Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

NHLBI TOPMed Lipids Working Group; Pradeep Natarajan; Gina M. Peloso; Seyedeh Maryam Zekavat; May Montasser; Andrea Ganna; Mark Chaffin; Amit V. Khera; Wei Zhou; Jonathan M. Bloom; Jesse M. Engreitz; Jason Ernst; Jeffrey R. O’Connell; Sanni E. Ruotsalainen; Maris Alver; Ani Manichaikul; W. Craig Johnson; James A. Perry; Timothy Poterba; Cotton Seed; Ida L. Surakka; Tonu Esko; Samuli Ripatti; Veikko Salomaa; Adolfo Correa; Ramachandran S. Vasan; Manolis Kellis; Benjamin M. Neale; Eric S. Lander; Goncalo Abecasis; Braxton Mitchell; Stephen S. Rich; James G. Wilson; L. Adrienne Cupples; Jerome I. Rotter; Cristen J. Willer; Sekar Kathiresan; Namiko Abe; Christine Albert; Nicholette (Nichole) Palmer Allred; Laura Almasy; Alvaro Alonso; Seth Ament; Peter Anderson; Pramod Anugu; Deborah Applebaum-Bowden; Susan Dutcher; Lucinda Fulton; C. Charles Gu; D. C. Rao; Yun Ju Sung

doi:10.1038/s41467-018-05747-8

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

NHLBI TOPMed Lipids Working Group, Pradeep Natarajan, Gina M. Peloso, Seyedeh Maryam Zekavat, May Montasser, Andrea Ganna, Mark Chaffin, Amit V. Khera, Wei Zhou, Jonathan M. Bloom, Jesse M. Engreitz, Jason Ernst, Jeffrey R. O’Connell, Sanni E. Ruotsalainen, Maris Alver, Ani Manichaikul, W. Craig Johnson, James A. Perry, Timothy Poterba, Cotton SeedIda L. Surakka, Tonu Esko, Samuli Ripatti, Veikko Salomaa, Adolfo Correa, Ramachandran S. Vasan, Manolis Kellis, Benjamin M. Neale, Eric S. Lander, Goncalo Abecasis, Braxton Mitchell, Stephen S. Rich, James G. Wilson, L. Adrienne Cupples, Jerome I. Rotter, Cristen J. Willer, Sekar Kathiresan, Namiko Abe, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Susan Dutcher, Lucinda Fulton, C. Charles Gu, D. C. Rao, Yun Ju Sung

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Abstract

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

Original language	English
Article number	3391
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05747-8
State	Published - Dec 1 2018

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NHLBI TOPMed Lipids Working Group, Natarajan, P., Peloso, G. M., Zekavat, S. M., Montasser, M., Ganna, A., Chaffin, M., Khera, A. V., Zhou, W., Bloom, J. M., Engreitz, J. M., Ernst, J., O’Connell, J. R., Ruotsalainen, S. E., Alver, M., Manichaikul, A., Johnson, W. C., Perry, J. A., Poterba, T., ... Sung, Y. J. (2018). Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nature communications, 9(1), Article 3391. https://doi.org/10.1038/s41467-018-05747-8

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title = "Deep-coverage whole genome sequences and blood lipids among 16,324 individuals",

abstract = "Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.",

author = "{NHLBI TOPMed Lipids Working Group} and Pradeep Natarajan and Peloso, {Gina M.} and Zekavat, {Seyedeh Maryam} and May Montasser and Andrea Ganna and Mark Chaffin and Khera, {Amit V.} and Wei Zhou and Bloom, {Jonathan M.} and Engreitz, {Jesse M.} and Jason Ernst and O{\textquoteright}Connell, {Jeffrey R.} and Ruotsalainen, {Sanni E.} and Maris Alver and Ani Manichaikul and Johnson, {W. Craig} and Perry, {James A.} and Timothy Poterba and Cotton Seed and Surakka, {Ida L.} and Tonu Esko and Samuli Ripatti and Veikko Salomaa and Adolfo Correa and Vasan, {Ramachandran S.} and Manolis Kellis and Neale, {Benjamin M.} and Lander, {Eric S.} and Goncalo Abecasis and Braxton Mitchell and Rich, {Stephen S.} and Wilson, {James G.} and Cupples, {L. Adrienne} and Rotter, {Jerome I.} and Willer, {Cristen J.} and Sekar Kathiresan and Namiko Abe and Christine Albert and Allred, {Nicholette (Nichole) Palmer} and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Deborah Applebaum-Bowden and Susan Dutcher and Lucinda Fulton and Gu, {C. Charles} and Rao, {D. C.} and Sung, {Yun Ju}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-05747-8",

language = "English",

volume = "9",

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NHLBI TOPMed Lipids Working Group, Natarajan, P, Peloso, GM, Zekavat, SM, Montasser, M, Ganna, A, Chaffin, M, Khera, AV, Zhou, W, Bloom, JM, Engreitz, JM, Ernst, J, O’Connell, JR, Ruotsalainen, SE, Alver, M, Manichaikul, A, Johnson, WC, Perry, JA, Poterba, T, Seed, C, Surakka, IL, Esko, T, Ripatti, S, Salomaa, V, Correa, A, Vasan, RS, Kellis, M, Neale, BM, Lander, ES, Abecasis, G, Mitchell, B, Rich, SS, Wilson, JG, Cupples, LA, Rotter, JI, Willer, CJ, Kathiresan, S, Abe, N, Albert, C, Allred, NP, Almasy, L, Alonso, A, Ament, S, Anderson, P, Anugu, P, Applebaum-Bowden, D, Dutcher, S , Fulton, L , Gu, CC , Rao, DC & Sung, YJ 2018, 'Deep-coverage whole genome sequences and blood lipids among 16,324 individuals', Nature communications, vol. 9, no. 1, 3391. https://doi.org/10.1038/s41467-018-05747-8

TY - JOUR

T1 - Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

AU - NHLBI TOPMed Lipids Working Group

AU - Natarajan, Pradeep

AU - Peloso, Gina M.

AU - Zekavat, Seyedeh Maryam

AU - Montasser, May

AU - Ganna, Andrea

AU - Chaffin, Mark

AU - Khera, Amit V.

AU - Zhou, Wei

AU - Bloom, Jonathan M.

AU - Engreitz, Jesse M.

AU - Ernst, Jason

AU - O’Connell, Jeffrey R.

AU - Ruotsalainen, Sanni E.

AU - Alver, Maris

AU - Manichaikul, Ani

AU - Johnson, W. Craig

AU - Perry, James A.

AU - Poterba, Timothy

AU - Seed, Cotton

AU - Surakka, Ida L.

AU - Esko, Tonu

AU - Ripatti, Samuli

AU - Salomaa, Veikko

AU - Correa, Adolfo

AU - Vasan, Ramachandran S.

AU - Kellis, Manolis

AU - Neale, Benjamin M.

AU - Lander, Eric S.

AU - Abecasis, Goncalo

AU - Mitchell, Braxton

AU - Rich, Stephen S.

AU - Wilson, James G.

AU - Cupples, L. Adrienne

AU - Rotter, Jerome I.

AU - Willer, Cristen J.

AU - Kathiresan, Sekar

AU - Abe, Namiko

AU - Albert, Christine

AU - Allred, Nicholette (Nichole) Palmer

AU - Almasy, Laura

AU - Alonso, Alvaro

AU - Ament, Seth

AU - Anderson, Peter

AU - Anugu, Pramod

AU - Applebaum-Bowden, Deborah

AU - Dutcher, Susan

AU - Fulton, Lucinda

AU - Gu, C. Charles

AU - Rao, D. C.

AU - Sung, Yun Ju

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

AB - Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

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U2 - 10.1038/s41467-018-05747-8

DO - 10.1038/s41467-018-05747-8

M3 - Article

C2 - 30140000

AN - SCOPUS:85052245414

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 3391

ER -

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

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