Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

NHLBI GO Exome Sequencing Project; 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 Fomage; 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 Holman; 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. Patele; John M. Starr; Igor Rudan; Caroline Hayward; Ozren Polasek; Ian J. Deary

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

NHLBI GO Exome Sequencing Project, 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 Fomage, Aaron Isaacs, Johanna Jakobsdottir, Mary F. Feitosa, Gail Davies, Jennifer E. Huffman, Ani Manichaikul, Brian Davis, Kurt Lohman, Aron Y. JoonAlbert 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 Holman, 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. Patele, John M. Starr, Igor Rudan, Caroline Hayward, Ozren Polasek, Ian J. Deary

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	223-232
Number of pages	10
Journal	American Journal of Human Genetics
Volume	94
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2014.01.009
Publication status	Published - 6 Feb 2014

Keywords / Materials (for Non-textual outputs)

PLATELET-ACTIVATING-FACTOR
DENSITY-LIPOPROTEIN CHOLESTEROL
FACTOR ACETYLHYDROLASES
PCSK9
PROTEIN
TRAITS
LDL

Access to Document

10.1016/j.ajhg.2014.01.009

Are water quality and air pollution involved in causing dementia in Scotland and Sweden?
Russ, T. & Starr, J.
UK-based charities
1/08/15 → 31/07/16
Project: Research
Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Maclullich, A.
1/09/13 → 31/08/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research

Cite this

NHLBI GO Exome Sequencing Project, Peloso, G. M., Auer, P. L., Bis, J. C., Voorman, A., Morrison, A. C., Stitziel, N. O., Brody, J. A., Khetarpal, S. A., Crosby, J. R., Fomage, M., Isaacs, A., Jakobsdottir, J., Feitosa, M. F., Davies, G., Huffman, J. E., Manichaikul, A., Davis, B., Lohman, K., ... Deary, I. J. (2014). Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks. American Journal of Human Genetics, 94(2), 223-232. https://doi.org/10.1016/j.ajhg.2014.01.009

@article{8c38154d8d954e588a6fd38be3fa4c93,

title = "Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks",

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.",

keywords = "PLATELET-ACTIVATING-FACTOR, DENSITY-LIPOPROTEIN CHOLESTEROL, FACTOR ACETYLHYDROLASES, PCSK9, PROTEIN, TRAITS, LDL",

author = "{NHLBI GO Exome Sequencing Project} and Peloso, {Gina M.} and Auer, {Paul L.} and Bis, {Joshua C.} and Arend Voorman and Morrison, {Alanna C.} and Stitziel, {Nathan O.} and Brody, {Jennifer A.} and Khetarpal, {Sumeet A.} and Crosby, {Jacy R.} and Myriam Fomage and Aaron Isaacs and Johanna Jakobsdottir and Feitosa, {Mary F.} and Gail Davies and Huffman, {Jennifer E.} and Ani Manichaikul and Brian Davis and Kurt Lohman and Joon, {Aron Y.} and Smith, {Albert V.} and Grove, {Megan L.} and Paolo Zanoni and Valeska Redon and Serkalem Demissie and Kim Lawson and Ulrike Peters and Christopher Carlson and Jackson, {Rebecca D.} and Ryckman, {Kelli K.} and Mackey, {Rachel H.} and Robinson, {Jennifer G.} and Siscovick, {David S.} and Schreiner, {Pamela J.} and Mychaleckyj, {Josyf C.} and Pankow, {James S.} and Albert Holman and Uitterlinden, {Andre G.} and Harris, {Tamara B.} and Taylor, {Kent D.} and Stafford, {Jeanette M.} and Reynolds, {Lindsay M.} and Marioni, {Riccardo E.} and Abbas Dehghan and Franco, {Oscar H.} and Patele, {Aniruddh P.} and Starr, {John M.} and Igor Rudan and Caroline Hayward and Ozren Polasek and Deary, {Ian J.}",

year = "2014",

month = feb,

day = "6",

doi = "10.1016/j.ajhg.2014.01.009",

language = "English",

volume = "94",

pages = "223--232",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

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NHLBI GO Exome Sequencing Project, Peloso, GM, Auer, PL, Bis, JC, Voorman, A, Morrison, AC, Stitziel, NO, Brody, JA, Khetarpal, SA, Crosby, JR, Fomage, M, Isaacs, A, Jakobsdottir, J, Feitosa, MF, Davies, G, Huffman, JE, Manichaikul, A, Davis, B, Lohman, K, Joon, AY, Smith, AV, Grove, ML, Zanoni, P, Redon, V, Demissie, S, Lawson, K, Peters, U, Carlson, C, Jackson, RD, Ryckman, KK, Mackey, RH, Robinson, JG, Siscovick, DS, Schreiner, PJ, Mychaleckyj, JC, Pankow, JS, Holman, A, Uitterlinden, AG, Harris, TB, Taylor, KD, Stafford, JM, Reynolds, LM, Marioni, RE, Dehghan, A, Franco, OH, Patele, AP, Starr, JM, Rudan, I , Hayward, C, Polasek, O & Deary, IJ 2014, 'Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks', American Journal of Human Genetics, vol. 94, no. 2, pp. 223-232. https://doi.org/10.1016/j.ajhg.2014.01.009

TY - JOUR

T1 - Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

AU - NHLBI GO Exome Sequencing Project

AU - Peloso, Gina M.

AU - Auer, Paul L.

AU - Bis, Joshua C.

AU - Voorman, Arend

AU - Morrison, Alanna C.

AU - Stitziel, Nathan O.

AU - Brody, Jennifer A.

AU - Khetarpal, Sumeet A.

AU - Crosby, Jacy R.

AU - Fomage, Myriam

AU - Isaacs, Aaron

AU - Jakobsdottir, Johanna

AU - Feitosa, Mary F.

AU - Davies, Gail

AU - Huffman, Jennifer E.

AU - Manichaikul, Ani

AU - Davis, Brian

AU - Lohman, Kurt

AU - Joon, Aron Y.

AU - Smith, Albert V.

AU - Grove, Megan L.

AU - Zanoni, Paolo

AU - Redon, Valeska

AU - Demissie, Serkalem

AU - Lawson, Kim

AU - Peters, Ulrike

AU - Carlson, Christopher

AU - Jackson, Rebecca D.

AU - Ryckman, Kelli K.

AU - Mackey, Rachel H.

AU - Robinson, Jennifer G.

AU - Siscovick, David S.

AU - Schreiner, Pamela J.

AU - Mychaleckyj, Josyf C.

AU - Pankow, James S.

AU - Holman, Albert

AU - Uitterlinden, Andre G.

AU - Harris, Tamara B.

AU - Taylor, Kent D.

AU - Stafford, Jeanette M.

AU - Reynolds, Lindsay M.

AU - Marioni, Riccardo E.

AU - Dehghan, Abbas

AU - Franco, Oscar H.

AU - Patele, Aniruddh P.

AU - Starr, John M.

AU - Rudan, Igor

AU - Hayward, Caroline

AU - Polasek, Ozren

AU - Deary, Ian J.

PY - 2014/2/6

Y1 - 2014/2/6

N2 - 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.

AB - 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.

KW - PLATELET-ACTIVATING-FACTOR

KW - DENSITY-LIPOPROTEIN CHOLESTEROL

KW - FACTOR ACETYLHYDROLASES

KW - PCSK9

KW - PROTEIN

KW - TRAITS

KW - LDL

U2 - 10.1016/j.ajhg.2014.01.009

DO - 10.1016/j.ajhg.2014.01.009

M3 - Article

C2 - 24507774

SN - 0002-9297

VL - 94

SP - 223

EP - 232

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

Are water quality and air pollution involved in causing dementia in Scotland and Sweden?

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Cite this