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 | |
| State | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
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 journal › Article
}
TY - JOUR
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 S
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.
UR - http://www.scopus.com/inward/record.url?scp=85045881805&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045881805&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03911-8
DO - 10.1038/s41467-018-03911-8
M3 - Article
C2 - 29691411
AN - SCOPUS:85045881805
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1613
ER -