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

Publication ,  Journal Article
Natarajan, P; Peloso, GM; Zekavat, SM; Montasser, M; Ganna, A; Chaffin, M; Khera, AV; Zhou, W; Bloom, JM; Engreitz, JM; Ernst, J; Alver, M ...
Published in: Nat Commun
August 23, 2018

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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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

August 23, 2018

Volume

9

Issue

1

Start / End Page

3391

Location

England

Related Subject Headings

  • Mutation
  • Models, Genetic
  • Lipids
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genome-Wide Association Study
  • Genome, Human
  • Gene Frequency
  • Cholesterol, LDL
  • Base Sequence
 

Citation

APA
Chicago
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MLA
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Natarajan, P., Peloso, G. M., Zekavat, S. M., Montasser, M., Ganna, A., Chaffin, M., … NHLBI TOPMed Lipids Working Group, . (2018). Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat Commun, 9(1), 3391. https://doi.org/10.1038/s41467-018-05747-8
Natarajan, Pradeep, Gina M. Peloso, Seyedeh Maryam Zekavat, May Montasser, Andrea Ganna, Mark Chaffin, Amit V. Khera, et al. “Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.Nat Commun 9, no. 1 (August 23, 2018): 3391. https://doi.org/10.1038/s41467-018-05747-8.
Natarajan P, Peloso GM, Zekavat SM, Montasser M, Ganna A, Chaffin M, et al. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat Commun. 2018 Aug 23;9(1):3391.
Natarajan, Pradeep, et al. “Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.Nat Commun, vol. 9, no. 1, Aug. 2018, p. 3391. Pubmed, doi:10.1038/s41467-018-05747-8.
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, NHLBI TOPMed Lipids Working Group. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat Commun. 2018 Aug 23;9(1):3391.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

August 23, 2018

Volume

9

Issue

1

Start / End Page

3391

Location

England

Related Subject Headings

  • Mutation
  • Models, Genetic
  • Lipids
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genome-Wide Association Study
  • Genome, Human
  • Gene Frequency
  • Cholesterol, LDL
  • Base Sequence