Polygenic and clinical risk scores and their impact on age at onset of cardiometabolic diseases and common cancers

ABSTRACTBackgroundPolygenic risk scores (PRS) have shown promise in predicting susceptibility to common diseases. However, the extent to which PRS and clinical risk factors act jointly and identify high-risk individuals for early onset of disease is unknown.MethodsWe used large-scale biobank data (the FinnGen study; n=135,300), with up to 46 years of prospective follow-up, and the FINRISK study with standardized clinical risk factor measurements to build genome-wide PRSs with >6M variants for coronary heart disease (CHD), type 2 diabetes (T2D), atrial fibrillation (AF), and breast and prostate cancer. We evaluated their associations with first disease events, age at disease onset, and impact together with routinely used clinical risk scores for predicting future disease.ResultsCompared to the 20-80th percentiles, a PRS in the top 2.5% translated into hazard ratios (HRs) for incident disease ranging from 2.03 to 4.28 (p-values 1.96×10−59 to <1.00×10−100) and the bottom 2.5% into HRs ranging from 0.20 to 0.61. The estimated difference in age at disease onset between top and bottom 2.5% of PRSs was 6 to 13 years. Among early-onset cases, 21.3-32.9% had a PRS in the highest decile and in CHD and AF.ConclusionsThe properties of PRS were similar in all five diseases. PRS identified a considerable proportion early-onset cases, and for all ages the performance of PRS was comparable to established clinical risk scores. These findings warrant further clinical studies on application of polygenic risk information for stratified screening or for guiding lifestyle and preventive medical interventions.

Download Full-text

Polygenic Risk Scores Predict Hypertension Onset and Cardiovascular Risk

Hypertension ◽

10.1161/hypertensionaha.120.16471 ◽

2021 ◽

Vol 77 (4) ◽

pp. 1119-1127 ◽

Cited By ~ 3

Author(s):

Felix Vaura ◽

Anni Kauko ◽

Karri Suvila ◽

Aki S. Havulinna ◽

Nina Mars ◽

...

Keyword(s):

Risk Prediction ◽

Early Onset ◽

Late Onset ◽

Risk Scores ◽

Event Analysis ◽

Cvd Risk ◽

Polygenic Risk ◽

Clinical Risk ◽

Traditional Risk Factors ◽

Association Data

Although genetic risk scores have been used to predict hypertension, their utility in the clinical setting remains uncertain. Our study comprised N=218 792 FinnGen participants (mean age 58 years, 56% women) and N=22 624 well-phenotyped FINRISK participants (mean age 50 years, 53% women). We used public genome-wide association data to compute polygenic risk scores (PRSs) for systolic and diastolic blood pressure (BP). Using time-to-event analysis, we then assessed (1) the association of BP PRSs with hypertension and cardiovascular disease (CVD) in FinnGen and (2) the improvement in model discrimination when combining BP PRSs with the validated 4- and 10-year clinical risk scores for hypertension and CVD in FINRISK. In FinnGen, compared with having a 20 to 80 percentile range PRS, a PRS in the highest 2.5% conferred 2.3-fold (95% CI, 2.2–2.4) risk of hypertension and 10.6 years (95% CI, 9.9–11.4) earlier hypertension onset. In subgroup analyses, this risk was only 1.6-fold (95% CI, 1.5–1.7) for late-onset hypertension (age ≥55 years) but 2.8-fold (95% CI, 2.6–2.9) for early-onset hypertension (age <55 years). Elevated systolic BP PRS also conferred 1.3-fold (95% CI, 1.2–1.4) risk of CVD and 2.3 years (95% CI, 1.6–3.1) earlier onset. In FINRISK, systolic and diastolic BP PRSs improved clinical risk prediction of hypertension (but not CVD), increasing the C statistics by 0.7% (95% CI, 0.3–1.1). We demonstrate that genetic information improves hypertension risk prediction. BP PRSs together with traditional risk factors could improve prediction of hypertension and particularly early-onset hypertension, which confers substantial CVD risk.

Download Full-text

Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

10.1101/165209 ◽

2017 ◽

Cited By ~ 1

Author(s):

Jorge L Del-Aguila ◽

Benjamin Saef ◽

Kathleen Black ◽

Maria Victoria Fernandez ◽

John Budde ◽

...

Keyword(s):

Early Onset ◽

Genetic Architecture ◽

Late Onset ◽

Age At Onset ◽

Risk Scores ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Risk Variants ◽

Genome Wide ◽

Load Risk

AbstractObjective:To determine whether the genetic architecture of sporadic late-onset Alzheimer’s Disease (sLOAD) has an effect on familial late-onset AD (fLOAD), sporadic early-onset (sEOAD) and autosomal dominant early-onset (eADAD).Methods:Polygenic risk scores (PRS) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.Results:We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29×10-7), followed by fLOAD (OR=1.75; p=1.12×10-7) and sLOAD (OR=1.40; p=1.21×10-3). PRS is associated with cerebrospinal fluid ptau181-Aβ42on eADAD.Conclusion:Our analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier-onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.

Download Full-text

An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

10.1101/467910 ◽

2018 ◽

Cited By ~ 1

Author(s):

Tom G. Richardson ◽

Sean Harrison ◽

Gibran Hemani ◽

George Davey Smith

Keyword(s):

Web Application ◽

Large Scale ◽

Complex Disease ◽

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Genetic Liability ◽

Polygenic Risk ◽

The Uk

AbstractThe age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (P<5×l0 05) derived from GWAS and 551 heritable traits from the UK Biobank study (N=334,398). Findings can be investigated using a web application (http://mrcieu.mrsoftware.org/PRS_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility.To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.

Download Full-text

Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition

Neurology ◽

10.1212/wnl.0000000000005415 ◽

2018 ◽

Vol 90 (18) ◽

pp. e1605-e1612 ◽

Cited By ~ 24

Author(s):

Tian Ge ◽

Mert R. Sabuncu ◽

Jordan W. Smoller ◽

Reisa A. Sperling ◽

Elizabeth C. Mormino ◽

...

Keyword(s):

Cognitive Decline ◽

Genetic Risk ◽

Large Scale ◽

Association Studies ◽

Specific Effect ◽

Hippocampal Volume ◽

Risk Scores ◽

Hippocampal Atrophy ◽

Genome Wide Association Studies ◽

Polygenic Risk

ObjectiveTo investigate the effects of genetic risk of Alzheimer disease (AD) dementia in the context of β-amyloid (Aβ) accumulation.MethodsWe analyzed data from 702 participants (221 clinically normal, 367 with mild cognitive impairment, and 114 with AD dementia) with genetic data and florbetapir PET available. A subset of 669 participants additionally had longitudinal MRI scans to assess hippocampal volume. Polygenic risk scores (PRSs) were estimated with summary statistics from previous large-scale genome-wide association studies of AD dementia. We examined relationships between APOE ε4 status and PRS with longitudinal Aβ and cognitive and hippocampal volume measurements.ResultsAPOE ε4 was strongly related to baseline Aβ, whereas only weak associations between PRS and baseline Aβ were present. APOE ε4 was additionally related to greater memory decline and hippocampal atrophy in Aβ+ participants. When APOE ε4 was controlled for, PRS was related to cognitive decline in Aβ+ participants. Finally, PRSs were associated with hippocampal atrophy in Aβ− participants and weakly associated with baseline hippocampal volume in Aβ+ participants.ConclusionsGenetic risk factors of AD dementia demonstrate effects related to Aβ, as well as synergistic interactions with Aβ. The specific effect of faster cognitive decline in Aβ+ individuals with higher genetic risk may explain the large degree of heterogeneity in cognitive trajectories among Aβ+ individuals. Consideration of genetic variants in conjunction with baseline Aβ may improve enrichment strategies for clinical trials targeting Aβ+ individuals most at risk for imminent cognitive decline.

Download Full-text

Left Atrial Spontaneous Echo Contrast Occurring in Patients with Low CHADS2 or CHA2DS2-VASc Scores

10.21203/rs.3.rs-22138/v2 ◽

2020 ◽

Author(s):

Kanako Akamatsu ◽

Takahide Ito ◽

Michishige Ozeki ◽

Masatoshi Miyamura ◽

Koichi Sohmiya ◽

...

Keyword(s):

Odds Ratio ◽

Left Atrial ◽

Large Scale ◽

Elevated Serum ◽

Multivariate Logistic Regression Analysis ◽

Left Ventricular ◽

Risk Scores ◽

Considerable Proportion ◽

Thromboembolic Risk ◽

Spontaneous Echo Contrast

Abstract Background: Left atrial spontaneous echo contrast (LASEC) is common in patients with atrial fibrillation (AF), although scarce information exists on LASEC occurring in nonvalvular AF patients who have low thromboembolic risk scores. We therefore examined prevalence and determinants of LASEC under low CHADS 2 or CHA 2 DS 2 -VASc scores in these patients. Methods: Among 713 patients who underwent transesophageal echocardiography, 349 with a CHADS 2 score <2 (CHADS 2 group) (93 women, mean age 65 years) and 221 with a CHA 2 DS 2 -VASc score <2 (CHA 2 DS 2 -VASc group) (39 women, mean age 62 years) were separately examined for clinical and echocardiographic findings. Results: LASEC was found in 77 patients of CHADS 2 group (22%) and in 41 of CHA 2 DS 2 -VASc group (19%). Multivariate logistic regression analysis, adjusted for parameters including non-paroxysmal AF, LA diameter ≥50 mm, left ventricular (LV) hypertrophy, and an elevated serum B-type natriuretic peptide (BNP) (≥200 pg/mL), revealed that for CHADS 2 group, non-paroxysmal AF (Odds ratio 5.65, 95%CI 3.08-10.45, P <0.001), BNP elevation (Odds ratio 3.42, 95%CI 1.29-9.06, P = 0.013), and LV hypertrophy (Odds ratio 2.26, 95%CI 1.19-4.28, P = 0.013) were significant independent determinants of LASEC, and that for CHA 2 DS 2 -VASc group, non-paroxysmal AF (Odds ratio 3.38, 95%CI 1.51-7.54, P = 0.003) and LV hypertrophy (Odds ratio 2.53, 95%CI 1.13-5.70, P = 0.025) were significant independent determinants of LASEC.Conclusions: LASEC was present in a considerable proportion of patients with nonvalvular AF under low thromboembolic risk scores. Information on AF chronicity, BNP, and LV hypertrophy may help avoid transesophageal echocardiographic assessment of LASEC, but large-scale studies are necessary to confirm our observations.

Download Full-text

Comparisons of Polyexposure, Polygenic, and Clinical Risk Scores in Risk Prediction of Type 2 Diabetes

10.2337/figshare.13607828 ◽

2021 ◽

Author(s):

Yixuan He ◽

Chirag M Lakhani ◽

Danielle Rasooly ◽

Arjun K Manrai ◽

Ioanna Tzoulaki ◽

...

Keyword(s):

Risk Factors ◽

Risk Prediction ◽

Risk Score ◽

Prediction Models ◽

Disease Risk ◽

Clinical Risk Factors ◽

Risk Scores ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Clinical Risk

OBJECTIVE: <p>Establish a polyexposure score for T2D incorporating 12 non-genetic exposure and examine whether a polyexposure and/or a polygenic risk score improves diabetes prediction beyond traditional clinical risk factors.</p> <h2><a></a>RESEARCH DESIGN AND METHODS:</h2> <p>We identified 356,621 unrelated individuals from the UK Biobank of white British ancestry with no prior diagnosis of T2D and normal HbA1c levels. Using self-reported and hospital admission information, we deployed a machine learning procedure to select the most predictive and robust factors out of 111 non-genetically ascertained exposure and lifestyle variables for the polyexposure risk score (PXS) in prospective T2D. We computed the clinical risk score (CRS) and polygenic risk score (PGS) by taking a weighted sum of eight established clinical risk factors and over six million SNPs, respectively.</p> <h2><a></a>RESULTS:</h2> <p>In the study population, 7,513 had incident T2D. The C-statistics for the PGS, PXS, and CRS models were 0.709, 0.762, and 0.839, respectively. Hazard ratios (HR) associated with risk score values in the top 10% percentile versus the remaining population is 2.00, 5.90, and 9.97 for PGS, PXS, and CRS respectively. Addition of PGS and PXS to CRS improves T2D classification accuracy with a continuous net reclassification index of 15.2% and 30.1% for cases, respectively, and 7.3% and 16.9% for controls, respectively. </p> <h2><a></a>CONCLUSIONS:</h2> <p>For T2D, the PXS provides modest incremental predictive value over established clinical risk factors. The concept of PXS merits further consideration in T2D risk stratification and is likely to be useful in other chronic disease risk prediction models.</p>

Download Full-text

EFFECTS OF SCHIZOPHRENIA AND BIPOLAR POLYGENIC RISK SCORES ON AGE AT ONSET IN BIPOLAR DISORDER

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2017.08.331 ◽

2019 ◽

Vol 29 ◽

pp. S967

Author(s):

Janos Kalman ◽

Sergi Papiol ◽

Urs Heilbronner ◽

Till F.M. Andlauer ◽

Heike Anderson-Schmidt ◽

...

Keyword(s):

Bipolar Disorder ◽

Age At Onset ◽

Risk Scores ◽

Polygenic Risk

Download Full-text

Heterogeneity of the Predictive Polygenic Risk Scores for Coronary Heart Disease Age-at-onset in Three Different CHD Family-based Ascertainments

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003201 ◽

2021 ◽

Author(s):

Mary F. Feitosa ◽

Allison L. Kuipers ◽

Mary K. Wojczynski ◽

Lihua Wang ◽

Emma Barinas-Mitchell ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Family History ◽

High Risk ◽

Healthy Aging ◽

Age At Onset ◽

Risk Scores ◽

Polygenic Risk ◽

Chd Risk ◽

Family Based

Background - Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly. Methods - Our study included three family-based ascertainments: Long Life Family Study (LLFS, N Individuals =4,572), which represents a low CHD risk, and Family Heart Study, which consists of randomly selected families (FamHS-Random, N Individuals =1,806), and high CHD risk families (FamHS-High Risk, N Individuals =2,301). We examined the effects of PRS, sex, family ascertainment, PRS interaction with sex (PRS*Sex) and with family ascertainment (PRS*LLFS and PRS*FamHS-High Risk) on CHD, corrected for traditional cardiovascular risk factors using Cox proportional hazard regression models. Results - Healthy-aging LLFS presented ~17 years delayed for CHD age-at-onset compared with FamHS-High Risk ( P <1.0x10 -4 ). Sex-specific association ( P <1.0x10 -17 ) and PRS*Sex ( P =2.7x10 -3 ) predicted prevalent CHD. CHD age-at-onset was associated with PRS (HR=1.57, P =1.3x10 -5 ), LLFS (HR=0.54, P =2.6x10 -5 ) and FamHS-High Risk (HR=2.86, P =6.70x10 -15 ) in men, and with PRS (HR=1.76, P =7.70x10 -3 ), FamHS-High Risk (HR=4.88, P =8.70x10 -10 ) and PRS*FamHS-High Risk (HR=0.61, P =3.60x10 -2 ) in women. In the PRS extreme quartile distributions, CHD age-at-onset was associated ( P <0.05) with PRS, FamHS-High Risk, and PRS interactions with both low and high CHD risk families for women. For men, the PRS quartile results remained similar to the whole distribution. Conclusions - Differences in CHD family-based ascertainments show evidence of PRS interacting with sex to predict CHD risk. In women, CHD age-at-onset was associated with PRS, CHD family history, and interactions of PRS with family history. In men, PRS and CHD family history were the major effects on the CHD age-at-onset. Understanding the heterogeneity of risks associated with CHD endpoints at both the personal and familial levels may shed light on the underlying genetic effects influencing CHD and lead to more personalized risk prediction.

Download Full-text