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2.
Nat Genet ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.

3.
Blood ; 134(19): 1645-1657, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

4.
Nat Med ; 25(8): 1274-1279, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285632

RESUMO

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.


Assuntos
Estudo de Associação Genômica Ampla , Doença Arterial Periférica/genética , Idoso , LDL-Colesterol/genética , Fator V/genética , Inibidores do Fator Xa/uso terapêutico , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Receptores de LDL/genética , Veteranos
5.
J Am Coll Cardiol ; 74(4): 578-586, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31345433

RESUMO

The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31326481

RESUMO

OBJECTIVES: This study sought to assess medical management of patients found to have nonobstructive coronary artery disease (CAD) on coronary computed tomography angiography (CCTA) performed in the emergency department (ED). BACKGROUND: Contemporary recognition and management of nonobstructive CAD discovered on CCTA performed in the ED is unknown. METHODS: Patients undergoing CCTA in the authors' hospital's ED between November 2013 and March 2018 who also received primary care within the authors' health system were studied. All patients with nonobstructive CAD, defined as 1% to 49% maximum luminal stenosis on CCTA, were included, along with a control group without CAD in a 1 case:1 control fashion. Ten-year atherosclerotic cardiovascular disease (ASCVD) risk prior to CCTA was estimated using the Pooled Cohort Equations. Management changes were recorded until 6 months after CCTA. Multivariate logistic regression tested the association between CCTA result and follow-up statin prescription, adjusting for cardiovascular risk factors and baseline statin use. RESULTS: The cohort included 510 patients with nonobstructive CAD and 510 controls. Prevalence of statin prescription increased from 38.8% to 56.1% among patients with nonobstructive CAD (p < 0.001) and 18.0% to 20.4% among controls (p = 0.01), representing a 7.1-fold relative difference (95% confidence interval [CI]: 4.4 to 23.0; p < 0.001) in multivariate analysis. However, 30.0% of patients with nonobstructive CAD and ≥20% 10-year ASCVD risk were not prescribed a statin at the end of follow-up. Cardiologist evaluation was independently associated with statin prescription after adjustment for ASCVD risk factors (odds ratio [OR] 4.4; 95% CI: 2.4 to 8.5; p < 0.001). A Coronary Artery Disease Reporting and Data System class 1 to 2 result was associated with lower low-density lipoprotein cholesterol by 12.1 mg/dl at mean 1.9-year follow-up (p < 0.001). CONCLUSIONS: Incidental subclinical atherosclerosis on CCTA performed in the ED increases the likelihood of statin prescription, but opportunities to improve allocation of indicated preventive therapies remain.

7.
Circulation ; 140(12): 1031-1040, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

9.
J Am Coll Cardiol ; 73(17): 2135-2145, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047001

RESUMO

BACKGROUND: Concentrations of circulating apolipoproteins are strongly linked to risk for coronary artery disease (CAD). The relative importance of the additional knowledge of apolipoprotein concentrations within specific lipoprotein species for CAD risk prediction is limited. OBJECTIVES: This study sought to evaluate the performance of a high-density lipoprotein (HDL) apolipoproteomic score, based on targeted mass spectrometry of HDL-associated apolipoproteins, for the detection of angiographic CAD and outcomes. METHODS: HDL-associated apolipoprotein (apo) A-1, apoC-1, apoC-2, apoC-3, and apoC-4 were measured in 943 participants without prevalent myocardial infarction (MI) referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study. A composite HDL apolipoproteomic score (pCAD) was associated with likelihood of obstructive CAD (≥70% lesion in ≥1 vessel) and with incident cardiovascular outcomes over 4-year follow-up. RESULTS: There were 587 (62.2%) patients with coronary stenosis. The pCAD score was associated with the presence of obstructive CAD (odds ratio: 1.39; 95% confidence interval [CI]: 1.14 to 1.69; p < 0.001), independently of conventional cardiovascular risk factors including circulating plasma apoA-1 and apoB. The C-index for pCAD was 0.63 (95% CI: 0.59 to 0.67) for the presence of obstructive CAD. Although pCAD was not associated with cardiovascular mortality among all individuals (hazard ratio: 1.24; 95% CI: 0.93 to 1.66; p = 0.15), there was evidence of association for individuals with obstructive CAD (hazard ratio: 1.48; 95% CI: 1.07 to 2.05; p = 0.019). CONCLUSIONS: An HDL apolipoproteomic score is associated with the presence of CAD, independent of circulating apoA-1 and apoB concentrations and other conventional cardiovascular risk factors. Among individuals with CAD, this score may be independently associated cardiovascular death. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).

10.
Arterioscler Thromb Vasc Biol ; 39(6): 1253-1261, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31070453

RESUMO

Objective- Arterial stiffness index (ASI) is independently associated with blood pressure (BP) and coronary artery disease (CAD) epidemiologically. However, it is unknown whether these associations represent causal relationships. Here, we assess whether genetic predisposition to increased ASI is associated with elevated BP and CAD risk. Approach and Results- We first performed a large-scale epidemiological association of finger photoplethysmography-derived ASI in the UK Biobank, finding significant associations with systolic BP (ß=0.55 mm Hg; [95% CI, 0.45-0.65]; P=5.77×10-24; N=137 858), diastolic BP (ß=1.05 mm Hg; [95% CI, 0.99-1.11]; P=7.27×10-272; N=137 862), and incident CAD (hazard ratio, 1.08; [95% CI, 1.04-1.11]; P=1.5×10-6; N=3692 cases, 126 615 controls) in multivariable models. We then performed an ASI genome-wide association study analysis in 131 686 participants from the UK Biobank. Across participants not in the ASI genome-wide association study, a 6-variant ASI polygenic risk score was calculated. Each SD increase in genetic ASI was associated with systolic BP (ß=4.63 mm Hg; [95% CI, 2.1-7.2]; P=3.37×10-4; N=208 897), and diastolic BP (ß=2.61 mm Hg; [95% CI, 1.2-4.0]; P=2.85×10-4; N=208 897); however, no association was observed with incident CAD (hazard ratio, 1.12; [95% CI, 0.55-2.3]; P=0.75; N=223 061; 7534 cases). The lack of CAD association observed was replicated among 184 305 participants (60 810 cases) from the CARDIOGRAMplusC4D (Coronary Artery Disease Genetics Consortium; odds ratio, 0.56; [95% CI, 0.26-1.24]; P=0.15). Conclusions- Our data support the conclusion that finger photoplethysmography-derived ASI is an independent, genetically causal risk factor for BP, but do not support the notion that ASI is a suitable surrogate for CAD risk.

11.
Cardiovasc Res ; 115(5): 830-843, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30789660

RESUMO

Genetic and environmental factors influence the development of coronary artery disease (CAD). Genetic analyses of families and the population continue to yield important fundamental insights for CAD. For the past four decades, CAD human genetic research focused largely on the study of germline genetic variation in CAD and its risk factors. The first genes associated with CAD were discovered using basic Mendelian principles and pedigree analysis. Mapping of the human genome and advancement in sequencing technology sparked further discovery of novel genetic associations through exome sequencing and genome wide association analysis in increasingly larger populations. While prior work implicated in situ DNA damage as a feature of atherosclerosis, more recently, somatic mutagenesis in and clonal expansion of haematopoietic stem cells was found to influence risk of CAD. Mutations observed for this condition, termed clonal haematopoiesis of indeterminate potential, frequently occur within epigenetic regulator genes (e.g. DNMT3A, TET2, ASXL1, etc.), which are also implicated in leukaemogenesis. Hypercholesterolaemic mice with Tet2 bone marrow deficiency are predisposed to the development of atherosclerosis that may be partly related to inflammatory cytokines. As the genetic basis of CAD expands from the germline to somatic genome, our fundamental understanding of CAD continues to evolve; these new discoveries represent new opportunities for risk prediction and prevention, and a new facet of cardio-oncology.

12.
Nat Genet ; 51(3): 568-576, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804563

RESUMO

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.


Assuntos
Transcriptoma/genética , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética
13.
Circulation ; 139(13): 1593-1602, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30586733

RESUMO

BACKGROUND: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual. METHODS: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations. RESULTS: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008). CONCLUSIONS: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

14.
Diabetes ; 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389748

RESUMO

A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C, encoding the activin-receptor like kinase 7 receptor expressed on adipocytes and pancreatic beta cells, which independently associated with reduced WHRadjBMI: Asn150His (-0.09 standard deviations, p=3.4*10-17), Ile195Thr (-0.15 SD, p=1.0*10-9), Ile482Val (-0.019 SD, p=1.6*10-5) and rs72927479 (-0.035 SD, p=2.6*10-12). Carriers of these variants exhibited reduced percent abdominal fat in dual energy X-ray imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (OR 0.70, CI 0.63, 0.77; p = 5.6*10-13). In an analysis of exome sequences from 55516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46 CI 0.27, 0.81; p=0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.

15.
J Am Coll Cardiol ; 72(16): 1894-1897, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30309465
16.
Nat Genet ; 50(11): 1514-1523, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30275531

RESUMO

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

17.
Genet Med ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30270359

RESUMO

PURPOSE: Large-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy. METHODS: The Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants. RESULTS: Via genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations. CONCLUSION: Genotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.

18.
Nat Commun ; 9(1): 3391, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30140000

RESUMO

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

20.
Nat Genet ; 50(9): 1219-1224, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30104762

RESUMO

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2-5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

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