W.; Hishigaki, H.; Hoyng, C.B.; Huang, P.L.; Huang, W.; Hunt, S.C.; Hveem, K.; Hyppönen, E.; Iacono, W.G.; Ichihara, S.; Ikram, M.A.; Isasi, C.R.; Jackson, R.D.; Jarvelin, M.R.; Jin, Z.B.; Jöckel, K.H.; Joshi, P.K.; Jousilahti, P.; Jukema, J.W.; Kähönen, M.; Kamatani, Y.; Kang, K.D.; Kaprio, J.; Kardia, S.L.R.; Karpe, F.; Kato, N.; Kee, F.; Kessler, T.; Khera, A.V.; Khor, C.C.; Kiemeney, L.A.L.M.; Kim, B.J.; Kim, E.K.; Kim, H.L.; Kirchhof, P.; Kivimaki, M.; Koh, W.P.; Koistinen, H.A.; Kolovou, G.D.; Kooner, J.S.; Kooperberg, C.; Köttgen, A.; Kovacs, P.; Kraaijeveld, A.; Kraft, P.; Krauss, R.M.; Kumari, M.; Kutalik, Z.; Laakso, M.; Lange, L.A.; Langenberg, C.; Launer, L.J.; Le Marchand, L.; Lee, H.; Lee, N.R.; Lehtimäki, T.; Li, H.; Li, L.; Lieb, W.; Lin, X.; Lind, L.; Linneberg, A.; Liu, C.T.; Liu, J.; Loeffler, M.; London, B.; Lubitz, S.A.; Lye, S.J.; Mackey, D.A.; Mägi, R.; Magnusson, P.K.E.; Marcus, G.M.; Vidal, P.M.; Martin, N.G.; Martin, N.G.; Lieb, W.; Lin, X.; Lind, L.; Linneberg, A.; Liu, C.T.; Liu, J.; Loeffler, M.; London, B.; Lubitz, S.A.; Lye, S.J.; Mackey, D.A.; Mägi, R.; Mägi, R.; Magnusson, P.K.E.; Marcus, G.M.; Vidal, P.M.; Martin, N.G.; März, W.; Matsuda, F.; McGarrah, R.W.; McGue, M.; McKnight, A.J.; Medland, S.E.; Mellström, D.; Metspalu, A.; Mitchell, B.D.; Mitchell, P.; Mook-Kanamori, D.O.; Morris, A.D.; Mucci, L.A.; Munroe, P.B.; Nalls, M.A.; Nazarian, S.; Nelson, A.E.; Neville, M.J.; Newton-Cheh, C.; Nielsen, C.S.; Nöthen, M.M.; Ohlsson, C.; Oldehinkel, A.J.; Oldehinkel, A.J.; Orozco, L.; Pahkala, K.; Pajukanta, P.; Palmer, C.N.A.; Parra, E.J.; Pattaro, C.; Pedersen, O.; Pennell, C.E.; Penninx, B.W.J.H.; Perusse, L.; Peters, A.; Peyser, P.A.; Porteous, D.J.; Posthuma, D.; Power, C.; Pramstaller, P.P.; Province, M.A.; Qi, Q.; Qu, J.; Rader, D.J.; Raitakari, O.T.; Ralhan, S.; Rallidis, L.S.; Rao, D.C.; Redline, S.; Reilly, D.F.; Reiner, A.P.; Rhee, S.Y.; Ridker, P.M.; Rienstra, M.; Ripatti, S.; Ritchie, M.D.; Roden, D.M.; Rosendaal, F.R.; Rotter, J.I.; Rudan, I.; Rutters, F.; Sabanayagam, C.; Saleheen, D.; Salomaa, V.; Samani, N.J.; Sanghera, D.K.; Sattar, N.; Schmidt, B.; Schmidt, H.; Schmidt, R.; Schulze, M.B.; Schunkert, H.; Scott, L.J.; Scott, R.J.; Sever, P.; Shiroma, E.J.; Shoemaker, M.B.; Shu, X.O.; Simonsick, E.M.; Sims, M.; Singh, J.R.; Singleton, A.B.; Sinner, M.F.; Smith, J.G.; Snieder, H.; Spector, T.D.; Stampfer, M.J.; Stark, K.J.; Strachan, D.P.; 't Hart, L.M.; Tabara, Y.; Tang, H.; Tardif, J.C.; Thanaraj, T.A.; Timpson, N.J.; Tönjes, A.; Tremblay, A.; Tuomi, T.; Tuomilehto, J.; Tusié-Luna, M.T.; Uitterlinden, A.G.; van Dam, R.M.; van der Harst, P.; Van der Velde, N.; van Duijn, C.M.; van Schoor, N.M.; Vitart, V.; Völker, U.; Vollenweider, P.; Völzke, H.; Wacher-Rodarte, N.H.; Walker, M.; Wang, Y.X.; Wareham, N.J.; Watanabe, R.M.; Watkins, H.; Weir, D.R.; Werge, T.M.; Widen, E.; Wilkens, L.R.; Willemsen, G.; Willett, W.C.; Wilson, J.F.; Wong, T.Y.; Woo, J.T.; Wright, A.F.; Wu, J.Y.; Xu, H.; Yajnik, C.S.; Yokota, M.; Yuan, J.M.; Zeggini, E.; Zemel, B.S.; Zheng, W.; Zhu, X.; Zmuda, J.M.; Zonderman, A.B.; Zwart, J.A.; 23andMe Research Team; VA Million Veteran Program.; DiscovEHR (DiscovEHR and MyCode Community Health Initiative).; eMERGE (Electronic Medical Records and Genomics Network).; Lifelines Cohort Study.; PRACTICAL Consortium.; Understanding Society Scientific Group.; Chasman, D.I.; Cho, Y.S.; Heid, I.M.; McCarthy, M.I.; Ng, M.C.Y.; O'Donnell, C.J.; Rivadeneira, F.; Thorsteinsdottir, U.; Sun, Y.V.; Tai, E.S.; Boehnke, M.; Deloukas, P.; Justice, A.E.; Lindgren, C.M.; Loos, R.J.F.; Mohlke, K.L.; North, K.E.; Stefansson, K.; Walters R.G.v.; Winkler, T.W.; Young, K.L.; Loh, P.R.; Yang, J.; Esko, T.; Assimes, T.L.; Auton, A.; Abecasis, G.R.; Willer, C.J.; Locke, A.E.; Berndt, S.I.; Lettre, G.; Frayling, T.M.; Frayling, T.M.; Okada, Y.; Wood, A.R.; Visscher, P.M.; Hirschhorn, J.N.Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.Item A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids(American Society of Human Genetics., 2022) Ramdas, S.; Judd, J.; Graham, S.E.; Kanoni, S.; Wang, Y.; Surakka, I.; Wenz, B.; Clarke, S.L.; Chesi, A.; Wells, A.; Bhatti, K.F.; Vedantam, S.; Winkler, T.W.; Locke, A.E.; Marouli, E.; Zajac, G.J.M.; Wu, K.H.; Ntalla, I.; Hui, Q.; Klarin, D.; Hilliard, A.T.; Wang, Z.; Xue, C.; Thorleifsson, G.; Helgadottir, A.; Gudbjartsson, D.F.; Holm, H.; Olafsson, I.; Hwang, M.Y.; Han, S.; Akiyama, M.; Sakaue, S.; Terao, C.; Kanai, M.; Zhou, W.; Brumpton, B.M.; Rasheed, H.; Havulinna, A.S.; Veturi, Y.; Pacheco, J.A.; Rosenthal, E.A.; Lingren, T.; Feng, Q.; Kullo, I.J.; Narita, A.; Takayama, J.; Martin, H.C.; Hunt, K.A.; Trivedi, B.; Haessler, J.; Giulianini, F.; Bradford, Y.; Miller, J.E.; Campbell, A.; Lin, K.; Millwood, I.Y.; Rasheed, A.; Hindy, G.; Faul, J.D.; Zhao, W.; Weir, D.R.; Turman, C.; Huang, H.; Graff, M.; Choudhury, A.; Sengupta, D.; Mahajan, A.; Brown, M.R.; Zhang, W.; Yu, K.; Schmidt, E.M.; Pandit, A.; Gustafsson, S.; Yin, X.; Luan, J.; Zhao, J.H.; Matsuda, F.; Jang, H.M.; Yoon, K.; Gomez, C.M.; Pitsillides, A.; Hottenga, J.J.; Wood, A.R.; Ji, Y.; Gao, Z.; Haworth, S.; Mitchell, R.E.; Chai, J.F.; Aadahl, M.; Bjerregaard, A.A.; Yao, J.; Manichaikul, A.; JaneLee, W.; Hsiung, C.A.; Warren, H.R.; Ramirez, J.; Jensen, J.B.; Kårhus, L.; Goel, A.; Lleal, M.S.; Noordam, R.; Mauro, P.; Matteo, F.; McDaid, A.F.; Marques-Vidal, P.; Wielscher, M.; Trompet, S.; Sattar, N.; Møllehave, L.T.; Munz, M.; Zeng, L.; Huang, J.; Yang, B.; Poveda, A.; Kurbasic, A.; Schönherr, S.; Forer, L.; Scholz, M.; Galesloot, T.E.; Bradfield, J.P.; Ruotsalainen, S.E.; Daw, E.W.; Zmuda, J.M; Mitchell, J.S.; Fuchsberger, C.; Christensen, H.; Brody, J.A.; Le, P.; Feitosa, M.F.; Wojczynski, M.K.; Hemerich, D.; Preuss, M.; Mangino, M.; Christofidou, P.; Verweij, N.; Benjamins, J.W.; Engmann, J.; Noah, T.L.; Verma, A.; Slieker, R.C.; Lo, K.S.; Zilhao, N.R.; Kleber, M.E.; Delgado, G.E.; Huo, S.; Ikeda, D.D.; Iha, H.; Yang, J.; Liu, J.; Demirkan, A.; Leonard, H.L.; Marten,J.; Emmel, C.; Schmidt, B.; Smyth, L.J.; Cañadas-Garre, M.; Wang, C.; Nakatochi, M.; Wong, A.; Hutri-Kähönen , N.; Sim, X.; Xia, R.; Huerta-Chagoya, A.; Fernandez-Lopez, J.C.; Lyssenko, V; Nongmaithem, S.S.; Sankareswaran, A.; Irvin, M.R.; Oldmeadow, C.; Kim, H.N.; Ryu, S.; Timmers, P.R.H.J; Arbeeva, L.; Dorajoo, R.; Lange, L.A.; Prasad, G.; Lorés-Motta, L.; Pauper, M.; Long, J.; Li, X.; Theusch, E.; Takeuchi, F.; Spracklen, C.N.; Loukola, A.; Bollepalli, S.; Warner, S.C.; Wang, Y.X.; Wei, W.B.; Nutile, T.; Ruggiero, D.; Sung,Y.J.; Chen, S.; Liu, F.; Yang, J.; Kentistou, K.A.; Banas, B.; Morgan, A.; Meidtner, K.; Bielak, L.F.; Smith, J.A.; Hebbar, P.; Farmaki, A.E.; Hofer, E.; Lin, M.; Concas, M.P.; Vaccargiu, S.; Most, P.J.; Pitkänen, N.; Cade, B.E.; Laan, S.W.; Chitrala, K.N.; Weiss, S.; Bentley, A.R.; Doumatey, A.P.; Adeyemo, A.A.; Lee, J.Y.; Petersen, E.R.B.; Nielsen, A.A.; Choi, H.S.; Nethander, M.; Nethander, M.; Freitag-Wolf, S.; Southam, L.; Rayner, N.W.; Wang, C.A.; Lin, S.; Wang, J.S.; Couture, C.; Lyytikäinen, L.P.; Nikus, K.; Partida, G.C.; Vestergaard, H.; Hidalgo, B.; Giannakopoulou, O.; Cai, Q.; Obura, M.O.; Setten, J.; He, K.Y.; Tang, H.; Terzikhan, N.; Shin, J.H.; Jackson, R.D.; Reiner, A.P.; Martin, L.W.; Chen, Z.; Li, L.; Kawaguchi, T.; Thiery, J.; Bis, J.C.; Launer, L.J.; Li, H.; Nalls, M.A.; Raitakari, O.T.; Ichihara, S.; Wild, S.H.; Nelson, C.P.; Campbell, H.; Jäger, S.; Nabika, T.; Al-Mulla, F.; Niinikoski, H.; Braund, P.S.; Kolcic, I.; Kovacs, P.; Giardoglou, T.; Katsuya, T.; Kleijn, D.; Borst, G.J.; Kim, E.K.; Adams, H.H.H.; Ikram, M.A.; Zhu, X.; Asselbergs, F.W.; Kraaijeveld, A.O.; Beulens, J.W.J.; Shu, X.O.; Rallidis, L.S.; Pedersen, O.; Hansen, T.; Mitchell, P.; Hewitt, A.W.; Kähönen, M.; Pérusse, L.; Bouchard, C.; Tönjes, A.; Chen, Y.D.I; Pennell, C.E.; Mori, T.A.; Lieb, W.; Franke, A.; Ohlsson, C.; Mellström, D.; Cho, Y.S.; Lee, H.; Yuan, J.M.; Koh, W.P.; Rhee, S.Y.; Woo, J.T.; Heid, I.M.; Stark, K.J.; Zimmermann, M.E.; Völzke, H.; Homuth, G.; Homuth, G.; Evans, M.K.; Zonderman, A.B.; Polasek, O.; Pasterkamp, G.; Hoefer, I.E.; Redline, S.; Pahkala, K.; Oldehinkel, A.J.; Snieder, H.; Biino, G.; Schmidt, R.; Schmidt, H.; Bandinelli , S; Dedoussis, G.; Thanaraj, T.A.; Peyser, P.A.; Kato, N.; Schulze, M.B.; Girotto, G.; Böger, C.A.; Jung, B.; Joshi, P.K.; Bennett, D.A.; Jager, P.L.D.; Lu, X.; Mamakou, V.; Brown, M.; Caulfield, M.J.; Munroe, P.B.; Guo, X.; Ciullo, M.; Jonas, J.B.; Samani, N.J.; Kaprio, J.; Pajukanta, P.; Luna, T.T.; Salinas, C.A.A.; Adair, L.S.; Bechayda, S.A.; de Silva, H.J.; Wickremasinghe, A.R.; Krauss, R.M.; Wu, J.Y.; Zheng,W.; Hollander, A.I.; Bharadwaj, D.; Correa, A,; Wilson, J.G.; Lind, L.; Heng, C.K.; Nelson, A.E.; Golightly, Y.M.; Wilson, J.F.; Penninx, B.; Kim, H.L.; Attia, J.; Scott, R.J.; Rao, D.C.; Arnett, D.K.; Walker, M.; Scott, L.J.; Koistinen, H.A.; Chandak, G.R.; Mercader, J.M.; Villalpando, C.G.; Orozco, L.; Fornage, M.; Tai, E.S.; Dam, R.M.; Lehtimäki, T.; Chaturvedi, N.; Yokota, M.; Liu, J.; Reilly, D.F.; McKnight, A.J.; Kee, F.; Jöckel, K.H.; McCarthy, M.I.; Palmer, C.N.A.; Vitart, V.; Hayward, C.; Simonsick, E.; Duijn, C.M; Jin, Z.B.; Jin, Z.B.; Lu, F.; Hishigaki, H.; Lin, X.; März, W.; Gudnason, V.; Tardif, J.C.; Lettre, G.; Hart, L.M.T.; Elders, P.J.M.; Rader, D.J.; Loos, S.M.; Province, M.A.; Parra, E.J.; Cruz, M.; Psaty, B.M.; Brandslund, I.; Pramstaller, P.P.; Rotimi, C.N.; Christensen, K.; Ripatti, S.; Widén, E.; Hakonarson, H.; Grant, S.F.A.; Kiemeney, L.; de Graaf, J.; Loeffler, M.; Kronenberg, F.; Gu, D.; Erdmann, J.; Schunkert, H.; Franks,P.W.; Linneberg, A.; Jukema, J.W.; Khera, A.V.; Männikkö, M.; Jarvelin, M.R.; Kutalik, Z.; Francesco, C.; Kanamori, D.O.M.; Dijk, K.W.; Watkins, H.; Strachan, D.P.; Grarup, N.; Sever, P.; Poulter, N.; Sheu, W.H.H.; Rotter, J.I.; Dantoft, T.M.; Karpe, F.; Neville, M.J.; Timpson, N.J.; Cheng, C.Y.; Wong, T.Y.; Khor, C.C.; Li, H.; Sabanayagam, C.; Peters, A.; Gieger, C.; Hattersley, A.T.; Pedersen, N.L.; Magnusson, P.K.E.; Boomsma, D.I.; de Geus, E.J.C.; Cupples, L.A.; Meurs, J.B.J.; Ikram, A.; Ghanbari, M.; Larsen, P.G.; Huang, W.; Kim, Y.J.; Tabara, Y.; Wareham, N.J.; Langenberg, C.; Zeggini, E.; Tuomilehto, J.; Kuusisto, J.; Laakso, M.; Ingelsson, E.; Abecasis, G.; Chambers, J.C.; Kooner, J.S.; de Vries, P.S.; Morrison, A.C.; Hazelhurst, S.; Ramsay, M.; North, K.E.; Daviglus, M.; Kraft, P.; Martin, N.G.; Whitfield, J.B.; Abbas, S.; Saleheen, D.; Walters, R.G.; Holmes, M.V.; Black, C.; Smith, B.H.; Baras, A.; Justice, A.E.; Buring, J.E.; Ridker, P.M.; Chasman, D.I.; Kooperberg, C.; Tamiya, G.; Yamamoto, M.; Heel, D.A.; Trembath, R.C.; Wei, W.Q.; Jarvik, G.P.; Namjou, B.; Hayes, M.G.; Ritchie, M.D.; Jousilahti, P.; Salomaa, V.; Hveem, K.; Åsvold, B.O.; Kubo, M.; Kamatani, Y.; Okada, Y.; Murakami, Y.; Kim, B.J.; Thorsteinsdottir, U.; Stefansson, K.; Zhang, J.; Chen, Y.E.; Ho, Y.L.; Lynch, J.A.; Tsao, P.S.; Chang, K.M.; Cho, K.; O'Donnell, C.J.; Gaziano, J.M.; Wilson, P.; Mohlke, K.L.; Frayling, T.M.; Hirschhorn, J.N.; Kathiresan, S.; Boehnke, M.; Million Veterans Program; Global Lipids Genetics Consortium; Grant, S.; Natarajan, P.; Sun, Y.V.; Morris, A.P.; Deloukas, P.; Peloso, G.; Assimes, T.L.; Willer, C.J.; Zhu, X.; Brown, C.D.A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.Item The power of genetic diversity in genome-wide association studies of lipids(Macmillan Journals Ltd, 2021) Graham, S.E.; Clarke, S.L.; Wu, K.H.; Kanoni, S.; Zajac, G.J.M.; Ramdas, S.; Surakka, I.; Ntalla, I.; Vedantam, S.; Winkler, T.W.; Locke, A.E.; Marouli, E.; Hwang, M.Y.; Han, S.; Narita, A.; Choudhury, A.; Bentley, A.R.; Ekoru, K.; Verma, A.; Trivedi, B.; Martin, H.C.; Hunt, K.A.; Hui, Q.; Klarin, D.; Zhu, X.; Thorleifsson, G.; Helgadottir, A.; Gudbjartsson, D.F.; Holm, H.; Olafsson, I.; Akiyama, M.; Sakaue, S.; Terao, C.; Kanai, M.; Zhou, W.; Brumpton, B.M.; Rasheed, H.; Ruotsalainen, S.E.; Havulinna, A.S.; Veturi, Y.; Feng, Q.; Rosenthal, E.A.; Lingren, T.; Pacheco, J.A.; Pendergrass, S.A.; Haessler, J.; Giulianini, F.; Bradford, Y.; Miller, J.E.; Campbell, A.; Lin, K.; Millwood, I.Y.; Hindy, G.; Rasheed, A.; Faul, J.D.; Zhao, W.; Weir, D.R.; Turman, C.; Huang, H.; Graff, M.; Mahajan, A.; Brown, M.R.; Zhang, W.; Yu, K.; Schmidt, E.M.; Pandit, A.; Gustafsson, S.; Yin, X.; Luan, J.; Zhao, J.H.; Matsuda, F.; Jang, H.M.; Yoon, K.; Medina-Gomez, C.; Pitsillides, A.; Hottenga, J.J.; Willemsen, G.; Wood, A.R.; Ji, Y.; Gao, Z.; Haworth, S.; Mitchell, R.E.; Chai, J.F.; Aadahl, M.; Yao, J.; Manichaikul, A.; Warren, H.R.; Ramirez, J.; Bork-Jensen, J.; Kårhus, L.L.; Goel, A.; Sabater-Lleal, M.; Noordam, R.; Sidore, C.; Fiorillo, E.; McDaid, A.F.; Marques-Vidal, P.; Wielscher, M.; Trompet, S.; Sattar, N.; Møllehave, L.T.; Thuesen, B.H.; Munz, M.; Zeng, L.; Huang, J.; Yang, B.; Poveda, A.; Kurbasic, A.; Lamina, C.; Forer, L.; Scholz, M.; Galesloot, T.E.; Bradfield, J.P.; Daw, E.W.; Zmuda, J.M.; Mitchell, J.S.; Fuchsberger, C.; Christensen, H.; Brody, J.A.; Feitosa, M.F.; Wojczynski, M.K.; Preuss, M.; Mangino, M.; Christofidou, P.; Verweij, N.; Benjamins, J.W.; Engmann, J.; Kember, R.L.; Slieker, R.C.; Lo, K.S.; Zilhao, N.R.; Le, P.; Kleber, M.E.; Delgado, G.E.; Huo, S.; Ikeda, D.D.; Iha, H.; Yang, J.; Liu, J.; Leonard, H.L.; Marten, J.; Schmidt, B.; Arendt, M.; Smyth, L.J.; Cañadas-Garre, M.; Wang, C.; Nakatochi, M.; Wong, A.; Hutri-Kähönen, N.; Sim, X.; Xia, R.; Huerta-Chagoya, A.; Fernandez-Lopez, J.C.; Lyssenko, V.; Ahmed, M.; Jackson, A.U.; Irvin, M.R.; Oldmeadow, C.; Kim, H.N.; Ryu, S.; Timmers, P.R.H.J.; Arbeeva, L.; Dorajoo, R.; Lange, L.A.; Chai, X.; Prasad, G.; Lorés-Motta, L.; Pauper, M.; Long, J.; Li, X.; Theusch, E.; Takeuchi, F.; Spracklen, C.N.; Loukola, A.; Bollepalli, S.; Warner, S.C.; Wang, Y.X.; Wei, W.B.; Nutile, T.; Ruggiero, D.; Sung, Y.J.; Hung, Y.J.; Chen, S.; Liu, F.; Yang, J.; Kentistou, K.A.; Gorski, M.; Brumat, M.; Meidtner, K.; Bielak, L.F.; Smith, J.A.; Hebbar, P.; Farmaki, A.E.; Hofer, E.; Lin, M.; Xue, C.; Zhang, J.; Concas, M.P.; Vaccargiu, S.; van der Most, P.J.; Pitkänen, N.; Cade, B.E.; Lee, J.; van der Laan, S.W.; Chitrala, K.N.; Weiss, S.; Zimmermann, M.E.; Lee, J.Y.; Choi, H.S.; Nethander, M.; Freitag-Wolf, S.; Southam, L.; Rayner, N.W.; Wang, C.A.; Lin, S.Y.; Wang, J.S.; Couture, C.; Lyytikäinen, L.P.; Nikus, K.; Cuellar-Partida, G.; Vestergaard, H.; Hildalgo, B.; Giannakopoulou, O.; Cai, Q.; Obura, M.O.; van Setten, J.; Li, X.; Schwander, K.; Terzikhan, N.; Shin, J.H.; Jackson, R.D.; Reiner, A.P.; Martin, L.W.; Chen, Z.; Li, L.; Highland, H.M.; Young, K.L.; Kawaguchi, T.; Thiery, J.; Bis, J.C.; Nadkarni, G.N.; Launer, L.J.; Li, H.; Nalls, M.A.; Raitakari, O.T.; Ichihara, S.; Wild, S.H.; Nelson, C.P.; Campbell, H.; Jäger, S.; Nabika, T.; Al-Mulla, F.; Niinikoski, H.; Braund, P.S.; Kolcic, I.; Kovacs, P.; Giardoglou, T.; Katsuya, T.; Bhatti, K.F.; de Kleijn, D.; de Borst, G.J.; Kim, E.K.; Adams, H.H.H.; Ikram, M.A.; Zhu, X.; Asselbergs, F.W.; Kraaijeveld, A.O.; Beulens, J.W.J.; Shu, X.O.; Rallidis, L.S.; Pedersen, O.; Hansen, T.; Mitchell, P.; Hewitt, A.W.; Kähönen, M.; Pérusse, L.; Bouchard, C.; Tönjes, A.; Chen, Y.I.; Pennell, C.E.; Mori, T.A.; Lieb, W.; Franke, A.; Ohlsson, C.; Mellström, D.; Cho, Y.S.; Lee, H.; Yuan, J.M.; Koh, W.P.; Rhee, S.Y.; Woo, J.T.; Heid, I.M.; Stark, K.J.; Völzke, H.; Homuth, G.; Evans, M.K.; Zonderman, A.B.; Polasek, O.; Pasterkamp, G.; Hoefer, I.E.; Redline, S.; Pahkala, K.; Oldehinkel, A.J.; Snieder, H.; Biino, G.; Schmidt, R.; Schmidt, H.; Chen, Y.E.; Bandinelli, S.; Dedoussis, G.; Thanaraj, T.A.; Kardia, S.L.R.; Kato, N.; Schulze, M.B.; Girotto, G.; Jung, B.; Böger, C.A.; Joshi, P.K.; Bennett, D.A.; de Jager, P.L.; Lu, X.; Mamakou, V.; Brown, M.; Caulfield, M.J.; Munroe, P.B.; Guo, X.; Ciullo, M.; Jonas, J.B.; Samani, N.J.; Kaprio, J.; Pajukanta, P.; Adair, L.S.; Bechayda, S.A.; de Silva, H.J.; Wickremasinghe, A.R.; Krauss, R.M.; Wu, J.Y.; Zheng, W.; den Hollander, A.I.; Bharadwaj, D.; Correa, A.; Wilson, J.G.; Lind, L.; Heng, C.K.; Nelson, A.E.; Golightly, Y.M.; Wilson, J.F.; Penninx, B.; Kim, H.L.; Attia, J.; Scott, R.J.; Rao, D.C.; Arnett, D.K.; Walker, M.; Koistinen, H.A.; Chandak, G.R.; Yajnik, C.S.; Mercader, J.M.; Tusié-Luna, T.; Aguilar-Salinas, C.A.; Villalpando, C.G.; Orozco, L.; Fornage, M.; Tai, E.S.; van Dam, R.M.; Lehtimäki, T.; Chaturvedi, N.; Yokota, M.; Liu, J.; Reilly, D.F.; McKnight, A.J.; Kee, F.; Jöckel, K.H.; McCarthy, M.I.; Palmer, C.N.A.; Vitart, V.; Hayward, C.; Simonsick, E.; van Duijn, C.M.; Lu, F.; Qu, J.; Hishigaki, H.; Lin, X.; März, W.; Parra, E.J.; Cruz, M.; Gudnason, V.; Tardif, J.C.; Lettre, G.; 't Hart, L.M.; Elders, P.J.M.; Damrauer, S.M.; Kumari, M.; Kivimaki, M.; van der Harst, P.; Spector, T.D.; Loos, R.J.F.; Province, M.A.; Psaty, B.M.; Brandslund, I.; Pramstaller, P.P.; Christensen, K.; Ripatti, S.; Widén, E.; Hakonarson, H.; Grant, S.F.A.; Kiemeney, L.A.L.M.; de Graaf, J.; Loeffler, M.; Kronenberg, F.; Gu, D.; Erdmann, J.; Schunkert, H.; Franks, P.W.; Linneberg, A.; Jukema, J.W.; Khera, A.V.; Männikkö, M.; Jarvelin, M.R.; Kutalik, Z.; Cucca, F.; Mook-Kanamori, D.O.; van Dijk, K.W.; Watkins, H.; Strachan, D.P.; Grarup, N.; Sever, P.; Poulter, N.; Rotter, J.I.; Dantoft, T.M.; Karpe, F.; Neville, M.J.; Timpson, N.J.; Cheng, C.Y.; Wong, T.Y.; Khor, C.C.; Sabanayagam, C.; Peters, A.; Gieger, C.; Hattersley, A.T.; Pedersen, N.L.; Magnusson, P.K.E.; Boomsma, D.I.; de Geus, E.J.C.; Cupples, L.A.; van Meurs, J.BJ.; Ghanbari, M.; Gordon-Larsen, P.; Huang, W.; Kim, Y.T.; Tabara, Y.; Wareham, N.J.; Langenberg, C.; Zeggini, E.; Kuusisto, J.; Laakso, M.; Ingelsson, E.; Abecasis, G.; Chambers, J.C.; Kooner, J.S.; de Vries, P.S.; Morrison, A.C.; North, K.E.; Daviglus, M.; Kraft, P.; Martin, N.G.; Whitfield, J.B.; Abbas, S.; Saleheen, D.; Walters, R.G.; Holmes, M.V.; Black, C.; Smith, B.H.; Justice, A.E.; Baras, A.; Buring, J.E.; Ridker, P.M.; Chasman, D.I.; Kooperberg, C.; Wei, W.Q.; Jarvik, G.P; Namjou, B.; Hayes, M.G.; Ritchie, M.D.; Jousilahti, P.; Salomaa, V.; Hveem, K.; Åsvold, B.O.; Kubo, M.; Kamatani, Y.; Okada, Y.; Murakami, Y.; Thorsteinsdottir, U.; Stefansson, K.; Ho, Y.L.; Lynch, J.A.; Rader, D.J.; Tsao, P.S.; Chang, K.M.; Cho, K.; O'Donnell, C.J.; Gaziano, J.M.; Wilson, P.; Rotimi, C.N.; Hazelhurst, S.; Ramsay, M.; Trembath, R.C.; van Heel, D.A.; Tamiya, G.; Yamamoto, M.; Kim, B.J.; Mohlke, K.L.; Frayling, T.M.; Hirschhorn, J.N.; Kathiresan, S.; Boehnke, M.; Natarajan, P.; Peloso, G.M.; Brown, C.D.; Morris, A.P.; Assimes, T.L.; Deloukas, P.; Sun, Y.V.; Willer, C.J.; VA Million Veteran Program; Global Lipids Genetics ConsortiumIncreased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.Item The Trans-ancestral genomic architecture of glycemic traits(Nature Pub. Co., 2021) Chen, J.; Spracklen, C.N.; Marenne, G.; Varshney, A.; Corbin, L.J.; Luan, J.; Willems, S.M.; Wu, Y.; Zhang, X.; Horikoshi, M.; Boutin, T.S.; Mägi, R.; Waage, J.; Li-Gao, R.; Chan, K.H.K; Yao, J.; Anasanti, M.D.; Chu, A.Y.; Claringbould, A.; Heikkinen, J.; Hong, J.; Hottenga, J.J.; Huo, S.; Kaakinen, M.A.; Louie, T.; März, W.; Moreno-Macias, H.; Ndungu, A.; Nelson, S.C.; Nolte, I.M.; North, K.E.; Raulerson, C.K.; Ray, D.; Rohde, R.; Rybin, D.; Schurmann, C.; Sim, X.; Southam, L.; Stewart, I.D.; Wang, C.A.; Wang, Y.; Wu, P.; Zhang, W.; Ahluwalia, T.S.; Appel, E.V.R.; Bielak, L.F.; Brody, J.A.; Burtt, N.P.; Cabrera, C.P.; Cade, B.E.; Chai, J.F.; Chai, X.; Chang, L.C.; Chen, C.H.; Chen, B.H.; Chitrala, K.N.; Chiu, Y.F.; De Haan, H.G.; Delgado, G.E.; Demirkan, A.; Duan, Q.; Engmann, J.; Fatumo, S.A.; Gayán, J.; Giulianini, F.; Gong, J.H.; Gustafsson, S.; Hai, Y.; Hartwig, F.P.; He, J.; Heianza, Y.; Huang, T.; Huerta-Chagoya, A.; Hwang, M.Y.; Jensen, R.A.; Kawaguchi, T.; Kentistou, K.A.; Kim, Y.J.; Kleber, M.E.; Kooner, I.K.; Lai, S.; Lange, L.A.; Langefeld, C.D.; Lauzon, M.; Li, M.; Ligthart, S.; Liu, J.; Loh, M.; Long, J.; Lyssenko, V.; Mangino, M.; Marzi, C.; Montasser, M.E.; Nag, A.; Nakatochi, M.; Noce, D.; Noordam, R.; Pistis, G.; Preuss, M.; Raffield, L.; Rasmussen-Torvik, L.J.; Rich, S.S.; Robertson, N.R.; Rueedi, R.; Ryan, K.; Sanna, S.; Saxena, R.; Schraut, K.E.; Sennblad, B.; Setoh, K.; Smith, A.V.; Sparsø, T.; Strawbridge, R.J.; Takeuchi, F.; Tan, J.; Trompet, S.; Van den Akker, E.; Van der Most, P.J.; Verweij, N.; Vogel, M.; Wang, H.; Wang, C.; Wang, N.; Warren, H.R.; Wen, W.; Wilsgaard, T.; Wong, A.; Wood, A.R.; Xie, T.; Zafarmand, M.H.; Zhao, J.H.; Zhao, W.; Amin, N.; Arzumanyan, Z.; Astrup, A.; Bakker, S.J.L.; Baldassarre, D.; Beekman, M.; Bergman, R.N.; Bertoni, A.; Blüher, M.; Bonnycastle, L.L.; Bornstein, S.R.; Bowden, D.W.; Cai, Q.; Campbell, A.; Campbell, H.; Chang, Y.C.; de Geus, E.J.C.; Dehghan, A.; Du, S.; Eiriksdottir, G.; Farmaki, A.E.; Frånberg, M.; Fuchsberger, C.; Gao, Y.; Gjesing, A.P.; Goel, A.; Han, S.; Hartman, C.A.; Herder, C.; Hicks, A.A.; Hsieh, C.H.; Hsueh, W.A.; Ichihara, S.; Igase, M.; Ikram, M.A.; Johnson, W.C.; Jørgensen, M.E.; Joshi, P.K.; Kalyani, R.R.; Kandeel, F.R.; Katsuya, T.; Khor, C.C.; Kiess, W.; Kolcic, I.; Kuulasmaa, T.; Kuusisto, J.; Läll, K.; Lam, K.; Lawlor, D.A.; Lee, N.R.; Lemaitre, R.N.; Li, H.; Lifelines Cohort Study; Lin, S.Y.; Lindström, J.; Linneberg, A.; Liu, J.; Lorenzo, C.; Matsubara, T.; Matsuda, F.; Mingrone, G.; Mooijaart, S.; Moon, S.; Nabika, T.; Nadkarni, G.N.; Nadler, J.L.; Nelis, M.; Neville, M.J.; Norris, J.M.; Ohyagi, Y.; Peters, A.; Peyser, P.A.; Polasek, O.; Qi, Q.; Raven, D.; Reilly, D.F.; Reiner, A.; Rivideneira, F.; Roll, K.; Rudan, I.; Sabanayagam, C.; Sandow, K.; Sattar, N.; Schürmann, A.; Shi, J.; Stringham, H.M.; Taylor, K.D.; Teslovich, T.M.; Thuesen, B.; Timmers, P.R.H.J.; Tremoli, E.; Tsai, M.Y.; Uitterlinden, A.; van Dam, R.M.; van Heemst, D.; van Hylckama Vlieg, A.; van Vliet-Ostaptchouk, J.V.; Vangipurapu, J.; Vestergaard, H.; Wang, T.; Willems van Dijk, K.; Zemunik, T.; Abecasis, G.R.; Adair, L.S.; Aguilar-Salinas, C.A.; Alarcón-Riquelme, M.E.; An, P.; Aviles-Santa, L.; Becker, D.M.; Beilin, L.J.; Bergmann, S.; Bisgaard, H.; Black, C.; Boehnke, M.; Boerwinkle, E.; Böhm, B.O.; Bønnelykke, K.; Boomsma, D.I.; Bottinger, E.P.; Buchanan, T.A.; Canouil, M.; Caulfield, M.J.; Chambers, J.C.; Chasman, D.I.; Chen, Y.I.; Cheng, C.Y.; Collins, F.S.; Correa, A.; Cucca, F.; de Silva, H.J.; Dedoussis, G.; Elmståhl, S.; Evans, M.K.; Ferrannini, E.; Ferrucci, L.; Florez, J.C.; Franks, P.W.; Frayling, T.M.; Froguel, P.; Gigante, B.; Goodarzi, M.O.; Gordon-Larsen, P.; Grallert, H.; Grarup, N.; Grimsgaard, S.; Groop, L.; Gudnason, V.; Guo, X.; Hamsten, A.; Hansen, T.; Hayward, C.; Heckbert, S.R.; Horta, B.L.; Huang, W.; Ingelsson, E.; James, P.S.; Jarvelin, M.R.; Jonas, J.B.; Jukema, J.W.; Kaleebu, P.; Kaplan, R.; Kardia, S.L.R.; Kato, N.; Keinanen-Kiukaanniemi, S.M.; Kim, B.J.; Kivimaki, M.; Koistinen, H.A.; Kooner, J.S.; Körner, A.; Kovacs, P.; Kuh, D.; Kumari, M.; Kutalik, Z.; Laakso, M.; Lakka, T.A.; Launer, L.J.; Leander, K.; Li, H.; Lin, X.; Lind, L.; Lindgren, C.; Liu, S.; Loos, R.J.F.; Magnusson, P.K.E.; Mahajan, A.; Metspalu, A.; Mook-Kanamori, D.O.; Mori, T.A.; Munroe, P.B.; Njølstad, I.; O'Connell, J.R.; Oldehinkel, A.J.; Ong, K.K.; Padmanabhan, S.; Palmer, C.N.A.; Palmer, N.D.; Pedersen, O.; Pennell, C.E.; Porteous, D.J.; Pramstaller, P.P.; Province, M.A.; Psaty, B.M.; Qi, L.; Raffel, L.J.; Rauramaa, R.; Redline, S.; Ridker, P.M.; Rosendaal, F.R.; Saaristo, T.E.; Sandhu, M.; Saramies, J.; Schneiderman, N.; Schwarz, P.; Scott, L.J.; Selvin, E.; Sever, P.; Shu, X.O.; Slagboom, P.E.; Small, K.S.; Smith, B.H.; Snieder, H.; Sofer, T.; Sørensen, T.I.A.; Spector, T.D.; Stanton, A.; Steves, C.J.; Stumvoll, M.; Sun, L.; Tabara, Y.; Tai, E.S.; Timpson, N.J.; Tönjes, A.; Tuomilehto, J.; Tusie, T.; Uusitupa, M.; van der Harst, P.; van Duijn, C.; Vitart, V.; Vollenweider, P.; Vrijkotte, T.G.M.; Wagenknecht, L.E.; Walker, M.; Wang, Y.X.; Wareham, N.J.; Watanabe, R.M.; Watkins, H.; Wei, W.B.; Wickremasinghe, A.R.; Willemsen, G.; Wilson, J.F.; Wong, T.Y.; Wu, J.Y.; Xiang, A.H.; Yanek, L.R.; Yengo, L.; Yokota, M.; Zeggini, E.; Zheng, W.; Zonderman, A.B.; Rotter, J.I.; Gloyn, A.L.; McCarthy, M.I.; Dupuis, J.; Meigs, J.B.; Scott, R.A.; Prokopenko, I.; Leong, A.; Liu, C.T.; Parker, S.C.J.; Mohlke, K.L.; Langenberg, C.; Wheeler, E.; Morris, A.P.; Barroso, I.; Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) Collaborators.ABSTRACT: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.Item A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure(IRL Press at Oxford University Press., 2019) Sung, Y.J.; de Las Fuentes, L.; Winkler, T.W.; Chasman, D.I.; Bentley, A.R.; Kraja, A.T.; Ntalla, I.; Warren, H.R.; Guo, X.; Schwander, K.; Manning, A.K.; Brown, M.R.; Aschard, H.; Feitosa, M.F.; Franceschini, N.; Lu, Y.; Cheng, C.Y.; Sim, X.; Vojinovic, D.; Marten, J.; Musani, S.K.; Kilpeläinen, T.O.; Richard, M.A.; Aslibekyan, S.; Bartz, T.M.; Dorajoo, R.; Li, C.; Liu, Y.; Rankinen, T.; Smith, A.V.; Tajuddin, S.M.; Tayo, B.O.; Zhao, W.; Zhou, Y.; Matoba, N.; Sofer, T.; Alver, M.; Amini, M.; Boissel, M.; Chai, J.F.; Chen, X.; Divers, J.; Gandin, I.; Gao, C.; Giulianini, F.; Goel, A.; Harris, S.E.; Hartwig, F.P.; He, M.; Horimoto, A.R.V.R.; Hsu, F.C.; Jackson, A.U.; Kammerer, C.M.; Kasturiratne, A.; Komulainen, P.; Kühnel, B.; Leander, K.; Lee, W.J.; Lin, K.H.; Luan, J.; Lyytikäinen, L.P.; McKenzie, C.A.; Nelson, C.P.; Noordam, R.; Scott, R.A.; Sheu, W.H.H.; Stančáková, A.; Takeuchi, F.; van der Most, P.J.; Varga, T.V.; Waken, R.J.; Wang, H.; Wang, Y.; Ware, E.B.; Weiss, S.; Wen, W.; Yanek, L.R.; Zhang, W.; Zhao, J.H.; Afaq, S.; Alfred, T.; Amin, N.; Arking, D.E.; Aung, T.; Barr, R.G.; Bielak, L.F.; Boerwinkle, E.; Bottinger, E.P.; Braund, P.S.; Brody, J.A.; Broeckel, U.; Cade, B.; Campbell, A.; Canouil, M.; Chakravarti, A.; Cocca, M.; Collins, F.S.; Connell, J.M.; de Mutsert, R.; de Silva, H.J.; Dörr, M.; Duan, Q.; Eaton, C.B.; Ehret, G.; Evangelou, E.; Faul, J.D.; Forouhi, N.G.; Franco, O.H.; Friedlander, Y.; Gao, H.; Gigante, B.; Gu, C.C.; Gupta, P.; Hagenaars, S.P.; Harris, T.B.; He, J.; Heikkinen, S.; Heng, C.K.; Hofman, A.; Howard, B.V.; Hunt, S.C.; Irvin, M.R.; Jia, Y.; Katsuya, T.; Kaufman, J.; Kerrison, N.D.; Khor, C.C.; Koh, W.P.; Koistinen, H.A.; Kooperberg, C.B.; Krieger, J.E.; Kubo, M.; Kutalik, Z.; Kuusisto, J.; Lakka, T.A.; Langefeld, C.D.; Langenberg, C.; Launer, L.J.; Lee, J.H.; Lehne, B.; Levy, D.; Lewis, C.E.; Li, Y.; Lifelines Cohort Study; Lim, S.H.; Liu, C.T.; Liu, J.; Liu, J.; Liu, Y.; Loh, M.; Lohman, K.K.; Louie, T.; Mägi, R.; Matsuda, K.; Meitinger, T.; Metspalu, A.; Milani, L.; Momozawa, Y.; Mosley, T.H. Jr; Nalls, M.A.; Nasri, U.; O'Connell, J.R.; Ogunniyi, A.; Palmas, W.R.; Palmer, N.D.; Pankow, J.S.; Pedersen, N.L.; Peters, A.; Peyser, P.A.; Polasek, O.; Porteous, D.; Raitakari, O.T.; Renström, F.; Rice, T.K.; Ridker, P.M.; Robino, A.; Robinson, J.G.; Rose, L.M.; Rudan, I.; Sabanayagam, C.; Salako, B.L.; Sandow, K.; Schmidt, C.O.; Schreiner, P.J.; Scott, W.R.; Sever, P.; Sims, M.; Sitlani, C.M.; Smith, B.H.; Smith, J.A.; Snieder, H.; Starr, J.M.; Strauch, K.; Tang, H.; Taylor, K.D.; Teo, Y.Y.; Tham, Y.C.; Uitterlinden, A.G.; Waldenberger, M.; Wang, L.; Wang, Y.X.; Wei, W.B.; Wilson, G.; Wojczynski, M.K.; Xiang, Y.B.; Yao, J.; Yuan, J.M.; Zonderman, A.B.; Becker, D.M.; Boehnke, M.; Bowden, D.W.; Chambers, J.C.; Chen, Y.I.; Weir, D.R.; de Faire, U.; Deary, I.J.; Esko, T.; Farrall, M.; Forrester, T.; Freedman, B.I.; Froguel, P.; Gasparini, P.; Gieger, C.; Horta, B.L.; Hung, Y.J.; Jonas, J.B.; Kato, N.; Kooner, J.S.; Laakso, M.; Lehtimäki, T.; Liang, K.W.; Magnusson, P.K.E.; VOldehinkel, A.J.; Pereira, A.C.; Perls, T.; Rauramaa, R.; Redline, S.; Rettig, R.; Samani, N.J.; Scott, J.; Shu, X.O.; van der Harst, P.; Wagenknecht, L.E.; Wareham, N.J.; Watkins, H.; Wickremasinghe, A.R.; Wu, T.; Kamatani, Y.; Laurie, C.C.; Bouchard, C.; Cooper, R.S.; Evans, M.K.; Gudnason, V.; Hixson, J.; Kardia, S.L.R.; Kritchevsky, S.B.; Psaty, B.M.; van Dam, R.M.; Arnett, D.K.; Mook-Kanamori, D.O.; Fornage, M.; Fox, E.R.; Hayward, C.; van Duijn, C.M.; Tai, E.S.; Wong, T.Y.; Loos, R.J.F.; Reiner, A.P.; Rotimi, C.N.; Bierut, L.J.; Zhu, X.; Cupples, L.A.; Province, M.A.; Rotter, J.I.; Franks, P.W.; Rice, K.; Elliott, P.; Caulfield, M.J.; Gauderman, W.J.; Munroe, P.B.; Rao, D.C.; Morrison, A.C.ABSTRACT: Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.Item Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci(Stockton Press., 2021) de Las Fuentes, L.; Sung, Y. J.; Noordam, R.; Winkler, T.; Feitosa, M.F.; Schwander, K.; Bentley, A.R.; Brown, M.R.; Guo, X.; Manning, A.; Chasman, D.I.; Aschard, H.; Bartz, T. M.; Bielak, L.F.; Campbell, A.; Cheng, C.Y.; Dorajoo, R.; Hartwig, F. P.; Horimoto, A.R.V.R.; Li, C.; Li-Gao, R.; Liu, Y.; Marten, J.; Musani, S.K.; Ntalla, I.; Rankinen, T.; Richard, M.; Sim, X.; Smith, A.V.; Tajuddin, S.M.; Tayo, B.O.; Vojinovic, D.; Warren, H.R.; Xuan, D.; Alver, M.; Boissel, M.; Chai, J.F.; Chen, X.; Christensen, K.; Divers, J.; Evangelou, E.; Gao, C.; Girotto, G.; Harris, S.E.; He, M.; Hsu, F.C.; Kühnel, B.; Laguzzi, F.; Li, X.; Lyytikäinen, L. P.; Nolte, I. M.; Poveda, A.; Rauramaa, R.; Riaz, M.; Rueedi, R.; Shu, X.O.; Snieder, H.; Sofer, T.; Takeuchi, F.; Verweij, N.; Ware, E.B.; Weiss, S.; Yanek, L.R.; Amin, N.; Arking, D.E.; Arnett, D.K.; Bergmann, S.; Boerwinkle, E.; Brody, J.A.; Broeckel, U.; Brumat, M.; Burke, G.; Cabrera, C.P.; Canouil, M.; Chee, M.L.; Chen, Y. I.; Cocca, M.; Connell, J.; de Silva, H.J.; de Vries, P. S.; Eiriksdottir, G.; Faul, J.D.; Fisher, V.; Forrester, T.; Fox, E.F.; Friedlander, Y.; Gao, H.; Gigante, B.; Giulianini, F.; Gu, C.C.; Gu, D.; Harris, T. B.; He, J.; Heikkinen, S.; Heng, C. K.; Hunt, S.; Ikram, M. A.; Irvin, M.R.; Kähönen, M.; Kavousi, M.; Khor, C.C.; Kilpeläinen, T.O.; Koh, W.P.; Komulainen, P.; Kraja, A.T.; Krieger, J.E.; Langefeld, C. D.; Li, Y.; Liang, J.; Liewald, D.C.M.; Liu, C.T.; Liu, J.; Lohman, K.K.; Mägi, R.; McKenzie, C.A.; Meitinger, T.; Metspalu, A.; Milaneschi, Y.; Milani, L.; Mook-Kanamori, D.O.; Nalls, M.A.; Nelson, C.P.; Norris, J. M.; O'Connell, J.; Ogunniyi, A.; Padmanabhan, S.; Palmer, N.D.; Pedersen, N. L.; Perls, T.; Peters, A.; Petersmann, A.; Peyser, P. A.; Polasek, O.; Porteous, D. J.; Raffel, L. J.; Rice, T. K.; Rotter, J.I.; Rudan, I.; Rueda-Ochoa, O.L.; Sabanayagam, C.; Salako, B. L.; Schreiner, P.J.; Shikany, J.M.; Sidney, S.S.; Sims, M.; Sitlani, C.M.; Smith, J. A.; Starr, J. M.; Strauch, K.; Swertz, M. A.; Teumer, A.; Tham, Y. C.; Uitterlinden, A.G.; Vaidya, D.; van der Ende, M.Y.; Waldenberger, M.; Wang, L.; Wang, Y. X.; Wei, W.B.; Weir, D.R.; Wen, W.; Yao, J.; Yu, B.; Yu, C.; Yuan, J. M.; Zhao, W.; Zonderman, A.B.; Becker, D.M.; Bowden, D.W.; Deary, I. J.; Dörr, M.; Esko, T.; Freedman, B. I.; Froguel, P.; Gasparini, P.; Gieger, C.; Jonas, J.B.; Kammerer, C.M.; Kato, N.; Lakka, T. A.; Leander, K.; Lehtimäki, T.; Lifelines Cohort Study; Magnusson, P. K. E.; Marques-Vidal, P.; Penninx, B. W. J. H.; Samani, N. J.; van der Harst, P.; Wagenknecht, L. E.; Wu, T.; Zheng, W.; Zhu, X.; Bouchard, C.; Cooper, R. S.; Correa, A.; Evans, M. K.; Gudnason, V.; Hayward, C.; Horta, B. L.; Kelly, T. N.; Kritchevsky, S. B.; Levy, D.; Palmas, W. R.; Pereira, A. C.; Province, M. M.; Psaty, B. M.; Ridker, P. M.; Rotimi, C. N.; Tai, E. S.; van Dam, R. M.; van Duijn, C. M.; Wong, T. Y.; Rice, K.; Gauderman, W. J.; Morrison, A. C.; North, K. E.; Kardia, S. L. R.; Caulfield, M. J.; Elliott, P.; Munroe, P. B.; Franks, P. W.; Rao, D. C.; Fornage, M.ABSTRACT:Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.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.