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Polygenic risk score for disability and insights into disability-related molecular mechanisms.

ABSTRACT: Late life disability is a highly devastating condition affecting 20% or more of persons aged 65 years and older in the USA; it is an important determinant of acute medical and long-term care costs which represent a growing burden on national economies. Disability is a multifactorial trait that contributes substantially to decline of health/wellbeing. Accordingly, gaining insights into the genetics of disability could help in identifying molecular mechanisms of this devastating condition and age-related processes contributing to a large fraction of specific geriatric conditions, concordantly with geroscience. We performed a genome-wide association study of disability in a sample of 24,068 subjects from five studies with 12,550 disabled individuals. We identified 30 promising disability-associated polymorphisms in 19 loci at p < 10-4; four of them attained suggestive significance, p < 10-5. In contrast, polygenic risk scores aggregating effects of minor alleles of independent SNPs that were adversely or beneficially associated with disability showed highly significant associations in meta-analysis, p = 3.13 × 10-45 and p = 5.60 × 10-23, respectively, and were replicated in each study. The analysis of genetic pathways, related diseases, and biological functions supported the connections of genes for the identified SNPs with disabling and age-related conditions primarily through oxidative/nitrosative stress, inflammatory response, and ciliary signaling. We identified musculoskeletal system development, maintenance, and regeneration as important components of gene functions. The beneficial and adverse gene sets may be differently implicated in the development of musculoskeletal-related disability with the beneficial set characterized, e.g., by regulation of chondrocyte proliferation and bone formation, and the adverse set by inflammation and bone loss.

SUBMITTER: Kulminski AM

PROVIDER: S-EPMC6925082 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Polygenic risk score for disability and insights into disability-related molecular mechanisms.

Kulminski Alexander M AM Kang Chansuk C Kolpakov Stanislav A SA Loika Yury Y Nazarian Alireza A Yashin Anatoliy I AI Stallard Eric E Culminskaya Irina I

GeroScience 20191109 6

Late life disability is a highly devastating condition affecting 20% or more of persons aged 65 years and older in the USA; it is an important determinant of acute medical and long-term care costs which represent a growing burden on national economies. Disability is a multifactorial trait that contributes substantially to decline of health/wellbeing. Accordingly, gaining insights into the genetics of disability could help in identifying molecular mechanisms of this devastating condition and age- ...[more]

PMID: 31707593

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Project description:BACKGROUND:The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS:Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and two polygenic risk scores were constructed with 186 and 11 (PRS186 and PRS11) single nucleotide polymorphisms previously associated with body mass index (BMI). RESULTS:The accuracy of the %EBWL logistic prediction model - including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism (AUCadj = 0.867) - significantly increased after the inclusion of PRS186 (?AUCadj = 0.021; 95% CI of the difference [95% CIdiff] = 0.005-0.038) but not PRS11 (?AUCadj= 0.008; 95% CIdiff= -0.003-0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS186 (-2 log-likelihood = 12.3; P = 0.002) and PRS11 (-2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS186 (? = -0.003; P = 0.008) and PRS11 (? = -0.008; P = 0.03). The inclusion of PRS186 and PRS11 in the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION:These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity. FUNDING:Heart and Stroke Foundation of Canada (G-17-0016627) and Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health (no. 950-231-580).

Project description:Endometriosis is a major health care challenge because many young women with endometriosis go undetected for an extended period, which may lead to pain sensitization. Clinical tools to better identify candidates for laparoscopy-guided diagnosis are urgently needed. Since endometriosis has a strong genetic component, there is a growing interest in using genetics as part of the clinical risk assessment. The aim of this work was to investigate the discriminative ability of a polygenic risk score (PRS) for endometriosis using three different cohorts: surgically confirmed cases from the Western Danish endometriosis referral Center (249 cases, 348 controls), cases identified from the Danish Twin Registry (DTR) based on ICD-10 codes from the National Patient Registry (140 cases, 316 controls), and replication analysis in the UK Biobank (2,967 cases, 256,222 controls). Patients with adenomyosis from the DTR (25 cases) and from the UK Biobank (1,883 cases) were included for comparison. The PRS was derived from 14 genetic variants identified in a published genome-wide association study with more than 17,000 cases. The PRS was associated with endometriosis in surgically confirmed cases [odds ratio (OR) = 1.59, p = 2.57× 10-7] and in cases from the DTR biobank (OR = 1.50, p = 0.0001). Combining the two Danish cohorts, each standard deviation increase in PRS was associated with endometriosis (OR = 1.57, p = 2.5× 10-11), as well as the major subtypes of endometriosis; ovarian (OR = 1.72, p = 6.7× 10-5), infiltrating (OR = 1.66, p = 2.7× 10-9), and peritoneal (OR = 1.51, p = 2.6 × 10-3). These findings were replicated in the UK Biobank with a much larger sample size (OR = 1.28, p < 2.2× 10-16). The PRS was not associated with adenomyosis, suggesting that adenomyosis is not driven by the same genetic risk variants as endometriosis. Our results suggest that a PRS captures an increased risk of all types of endometriosis rather than an increased risk for endometriosis in specific locations. Although the discriminative accuracy is not yet sufficient as a stand-alone clinical utility, our data demonstrate that genetics risk variants in form of a simple PRS may add significant new discriminatory value. We suggest that an endometriosis PRS in combination with classical clinical risk factors and symptoms could be an important step in developing an urgently needed endometriosis risk stratification tool.

Project description:Background: Asthma is common chronic inflammatory disease of the airways with a heterogenous clinical presentation. Individual differences in asthma susceptibility remain poorly understood, although genetics is thought to play a major role. Aim: To build a polygenic risk score (PRS) for asthma and determine whether predictive genetic variants can be epigenomically linked to specific pathophysiological mechanisms. Methods: PRSs were constructed using data from genome-wide association studies and performance was validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14,926 individuals. Outcomes used were asthma, childhood-onset asthma, adulthood-onset asthma, eosinophilic asthma and exacerbations. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from 14 primary cell types, including lung epithelial cells and T lymphocytes was used for epigenomic PRS partitioning. Results: All PRSs successfully predicted risk to develop asthma and related outcomes, with the strongest predictive power (2.42 odds ratios per PRS standard deviation, area under the curve of 0.736) achieved for childhood-onset asthma. PRSs allowed for stratification of the Rotterdam Study cohort into groups at low or high risk to develop asthma. PRS partitioning using genome-wide epigenomic profiles identified 5 clusters of variants within gene regulatory regions linked to specific asthma-relevant cells, genes and biological pathways. Conclusions: PRSs can predict whether individuals in a Dutch cohort developed asthma and asthma-related phenotypes, which is most effective for childhood-onset asthma. Importantly, we show that PRS partitioning based on epigenomics data dissects a genetic risk score into blocks of regulatory variants with differential predictive power, which likely represent distinct genetically driven disease pathways. These findings have potential implications for personalized risk mitigation and treatment strategies.

Project description:BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer deaths worldwide, seriously affecting human community health and care. Emerging evidence has shown that aberrant glycosylation is associated with tumor progression and metastasis. However, the role of glycosylation-related genes in HCC has notbeen reported.MethodsWeighted gene coexpression network analysis and non-negative matrix factorization analysis were applied to identify functional modules and molecularm subtypes in HCC. The least absolute shrinkage and selection operator Cox regression was used to construct the glycosylation-related signature. The independent prognostic value of the risk model was confirmed and validated by systematic techniques, including principal component analysis, T-distributed random neighbor embedding analysis, Kaplan-Meier survival analysis, the ROC curve, multivariate Cox regression, the nomogram, and the calibration curve. The single-sample gene set enrichment analysis, gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were evaluated by the immune microenvironment and potential biological processes. The quantitative real-time polymerase chain reaction and immunohistochemistry analysis were used to verify the expression of five genes.ResultsWe identified the glycosylation-related genes with bioinformatics analysis to construct and validate a five-gene signature for the prognosis of HCC patients. Patients with HCC in the high-risk group had a worse prognosis. The risk score could be an independent factor and was associated with clinical features, such as the grade and stage. The nomogram exhibited an accurate score that included the risk score and clinical parameters. The infiltration levels of antitumor cells were upregulated in the low-risk group, including B_cells, Mast_cells, neutrophils, NK_cells, and T_helper_cells. Moreover, glycosylation was more sensitive to immunotherapy, and may play a critical role in the metabolic processes of HCC, such as bile acid metabolism and fatty acid metabolism. In addition, the five-gene messenger RNA (mRNA) and protein expression were overexpressed in HCC cells and tissues.ConclusionsThe glycosylation-related signature is effective for prognostic recognition, immune efficacy evaluation, and substance metabolism in HCC, providing a novel insight for therapeutic target prediction and clinical decision-making.

Project description:BackgroundAsthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.ObjectivesThis study aimed to train and validate a PRS relying on genetic determinants for asthma to provide predictions for disease occurrence in pediatric cohorts of diverse ancestries.MethodsThis study applied a Bayesian regression framework method using the Trans-National Asthma Genetic Consortium genome-wide association study summary statistics to derive a multiancestral PRS score, used one Electronic Medical Records and Genomics (eMERGE) cohort as a training set, used a second independent eMERGE cohort to validate the score, and used the UK Biobank data to replicate the findings. A phenome-wide association study was performed using the PRS to identify shared genetic etiology with other phenotypes.ResultsThe multiancestral asthma PRS was associated with asthma in the 2 pediatric validation datasets. Overall, the multiancestral asthma PRS has an area under the curve (AUC) of 0.70 (95% CI, 0.69-0.72) in the pediatric validation 1 and AUC of 0.66 (0.65-0.66) in the pediatric validation 2 datasets. We found significant discrimination across pediatric subcohorts of European (AUC, 95% CI, 0.60 and 0.66), African (AUC, 95% CI, 0.61 and 0.66), admixed American (AUC, 0.64 and 0.70), Southeast Asian (AUC, 0.65), and East Asian (AUC, 0.73) ancestry. Pediatric participants with the top 5% PRS had 2.80 to 5.82 increased odds of asthma compared to the bottom 5% across the training, validation 1, and validation 2 cohorts when adjusted for ancestry. Phenome-wide association study analysis confirmed the strong association of the identified PRS with asthma (odds ratio, 2.71, PFDR = 3.71 × 10-65) and related phenotypes.ConclusionsA multiancestral PRS for asthma based on Bayesian posterior genomic effect sizes identifies increased odds of pediatric asthma.

Project description:Importance:Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. Objectives:To examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. Design, Setting, and Participants:Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. Main Outcomes and Measures:The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to -0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to -5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n?=?95?619), age of onset of spectacle wear (n?=?287?448), and educational attainment (n?=?328?917). Results:A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P?=?.02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4-10.9) of high myopia. Conclusions and Relevance:A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).

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Polygenic risk score for disability and insights into disability-related molecular mechanisms.

Publications

Polygenic risk score for disability and insights into disability-related molecular mechanisms.

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