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; NHLBI GO Exome Sequencing Project; 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

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 SmithMegan 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, NHLBI GO Exome Sequencing Project, L. Adrienne Cupples^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › 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)	223-32
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
Externally published	Yes

Keywords

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

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10.1016/j.ajhg.2014.01.009Licence: Free access - publisher

Cite this

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., Fornage, M., Isaacs, A., Jakobsdottir, J., Feitosa, M. F., Davies, G., Huffman, J. E., Manichaikul, A., Davis, B., Lohman, K., Joon, A. Y., ... Cupples, L. A. (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), 223-32. https://doi.org/10.1016/j.ajhg.2014.01.009

@article{590da0016313422d8dddebec010d500c,

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 = "1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics, Adult, African Continental Ancestry Group/genetics, Aged, Alleles, Animals, Cholesterol, HDL/blood, Cholesterol, LDL/blood, Cohort Studies, Coronary Disease/blood, European Continental Ancestry Group/genetics, Female, Gene Frequency, Genetic Association Studies, Genetic Code, Genetic Variation, Humans, Linear Models, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins/genetics, Middle Aged, Phenotype, Sequence Analysis, DNA, Subtilisins/genetics, Triglycerides/blood",

author = "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 Fornage 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 Hofman 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 Patel, {Aniruddh P} and Yingchang Lu and George Hindy and Omri Gottesman and Bottinger, {Erwin P} and Olle Melander and {NHLBI GO Exome Sequencing Project} and Cupples, {L. Adrienne}",

year = "2014",

month = feb,

day = "6",

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

language = "English",

volume = "94",

pages = "223--32",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Peloso, GM, Auer, PL, Bis, JC, Voorman, A, Morrison, AC, Stitziel, NO, Brody, JA, Khetarpal, SA, Crosby, JR, Fornage, 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, Hofman, A, Uitterlinden, AG, Harris, TB, Taylor, KD, Stafford, JM, Reynolds, LM, Marioni, RE, Dehghan, A, Franco, OH, Patel, AP, Lu, Y, Hindy, G, Gottesman, O, Bottinger, EP, Melander, O, NHLBI GO Exome Sequencing Project & Cupples, LA 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. 223-32. 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 - 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 - Fornage, 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 - Hofman, 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 - Patel, Aniruddh P

AU - Lu, Yingchang

AU - Hindy, George

AU - Gottesman, Omri

AU - Bottinger, Erwin P

AU - Melander, Olle

AU - NHLBI GO Exome Sequencing Project

AU - Cupples, L. Adrienne

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 - 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics

KW - Adult

KW - African Continental Ancestry Group/genetics

KW - Aged

KW - Alleles

KW - Animals

KW - Cholesterol, HDL/blood

KW - Cholesterol, LDL/blood

KW - Cohort Studies

KW - Coronary Disease/blood

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Gene Frequency

KW - Genetic Association Studies

KW - Genetic Code

KW - Genetic Variation

KW - Humans

KW - Linear Models

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Microtubule-Associated Proteins/genetics

KW - Middle Aged

KW - Phenotype

KW - Sequence Analysis, DNA

KW - Subtilisins/genetics

KW - Triglycerides/blood

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

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