Browsing by Author "Lee, J."

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Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs
(Hacettepe Medical Center, 2023) Lee, J.; Millington, P.; Dayasiri, K.; Ramdas, S.; Jayawant, S.; Anand, G.
BACKGROUND: Spinal muscular atrophy with lower extremity predominance (SMA-LED) is an autosomal dominant disorder. Since SMA-LED affects lower motor neurons, the disease is characterized by weakness and atrophy of lower limb muscles. We present a familial case series of SMA-LED with upper motor neuron signs associated with a rare variant in DYNC1H1. CASE: The index case was referred to Pediatric Neurology at the age of two and half years, due to delayed mobility. The child was diagnosed with congenital vertical talus at birth, which was managed with serial bilateral casting and surgery. The delayed mobility was initially attributed to lower limb weakness secondary to prolonged periods of immobilization from casting of his lower limbs. He had a striking waddling gait and proximal muscle weakness on neurological assessment. He had lower motor neuron signs predominantly in his lower limbs that were in keeping with SMA-LED. Surprisingly, he also demonstrated a brisk crossed adductor response that was not in keeping with an isolated primary neuro-muscular disorder and suggested a mixed upper and lower motor neuron pathology. The inherited neuropathy gene panel revealed a heterozygous sequence change in the DYNC1H1 gene which was present in all affected family members. CONCLUSIONS: We present the first report of a familial case series of SMA-LED with upper motor neuron signs associated with an extremely rare variant in DYNC1H1: c.1808A > T (p.Glu603Val). As per the American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, we would recommend that this variant be reclassified as `Likely Pathogenic` due to matching 1 moderate (PM1-PM6) and ≥4 supporting (PP1-PP5) criteria in the reported case series.
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.
Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
(Nature Publishing Company, New York, 2022) Mahajan, A.; Spracklen, C.N.; Zhang, W.; Ng, M.C.Y.; Petty, L.E.; Kitajima, H.; Yu, G.Z.; Rüeger, S.; Speidel, L.; Kim, Y.J.; Horikoshi, M.; Mercader, J.M .; Taliun, D.; Moon, S.; Kwak, S.H.; Robertson, N.R.; Rayner, N.W.; Loh, M.; Kim, B.; Chiou, J.; Miguel-Escalada, I.; Parolo, P.D.B.; Lin, K.; Bragg, F.; Preuss, M.H.; Takeuchi, F.; Nano, J.; Guo, X.; Lamri, A.; Nakatoch, M.; Scott, R.A.; Lee, J.J.; Huerta-Chagoya, A.; Graff, M.; Chai, J.F.; Parra, E. J.; Yao, J.; Bielak, L.F.; Tabara, Y.; Hai, Y.; Steinthorsdottir, V.; Cook, J.P.; Kals, M.; Grarup, N.; Schmidt, E.M.; Pan, I.; Sofer, T.; Wuttke, M.; Sarnowski, C.; Gieger, C.; Nousome, D.; Trompet, S.; Long, J.; Sun, M.; Tong, L.; Chen, W.M.; Ahmad, M.; Noordam, R.; Lim, V.J.Y.; Tam, C.H.T.; Joo, Y.Y.; Chen, C.H.; Raffield, L.M.; Lecoeur, C.; Prins, B.P.; Nicolas, A.; Yanek, L.R.; Chen, G.; Jensen, R.A.; Tajuddin, S.; Kabagambe, E.K.; An, P.; Xiang, A.H.; Choi, H.S.; Cade, B.E.; Tan, J.; Flanagan, J.; Abaitua, F.; Adair, L.S.; Adeyemo, A.; Aguilar-Salinas, C.A.; Akiyama, M.; Anand, S.S.; Bertoni, A.; Bian, Z.; Bork-Jensen, J.; Brandslund, I.; Brody, J.A.; Brummett, C.M.; Buchanan, T.A.; 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.; 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.; Fornage, M.; Franco, O.H.; Frayling, T.M.; Freedman, B.I.; Fuchsberger, C.; Genter, P.; Gerstein, H.C.; Giedraitis, V.; Villalpando, C.G.; Villalpando, M.E.G.; Goodarzi, M.O.; Larsen, P.G.; Gorkin, D.; Gross, M.; Guo, Y.; Hackinger, S.; Han, S.; Hattersley, A.T.; Herder, C.; Howard, A.G.; 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.M.; Jasmine, F.; Jiang, G.; Jonas, J.B.; Jørgensen, M.E.; Jørgensen, T.; Kamatani, Y.; Kandeel, F.R.; Kasturiratne, A.; Katsuya, T.; Kaur, V.; Kawaguchi, T.; Keaton, J.M.; Kho, A.N.; Khor, C.C.; Kibriya, M.G.; Kim, D.H.; Kohara, K.; Kriebel, J.; Kronenberg, F.; Kuusisto, J.; Läll, K.; Lange, L.A.; 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.; Lyssenko, V.; Mamakou, V.; Mani, K.R.; Meitinger, T.; Metspalu, A.; Morris, A.D.; Nadkarni, G.N.; Nadler, J.L.; Nalls, M.A.; Nayak, U.; Nongmaithem, S.S.; Ntalla, I.; Okada, Y.; Orozco, L.; Patel, S.R.; Pereira, M.A.; Peters, A.; Pirie, F.J.; Porneala, B.; Prasad, G.; Preissl, S.; Rasmussen-Torvik, L.J.; Reiner, A.P.; Roden, M.; Rohde, R.; Roll, K.; Sabanayagam, C.; Sander, M.; Sandow, K.; Sattar, N.; Schönherr, S.; Schurmann, C.; Shahriar, M.; Shi, J.; Shin, D.M.; Shriner, D.; Smith, J.A.; So, W.Y.; Stančáková, A.; Stilp, A.M.; Strauch, K.; Suzuki, K.; Takahashi, A.; Taylor, K.D.; Thorand, B.; Thorleifsson, G.; Thorsteinsdottir, U.; Tomlinson, B.; Torres, J.M.; Tsai, F.; Tuomilehto, J.; Tusie-Luna, T.; Udler, M.S.; Salgado, A.V.; Dam, R.M.; Klinken, J.B.; Varma, R.; Vujkovic, M.; Wacher-Rodarte, N.; Wheeler, E.; Whitsel, E.A.; Wickremasinghe, A.R.; Dijk, K.W.; Witte, D.R.; Yajnik, C.S; Yamamoto, K.; Yamauchi, T.; Yengo, L.; Yoon, K.; Yu, C.; Yuan, J.M.; Yusuf, S.; Zhang, L.; Zheng, W.; FinnGen; eMERGE Consortium; Leslie J Raffel; Igase, M.; Ipp, E.; Redline, S.; Cho, Y.S.; Lind, L.; Province, M.A.; Hanis, C.L.; Peyser, P.A.; Ingelsson, E.; Zonderman, A.B.; Psaty, B.M.; Wang, Y.; Rotimi, C.N.; Becker, D.M.; Matsuda, F.; Liu, Y.; Zeggini, E.; Yokota, M.; Rich, S.S.; Kooperberg, C.; Pankow, J.S.; Engert, J.C.; Chen, Y.I.; Froguel, P.; Wilson, J.G.; Sheu, W.H.H.; Kardia, S.L.R.; Wu, J.Y.; Hayes, M.G.; Ma, R.C.W.; Wong, T.Y.; Groop, L.; Mook-Kanamori, D.O.; Chandak, G.R.; Collins, F.S.; Bharadwaj, D.; Paré, G.; Sale, M.M.; Ahsan, H.; Motala, A.A.; Shu, X.O.; Park, K.S.; Jukema, J.W.; Cruz, M.; Cowdin, R.M.; Grallert, H.; Cheng, C.Y.; Bottinger, E.P.; Dehghan, A.; Tai, E.S.; Dupuis, J.; Kato, N.; Laakso, M.; Köttgen, A.; Koh, W.P.; Palmer, C.N.A.; Liu, S.; Abecasis, G.; Kooner, J.S.; Loos, R.J.F.; North, K.E.; Haiman, C.A.; Florez, J.C.; Saleheen, D.; Hansen, T.; Pedersen, O.; Mägi, R.; Langenberg, C.; Wareham, N.J.; Maeda, S.; Kadowaki, T.; Lee, J.; Millwood, I.Y.; Walters, R.G.; Stefansson, K.; Myers, S.R.; Ferrer, J.; Gaulton, K.J.; Meigs, J.B.; Mohlke, K.L.; Gloyn, A.L.; Bowden, D.W.; Below, J.E.; Chambers, J.C.; Sim, X.; Boehnke, M.; Rotter, J.I.; McCarthy, M.I.; Morris, A.P.
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
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 Consortium
Increased 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.
Reference equations for evaluation of spirometry function tests in South Asia, and amongst south asians living in other countries
(European Respiratory Society, 2022) Leong, W.Y.; Gupta, A.; Hasan, M.; Mahmood, S.; Siddiqui, S.; Ahmed, S.; Goon, I.Y.; Loh, M.; Mina, T.H.; Lam, B.; Yew, Y.W.; Ngeow, J.; Lee, J.; Lee, E.S.; Riboli, E.; Elliott, P.; Tan, G.P.; Chotirmall, S.H.; Wickremasinghe, A.R.; Kooner, J.S.; Khawaja, K.I.; Katulanda, P.; Mridha, M.K.; Jha, S.; Ranjit, M.A.; Pradeepa, G.; Kasturiratne, A.; Chambers, J.C.
Background: There is little data to accurate interpretation of spirometry data in South Asia, a major global region with high reported burden for chronic respiratory disease. Method: We measured lung function in 7,453 healthy men and women aged over 18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. We first assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio. We then used our data to derive (N=5589) and internally validate (N=1864) new prediction equations amongst South Asians, with further external validation amongst 339 healthy South Asians living in Singapore. Results: GLI2012 and NHANESIII consistently overestimated expiratory volumes (best fit GLI-African American, mean [sd] z-score (n=7453): FEV1 -0.94 [1.05]; FVC -0.91 [1.10]). Age, height and weight were strong predictors of lung function in our participants (p<0.001), and sex specific reference equations using these three variables were highly accurate in both internal validation (z-scores: FEV1 0.03 [0.99]; FVC 0.04 [0.97]; FEV1/FVC -0.03 [0.99]) and external validation (z-scores: FEV1 0.31 [0.99]; FVC 0.24 [0.97]; FEV1/FVC 0.16 [0.91]). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region specific lung function in South Asia. Conclusion: We present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
(Nature Publishing Company, 2015) Kato, N.; Loh, M.; Takeuchi, F.; Verweij, N.; Wang, X.; Zhang, W.; Kelly, T.N.; Saleheen, D.; Lehne, B.; Leach, I.M.; Drong, A.W.; Abbott, J.; Wahl, S.; Tan, S.T.; Scott, W.R.; Campanella, G.; Chadeau-Hyam, M.; Afzal, U.; Ahluwalia, T.S.; Bonder, M.J.; Chen, P.; Dehghan, A.; Edwards, T.L.; Esko, T.; Go, M.J.; Harris, S.E.; Hartiala, J.; Kasela, S.; Kasturiratne, A.; Khor, C.C.; Kleber, M.E.; Li, H.; Mok, Z.Y.; Nakatochi, M.; Sapari, N.S.; Saxena, R.; Stewart, A.F.; Stolk, L.; Tabara, Y.; Teh, A.L.; Wu, Y.; Wu, J.Y.; Zhang, Y.; Aits, I.; Da Silva Couto Alves, A.; Das, S.; Dorajoo, R.; Hopewell, J.C.; Kim, Y.K.; Koivula, R.W.; Luan, J.; Lyytikäinen, L.P.; Nguyen, Q.N.; Pereira, M.A.; Postmus, I.; Raitakari, O.T.; Bryan, M.S.; Scott, R.A.; Sorice, R.; Tragante, V.; Traglia, M.; White, J.; Yamamoto, K.; Zhang, Y.; Adair, L.S.; Ahmed, A.; Akiyama, K.; Asif, R.; Aung, T.; Barroso, I.; Bjonnes, A.; Braun, T.R.; Cai, H.; Chang, L.C.; Chen, C.H.; Cheng, C.Y.; Chong, Y.S.; Collins, R.; Courtney, R.; Davies, G.; Delgado, G.; Do, L.D.; Doevendans, P.A.; Gansevoort, R.T.; Gao, Y.T.; Grammer, T.B.; Grarup, N.; Grewal, J.; Gu, D.; Wander, G.S.; Hartikainen, A.L.; Hazen, S.L.; He, J.; Heng, C.K.; Hixson, J.E.; Hofman, A.; Hsu, C.; Huang, W.; Husemoen, L.L.; Hwang, J.Y.; Ichihara, S.; Igase, M.; Isono, M.; Justesen, J.M.; Katsuya, T.; Kibriya, M.G.; Kim, Y.J.; Kishimoto, M.; Koh, W.P.; Kohara, K.; Kumari, M.; Kwek, K.; Lee, N.R.; Lee, J.; Liao, J.; Lieb, W.; Liewald, D.C.; Matsubara, T.; Matsushita, Y.; Meitinger, T.; Mihailov, E.; Milani, L.; Mills, R.; Mononen, N.; Müller-Nurasyid, M.; Nabika, T.; Nakashima, E.; Ng, H.K.; Nikus, K.; Nutile, T.; Ohkubo, T.; Ohnaka, K.; Parish, S.; Paternoster, L.; Peng, H.; Peters, A.; Pham, S.T.; Pinidiyapathirage, M.J.; Rahman, M.; Rakugi, H.; Rolandsson, O.; Rozario, M.A.; Ruggiero, D.; Sala, C.F.; Sarju, R.; Shimokawa, K.; Snieder, H.; Sparso, T.; Spiering, W.; Starr, J.M.; Stott, D.J.; Stram, D.O.; Sugiyama, T.; Szymczak, S.; Tang, W.H.; Tong, L.; Trompet, S.; Turjanmaa, V.; Ueshima, H.; Uitterlinden, A.G.; Umemura, S.; Vaarasmaki, M.; van Dam, R.M.; van Gilst, W.H.; van Veldhuisen, D.J.; Viikari, J.S.; Waldenberger, M.; Wang, Y.; Wang, A.; Wilson, R.; Wong, T.Y.; Xiang, Y.B.; Yamaguchi, S.; Ye, X.; Young, R.D.; Young, T.L.; Yuan, J.M.; Zhou, X.; Asselbergs, F.W.; Ciullo, M.; Clarke, R.; Deloukas, P.; Franke, A.; Franks, P.W.; Franks, S.; Friedlander, Y.; Gross, M.D.; Guo, Z.; Hansen, T.; Jarvelin, M.R.; Jorgensen, T.; Jukema, J.W.; Kähönen, M.; Kajio, H.; Kivimaki, M.; Lee, J.Y.; Lehtimäki, T.; Linneberg, A.; Miki, T.; Pedersen, O.; Samani, N.J.; Sorensen, T.I.; Takayanagi, R.; Toniolo, D.; BIOS-consortium; CARDIo GRAMplusCD; LifeLines Cohort Study; InterAct Consortium; Ahsan, H.; Allayee, H.; Chen, Y.T.; Danesh, J.; Deary, I.J.; Franco, O.H.; Franke, L.; Heijman, B.T.; Holbrook, J.D.; Isaacs, A.; Kim, B.J.; Lin, X.; Liu, J.; März, W.; Metspalu, A.; Mohlke, K.L.; Sanghera, D.K.; Shu, X.O.; van Meurs, J.B.; Vithana, E.; Wickremasinghe, A.R.; Wijmenga, C.; Wolffenbuttel, B.H.; Yokota, M.; Zheng, W.; Zhu, D.; Vineis, P.; Kyrtopoulos, S.A.; Kleinjans, J.C.; McCarthy, M.I.; Soong, R.; Gieger, C.; Scott, J.; Teo, Y.Y.; He, J.; Elliott, P.; Tai, E.S.; van der Harst, P.; Kooner, J.S.; Chambers, J.C.
We carried out a trans-ancestry genome-wide association and replication study of blood pressurephenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNAmethylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNAmethylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.