Polygenic Background Modifies Penetrance of Monogenic Variants for Tier 1 Genomic Conditions

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Aug 22

PMID 32820175

Citations 174

Authors

Akl C Fahed

Minxian Wang

Julian R Homburger

Aniruddh P Patel

Alexander G Bick

Cynthia L Neben

Carmen Lai

Deanna Brockman

Anthony Philippakis

Patrick T Ellinor

Christopher A Cassa

Matthew Lebo

Kenney Ng

Eric S Lander

Alicia Y Zhou

Sekar Kathiresan

Amit V Khera

Affiliations

Soon will be listed here.

Abstract

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

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References

Claussnitzer M, Cho J, Collins R, Cox N, Dermitzakis E, Hurles M . A brief history of human disease genetics. Nature. 2020; 577(7789):179-189. PMC: 7405896. DOI: 10.1038/s41586-019-1879-7. View

Pharoah P, Antoniou A, Easton D, Ponder B . Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med. 2008; 358(26):2796-803. DOI: 10.1056/NEJMsa0708739. View

Kathiresan S, Willer C, Peloso G, Demissie S, Musunuru K, Schadt E . Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2008; 41(1):56-65. PMC: 2881676. DOI: 10.1038/ng.291. View

Chatterjee N, Shi J, Garcia-Closas M . Developing and evaluating polygenic risk prediction models for stratified disease prevention. Nat Rev Genet. 2016; 17(7):392-406. PMC: 6021129. DOI: 10.1038/nrg.2016.27. View

Craig J, Han X, Qassim A, Hassall M, Cooke Bailey J, Kinzy T . Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression. Nat Genet. 2020; 52(2):160-166. PMC: 8056672. DOI: 10.1038/s41588-019-0556-y. View

Khera A, Chaffin M, Aragam K, Haas M, Roselli C, Choi S . Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018; 50(9):1219-1224. PMC: 6128408. DOI: 10.1038/s41588-018-0183-z. View

Hensman Moss D, Pardinas A, Langbehn D, Lo K, Leavitt B, Roos R . Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study. Lancet Neurol. 2017; 16(9):701-711. DOI: 10.1016/S1474-4422(17)30161-8. View

Lecarpentier J, Silvestri V, Kuchenbaecker K, Barrowdale D, Dennis J, McGuffog L . Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores. J Clin Oncol. 2017; 35(20):2240-2250. PMC: 5501359. DOI: 10.1200/JCO.2016.69.4935. View

Bowen M, Kolor K, Dotson W, Ned R, Khoury M . Public health action in genomics is now needed beyond newborn screening. Public Health Genomics. 2012; 15(6):327-34. PMC: 4748713. DOI: 10.1159/000341889. View

10.

Dewey F, Murray M, Overton J, Habegger L, Leader J, Fetterolf S . Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science. 2016; 354(6319). DOI: 10.1126/science.aaf6814. View

11.

Manickam K, Buchanan A, Schwartz M, Hallquist M, Williams J, Rahm A . Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants. JAMA Netw Open. 2019; 1(5):e182140. PMC: 6324494. DOI: 10.1001/jamanetworkopen.2018.2140. View

12.

Abul-Husn N, Manickam K, Jones L, Wright E, Hartzel D, Gonzaga-Jauregui C . Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016; 354(6319). DOI: 10.1126/science.aaf7000. View

13.

Bycroft C, Freeman C, Petkova D, Band G, Elliott L, Sharp K . The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018; 562(7726):203-209. PMC: 6786975. DOI: 10.1038/s41586-018-0579-z. View

14.

Neben C, Zimmer A, Stedden W, van den Akker J, OConnor R, Chan R . Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines. J Mol Diagn. 2019; 21(4):646-657. DOI: 10.1016/j.jmoldx.2019.03.001. View

15.

Mavaddat N, Michailidou K, Dennis J, Lush M, Fachal L, Lee A . Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. Am J Hum Genet. 2018; 104(1):21-34. PMC: 6323553. DOI: 10.1016/j.ajhg.2018.11.002. View

16.

Huyghe J, Bien S, Harrison T, Kang H, Chen S, Schmit S . Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet. 2018; 51(1):76-87. PMC: 6358437. DOI: 10.1038/s41588-018-0286-6. View

17.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

18.

Khera A, Kathiresan S . Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017; 18(6):331-344. PMC: 5935119. DOI: 10.1038/nrg.2016.160. View

19.

Michailidou K, Lindstrom S, Dennis J, Beesley J, Hui S, Kar S . Association analysis identifies 65 new breast cancer risk loci. Nature. 2017; 551(7678):92-94. PMC: 5798588. DOI: 10.1038/nature24284. View

20.

Liede A, Mansfield C, Metcalfe K, Price M, Snyder C, Lynch H . Preferences for breast cancer risk reduction among BRCA1/BRCA2 mutation carriers: a discrete-choice experiment. Breast Cancer Res Treat. 2017; 165(2):433-444. PMC: 5543193. DOI: 10.1007/s10549-017-4332-3. View