Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Connor A. Emdin; Amit V. Khera; Mark Chaffin; Derek Klarin; Pradeep Natarajan; Krishna Aragam; Mary Haas; Alexander Bick; Seyedeh M. Zekavat; Akihiro Nomura; Diego Ardissino; James G. Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J. Bown; Nilesh J. Samani; Usman Baber; Jeanette Erdmann; Namrata Gupta; John Danesh; Daniel Chasman; Paul Ridker; Joshua Denny; Lisa Bastarache; Judith H. Lichtman; Gail D'Onofrio; Jennifer Mattera; John A. Spertus; Wayne H.H. Sheu; Kent D. Taylor; Bruce M. Psaty; Stephen S. Rich; Wendy Post; Jerome I. Rotter; Yii Der Ida Chen; Harlan Krumholz; Danish Saleheen; Stacey Gabriel; Sekar Kathiresan

doi:10.1038/s41467-018-03911-8

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Connor A. Emdin, Amit V. Khera, Mark Chaffin, Derek Klarin, Pradeep Natarajan, Krishna Aragam, Mary Haas, Alexander Bick, Seyedeh M. Zekavat, Akihiro Nomura, Diego Ardissino, James G. Wilson, Heribert Schunkert, Ruth McPherson, Hugh Watkins, Roberto Elosua, Matthew J. Bown, Nilesh J. Samani, Usman Baber, Jeanette ErdmannNamrata Gupta, John Danesh, Daniel Chasman, Paul Ridker, Joshua Denny, Lisa Bastarache, Judith H. Lichtman, Gail D'Onofrio, Jennifer Mattera, John A. Spertus, Wayne H.H. Sheu, Kent D. Taylor, Bruce M. Psaty, Stephen S. Rich, Wendy Post, Jerome I. Rotter, Yii Der Ida Chen, Harlan Krumholz, Danish Saleheen, Stacey Gabriel, Sekar Kathiresan

School of Medicine

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

25 Scopus citations

Abstract

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

Original language	English (US)
Article number	1613
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03911-8
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Emdin, C. A., Khera, A. V., Chaffin, M., Klarin, D., Natarajan, P., Aragam, K., Haas, M., Bick, A., Zekavat, S. M., Nomura, A., Ardissino, D., Wilson, J. G., Schunkert, H., McPherson, R., Watkins, H., Elosua, R., Bown, M. J., Samani, N. J., Baber, U., ... Kathiresan, S. (2018). Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nature communications, 9(1), Article 1613. https://doi.org/10.1038/s41467-018-03911-8

Emdin, CA, Khera, AV, Chaffin, M, Klarin, D, Natarajan, P, Aragam, K, Haas, M, Bick, A, Zekavat, SM, Nomura, A, Ardissino, D, Wilson, JG, Schunkert, H, McPherson, R, Watkins, H, Elosua, R, Bown, MJ, Samani, NJ, Baber, U, Erdmann, J, Gupta, N, Danesh, J, Chasman, D, Ridker, P, Denny, J, Bastarache, L, Lichtman, JH, D'Onofrio, G, Mattera, J, Spertus, JA, Sheu, WHH, Taylor, KD, Psaty, BM, Rich, SS, Post, W, Rotter, JI, Chen, YDI, Krumholz, H, Saleheen, D, Gabriel, S & Kathiresan, S 2018, 'Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease', Nature communications, vol. 9, no. 1, 1613. https://doi.org/10.1038/s41467-018-03911-8

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title = "Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease",

abstract = "Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.",

author = "Emdin, {Connor A.} and Khera, {Amit V.} and Mark Chaffin and Derek Klarin and Pradeep Natarajan and Krishna Aragam and Mary Haas and Alexander Bick and Zekavat, {Seyedeh M.} and Akihiro Nomura and Diego Ardissino and Wilson, {James G.} and Heribert Schunkert and Ruth McPherson and Hugh Watkins and Roberto Elosua and Bown, {Matthew J.} and Samani, {Nilesh J.} and Usman Baber and Jeanette Erdmann and Namrata Gupta and John Danesh and Daniel Chasman and Paul Ridker and Joshua Denny and Lisa Bastarache and Lichtman, {Judith H.} and Gail D'Onofrio and Jennifer Mattera and Spertus, {John A.} and Sheu, {Wayne H.H.} and Taylor, {Kent D.} and Psaty, {Bruce M.} and Rich, {Stephen S.} and Wendy Post and Rotter, {Jerome I.} and Chen, {Yii Der Ida} and Harlan Krumholz and Danish Saleheen and Stacey Gabriel and Sekar Kathiresan",

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

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doi = "10.1038/s41467-018-03911-8",

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T1 - Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

AU - Emdin, Connor A.

AU - Khera, Amit V.

AU - Chaffin, Mark

AU - Klarin, Derek

AU - Natarajan, Pradeep

AU - Aragam, Krishna

AU - Haas, Mary

AU - Bick, Alexander

AU - Zekavat, Seyedeh M.

AU - Nomura, Akihiro

AU - Ardissino, Diego

AU - Wilson, James G.

AU - Schunkert, Heribert

AU - McPherson, Ruth

AU - Watkins, Hugh

AU - Elosua, Roberto

AU - Bown, Matthew J.

AU - Samani, Nilesh J.

AU - Baber, Usman

AU - Erdmann, Jeanette

AU - Gupta, Namrata

AU - Danesh, John

AU - Chasman, Daniel

AU - Ridker, Paul

AU - Denny, Joshua

AU - Bastarache, Lisa

AU - Lichtman, Judith H.

AU - D'Onofrio, Gail

AU - Mattera, Jennifer

AU - Spertus, John A.

AU - Sheu, Wayne H.H.

AU - Taylor, Kent D.

AU - Psaty, Bruce M.

AU - Rich, Stephen S.

AU - Post, Wendy

AU - Rotter, Jerome I.

AU - Chen, Yii Der Ida

AU - Krumholz, Harlan

AU - Saleheen, Danish

AU - Gabriel, Stacey

AU - Kathiresan, Sekar

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

AB - Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

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JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1613

ER -

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Abstract

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