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 S Post, Jerome I. Rotter, Yii Der Ida Chen, Harlan Krumholz, Danish Saleheen, Stacey Gabriel, Sekar Kathiresan

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article number1613
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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genes
Genes
Body Fat Distribution
allergic diseases
Terminator Codon
asthma
coronary artery disease
obesity
Hypothyroidism
Gene Frequency
proteins
effectors
Type 2 Diabetes Mellitus
phenotype
Coronary Artery Disease
biological effects
Proteins
Asthma
fats
Obesity

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Emdin, C. A., Khera, A. V., Chaffin, M., Klarin, D., Natarajan, P., Aragam, K., ... Kathiresan, S. (2018). Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nature Communications, 9(1), [1613]. https://doi.org/10.1038/s41467-018-03911-8

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

In: Nature Communications, Vol. 9, No. 1, 1613, 01.12.2018.

Research output: Contribution to journalArticle

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, WS, 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
Emdin, Connor A. ; Khera, Amit V. ; Chaffin, Mark ; Klarin, Derek ; Natarajan, Pradeep ; Aragam, Krishna ; Haas, Mary ; Bick, Alexander ; Zekavat, Seyedeh M. ; Nomura, Akihiro ; Ardissino, Diego ; Wilson, James G. ; Schunkert, Heribert ; McPherson, Ruth ; Watkins, Hugh ; Elosua, Roberto ; Bown, Matthew J. ; Samani, Nilesh J. ; Baber, Usman ; Erdmann, Jeanette ; Gupta, Namrata ; Danesh, John ; Chasman, Daniel ; Ridker, Paul ; Denny, Joshua ; Bastarache, Lisa ; Lichtman, Judith H. ; D'Onofrio, Gail ; Mattera, Jennifer ; Spertus, John A. ; Sheu, Wayne H.H. ; Taylor, Kent D. ; Psaty, Bruce M. ; Rich, Stephen S. ; Post, Wendy S ; Rotter, Jerome I. ; Chen, Yii Der Ida ; Krumholz, Harlan ; Saleheen, Danish ; Gabriel, Stacey ; Kathiresan, Sekar. / Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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AU - Haas, Mary

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AU - Nomura, Akihiro

AU - Ardissino, Diego

AU - Wilson, James G.

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AU - Chen, Yii Der Ida

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