scholarly journals Precision Colorectal Cancer Screening with Polygenic Risk Score

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.

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

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.

Distinct Genetic Profiles in Postpartum Depression With Different Trajectory of Illness

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.

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

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]

scholarly journals Genomic Prediction of Depression Risk and Resilience Under Stress

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.

scholarly journals Analysis of the Interaction between Polygenic Risk Score and Calorie Intake in Obesity in the Korean Population

2020 ◽  
pp. 1-10
Author(s):  
Won-Jun Lee ◽  
Ji Eun Lim ◽  
Hae Un Jung ◽  
Ji-One Kang ◽  
Taesung Park ◽  
...  
Keyword(s):  
Risk Score ◽  
Significant Interaction ◽  
Association Studies ◽  
Calorie Intake ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Polygenic Risk ◽  
Total Calorie ◽  
Total Calorie Intake

<b><i>Introduction:</i></b> Obesity results from an imbalance in the intake and expenditure of calories that leads to lifestyle-related diseases. Although genome-wide association studies (GWAS) have revealed many obesity-related genetic factors, the interactions of these factors and calorie intake remain unknown. This study aimed to investigate interactions between calorie intake and the polygenic risk score (PRS) of BMI. <b><i>Methods:</i></b> Three cohorts, i.e., from the Korea Association REsource (KARE; <i>n</i> = 8,736), CArdioVAscular Disease Association Study (CAVAS; <i>n</i> = 9,334), and Health EXAminee (HEXA; <i>n</i> = 28,445), were used for this study. BMI-related genetic loci were selected from previous GWAS. Two scores, PRS, and association (a)PRS, were used; the former was determined from 193 single-nucleotide polymorphisms (SNPs) from 5 GWAS datasets, and the latter from 62 SNPs (potentially associated) from 3 Korean cohorts (meta-analysis, <i>p</i> &#x3c; 0.01). <b><i>Results:</i></b> PRS and aPRS were significantly associated with BMI in all 3 cohorts but did not exhibit a significant interaction with total calorie intake. Similar results were obtained for obesity. PRS and aPRS were significantly associated with obesity but did not show a significant interaction with total calorie intake. We further analyzed the interaction with protein, fat, and carbohydrate intake. The results were similar to those for total calorie intake, with PRS and aPRS found to not be associated with the interaction of any of the 3 nutrition components for either BMI or obesity. <b><i>Discussion:</i></b> The interaction of BMI PRS with calorie intake was investigated in 3 independent Korean cohorts (total <i>n</i> = 35,094) and no interactions were found between PRS and calorie intake for obesity.

scholarly journals A polygenic risk score for multiple myeloma risk prediction

2021 ◽  
Author(s):  
Federico Canzian ◽  
Chiara Piredda ◽  
Angelica Macauda ◽  
Daria Zawirska ◽  
Niels Frost Andersen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Score ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Epidemiologic Evidence ◽  
Risk Variants ◽  
Genome Wide ◽  
Weighted Score

AbstractThere is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53–4.69, p = 3.55 × 10−15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34–4.33, p = 1.62 × 10−13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Kaoru Suzuki ◽  
Yoichi Kakuta ◽  
Takeo Naito ◽  
Tetsuya Takagawa ◽  
Hiroyuki Hanai ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Background ◽  
Association Studies ◽  
Meta Analysis ◽  
Area Under The Curve ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

Abstract Background Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called “mesalamine allergy,” which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. Methods Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. Results In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn’s disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). Conclusions Mesalamine allergy was more common in ulcerative colitis than in Crohn’s disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

scholarly journals A/T/N polygenic risk score for cognitive decline in old age

2019 ◽  
Author(s):  
Annah M. Moore ◽  
Teresa J. Filshtein ◽  
Logan Dumitrescu ◽  
Amal Harrati ◽  
Fanny Elahi ◽  
...  
Keyword(s):  
Executive Function ◽  
Cognitive Decline ◽  
Risk Score ◽  
Genetic Risk ◽  
Clinical Utility ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Phosphorylated Tau ◽  
Polygenic Risk

AbstractINTRODUCTIONWe developed a novel polygenic risk score (PRS) based on the A/T/N (amyloid plaques (A), phosphorylated tau tangles (T), and neurodegeneration (N)) framework and compared a PRS based on clinical AD diagnosis to assess which was a better predictor of cognitive decline.METHODSWe used summary statistics from genome wide association studies of cerebrospinal fluid amyloid-β (Aβ42) and phosphorylated-tau (ptau181), left hippocampal volume (LHIPV), and late-onset AD dementia to calculate PRS for 1181 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Individual PRS were averaged to generate a composite A/T/N PRS. We assessed the association of PRS with baseline and longitudinal cognitive composites of executive function and memory.RESULTSThe A/T/N PRS showed superior predictive performance on AD biomarkers and executive function decline compared to the clinical AD PRS.DISCUSSIONResults suggest that integration of genetic risk across AD biomarkers may improve prediction of disease progression.Research in ContextSystematic ReviewAuthors reviewed relevant literature using PubMed and Google Scholar. Key studies that generated and validated polygenic risk scores (PRS) for clinical and pathologic AD were cited. PRS scores have been increasingly used in the literature but clinical utility continues to be questioned.InterpretationIn the current research landscape concerning PRS clinical utility in the AD space, there is room for model improvement and our hypothesis was that a PRS with integrated risk for AD biomarkers could yield a better model for cognitive decline.Future DirectionsThis study serves as proof-of-concept that encourages future study of integrated PRS across disease markers and utility in taking an A/T/N (amyloidosis, tauopathy and neurodegeneration) focused approach to genetic risk for cognitive decline and AD.

A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break With Early Markers of Pubertal Onset in Boys

2020 ◽  
Vol 105 (3) ◽  
pp. e349-e357 ◽  
Author(s):  
María C Lardone ◽  
Alexander S Busch ◽  
José L Santos ◽  
Patricio Miranda ◽  
Susana Eyheramendy ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Architecture ◽  
Pubertal Timing ◽  
Association Studies ◽  
Pubic Hair ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Polygenic Risk ◽  
Risk Alleles

Abstract Context Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. Objective To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. Experimental Design Longitudinal study. Subjects and Methods 401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys). Main Outcome Measures Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. Results The PRS was associated with AAG (β=0.01, P = 0.04) and AAP (β=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007). Conclusions Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.

scholarly journals A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Moeen Riaz ◽  
Jonas Mattisson ◽  
Galina Polekhina ◽  
Andrew Bakshi ◽  
Jonatan Halvardson ◽  
...  
Keyword(s):  
Risk Score ◽  
Blood Cells ◽  
Association Studies ◽  
Older Men ◽  
Common Disease ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Independent Population ◽  
Increased Risk

Abstract Background Mosaic loss of Y chromosome (LOY) is the most common somatic change that occurs in circulating white blood cells of older men. LOY in leukocytes is associated with increased risk for all-cause mortality and a range of common disease such as hematological and non-hematological cancer, Alzheimer’s disease, and cardiovascular events. Recent genome-wide association studies identified up to 156 germline variants associated with risk of LOY. The objective of this study was to use these variants to calculate a novel polygenic risk score (PRS) for LOY, and to assess the predictive performance of this score in a large independent population of older men. Results We calculated a PRS for LOY in 5131 men aged 70 years and older. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio [OR] = 1.74 per standard deviation of the PRS, 95% confidence intervals [CI] 1.62–1.86, p < 0.001). Men in the highest quintile of the PRS distribution had > fivefold higher risk of LOY than the lowest (OR = 5.05, 95% CI 4.05–6.32, p < 0.001). Adding the PRS to a LOY prediction model comprised of age, smoking and alcohol consumption significantly improved prediction (AUC = 0.628 [CI 0.61–0.64] to 0.695 [CI 0.67–0.71], p < 0.001). Conclusions Our results suggest that a PRS for LOY could become a useful tool for risk prediction and targeted intervention for common disease in men.

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