Browsing by Author "Ramdas, S."

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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.
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.
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.
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.