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

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.

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

eLife ◽

10.7554/elife.43657 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 59

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

The 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<5×10−05) 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.

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Validation of a Trans-Ancestry Polygenic Risk Score for Type 2 Diabetes in Diverse Populations

10.1101/2021.09.11.21263413 ◽

2021 ◽

Author(s):

Tian Ge ◽

Amit Patki ◽

Vinodh Srinivasasainagendra ◽

Yen-Feng Lin ◽

Marguerite Ryan Irvin ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

African American ◽

Large Scale ◽

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk

ABSTRACTType 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for an equitable deployment of PRS to clinical practice that benefits global populations. Here we integrate T2D GWAS in European, African American and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and evaluate the PRS in the multi-ethnic eMERGE study, four African American cohorts, and the Taiwan Biobank. The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined, and the top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5 fold of increase in T2D risk, suggesting the potential of using the trans-ancestry PRS as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

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Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa289 ◽

2020 ◽

Author(s):

Niccolo’ Tesi ◽

Sven J van der Lee ◽

Marc Hulsman ◽

Iris E Jansen ◽

Najada Stringa ◽

...

Keyword(s):

Older Adults ◽

Cellular Response ◽

Molecular Mechanisms ◽

Association Studies ◽

Risk Scores ◽

Human Longevity ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

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Performance of polygenic risk scores for cancer prediction in an academic biobank.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.1528 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 1528-1528

Author(s):

Heena Desai ◽

Anh Le ◽

Ryan Hausler ◽

Shefali Verma ◽

Anurag Verma ◽

...

Keyword(s):

Risk Score ◽

Genetic Variants ◽

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

European Americans ◽

Genome Wide ◽

Common Genetic Variants

1528 Background: The discovery of rare genetic variants associated with cancer have a tremendous impact on reducing cancer morbidity and mortality when identified; however, rare variants are found in less than 5% of cancer patients. Genome wide association studies (GWAS) have identified hundreds of common genetic variants significantly associated with a number of cancers, but the clinical utility of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear. Methods: We tested the ability of polygenic risk score (PRS) models developed from genome-wide significant variants to differentiate cases versus controls in the Penn Medicine Biobank. Cases for 15 different cancers and cancer-free controls were identified using electronic health record billing codes for 11,524 European American and 5,994 African American individuals from the Penn Medicine Biobank. Results: The discriminatory ability of the 15 PRS models to distinguish their respective cancer cases versus controls ranged from 0.68-0.79 in European Americans and 0.74-0.93 in African Americans. Seven of the 15 cancer PRS trended towards an association with their cancer at a p<0.05 (Table), and PRS for prostate, thyroid and melanoma were significantly associated with their cancers at a bonferroni corrected p<0.003 with OR 1.3-1.6 in European Americans. Conclusions: Our data demonstrate that common variants with significant associations from GWAS studies can distinguish cancer cases versus controls for some cancers in an unselected biobank population. Given the small effects, future studies are needed to determine how best to incorporate PRS with other risk factors in the precision prediction of cancer risk. [Table: see text]

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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.

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Genomic Prediction of Depression Risk and Resilience Under Stress

10.1101/599456 ◽

2019 ◽

Author(s):

Yu Fang ◽

Laura Scott ◽

Peter Song ◽

Margit Burmeister ◽

Srijan Sen

Keyword(s):

Risk Score ◽

Large Scale ◽

Association Studies ◽

Health Study ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Risk And Resilience ◽

Polygenic Risk ◽

Response To Stress ◽

Training Stress

AbstractAdvancing our ability to predict who is likely to develop depression in response to stress holds great potential in reducing the burden of the disorder. Large-scale genome-wide association studies (GWAS) of depression have, for the first time, provided a basis for meaningful depression polygenic risk score construction (MDD-PRS). The Intern Health Study utilizes the predictable and large increase in depression with physician training stress to identify predictors of depression. Applying the MDD-PRS derived from the PGC2/23andMe GWAS to 5,227 training physicians, we found that MDD-PRS predicted depression under training stress (beta=0.082, p=2.1×10−12) and that MDD-PRS was significantly more strongly associated with depression under stress than at baseline (MDD-PRS × stress interaction - beta=0.029, p=0.02). While known risk factors accounted for 85.6% of the association between MDD-PRS and depression at baseline, they only accounted for 55.4% of the association between MDD-PRS and depression under stress, suggesting that MDD-PRS can add unique predictive power to existing models of depression under stress. Further, we found that low MDD-PRS may have particular utility in identifying individuals with high resilience. Together, these findings suggest that polygenic risk score holds promise in furthering our ability to predict vulnerability and resilience under stress.

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The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Schizophrenia Bulletin ◽

10.1093/schbul/sbz061 ◽

2019 ◽

Cited By ~ 7

Author(s):

Alexander L Richards ◽

Antonio F Pardiñas ◽

Aura Frizzati ◽

Katherine E Tansey ◽

Amy J Lynham ◽

...

Keyword(s):

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Related Factors ◽

Polygenic Risk ◽

Genome Wide ◽

A Genome ◽

Genetic Overlap ◽

Individual Variant

Abstract Background Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

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Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00754-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Anna Zettergren ◽

◽

Jodie Lord ◽

Nicholas J. Ashton ◽

Andrea L. Benedet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Studies ◽

Amyloid Β ◽

Total Sample ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Tau Pathology ◽

Polygenic Risk

Abstract Background Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer’s disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. Methods Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). Results Associations between plasma p-tau181 and APOE PRSs (p = 3e−18–7e−15) and non-APOE PRSs (p = 3e−4–0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e−5–1e−3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). Conclusions Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

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Genetic liability in individuals at ultra-high risk of psychosis: A comparison study of 9 psychiatric traits

PLoS ONE ◽

10.1371/journal.pone.0243104 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243104

Author(s):

Keane Lim ◽

Max Lam ◽

Hailiang Huang ◽

Jianjun Liu ◽

Jimmy Lee

Keyword(s):

High Risk ◽

Large Scale ◽

Association Studies ◽

Predictive Ability ◽

Risk Scores ◽

Psychotic Symptoms ◽

Genome Wide Association Studies ◽

Healthy Controls ◽

Genetic Liability ◽

Ultra High Risk

Individuals at ultra-high risk (UHR) of psychosis are characterised by the emergence of attenuated psychotic symptoms and deterioration in functioning. In view of the high non-psychotic comorbidity and low rates of transition to psychosis, the specificity of the UHR status has been called into question. This study aims to (i) investigate if the UHR construct is associated with the genetic liability of schizophrenia or other psychiatric conditions; (ii) examine the ability of polygenic risk scores (PRS) to discriminate healthy controls from UHR, remission and conversion status. PRS was calculated for 210 youths (nUHR = 102, nControl = 108) recruited as part of the Longitudinal Youth at Risk Study (LYRIKS) using nine psychiatric traits derived from twelve large-scale psychiatric genome-wide association studies as discovery datasets. PRS was also examined to discriminate UHR-Healthy control status, and healthy controls from UHR remission and conversion status. Result indicated that schizophrenia PRS appears to best index the genetic liability of UHR, while trend level associations were observed for depression and cross-disorder PRS. Schizophrenia PRS discriminated healthy controls from UHR (R2 = 7.9%, p = 2.59 x 10−3, OR = 1.82), healthy controls from non-remitters (R2 = 8.1%, p = 4.90 x 10−4, OR = 1.90), and converters (R2 = 7.6%, p = 1.61 x 10−3, OR = 1.82), with modest predictive ability. A trend gradient increase in schizophrenia PRS was observed across categories. The association between schizophrenia PRS and UHR status supports the hypothesis that the schizophrenia polygenic liability indexes the risk for developing psychosis.

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Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality

10.1101/2020.03.13.20035527 ◽

2020 ◽

Author(s):

Allison Meisner ◽

Prosenjit Kundu ◽

Yan Dora Zhang ◽

Lauren V. Lan ◽

Sungwon Kim ◽

...

Keyword(s):

Risk Factors ◽

Mortality Risk ◽

Association Studies ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Hazard Ratios ◽

Risk Of Mortality ◽

All Cause Mortality ◽

The Uk

ABSTRACTWhile genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data: the estimated hazard ratios per standard deviation were 1.10 (95% confidence interval: 1.05, 1.16) and 1.15 (1.10, 1.19) for women and men, respectively. Differences in life expectancy between the top and bottom 5% of the cPRS were estimated to be 4.79 (1.76, 7.81) years and 6.75 (4.16, 9.35) years for women and men, respectively. These associations were substantially attenuated after adjusting for non-genetic mortality risk factors measured at study entry. The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.

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