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^*

^*Corresponding author for this work

63 Citations (Scopus)

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
Article number	1613
Journal	Nature Communications
Volume	9
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-018-03911-8
Publication status	Published - 01.12.2018

Funding

This research has been conducted using the UK Biobank resource, application 7089. The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913) with funding for genotyping provided by Amgen. The VIRGO study was supported by grant R01 HL081153-01A1K from the National Heart, Lung, and Blood Institute. The TAICHI study was supported by the National Health Research Institutes, Taiwan (PH-099-PP-03, PH-100-PP-03, PH-101-PP-03), the National Science Council, Taiwan (Grant Nos NSC 101-2314-B-075A-006-MY3, MOST 104-2314-B-075A-006-MY3, MOST 104-2314-B-075A-007, MOST 105-2314-B-075A-003), the Taichung Veterans General Hospital, Taiwan (TCVGH-1020101C, TCVGH-1020102D, TCVGH-1023102B, TCVGH-1023107D, TCVGH-1030101C, TCVGH-1030105D, TCVGH-1033503C, TCVGH-1033102B, TCVGH-1033108D, TCVGH-1040101C, TCVGH-1040102D, TCVGH-1043504C, TCVGH-1043104B), and the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881. The MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Whole genome sequencing of the VIRGO and TAICHI cohorts was funded by grant 5UM1HG008895-02 from the National Human Genome Research Institute’s Center for Common Disease Genomics. Whole genome sequencing of the MESA cohort was funded through the Trans-Omics for Precision Medicine (TOPMed) Program of the National Heart, Lung, and Blood Institute. General study coordination was provided by the TOPMed Data Coordinating Center (3R01HL-12393-02S1). The contributions of the investigators of the NHLBI TOPMed Consortium (https://www.nhlbiwgs.org/topmed-banner-authorship) are gratefully acknowledged. The Atherosclerosis Risk in Communities study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Competing interests: A.V.K. is supported by a John S. LaDue Memorial Fellowship at Harvard Medical School, and a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst funded by the National Institutes of Health (NIH) (TR001100) and has received consulting fees from Merck and Amarin. P.N. reports funding from the John S. LaDue Memorial Fellowship at Harvard Medical School and has received consulting fees from Amarin. S.K. is supported by a research scholar award from Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564; he has received a research grant from Bayer Healthcare; and consulting fees from Merck, Novartis, Sanofi, AstraZeneca, Alnylam Pharmaceuticals, Leerink Partners, Noble Insights, MedGenome, Aegerion Pharmaceuticals, Regeneron Pharmaceuticals, Quest Diagnostics, Genomics PLC, and Eli Lilly and Company; and holds equity in San Therapeutics and Catabasis Pharmaceuticals. The remaining authors declare no competing interests.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 5 Gender Equality

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Research Area: Medical Genetics

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Cite this

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

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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",

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

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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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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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DO - 10.1038/s41467-018-03911-8

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SN - 1751-8628

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JO - Nature Communications

JF - Nature Communications

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M1 - 1613

ER -

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

Abstract

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