Coronary artery disease is a heritable disorder that remains the leading cause of global mortality despite advances in treatment and prevention strategies. Human genetics studies have started to unravel the genetic underpinnings of this disorder.
Gene discovery efforts have rapidly transitioned from family-based studies (for example, those that led to the discovery of familial hypercholesterolaemia) to large cohorts that facilitate both common and rare variant association studies.
Common variant association studies have confirmed ∼60 genetic loci with a robust association with coronary disease, the majority of which are of modest effect size and in non-coding regions. Rare variant association studies have linked inactivating mutations in at least nine genes with risk of coronary artery disease.
Human genetics and large-scale biobanks can facilitate drug development for coronary artery disease by highlighting causal biology and helping to understand the phenotypic consequences of lifelong deficiency of a given protein.
Genomic medicine may provide patients and their health care providers with genetic data that will aid in coronary artery disease prevention and treatment.
Genome editing to introduce mutations that are protective against coronary artery disease into the population could prove curative with a one-time injection, although substantial additional work is needed to confirm efficacy and safety, and to address the underlying ethics.
Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.
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Ford, E. S. et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N. Engl. J. Med. 356, 2388–2398 (2007).
Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2012).
Mozaffarian, D. et al. Heart disease and stroke statistics — 2016 update: a report from the American Heart Association. Circulation 133, e38–e360 (2016).
Khera, A. V. et al. Genetic risk, adherence to a healthy lifestyle, and risk of coronary disease. N. Engl. J. Med. 375, 2349–2358 (2016).
Gertler, M. M., Garn, S. M. & White, P. D. Young candidates for coronary heart disease. JAMA 147, 621–625 (1951).
Marenberg, M. E., Risch, N., Berkman, L. F., Floderus, B. & de Faire, U. Genetic susceptibility to death from coronary heart disease in a study of twins. N. Engl. J. Med. 330, 1041–1046 (1994). The first large-scale prospective study of twins to confirm an increased risk of early-onset CAD among highly related individuals.
Zdravkovic, S. et al. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J. Intern. Med. 252, 247–254 (2002).
Won, H. H. et al. Disproportionate contributions of select genomic compartments and cell types to genetic risk for coronary artery disease. PLoS Genet. 11, e1005622 (2015).
Lloyd-Jones, D. M. et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA 291, 2204–2211 (2004).
Murabito, J. M. et al. Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults. JAMA 294, 3117–3123 (2005).
Watkins, H. & Farrall, M. Genetic susceptibility to coronary artery disease: from promise to progress. Nat. Rev. Genet. 7, 163–173 (2006).
Müller, C. Xanthomata, hypercholesterolemia, angina pectoris. J. Intern. Med. 89, 75–84 (1938).
Lehrman, M. A. et al. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227, 140–146 (1985). The first family-based study to identify a discrete mutation in a single gene predisposing to CAD (familial hypercholesterolaemia).
Soria, L. F. et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc. Natl Acad. Sci. USA 86, 587–591 (1989).
Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).
Garcia, C. K. et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292, 1394–1398 (2001).
Berge, K. E. et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771–1775 (2000).
Wang, L., Fan, C., Topol, S. E., Topol, E. J. & Wang, Q. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302, 1578–1581 (2003).
Lieb, W. et al. Lack of association between the MEF2A gene and myocardial infarction. Circulation 117, 185–191 (2008).
Mani, A. et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315, 1278–1282 (2007).
Keramati, A. R. et al. A form of the metabolic syndrome associated with mutations in DYRK1B. N. Engl. J. Med. 370, 1909–1919 (2014).
MacArthur, D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014). Provides a framework for systematically assessing a potentially causal relationship between a given genetic variant and risk of human disease.
Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881–888 (2008).
Zuk, O. et al. Searching for missing heritability: designing rare variant association studies. Proc. Natl Acad. Sci. USA 111, E455–E464 (2014).
Samani, N. J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).
Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).
McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).
Ye, S., Willeit, J., Kronenberg, F., Xu, Q. & Kiechl, S. Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J. Am. Coll. Cardiol. 52, 378–384 (2008).
Helgadottir, A. et al. The same sequence variant on9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat. Genet. 40, 217–224 (2008).
Smith, J. G. et al. Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study. Circ. Cardiovasc. Genet. 2, 159–164 (2009).
Jarinova, O. et al. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler. Thromb. Vasc. Biol. 29, 1671–1677 (2009).
Holdt, L. M. et al. ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler. Thromb. Vasc. Biol. 30, 620–627 (2010).
Harismendy, O. et al. 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature 470, 264–268 (2011).
Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2010).
Erdmann, J. et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280–282 (2009).
Coronary Artery Disease Genetics (C4D) Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat. Genet. 43, 339–344 (2011).
IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet. 7, e1002260 (2011).
CARDIoGRAMplusC4D Consortium et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25–33 (2013).
Nikpay, M. et al. A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47, 1121–1130 (2015).
So, H. C., Gui, A. H., Cherny, S. S. & Sham, P. C. Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet. Epidemiol. 35, 310–317 (2011).
Flannick, J. & Florez, J. C. Type 2 diabetes: genetic data sharing to advance complex disease research. Nat. Rev. Genet. 17, 535–559 (2016).
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 511, 421–427 (2014).
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N. Engl. J. Med. 374, 1134–1144 (2016).
Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).
Ehret, G. B. et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat. Genet. 48, 1171–1184 (2016).
Erdmann, J. et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504, 432–436 (2013).
Lee, S., Abecasis, G. R., Boehnke, M. & Lin, X. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014).
Do, R. et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2015). The first large study to use whole-exome sequencing to examine the relationship of rare variants in each gene with CAD.
Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005).
Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006). Links inactivating mutations in PCSK9 with significantly reduced LDL cholesterol and risk of incident CAD.
Nioi, P. et al. Variant ASGR1 associated with a reduced risk of coronary artery disease. N. Engl. J. Med. 374, 2131–2141 (2016).
Khera, A. V. et al. Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease. JAMA http://dx.doi.org/10.1001/jama.2017.0972 (2017).
Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjærg-Hansen, A. Loss-of- function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).
Crosby, J. et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22–31 (2014).
Dewey, F. E. et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N. Engl. J. Med. 374, 1123–1133 (2016).
Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).
Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008).
Musunuru, K. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010). The first paper to characterize the mechanism linking a non-coding variant with changes in gene regulation related to LDL cholesterol metabolism.
Strong, A. et al. Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J. Clin. Invest. 122, 2807–2816 (2012).
Reilly, M. P. et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377, 383–392 (2011).
Pu, X. et al. ADAMTS7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant. Am. J. Hum. Genet. 92, 366–374 (2013).
Bauer, R. C. et al. Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice. Circulation 131, 1202–1213 (2015).
Kessler, T. et al. ADAMTS-7 inhibits re-endothelialization of injured arteries and promotes vascular remodeling through cleavage of thrombospondin-1. Circulation 131, 1191–1201 (2015).
DiMasi, J. A., Grabowski, H. G. & Hansen, R. W. Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20–33 (2016).
Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 9, 203–214 (2010).
Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013). This Review article describes the potential utility of human genetics to expedite drug development.
Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013).
Voight, B. F. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380, 572–580 (2012).
Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).
Do, R. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).
Myocardial Infarction Genetics Consortium Investigators. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371, 2072–2082 (2014).
Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).
Lp-PLA(2) Studies Collaboration et al. Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 375, 1536–1544 (2010).
Wilensky, R. L. et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat. Med. 14, 1059–1066 (2008).
The STABILITY Investigators. Darapladib for preventing ischemic events in stable coronary heart disease. N. Engl. J. Med. 370, 1702–1711 (2014).
O'Donoghue, M. L. et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA 312, 1006–1015 (2014).
Polfus, L. M. et al. Coronary heart disease and genetic variants with low phospholipase A2 activity. N. Engl. J. Med. 372, 295–296 (2015).
Casas, J. P. et al. PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry. Circulation 121, 2284–2293 (2010).
Robinson, J. G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).
Sabatine, M. S. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1500–1509 (2015).
Gaudet, D. et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373, 438–447 (2015).
Tsimikas, S. et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–1483 (2015).
Swerdlow, D. I. et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 385, 351–361 (2015).
Sattar, N. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375, 735–742 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01252953 (2016).
Neale, B. M. et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl Acad. Sci. USA 107, 7395–7400 (2010).
Chen, W. et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc. Natl Acad. Sci. USA 107, 7401–7406 (2010).
Cheng, C. Y. et al. New loci and coding variants confer risk for age-related macular degeneration in East Asians. Nat. Commun. 6, 6063 (2015).
Bush, W. S., Oetjens, M. T. & Crawford, D. C. Unravelling the human genome–phenome relationship using phenome-wide association studies. Nat. Rev. Genet. 17, 129–145 (2016).
Emdin, C. A. et al. Phenotypic characterization of genetically lowered human lipoprotein(a) levels. J. Am. Coll. Cardiol. 68, 2761–2772 (2016).
Sawabe, M. et al. Low lipoprotein(a) concentration is associated with cancer and all-cause deaths: a population-based cohort study (the JMS cohort study). PLoS ONE. 7, e31954 (2012).
Mora, S. et al. Lipoprotein(a) and risk of type 2 diabetes. Clin. Chem. 56, 1252–1260 (2010).
Lichtenstein, L. et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab. 12, 580–592 (2010).
Desai, U. et al. Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice. Proc. Natl Acad. Sci. USA 104, 11766–11771 (2007).
Gibson, G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2012).
McClellan, J. & King, M. C. Genetic heterogeneity in human disease. Cell 141, 210–217 (2010).
Nelson, M. R. et al. The genetics of drug efficacy: opportunities and challenges. Nat. Rev. Genet. 17, 197–206 (2016).
Paynter, N. P., Ridker, P. M. & Chasman, D. I. Are genetic tests for atherosclerosis ready for routine clinical use? Circ. Res. 118, 607–619 (2016).
Umans-Eckenhausen, M. A., Defesche, J. C., Sijbrands, E. J., Scheerder, R. L. & Kastelein, J. J. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357, 165–168 (2001).
Nordestgaard, B. G. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart J. 34, 3478–3490 (2013).
Khera, A. V. et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J. Am. Coll. Cardiol. 67, 2578–2589 (2016).
Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
Talmud, P. J. et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case–control study. Lancet 381, 1293–1301 (2013).
Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1138 (1994).
Cholesterol Treatment Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380, 581–590 (2012).
Chatterjee, N., Shi, J. & García-Closas, M. Developing and evaluating polygenic risk prediction models for stratified disease prevention. Nat. Rev. Genet. 17, 392–406 (2016).
Kathiresan, S. et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N. Engl. J. Med. 358, 1240–1249 (2008).
Ripatti, S. et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376, 1393–1400 (2010).
Tada, H. et al. Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history. Eur. Heart J. 37, 561–567 (2016).
Abraham, G. et al. Genomic prediction of coronary heart disease. Eur Heart J. 37, 3267–3278 (2016).
Mega, J. L. et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet 385, 2264–2271 (2015).
Kullo, I. J. et al. Incorporating a genetic risk score into coronary heart disease risk estimates: effect on low-density lipoprotein cholesterol levels (the MI-GENES clinical trial). Circulation 133, 1181–1188 (2016).
Wellcome Trust Case Control Consortium et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).
ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636–640 (2004).
GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).
Stylianou, I. M., Bauer, R. C., Reilly, M. P. & Rader, D. J. Genetic basis of atherosclerosis: insights from mice and humans. Circ. Res. 110, 337–355 (2012).
Nurnberg, S. T. et al. From loci to biology: functional genomics of genome-wide association for coronary disease. Circ. Res. 118, 586–606 (2016).
Narasimhan, V. M. et al. Health and population effects of rare gene knockouts in adult humans with related parents. Science 352, 474–477 (2016).
Saleheen, D. et al. Human knockouts in a cohort with a high rate of consanguinity. Preprint at bioRxiv http://dx.doi.org/10.1101/031518 (2015). Identifies humans with inactivating mutations ('knockouts') in ∼1,000 genes and genotype-based call back to understand relevant physiology.
Choudhry, N. K. et al. Full coverage for preventive medications after myocardial infarction. N. Engl. J. Med. 365, 2088–2097 (2011).
Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).
Ding, Q. et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ. Res. 115, 488–492 (2014). Proof-of-concept study in a mouse model that permanent disruption of PCSK9 using gene editing can decrease LDL cholesterol and atherosclerosis.
Lander, E. S. Brave new genome. N. Engl. J. Med. 373, 5–8 (2015).
Blendon, R. J., Gorski, M. T. & Benson, J. M. The public and the gene-editing revolution. N. Engl. J. Med. 374, 1406–1411 (2016).
Libby, P. in Braunwald's Heart Disease: a Textbook of Cardiovascular Medicine 10th edn (eds Bonow, R. O., Mann, D. L., Zipes, D. P. & Libby, P.) 873–890 (Saunders, 2014).
Ridker, P. M., Libby, P. & Buring, J. E. in Braunwald's Heart Disease: a Textbook of Cardiovascular Medicine 10th edn (eds Bonow, R. O., Mann, D. L., Zipes, D. P. & Libby, P.) 891–933 (Saunders, 2014).
Kessler, T., Vilne, B. & Schunkert, H. The impact of genome-wide association studies on the pathophysiology and therapy of cardiovascular disease. EMBO Mol. Med. 8, 688–701 (2016).
A.V.K. is supported by a John S. LaDue Memorial Fellowship in Cardiology and a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst. S.K. is supported by an Ofer and Shelley Nemirovsky MGH Research Scholar Award and by grants HL127564 and UM1HG008895 from the US National Institutes of Health.
A.V.K. has received consulting fees from Amarin Pharmaceuticals and Merck & Co. S.K. has received grant support from Bayer Healthcare and Amarin, equity in San Therapeutics, and Catabasis, and received personal fees for scientific advisory board participation for Bayer Healthcare, Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly & Company, Leerink Partners, Noble Insights and Ionis Pharmaceuticals.
Capable of being transmitted from parent to offspring via genetic variation.
- Genetic architecture
The full spectrum of common and rare genetic variation that contributes to a trait of interest.
- Linkage analysis
Systematic localization of a genetic region that is co-inherited with a trait of interest in members of a family.
- Monogenic drivers
Variations in a single gene dictates the observed variation in a trait of interest; also referred to as Mendelian disorders.
- Allele frequency
The relative frequency of an allele (specific genetic variant) in the population; typically reported as the proportion of all chromosomes in the population that carry an allele.
- Inactivating mutations
Variants that disrupt the ability of a given gene to produce its protein product, that is, due to premature truncation, scrambling of the amino acid code or disrupting gene splicing.
- Mendelian randomization
A human genetics tool that leverages the random assortment of genetic variants at time of conception to assess causality of observed associations.
Production of offspring by related individuals (for example, second cousins or closer).
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