Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Gina M Peloso; Paul L Auer; Joshua C Bis; Arend Voorman; Alanna C Morrison; Nathan O Stitziel; Jennifer A Brody; Sumeet A Khetarpal; Jacy R Crosby; Myriam Fornage; Aaron Isaacs; Johanna Jakobsdottir; Mary F Feitosa; Gail Davies; Jennifer E Huffman; Ani Manichaikul; Brian Davis; Kurt Lohman; Aron Y Joon; Albert V Smith; Megan L Grove; Paolo Zanoni; Valeska Redon; Serkalem Demissie; Kim Lawson; Ulrike Peters; Christopher Carlson; Rebecca D Jackson; Kelli K Ryckman; Rachel H Mackey; Jennifer G Robinson; David S Siscovick; Pamela J Schreiner; Josyf C Mychaleckyj; James S Pankow; Albert Hofman; Andre G Uitterlinden; Tamara B Harris; Kent D Taylor; Jeanette M Stafford; Lindsay M Reynolds; Riccardo E Marioni; Abbas Dehghan; Oscar H Franco; Aniruddh P Patel; Yingchang Lu; George Hindy; Omri Gottesman; Erwin P Bottinger; Olle Melander; Marju Orho-Melander; Ruth J F Loos; Stefano Duga; Piera Angelica Merlini; Martin Farrall; Anuj Goel; Rosanna Asselta; Domenico Girelli; Nicola Martinelli; Svati H Shah; William E Kraus; Mingyao Li; Daniel J Rader; Muredach P Reilly; Ruth McPherson; Hugh Watkins; Diego Ardissino; NHLBI GO Exome Sequencing Project; Qunyuan Zhang; Judy Wang; Michael Y Tsai; Herman A Taylor; Adolfo Correa; Michael E Griswold; Leslie A Lange; John M Starr; Igor Rudan; Gudny Eiriksdottir; Lenore J Launer; Jose M Ordovas; Daniel Levy; Y-D Ida Chen; Alexander P Reiner; Caroline Hayward; Ozren Polasek; Ian J Deary; Ingrid B Borecki; Yongmei Liu; Vilmundur Gudnason; James G Wilson; Cornelia M van Duijn; Charles Kooperberg; Stephen S Rich; Bruce M Psaty; Jerome I Rotter; Christopher J O'Donnell; Kenneth Rice; Eric Boerwinkle; Sekar Kathiresan; L Adrienne Cupples

doi:10.1016/j.ajhg.2014.01.009

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Am J Hum Genet. 2014 Feb 6;94(2):223-32. doi: 10.1016/j.ajhg.2014.01.009.

Authors

Gina M Peloso¹, Paul L Auer², Joshua C Bis³, Arend Voorman⁴, Alanna C Morrison⁵, Nathan O Stitziel⁶, Jennifer A Brody³, Sumeet A Khetarpal⁷, Jacy R Crosby⁸, Myriam Fornage⁹, Aaron Isaacs¹⁰, Johanna Jakobsdottir¹¹, Mary F Feitosa¹², Gail Davies¹³, Jennifer E Huffman¹⁴, Ani Manichaikul¹⁵, Brian Davis⁵, Kurt Lohman¹⁶, Aron Y Joon¹⁷, Albert V Smith¹⁸, Megan L Grove⁵, Paolo Zanoni⁷, Valeska Redon⁷, Serkalem Demissie¹⁹, Kim Lawson⁵, Ulrike Peters²⁰, Christopher Carlson²⁰, Rebecca D Jackson²¹, Kelli K Ryckman²², Rachel H Mackey²³, Jennifer G Robinson²², David S Siscovick²⁴, Pamela J Schreiner²⁵, Josyf C Mychaleckyj¹⁵, James S Pankow²⁵, Albert Hofman²⁶, Andre G Uitterlinden²⁶, Tamara B Harris²⁷, Kent D Taylor²⁸, Jeanette M Stafford¹⁶, Lindsay M Reynolds¹⁶, Riccardo E Marioni¹³, Abbas Dehghan²⁶, Oscar H Franco²⁶, Aniruddh P Patel²⁹, Yingchang Lu³⁰, George Hindy³¹, Omri Gottesman³², Erwin P Bottinger³², Olle Melander³¹, Marju Orho-Melander³³, Ruth J F Loos³⁴, Stefano Duga³⁵, Piera Angelica Merlini³⁶, Martin Farrall³⁷, Anuj Goel³⁷, Rosanna Asselta³⁵, Domenico Girelli³⁸, Nicola Martinelli³⁸, Svati H Shah³⁹, William E Kraus⁴⁰, Mingyao Li⁴¹, Daniel J Rader⁷, Muredach P Reilly⁷, Ruth McPherson⁴², Hugh Watkins⁴³, Diego Ardissino⁴⁴; NHLBI GO Exome Sequencing Project; Qunyuan Zhang¹², Judy Wang¹², Michael Y Tsai⁴⁵, Herman A Taylor⁴⁶, Adolfo Correa⁴⁷, Michael E Griswold⁴⁷, Leslie A Lange⁴⁸, John M Starr⁴⁹, Igor Rudan⁵⁰, Gudny Eiriksdottir¹¹, Lenore J Launer²⁷, Jose M Ordovas⁵¹, Daniel Levy⁵², Y-D Ida Chen²⁸, Alexander P Reiner⁵³, Caroline Hayward¹⁴, Ozren Polasek⁵⁴, Ian J Deary¹³, Ingrid B Borecki¹², Yongmei Liu¹⁶, Vilmundur Gudnason¹⁸, James G Wilson⁵⁵, Cornelia M van Duijn¹⁰, Charles Kooperberg²⁰, Stephen S Rich¹⁵, Bruce M Psaty⁵⁶, Jerome I Rotter²⁸, Christopher J O'Donnell⁵⁷, Kenneth Rice⁴, Eric Boerwinkle⁵⁸, Sekar Kathiresan⁵⁹, L Adrienne Cupples⁶⁰

Affiliations

¹ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
⁴ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁵ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁶ Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁷ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Biostatistics, Bioinformatics, and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
⁹ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹⁰ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
¹¹ Icelandic Heart Association, Kopavogur 201, Iceland.
¹² Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹³ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
¹⁴ MRC Human Genetics, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
¹⁵ Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
¹⁶ Wake Forest School of Medicine, Winston-Salem, NC 27106, USA.
¹⁷ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹⁸ Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
¹⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA.
²⁰ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²¹ Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
²² Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA.
²³ Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
²⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
²⁵ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
²⁶ Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
²⁷ National Institute on Aging, NIH, Bethesda, MD 20892, USA.
²⁸ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
²⁹ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; School of Medicine, Yale University, New Haven, CT 06510, USA.
³⁰ The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³¹ Department of Clinical Sciences in Malmö, Lund University, Clinical Research Center, Malmö 20502, Sweden.
³² The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³³ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö 20502, Sweden.
³⁴ The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁵ Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy.
³⁶ Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Ospedale Niguarda, Milano 20162, Italy.
³⁷ Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
³⁸ Department of Medicine, University of Verona School of Medicine, Verona 37134, Italy.
³⁹ Department of Obstetrics and Gynecology, Division of Urogynecology, Duke University, Durham, NC 27710, USA; Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
⁴⁰ Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA.
⁴¹ Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴² Atherogenomics Laboratory, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada.
⁴³ Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Merck Sharp & Dohme Corp., Rahway, NJ 07065, USA.
⁴⁴ Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Azienda Ospedaliero-Universitaria di Parma, Parma 43100, Italy.
⁴⁵ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
⁴⁶ Jackson State University, Jackson, MS 39217, USA; Tougaloo College, Tougaloo, MS 39174, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁴⁷ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁴⁸ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴⁹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK.
⁵⁰ Centre for Population Health Sciences, The University of Edinburgh Medical School, Edinburgh EH8 9AG, UK; Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
⁵¹ Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid 28049, Spain; IMDEA-Alimentacion, Madrid 28049, Spain; Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Medford, MA 02155, USA.
⁵² National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA; Division of Intramural Research, NHLBI, NIH, Bethesda, MD 20892, USA.
⁵³ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁵⁴ Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
⁵⁵ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁵⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98195, USA.
⁵⁷ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA; Division of Intramural Research, NHLBI, NIH, Bethesda, MD 20892, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵⁸ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁵⁹ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: [email protected].
⁶⁰ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA. Electronic address: [email protected].

Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
Adult
Aged
Alleles
Animals
Black People / genetics
Cholesterol, HDL / blood
Cholesterol, HDL / genetics*
Cholesterol, LDL / blood
Cholesterol, LDL / genetics*
Cohort Studies
Coronary Disease / blood
Coronary Disease / genetics*
Female
Gene Frequency*
Genetic Association Studies
Genetic Code
Genetic Variation*
Humans
Linear Models
Male
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Middle Aged
Phenotype
Sequence Analysis, DNA
Subtilisins / genetics
Subtilisins / metabolism
Triglycerides / blood*
White People / genetics

Substances

Cholesterol, HDL
Cholesterol, LDL
Microtubule-Associated Proteins
Triglycerides
1-Alkyl-2-acetylglycerophosphocholine Esterase
PAFAH1B2 protein, human
PCSK7 protein, human
Pcsk7 protein, mouse
Subtilisins

Abstract

Publication types

MeSH terms

Substances

Grants and funding