Recommendations for Primary Prevention of Skin Melanoma

Melanoma (MEL) is an aggressive form of skin cancer, causing over 60,000 deaths every year and it is considered one of the fastest-growing cancer forms. Genome-wide association studies have identified numerous genetic variants (SNPs) independently associated with MEL. The effects of such SNPs can be combined into a single polygenic risk score (PRS). Stratification of individuals according to PRS could be introduced to the primary prevention of melanoma. Our aim was to combine PRS with health behavior recommendations to develop a personalized recommendation for primary prevention of melanoma. Previously published PRS models for predicting the risk of melanoma were collected from the literature. Models were validated on the UK Biobank dataset consisting of a total of 487,410 quality-controlled genotypes with 3791 prevalent and 2345 incident cases. The best performing sex-specific models were selected based on the AUC in prevalent data and independently validated on an independent UKBB incident dataset for females and males separately. The best performing model included 28 SNPs. The C-index of the best performing model in the dataset was 0.59 (0.009) and hazard ratio (HR) per unit of PRS was 1.38 (standard error of log (HR) = 0.03) for both males and females. We performed absolute risk simulations on the Estonian population and developed individual risk-based clinical follow-up recommendations. Both models were able to identify individuals with more than a 2-fold risk increase. The observed 10-year risks of developing melanoma for individuals in the 99th percentile exceeded the risk of individuals in the 1st percentile more than 4.5-fold. We have developed a PRS-based recommendations pipeline for individual health behavior suggestions to support melanoma prevention.

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Precision Colorectal Cancer Screening with Polygenic Risk Score

10.1101/2020.08.19.20177931 ◽

2020 ◽

Author(s):

Tonis Tasa ◽

Mikk Puustusmaa ◽

Neeme Tonisson ◽

Berit Kolk ◽

Peeter Padrik

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Association Studies ◽

Absolute Risk ◽

Specific Model ◽

Background Information ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Common Cancer

Colorectal cancer (CRC) is the second most common cancer in women and third most common cancer in men. Genome-wide association studies have identified numerous genetic variants (SNPs) independently associated with CRC. The effects of such SNPs can be combined into a single polygenic risk score (PRS). Stratification of individuals according to PRS could be introduced to primary and secondary prevention. Our aim was to combine risk stratification of a sex-specific PRS model with recommendations for individualized CRC screening. Previously published PRS models for predicting the risk of CRC were collected from the literature. These were validated on the UK Biobank (UKBB) consisting of a total of 458 696 quality-controlled genotypes with 1810 and 1348 prevalent male cases, and 2410 and 1810 incident male and female cases. The best performing sex-specific model was selected based on the AUC in prevalent data and independently validated in the incident dataset. Using Estonian CRC background information, we performed absolute risk simulations and examined the ability of PRS in risk stratifying individual screening recommendations. The best-performing model included 91 SNPs. The C-index of the best performing model in the dataset was 0.613 (SE = 0.007) and hazard ratio (HR) per unit of PRS was 1.53 (1.47 - 1.59) for males. Respective metrics for females were 0.617 (SE = 0.006) and 1.50 (1.44 - 1.58). PRS risk simulations showed that a genetically average 50-year-old female doubles her risk by age 58 (55 in males) and triples it by age 63 (59 in males). In addition, the best performing PRS model was able to identify individuals in one of seven groups proposed by Naber et al. for different coloscopy screening recommendation regimens. We have combined PRS-based recommendations for individual screening attendance. Our approach is easily adaptable to other nationalities by using population-specific background data of other genetically similar populations.

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Precision Prostate Cancer Screening with a Polygenic Risk Score

10.1101/2020.08.23.20180570 ◽

2020 ◽

Author(s):

Tonis Tasa ◽

Mikk Puustusmaa ◽

Neeme Tonisson ◽

Berit Kolk ◽

Peeter Padrik

Keyword(s):

Prostate Cancer ◽

Cancer Screening ◽

Risk Score ◽

Prostate Cancer Screening ◽

Individual Risk ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Psa Testing ◽

Incident Cases

Prostate cancer (PC) is the second-most common type of cancer and the fifth-leading cause of cancer-related death in men worldwide. Genome-wide association studies have identified numerous genetic variants (SNPs) independently associated with PC. The effects of such SNPs can be combined into a single polygenic risk score (PRS). Stratification of men according to PRS could be applied in secondary prevention. We aimed to construct a PRS model and to develop a pipeline for personalized prostate cancer screening. Previously published PRS models for predicting the risk of prostate cancer were collected from the literature. These were validated on the Estonian Biobank (EGC) consisting of a total of 16,390 quality-controlled genotypes with 262 prevalent and 428 incident PC cases and on 209 634 samples in the UK Biobank with 3254 prevalent cases and 6959 incident cases. The best performing model was selected based on the AUC in prevalent data and independently validated in both incident datasets. Using Estonian PC background information, we performed absolute risk simulations and developed individual risk-based clinical follow-up recommendations. The best-performing PRS included 121 SNPs. The C-index of the Cox regression model associating PC status with PRS was 0.641 (SE = 0.015) with a hazard ratio of 1.65 (95% confidence interval 1.51 - 1.81) on the incident EGC dataset. The model is able to identify individuals with more than a 3-fold risk increase. The risk of an average 45-year old could be attained by individuals between the ages of 41 and 52. A 41-year old male on the 95th percentile has the same risk as an average 45-year old but by age 55, he has attained the same genetic risk as an average 68-year-old. PRS is a powerful predictor of prostate cancer risk that can be combined with current non-invasive practices of PC screening. We have developed PRS-based recommendations for personalized PSA testing. Our approach is easily adaptable to other nationalities by using population-specific background data of other genetically similar populations.

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Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept

Journal of Personalized Medicine ◽

10.3390/jpm11040319 ◽

2021 ◽

Vol 11 (4) ◽

pp. 319

Author(s):

Joanne E. Sordillo ◽

Sharon M. Lutz ◽

Michael J. McGeachie ◽

Jessica Lasky-Su ◽

Scott T. Weiss ◽

...

Keyword(s):

Standard Deviation ◽

Risk Score ◽

Association Studies ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Linear Regression Models ◽

Standard Deviation Increase ◽

Polygenic Risk ◽

Bronchodilator Response ◽

Children With Asthma

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma.

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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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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.

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Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score

Journal of Clinical Oncology ◽

10.1200/jco.20.01992 ◽

2021 ◽

pp. JCO.20.01992

Author(s):

Chi Gao ◽

Eric C. Polley ◽

Steven N. Hart ◽

Hongyan Huang ◽

Chunling Hu ◽

...

Keyword(s):

Breast Cancer ◽

General Population ◽

Association Studies ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

First Degree Relatives ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Brca1 Brca2

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

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Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

Journal of the American Society of Nephrology ◽

10.1681/asn.2020111599 ◽

2021 ◽

pp. ASN.2020111599

Author(s):

Zhi Yu ◽

Jin Jin ◽

Adrienne Tin ◽

Anna Köttgen ◽

Bing Yu ◽

...

Keyword(s):

Kidney Function ◽

Kidney Diseases ◽

Association Studies ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Plasma Proteome ◽

Uk Biobank ◽

Polygenic Risk ◽

Genome Wide ◽

A Genome

Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

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Distinct Genetic Profiles in Postpartum Depression With Different Trajectory of Illness

10.21203/rs.3.rs-29168/v1 ◽

2020 ◽

Author(s):

Nagahide Takahashi ◽

Hanae Tainaka ◽

Tomoko Nishimura ◽

Taeko Harada ◽

Akemi Okumura ◽

...

Keyword(s):

Bipolar Disorder ◽

Postpartum Depression ◽

Risk Score ◽

Association Studies ◽

Depression Scale ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Gene Set Enrichment ◽

Polygenic Risk ◽

Gene Set

Abstract BackgroundPostpartum depression (PPD) is a common and highly heritabledisorder in the postnatal period of new mothers. The development of PPD is shown to affectneurodevelopment in children and recent evidence suggests thatthe trajectory of PPDisalso associated with children’s neurodevelopment and mental conditions. Thus, early identification and intervention for individuals at high risk of PPD are urgently needed.Additionally, it is not clear whether genetic factors affect thetrajectory of PPD. Therefore, using a polygenic risk score (PRS) approach, we investigated if PRS for depression (Depression-PRS) and bipolar disorder (Bipolar-PRS) are associated with the development and clinical course of PPD.Methods Usingrecent large genome-wide association studies(GWAS) of depression and bipolar disorder as discovery cohorts, we calculatedDepression-PRS and Bipolar-PRS in each individual. Then, we investigated the possible association between Depression-PRS and Bipolar-PRS with the development andtrajectory of PPD insubjects from the Hamamatsu Birth Cohort for mothers and children (n = 136). Depressive symptoms were assessed using the Edinburgh Postpartum Depression Scale. Gene-set enrichment analyses were used to identify pathways underlying these conditions. ResultsDepression-PRS was significantly higher in subjects with PPD than in those without PPD(t = -3.283, P = 0.002)and logistic analysis showed that Depression-PRS significantly increases therisk of developing PPD(OR [SE] = 2.274 [0.585], P = 0.002). Furthermore, Depression-PRS was positively associated with continuity of PPD (β [SE]=1.621 [0.672]; P = 0.032).Gene-set enrichment analyses revealed that pathways such as“response to hormone”(β[SE] -2.285[1.002], P < 0.001) and “epigenetic regulation”(β[SE] 2.831 [1.317], P < 0.001) were involved in the continuity of PPD. ConclusionThese preliminary findings indicate that the genetic component plays an important role not only in the development but also inthe continuity of PPD. A polygenic risk score approach could be useful to identify subjects at risk for PPD, especially for persistent PPD,who needcareful monitoring and intervention after delivery.

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CONQUER: an interactive toolbox to understand functional consequences of GWAS hits

NAR Genomics and Bioinformatics ◽

10.1093/nargab/lqaa085 ◽

2020 ◽

Vol 2 (4) ◽

Author(s):

Gerard A Bouland ◽

Joline W J Beulens ◽

Joey Nap ◽

Arno R van der Slik ◽

Arnaud Zaldumbide ◽

...

Keyword(s):

Risk Factors ◽

Association Studies ◽

R Package ◽

Integrative Approach ◽

Individual Risk ◽

Genome Wide Association Studies ◽

Genome Database ◽

Intergenic Regions ◽

Functional Consequences ◽

Individual Risk Factors

Abstract Numerous large genome-wide association studies have been performed to understand the influence of genetics on traits. Many identified risk loci are in non-coding and intergenic regions, which complicates understanding how genes and their downstream pathways are influenced. An integrative data approach is required to understand the mechanism and consequences of identified risk loci. Here, we developed the R-package CONQUER. Data for SNPs of interest are acquired from static- and dynamic repositories (build GRCh38/hg38), including GTExPortal, Epigenomics Project, 4D genome database and genome browsers. All visualizations are fully interactive so that the user can immediately access the underlying data. CONQUER is a user-friendly tool to perform an integrative approach on multiple SNPs where risk loci are not seen as individual risk factors but rather as a network of risk factors.

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Polygenic Susceptibility of Aortic Aneurysms Associates to the Diameter of the Aneurysm Sac: the Aneurysm-Express Biobank Cohort

Scientific Reports ◽

10.1038/s41598-019-56230-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Constance J. H. C. M. van Laarhoven ◽

Jessica van Setten ◽

Joost A. van Herwaarden ◽

Gerard Pasterkamp ◽

Dominique P. V. de Kleijn ◽

...

Keyword(s):

Genetic Risk ◽

Association Studies ◽

Significant Risk ◽

Aortic Aneurysms ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Risk Variants ◽

Genome Wide ◽

Best Fit ◽

Genetic Risk Variants

AbstractRecent genome-wide association studies (GWAS) have discovered ten genetic risk variants for abdominal aortic aneurysms (AAA). To what extent these genetic variants contribute to the pathology of aneurysms is yet unknown. The present study aims to investigate whether genetic risk variants are associated with three clinical features: diameter of aneurysm sac, type of artery and aneurysm related-symptoms in aortic and peripheral aneurysm patients. Aneurysm tissue of 415 patients included in the Aneurysm-Express biobank was used. A best-fit polygenic risk score (PRS) based on previous GWAS effect estimates was modeled for each clinical phenotype. The best-fit PRS (including 272 variants at PT = 0.01015) showed a significant correlation with aneurysm diameter (R2 = 0.019, p = 0.001). No polygenic association was found with clinical symptoms or artery type. In addition, the ten genome-wide significant risk variants for AAA were tested individually, but no associations were observed with any of the clinical phenotypes. All models were corrected for confounders and data was normalized. In conclusion, a weighted PRS of AAA susceptibility explained 1.9% of the phenotypic variation (p = 0.001) in diameter in aneurysm patients. Given our limited sample size, future biobank collaborations need to confirm a potential causal role of susceptibility variants on aneurysmal disease initiation and progression.

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