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Hindy G, Dornbos P, Chaffin MD, et al. Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. Am J Hum Genet. 2021;109(1):81-96doi: 10.1016/j.ajhg.2021.11.021.
Hindy, G., Dornbos, P., Chaffin, M. D., Liu, D. J., Wang, M., Selvaraj, M. S., Zhang, D., Park, J., Aguilar-Salinas, C. A., Antonacci-Fulton, L., Ardissino, D., Arnett, D. K., Aslibekyan, S., Atzmon, G., Ballantyne, C. M., Barajas-Olmos, F., Barzilai, N., Becker, L. C., Bielak, L. F., Bis, J. C., Blangero, J., Boerwinkle, E., Bonnycastle, L. L., Bottinger, E., Bowden, D. W., Bown, M. J., Brody, J. A., Broome, J. G., Burtt, N. P., Cade, B. E., Centeno-Cruz, F., Chan, E., Chang, Y. C., Chen, Y. I., Cheng, C. Y., Choi, W. J., Chowdhury, R., Contreras-Cubas, C., Córdova, E. J., Correa, A., Cupples, L. A., Curran, J. E., Danesh, J., de Vries, P. S., DeFronzo, R. A., Doddapaneni, H., Duggirala, R., Dutcher, S. K., Ellinor, P. T., Emery, L. S., Florez, J. C., Fornage, M., Freedman, B. I., Fuster, V., Garay-Sevilla, M. E., García-Ortiz, H., Germer, S., Gibbs, R. A., Gieger, C., Glaser, B., Gonzalez, C., Gonzalez-Villalpando, M. E., Graff, M., Graham, S. E., Grarup, N., Groop, L. C., Guo, X., Gupta, N., Han, S., Hanis, C. L., Hansen, T., He, J., Heard-Costa, N. L., Hung, Y. J., Hwang, M. Y., Irvin, M. R., Islas-Andrade, S., Jarvik, G. P., Kang, H. M., Kardia, S. L. R., Kelly, T., Kenny, E. E., Khan, A. T., Kim, B. J., Kim, R. W., Kim, Y. J., Koistinen, H. A., Kooperberg, C., Kuusisto, J., Kwak, S. H., Laakso, M., Lange, L. A., Lee, J., Lee, J., Lee, S., Lehman, D. M., Lemaitre, R. N., Linneberg, A., Liu, J., Loos, R. J. F., Lubitz, S. A., Lyssenko, V., Ma, R. C. W., Martin, L. W., Martínez-Hernández, A., Mathias, R. A., McGarvey, S. T., McPherson, R., Meigs, J. B., Meitinger, T., Melander, O., Mendoza-Caamal, E., Metcalf, G. A., Mi, X., Mohlke, K. L., Montasser, M. E., Moon, J. Y., Moreno-Macías, H., Morrison, A. C., Muzny, D. M., Nelson, S. C., Nilsson, P. M., O'Connell, J. R., Orho-Melander, M., Orozco, L., Palmer, C. N. A., Palmer, N. D., Park, C. J., Park, K. S., Pedersen, O., Peralta, J. M., Peyser, P. A., Post, W. S., Preuss, M., Psaty, B. M., Qi, Q., Rao, D. C., Redline, S., Reiner, A. P., Revilla-Monsalve, C., Rich, S. S., Samani, N., Schunkert, H., Schurmann, C., Seo, D., Seo, J. S., Sim, X., Sladek, R., Small, K. S., So, W. Y., Stilp, A. M., Tai, E. S., Tam, C. H. T., Taylor, K. D., Teo, Y. Y., Thameem, F., Tomlinson, B., Tsai, M. Y., Tuomi, T., Tuomilehto, J., Tusié-Luna, T., Udler, M. S., van Dam, R. M., Vasan, R. S., Viaud Martinez, K. A., Wang, F. F., Wang, X., Watkins, H., Weeks, D. E., Wilson, J. G., Witte, D. R., Wong, T. Y., Yanek, L. R., Kathiresan, S., Rader, D. J., Rotter, J. I., Boehnke, M., McCarthy, M. I., Willer, C. J., Natarajan, P., Flannick, J. A., Khera, A. V., & Peloso, G. M. (2022). Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. American journal of human genetics, 109(1), 81-96. https://doi.org/10.1016/j.ajhg.2021.11.021
Hindy, George, et al. "Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes." American journal of human genetics vol. 109,1 (2022): 81-96. doi: https://doi.org/10.1016/j.ajhg.2021.11.021
Hindy G, Dornbos P, Chaffin MD, Liu DJ, Wang M, Selvaraj MS, Zhang D, Park J, Aguilar-Salinas CA, Antonacci-Fulton L, Ardissino D, Arnett DK, Aslibekyan S, Atzmon G, Ballantyne CM, Barajas-Olmos F, Barzilai N, Becker LC, Bielak LF, Bis JC, Blangero J, Boerwinkle E, Bonnycastle LL, Bottinger E, Bowden DW, Bown MJ, Brody JA, Broome JG, Burtt NP, Cade BE, Centeno-Cruz F, Chan E, Chang YC, Chen YI, Cheng CY, Choi WJ, Chowdhury R, Contreras-Cubas C, Córdova EJ, Correa A, Cupples LA, Curran JE, Danesh J, de Vries PS, DeFronzo RA, Doddapaneni H, Duggirala R, Dutcher SK, Ellinor PT, Emery LS, Florez JC, Fornage M, Freedman BI, Fuster V, Garay-Sevilla ME, García-Ortiz H, Germer S, Gibbs RA, Gieger C, Glaser B, Gonzalez C, Gonzalez-Villalpando ME, Graff M, Graham SE, Grarup N, Groop LC, Guo X, Gupta N, Han S, Hanis CL, Hansen T, He J, Heard-Costa NL, Hung YJ, Hwang MY, Irvin MR, Islas-Andrade S, Jarvik GP, Kang HM, Kardia SLR, Kelly T, Kenny EE, Khan AT, Kim BJ, Kim RW, Kim YJ, Koistinen HA, Kooperberg C, Kuusisto J, Kwak SH, Laakso M, Lange LA, Lee J, Lee J, Lee S, Lehman DM, Lemaitre RN, Linneberg A, Liu J, Loos RJF, Lubitz SA, Lyssenko V, Ma RCW, Martin LW, Martínez-Hernández A, Mathias RA, McGarvey ST, McPherson R, Meigs JB, Meitinger T, Melander O, Mendoza-Caamal E, Metcalf GA, Mi X, Mohlke KL, Montasser ME, Moon JY, Moreno-Macías H, Morrison AC, Muzny DM, Nelson SC, Nilsson PM, O'Connell JR, Orho-Melander M, Orozco L, Palmer CNA, Palmer ND, Park CJ, Park KS, Pedersen O, Peralta JM, Peyser PA, Post WS, Preuss M, Psaty BM, Qi Q, Rao DC, Redline S, Reiner AP, Revilla-Monsalve C, Rich SS, Samani N, Schunkert H, Schurmann C, Seo D, Seo JS, Sim X, Sladek R, Small KS, So WY, Stilp AM, Tai ES, Tam CHT, Taylor KD, Teo YY, Thameem F, Tomlinson B, Tsai MY, Tuomi T, Tuomilehto J, Tusié-Luna T, Udler MS, van Dam RM, Vasan RS, Viaud Martinez KA, Wang FF, Wang X, Watkins H, Weeks DE, Wilson JG, Witte DR, Wong TY, Yanek LR, Kathiresan S, Rader DJ, Rotter JI, Boehnke M, McCarthy MI, Willer CJ, Natarajan P, Flannick JA, Khera AV, Peloso GM. Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. Am J Hum Genet. 2022 Jan 06;109(1):81-96. doi: 10.1016/j.ajhg.2021.11.021. Epub 2021 Dec 20. PMID: 34932938.
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Am J Hum Genet. 2022 Jan 06;109(1):81-96. doi: 10.1016/j.ajhg.2021.11.021. Epub 2021 Dec 20.

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.

American journal of human genetics

George Hindy, Peter Dornbos, Mark D Chaffin, Dajiang J Liu, Minxian Wang, Margaret Sunitha Selvaraj, David Zhang, Joseph Park, Carlos A Aguilar-Salinas, Lucinda Antonacci-Fulton, Diego Ardissino, Donna K Arnett, Stella Aslibekyan, Gil Atzmon, Christie M Ballantyne, Francisco Barajas-Olmos, Nir Barzilai, Lewis C Becker, Lawrence F Bielak, Joshua C Bis, John Blangero, Eric Boerwinkle, Lori L Bonnycastle, Erwin Bottinger, Donald W Bowden, Matthew J Bown, Jennifer A Brody, Jai G Broome, Noël P Burtt, Brian E Cade, Federico Centeno-Cruz, Edmund Chan, Yi-Cheng Chang, Yii-Der I Chen, Ching-Yu Cheng, Won Jung Choi, Rajiv Chowdhury, Cecilia Contreras-Cubas, Emilio J Córdova, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, John Danesh, Paul S de Vries, Ralph A DeFronzo, Harsha Doddapaneni, Ravindranath Duggirala, Susan K Dutcher, Patrick T Ellinor, Leslie S Emery, Jose C Florez, Myriam Fornage, Barry I Freedman, Valentin Fuster, Ma Eugenia Garay-Sevilla, Humberto García-Ortiz, Soren Germer, Richard A Gibbs, Christian Gieger, Benjamin Glaser, Clicerio Gonzalez, Maria Elena Gonzalez-Villalpando, Mariaelisa Graff, Sarah E Graham, Niels Grarup, Leif C Groop, Xiuqing Guo, Namrata Gupta, Sohee Han, Craig L Hanis, Torben Hansen, Jiang He, Nancy L Heard-Costa, Yi-Jen Hung, Mi Yeong Hwang, Marguerite R Irvin, Sergio Islas-Andrade, Gail P Jarvik, Hyun Min Kang, Sharon L R Kardia, Tanika Kelly, Eimear E Kenny, Alyna T Khan, Bong-Jo Kim, Ryan W Kim, Young Jin Kim, Heikki A Koistinen, Charles Kooperberg, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Leslie A Lange, Jiwon Lee, Juyoung Lee, Seonwook Lee, Donna M Lehman, Rozenn N Lemaitre, Allan Linneberg, Jianjun Liu, Ruth J F Loos, Steven A Lubitz, Valeriya Lyssenko, Ronald C W Ma, Lisa Warsinger Martin, Angélica Martínez-Hernández, Rasika A Mathias, Stephen T McGarvey, Ruth McPherson, James B Meigs, Thomas Meitinger, Olle Melander, Elvia Mendoza-Caamal, Ginger A Metcalf, Xuenan Mi, Karen L Mohlke, May E Montasser, Jee-Young Moon, Hortensia Moreno-Macías, Alanna C Morrison, Donna M Muzny, Sarah C Nelson, Peter M Nilsson, Jeffrey R O'Connell, Marju Orho-Melander, Lorena Orozco, Colin N A Palmer, Nicholette D Palmer, Cheol Joo Park, Kyong Soo Park, Oluf Pedersen, Juan M Peralta, Patricia A Peyser, Wendy S Post, Michael Preuss, Bruce M Psaty, Qibin Qi, D C Rao, Susan Redline, Alexander P Reiner, Cristina Revilla-Monsalve, Stephen S Rich, Nilesh Samani, Heribert Schunkert, Claudia Schurmann, Daekwan Seo, Jeong-Sun Seo, Xueling Sim, Rob Sladek, Kerrin S Small, Wing Yee So, Adrienne M Stilp, E Shyong Tai, Claudia H T Tam, Kent D Taylor, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Michael Y Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Miriam S Udler, Rob M van Dam, Ramachandran S Vasan, Karine A Viaud Martinez, Fei Fei Wang, Xuzhi Wang, Hugh Watkins, Daniel E Weeks, James G Wilson, Daniel R Witte, Tien-Yin Wong, Lisa R Yanek, Sekar Kathiresan, Daniel J Rader, Jerome I Rotter, Michael Boehnke, Mark I McCarthy, Cristen J Willer, Pradeep Natarajan, Jason A Flannick, Amit V Khera, Gina M Peloso

Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.
  2. Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
  3. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  4. Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA.
  5. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  6. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  7. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  8. Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico.
  9. Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA; The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
  10. ASTC: Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy; Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Universitˆ, degli Studi di Parma, Parma, Italy.
  11. Dean's Office, College of Public Health, University of Kentucky, Lexington, KY 40536, USA.
  12. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  13. Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; University of Haifa, Faculty of Natural Science, Haifa, Israel.
  14. Houston Methodist Debakey Heart and Vascular Center, Houston, TX 77030, USA; Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX 77030, USA.
  15. Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  16. Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  17. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  18. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 49109, USA.
  19. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
  20. Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
  21. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  22. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  23. Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Digital Health Center, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany.
  24. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  25. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
  26. Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
  27. Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
  28. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA.
  29. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore.
  30. Institute of Biomedical Sciences, Academia Sinica, Taiwan.
  31. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  32. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
  33. Psomagen, Inc. (formerly Macrogen USA), 1330 Piccard Drive Ste 103, Rockville, MD 20850, USA.
  34. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Centre for Non-Communicable Disease Research, Bangladesh.
  35. Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
  36. Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; NHLBI Framingham Heart Study, Framingham, MA 01702, USA.
  37. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; The National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics at the University of Cambridge, Cambridge, UK.
  38. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  39. Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
  40. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  41. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  42. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  43. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 770030, USA.
  44. Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  45. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
  46. Department of Medical Science, Division of Health Science, University of Guanajuato, Guanajuanto, Mexico.
  47. New York Genome Center, New York, NY 10013, USA.
  48. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  49. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
  50. Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  51. Unidad de Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Pœblica, Cuernavaca, Morelos, Mexico.
  52. Centro de Estudios en Diabetes, Mexico City, Mexico.
  53. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
  54. Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  55. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  56. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Finnish Institute for Molecular Genetics, University of Helsinki, Helsinki, Finland.
  57. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  58. Division of Genome Science, Department of Precision Medicine, Chungcheongbuk-do, Republic of Korea.
  59. Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  60. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
  61. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Tulane University Translational Science Institute, New Orleans, LA 70112, USA.
  62. NHLBI Framingham Heart Study, Framingham, MA 01702, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
  63. Division of Endocrine and Metabolism, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan.
  64. Department of Epidemiology, School of Public Health, UAB, Birmingham, AL 35294, USA.
  65. Dirección de Investigación, Hospital General de México "Dr. Eduardo Liceaga," Secretaría de Salud, Mexico City, Mexico.
  66. Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA 98195, USA.
  67. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  68. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
  69. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  70. Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; University of Helsinki and Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
  71. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98103, USA.
  72. Institute of Clinical Medicine, University of Eastern Finland, and Kuopio University Hospital, Kuopio, Finland.
  73. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
  74. Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
  75. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
  76. Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  77. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
  78. Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  79. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; University of Bergen, Bergen, Norway.
  80. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  81. Division of Cardiology, Department of Medicine, George Washington University, Washington, DC 20037, USA.
  82. Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI 02912, USA.
  83. Ruddy Canadian Cardiovascuar Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.
  84. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; General Medicine Division, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  85. Deutsches Forschungszentrum fŸr Herz-Kreislauferkrankungen, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
  86. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Department of Emergency and Internal Medicine, SkŒne University Hospital, Malmö, Sweden.
  87. Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
  88. University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Baltimore, MD 21201, USA.
  89. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  90. Universidad Autónoma Metropolitana, Mexico City, Mexico.
  91. Department of Clinical Sciences, Lund University, Malmö, Sweden.
  92. Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
  93. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
  94. Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
  95. Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  96. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98101, USA.
  97. Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63108, USA.
  98. University of Washington, Seattle, WA 98101, USA.
  99. Instituto Mexicano del Seguro Social SXXI, Mexico City, Mexico.
  100. Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
  101. Deutsches Herzzentrum München, Technische UniversitŠt München, Deutsches Zentrum fŸr Herz-Kreislauf-Forschung, München, Germany.
  102. Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Digital Health Center, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany; Charles R. Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  103. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
  104. Department of Human Genetics, McGill University, Montreal, QC, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
  105. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
  106. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Duke-NUS Medical School Singapore, Singapore.
  107. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore.
  108. Department of Biochemistry, Faculty of Medicine, Health Science Center, Kuwait University, Safat, Kuwait.
  109. Faculty of Medicine, Macau University of Science & Technology, Macau, China.
  110. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  111. Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
  112. Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
  113. Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico; Departamento de Medicina Genómica y Toxicología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México/ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  114. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  115. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
  116. NHLBI Framingham Heart Study, Framingham, MA 01702, USA; Departments of Medicine & Epidemiology, Boston University Schools of Medicine & Public Health, Boston, MA 02118, USA.
  117. Illumina Laboratory Services, Illumina Inc., San Diego, CA 92122, USA.
  118. Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
  119. Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  120. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  121. Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  122. Department of Public Health, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus, Denmark.
  123. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Verve Therapeutics, Cambridge, MA 02139, USA.
  124. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  125. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  126. Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  127. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  128. Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. Electronic address: [email protected].

PMID: 34932938 DOI: 10.1016/j.ajhg.2021.11.021

Abstract

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

Copyright © 2021 American Society of Human Genetics. All rights reserved.

Keywords: association; cholesterol; exome sequencing; gene-based association; lipid

Conflict of interest statement

Declaration of interests The authors declare no competing interests for the present work. P.N. reports investigator-initiated grants from Amgen, Apple, and Boston Scientific; is a scientific advisor t

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