Higher Polygenic Risk Scores Research Articles

Genetic modifiers of asthma response to air pollution in children: An African ancestry GWAS and PM2.5 polygenic risk score study.

Ambient air pollution (AAP) is linked to asthma outcomes, but predicting individual risk remains challenging. Understanding genetic contributors to AAP sensitivity may help overcome this gap. To determine if single nucleotide polymorphisms (SNPs) are associated with AAP sensitivity in children with asthma. We complete a GWAS in pediatric patients with asthma frequently exposed to AAP, comparing patients with exacerbations following spikes in AAP to patients without this temporal association and calculate a polygenic risk score (PRS) for PM2.5. This PRS was validated using internal data and data from the All of Us cohort. We included 6023 patients in the GWAS, restricted to the African ancestry cohort due to the association between AAP exposure and race. Three loci reached genome-wide significance, including rs111970601, associated with CO sensitivity (odds ratio [OR] 6.58; P=1.63×10-8) and rs9836522 with PM2.5 sensitivity (OR 0.75; P=3,87×10-9), both externally validated. PRS z-scores were associated with increased asthma exacerbations in patients frequently exposed to poor air quality (β=0.15; P=2.67×10⁻⁵). Spirometry data from 4138 patients showed that having a high PRS was associated with lower FVC z-scores in patients frequently exposed to AAP (β=-0.44; P=0.035). External validation confirmed a significant interaction between high PRS and frequent AAP exposure (β=0.30; P=0.012) CONCLUSIONS: We associate specific SNPs with AAP-related asthma exacerbations and introduce a PM2.5 sensitivity PRS, paving the way for future research aimed at protecting genetically predisposed patients.

Associations between ambient benzene and stroke, and the mediating role of accelerated biological aging: Findings from the UK biobank.

Benzene can cause respiratory diseases. However, the associations between benzene and stroke are unclear. A total of 13,116 patients with stroke and 377,120 controls from the UK Biobank were included. The benzene exposure concentrations were matched on the basis of the address information of each participant via a data form from the UK Department for Environment, Food and Rural Affairs. Weighted Cox regression was used to investigate the association between benzene and stroke risk. The polygenic risk score (PRS) was used to observe the joint effects of benzene exposure and genetic factors on stroke risk. We conducted a mediation analysis to investigate the mediating role of accelerated biological aging in this cohort study. After adjusting for covariates, every 1μg/m3 increase in benzene exposure increased the risk of stroke by 70%, which may be mediated by accelerated biological aging. The population with high benzene exposure concentrations and high PRSs had a 44% greater risk of stroke than did those with low benzene exposure concentrations and low PRSs. Benzene exposure and the PRS have joint effects on the risk of stroke. Benzene exposure was associated with stroke risk, possibly through increased biological aging, and the PRS modified this association.

Association of Alzheimer's Disease Polygenic Risk Score with Concussion Severity and Recovery Metrics.

Identification of genetic alleles associated with both Alzheimer's disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset. We assessed six concussion outcomes in 931 participants, including two recovery measures (number of days to asymptomatic and to return to play (RTP)) and four severity measures (scores on SAC and BESS, SCAT symptom severity and total number of symptoms). We calculated thePRS using a published score and performed multiple linear regression to assess the relationship of thePRS with outcomes. We also used ANOVAs, t-tests, and chi-square tests to examine outcomes by APOE genotype. Higher PRS was associated with longer injury to RTP time in the normal RTP (< 24days) subgroup (p = 0.024). A one standard deviation increase in the PRS resulted in a 9.89hour increase to RTP time. This result was no longer significant after inclusion of covariates. There were no other consistently significant effects. Our findings suggest high AD genetic risk is not associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations.

The clinical value and most informative threshold of polygenic risk score in the Quebec City Case-Control Asthma Cohort

Genome-wide association studies (GWAS) have identified genetic variants robustly associated with asthma. A potential near-term clinical application is to calculate polygenic risk score (PRS) to improve disease risk prediction. The value of PRS, as part of numerous multi-source variables used to define asthma, remains unclear. This study aims to evaluate PRS and define most informative thresholds in relation to conventional clinical and physiological criteria of asthma using a multivariate statistical method. Clinical and genome-wide genotyping data were obtained from the Quebec City Case-Control Asthma Cohort (QCCCAC), which is an independent cohort from previous GWAS. PRS was derived using LDpred2 and integrated with other asthma phenotypes by means of Principal Component Analysis with Optimal Scaling (PCAOS). PRS was considered using ‘ordinal level of scaling’ to account for non-linear information. In two dimensional PCAOS space, the first component delineated individuals with and without asthma, whereas the severity of asthma was discerned on the second component. The positioning of high vs. low PRS in this space matched the presence and absence of airway hyperresponsiveness, showing that PRS delineated cases and controls at the same extent as a positive bronchial challenge test. The top 10% and the bottom 5% of the PRS were the most informative thresholds to define individuals at high and low genetic risk of asthma in this cohort. PRS used in a multivariate method offers a decision-making space similar to hyperresponsiveness in this cohort and highlights the most informative and asymmetrical thresholds to define high and low genetic risk of asthma.

Association of radiation-induced normal tissue toxicity with a high genetic risk for rheumatoid arthritis.

Overlapping genes are involved with rheumatoid arthritis (RA) and DNA repair pathways. Therefore, we hypothesised that patients with a high polygenic risk score (PRS) for RA will have an increased risk of radiotherapy (RT) toxicity given the involvement of DNA repair. Primary analysis was performed on 1494 prostate cancer, 483 lung cancer and 1820 breast cancer patients assessed for development of RT toxicity in the REQUITE study. Validation cohorts were available from the Radiogenomics Consortium. All patients had undergone curative-intent radiotherapy and were assessed prospectively for toxicity. Germline genomic data was available for all patients, allowing a PRS to be calculated using 101 RA risk variants. PRS was analysed as a continuous variable and with >90th percentile cut-off. Associations with acute and late standardised total average toxicity (STAT) scores and individual toxicity end-points were analysed in multivariable models with preselected adjustment variables. Increasing PRS for RA did not increase the risk of acute or late STAT in any cohort. There was an increased risk of late oesophagitis in the lung cancer cohort (coefficient 0.018, p = .01), however this was not validated (p = .79). No individual acute or late toxicity endpoints were significantly associated with PRS for the prostate or breast cohorts. No significant results were found in the validation cohorts in multivariable models. Patients with a high genetic risk for RA do not show increased levels of toxicity after radiotherapy suggesting treatment planning does not need to be modified for such patients.

Genomic Drivers of Coronary Artery Disease and Risk of Future Outcomes After Coronary Angiography

Disease characteristics of genetically mediated coronary artery disease (CAD) on coronary angiography and the association of genomic risk with outcomes after coronary angiography are not well understood. To assess the angiographic characteristics and risk of post-coronary angiography outcomes of patients with genomic drivers of CAD: familial hypercholesterolemia (FH), high polygenic risk score (PRS), and clonal hematopoiesis of indeterminate potential (CHIP). A retrospective cohort study of 3518 Mass General Brigham Biobank participants with genomic information who underwent coronary angiography was conducted between July 18, 2000, and August 1, 2023. The presence of a genomic risk factor of CAD, defined as FH variant, high CAD PRS, or CHIP driver variation. Coronary artery disease presentation (stable or acute), angiographic CAD characteristics (severity and burden), angiographic outcomes (repeat angiogram, revascularization, and in-stent restenosis), and clinical outcomes (heart failure and all-cause mortality). Among 3518 participants (2467 [70.1%] male; median age, 64.0 [IQR, 55.0-72.0] years), 1509 (42.9%) had at least 1 genomic driver of CAD (26 FH, 1191 high CAD PRS, and 466 CHIP) that was associated with the presentation of acute coronary syndromes (adjusted odds ratio, 2.67; 95% CI, 2.19-3.26) and with the presence, burden, and severity of angiographic CAD. This association was driven by FH and CAD PRS. One SD of CAD PRS was associated with a 12.51-point higher Gensini score. During 9 years of follow-up, there was an increased risk among FH carriers for a repeat angiogram (adjusted hazard ratio [AHR], 1.70; 95% CI, 1.02-2.83), and revascularization (AHR, 1.97; 95% CI, 1.02-3.80), and among people with high CAD PRS (repeat angiogram: AHR, 1.79; 95% CI, 1.45-2.22; revascularization: AHR, 1.85; 95% CI, 1.37-2.50; and in-stent restenosis: AHR, 3.89; 95% CI, 2.16-7.01). CHIP carriers had no significant increase in angiographic outcomes but were at higher risk of heart failure (AHR, 1.58; 95% CI, 1.04-2.40) and all-cause mortality (AHR, 1.78; 95% CI, 1.47-2.16). The findings of this study suggest that germline monogenic and polygenic risk are associated with acute coronary syndromes presentation, severity and burden of atherosclerosis, and risk of repeat angiogram, revascularization, and in-stent restenosis. CHIP variant status is associated with incident heart failure and mortality after coronary angiography.

Effects of Genetic Risk and Lifestyle Habits on Gout: A Korean Cohort Study.

Gout is a type of inflammatory arthritis caused by monosodium urate crystal deposits, and the prevalence of this condition has been increasing. This study aimed to determine the combined effects of genetic risk factors and lifestyle habits on gout, using data from a Korean cohort study. Identifying high-risk individuals in advance can help prevent gout and its associated disorders. We analyzed data from the Korean Genome and Epidemiology Study-Urban Health Examinees cohort (KoGES-HEXA). Genetic information of the participants was collected at baseline, and gout cases were identified based on patient statements. The polygenic risk score (PRS) was calculated using nine independent genome-wide association study datasets, and lifestyle factors and metabolic syndrome status were measured for each participant using the KoGES. Logistic regression models were used to estimate the odds ratios (ORs) for gout in relation to genetic risk, lifestyle habits, and metabolic health status, after adjusting for age and sex. Among 44,605 participants, 617 were diagnosed with gout. Gout was associated with older age, higher body mass index, and higher prevalence of hypertension, diabetes, and hypertriglyceridemia. High PRS, unfavorable lifestyle habits, and poor metabolic profiles were significantly associated with an increased risk of gout. Compared with that in the low-genetic-risk and healthy lifestyle group or ideal metabolic profile group, the risk of gout was increased in the high-genetic-risk plus unfavorable lifestyle (OR, 3.64; 95% confidence interval [CI], 2.32-6.03) or poor metabolic profile (OR, 7.78; 95% CI, 4.61-13.40) group. Conversely, adherence to favorable lifestyle habits significantly reduced gout risk, especially in high-genetic-risk groups. Genetic predisposition and unhealthy lifestyle habits significantly increase the risk of gout. Promoting healthy lifestyle habits is crucial to prevent the development of gout, particularly in individuals with high genetic susceptibility.

Mental illness and antibody responses after COVID-19 vaccination in a prospective population-based study in Catalonia.

The association between mental illness diagnoses (mood affective disorders, anxiety disorders, other) over ten years and psychotropic drug prescription based on electronic health records with antibody levels (IgG and IgA) post COVID-19 vaccination was assessed in 939 vaccinated adults from Catalonia, Spain. We employed linear regression models to assess associations between specific mental illnesses and psychotropic drugs with antibody levels, correcting for demographics, comorbidities and lifestyle factors. In a genotyped subset (n=247) we assessed the effect of polygenic risk scores (PRS) for mental illnesses and performed a two-sample mendelian randomization (MR) analysis to examine causality between mental illness and antibody responses. Mood affective disorders were associated with lower IgG to receptor binding domain (RBD) [percentage change=-26.37 (95% CI, -42.00, -6.54)]. Diagnosis of anxiety disorders was not associated with the outcome. The group of other diagnoses (mainly including insomnia and nicotine dependence) were associated with lower IgG RBD levels [percentage change: -21.53 (95% CI, -35.38, -4.71)] and recent onset cases (≤5years ago) showed greater decline in antibody levels. Participants on second-generation antipsychotics and multiple classes of psychotropic drugs in the last 6months exhibited lower antibody levels. In the genotyped population, higher genetic liability (higher PRS) to schizophrenia was associated with lower IgG RBD levels [percentage change=-35.49 (95% CI, -56.55, -4.23)]. MR analysis revealed a causal relationship between major depression genetic instrumental variables and lower IgG RBD and S levels. These findings raise concerns about the efficacy of COVID-19 vaccines and potentially of other vaccines as well, in individuals with mood affective disorders, current/recent insomnia and nicotine dependence and people on multiple psychotropic drugs. Whether these associations are translated into increased risk for breakthrough infections and immune mediated long-term sequels of the SARS-CoV-2 infection warrants further investigation.

Renin-independent aldosteronism and metabolic dysfunction-associated steatotic liver disease and cirrhosis: A genetic association study.

Renin-independent aldosteronism (RIA) refers to a spectrum of autonomous aldosterone hypersecretion. We aimed to explore the genetical relationship between RIA and metabolic dysfunction-associated steatotic liver disease (MASLD) and cirrhosis. We included 125357 participants from the cohort of United Kingdom Biobank. We calculated a polygenic risk score (PRS) for RIA on the basis of reported data from genome-wide association studies, and performed an analysis of Phenome Wide Association Studies (PheWAS) on diverse outcomes. We explored the genetical relationship between RIA and MASLD or cirrhosis by using Mendelian randomization analysis. An increased RIA PRS was associated with higher risks of MASLD and MASLD related cirrhosis, and the well-defined RIA related target organ damages such as hypertension or kidney diseases was also significant in the PheWAS analysis. When compared to individuals with low RIA PRS (tertile 1, 0.41-9.89), those with high RIA PRS (tertile 3, 13.58-23.16) showed significantly higher odds ratio (OR) of MASLD (OR 1.28, 95% confidence interval [CI] 1.09-1.49) and cirrhosis (OR 1.49, 95%CI 1.03-2.16). In analyses of two-sample Mendelian randomization, genetically predicted RIA significantly correlated with elevated risks of MASLD and cirrhosis (inverse variance weighted odds ratio [95% CI]: 1.05 [1.01-1.09]) for MASLD, 1.08 [1.02-1.13] for cirrhosis), meanwhile we observed no significant directional pleiotropy or heterogeneity. Renin-independent aldosteronism is genetically associated with higher risks of MASLD and cirrhosis. Targeted treatment of autonomous aldosterone secretion may alleviate MASLD progression.

The role of C-reactive protein and genetic predisposition in the risk of psoriasis: results from a national prospective cohort

BackgroundPsoriasis is an immune-mediated chronic inflammatory disease associated with multiple factors. To evaluate the extent to which C-reactive protein (CRP) and genetic predisposition affect the incidence of psoriasis.MethodsThe cohort study retrieved 420,040 participants without psoriasis at baseline from the UK Biobank. Serum CRP was categorized into two levels: < 2 mg/L (normal) and ≥ 2 mg/L (elevated). The polygenic risk score (PRS) was used to estimate genetic predisposition, and was characterized as low, moderate and high PRS. The possible interaction and joint associations between CRP and PRS were assessed using Cox proportional hazards models.ResultsParticipants with high CRP levels had an increased risk of incident psoriasis compared to those with low CRP levels (HR: 1.26, 95% CI: 1.18–1.34). Participants with high CRP levels and high PRS had the highest risk of incident psoriasis [2.24 (95% CI: 2.01, 2.49)], compared with those had low CRP levels and low PRS. Significant additive and multiplicative interaction were found between CRP and PRS in relation to the incidence of psoriasis.ConclusionsOur results suggest that higher CRP concentration may be associated with higher psoriasis incidence, with a more pronounced association observed in individuals with high PRS for psoriasis. So, clinicians should be aware that the risk of incident psoriasis may increase in general population with high CRP levels and high PRS, so that early investigation and intervention can be initiated.

A high polygenic risk score is associated with SSA/SSB antibody positivity and early onset in primary Sjögren's disease.

To calculate a polygenic risk score (PRS) based on single nucleotide variants (SNVs) previously associated with primary Sjögren's disease (SjD) with genome-wide significance, and determine the genetic risk for SjD stratified by antibodies, sex and age at diagnosis. Patients with SjD (n = 1065) were genotyped using Illumina OmniExpressExome chip. Control genotype data were available (n = 7742). Two PRSs were constructed, one including HLA gene variants (n = 21 SNVs), and one without HLA (n = 18 SNVs). High PRS quartile (Q4) individuals were compared with low PRS (Q1-3). A high PRS was associated with SSA antibody positive SjD (OR 9.16, 95% CI 7.75-10.85, p= 3.7x10-146), and strengthened in SjD positive for both SSA/SSB antibodies (OR 13.67, 95% CI 10.88-17.32, p= 4.6x10-108). High PRS classified SSA/SSB antibody positive SjD with very good accuracy (AUC 0.86). PRS without HLA showed a weaker association with SSA/SSB positive SjD (OR 2.09, 95% CI 1.71-2.55, p= 6.4x10-13). Antibody negative SjD displayed a PRS similar to controls. Patients in the high PRS quartile were significantly younger at diagnosis, 48.9 ± 14.9 vs 53.4 ± 13.4 years in the low PRS quartiles (Q1-3), p= 2.2x10-6, and presented higher frequencies of ANA, SSA and SSA/SSB antibodies, p < 1x10-5. A high PRS is associated with SSA/SSB antibody positivity and early disease onset, both largely attributed to the weight of the HLA alleles. Integration of PRS with other biomarkers applied to clinical phenotypes, could be a useful tool for disease risk stratification and treatment decisions.

Effects of the Interaction Between Oxidative Balance Score and Polygenic Risk Scores on Incidence of Metabolic Syndrome in Middle-Aged Korean Adults.

Oxidative stress is implicated in insulin resistance, obesity, and metabolic syndromes (MetSs). However, the interplay between oxidative stress and genetic predisposition during the development of MetS remains unclear. In this study, we aimed to investigate the effects of the interaction between oxidative balance score (OBS) and polygenic risk score (PRS) on the incidence of MetS in middle-aged Korean adults. We analyzed data from 25,879 participants aged ≥40 years from the Health Examinees Cohort of the Korean Genome and Epidemiology Study. The OBS was calculated using 11 antioxidant and five pro-oxidant factors. A genome-wide association study and clumping analysis identified 16 independent single-nucleotide polymorphisms associated with MetS that were used to calculate individual PRSs. Multivariable Cox proportional hazard models adjusted for confounding variables were used to assess the impact of OBS and PRS on the incidence of MetS. During a mean follow-up period of 4.3 years, we recorded 3153 cases of MetS. In both men and women, the group with the lowest OBS and a high PRS had a 1.50-fold (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.07-2.11) and 1.89-fold (HR 1.89, 95% CI 1.40-2.56) higher incidence, respectively, of MetS compared to those with the highest OBS and a low PRS. Among women with a high PRS, the HRs decreased significantly across OBS quintiles 1 through 5 (p for trend = 0.009). These findings suggest that managing the oxidative balance may be particularly crucial for individuals with a high genetic risk for MetS.

The additive interaction of healthy lifestyles and genetic susceptibility on colorectal cancer risk in prediabetes: a large population-based prospective cohort study

ObjectiveWe aimed to investigate the interrelationships among polygenic risk scores (PRS), healthy lifestyle factors (HLFs), and colorectal cancer (CRC) risk in individuals with prediabetes. To investigate whether adherence to HLFs influence CRC risk in those with elevated PRS within this specific population.MethodsData from 22,408 prediabetes participants without CRC at baseline were analyzed from the UK Biobank. HLFs were graded using healthy lifestyle scores (HLSs) and classified as favorable, intermediate, or unfavorable, while the PRS for CRC was categorized as high, medium, or low. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for CRC risk.ResultsHigh PRS (HR: 2.36; 95% CI: 1.86–3.00) and medium PRS (HR: 1.42; 95% CI: 1.09–1.83) prediabetes were associated with increased CRC risk compared to those with low PRS. HLFs were linked to lower CRC risk in a dose–response manner, with never smoking (HR: 0.69; 95% CI: 0.57–0.84) and maintaining a healthy BMI (HR: 0.64; 95% CI: 0.49–0.82) associated with reduced CRC risk. Adherence to favorable HLFs may reduce the CRC risk in those with medium (HR: 0.51; 95% CI: 0.27–0.95) and high PRS (HR: 0.62; 95% CI: 0.39–0.99) over 15 years of follow-up. In participants with high PRS and unfavorable HLFs, the excess risk due to the additive interaction between PRS and HLFs was 1.41% (p < 0.01), especially for women (1.07%).ConclusionsThere is an additive interaction of PRS and HLFs on CRC risk in individuals with prediabetes. Adopting favorable HLFs should be integrated into the management of prediabetes individuals to reduce the risk of CRC.

Alcohol consumption does not modify the polygenic risk score-based genetic risk of breast cancer in postmenopausal women: Atherosclerosis Risk in Communities study.

High genetic risk and alcohol consumption ≥1 drink/day are associated with increased breast cancer risk. However, the interaction between alcohol and genetics on breast cancer risk is poorly understood, including in populations not enriched with daily drinkers. We prospectively studied 5651 White and Black postmenopausal women in the Atherosclerosis Risk in Communities study. Alcohol intake was assessed by food frequency questionnaire. 313-SNPs polygenic risk score (PRS) was calculated. Breast cancer cases were ascertained primarily by cancer registry linkage through 2015. Multivariable Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of PRS and current ethanol intake with breast cancer, and their interaction. 50.6% were current drinkers, and of them 50.8% drank <1 drink/week and 12.8% drank >7 drinks/week. Higher PRS was associated with higher breast cancer risk among White (HR1-SD:1.48, 95%CI:1.34-1.65) and Black (HR1-SD:1.15, 95%CI:0.96-1.38) women. Positive associations were not observed between current ethanol intake and breast cancer risk (White, HR13g/week:1.00, 95%CI:0.98-1.03; Black, HR:0.83, 95%CI:0.69-1.00). Among both White and Black women, PRS generally appeared to be positively associated with risk in drinkers and non-drinkers. There was no evidence of an PRS-ethanol intake interaction in White or Black women. Patterns in Black women were similar when using an 89-SNP PRS developed among African-ancestry women. In conclusion, in a prospective analysis of White and Black postmenopausal women in a study population not enriched with daily drinkers, our findings suggest that alcohol drinking does not modify PRS-based genetic risk of breast cancer.

Association of Metabolic Diseases and Moderate Fat Intake with Myocardial Infarction Risk.

Myocardial infarction (MI) can range from mild to severe cardiovascular events and typically develops through complex interactions between genetic and lifestyle factors. We aimed to understand the genetic predisposition associated with MI through genetic correlation, colocalization analysis, and cells' gene expression values to develop more effective prevention and treatment strategies to reduce its burden. A polygenic risk score (PRS) was employed to estimate the genetic risk for MI and to analyze the dietary interactions with PRS that affect MI risk in adults over 45 years (n = 58,701). Genetic correlation (rg) between MI and metabolic syndrome-related traits was estimated with linkage disequilibrium score regression. Single-cell RNA sequencing (scRNA-seq) analysis was performed to investigate cellular heterogeneity in MI-associated genes. Ten significant genetic variants associated with MI risk were related to cardiac, immune, and brain functions. A high PRS was associated with a threefold increase in MI risk (OR: 3.074, 95% CI: 2.354-4.014, p < 0.001). This increased the risk of MI plus obesity, hyperglycemia, dyslipidemia, and hypertension by about twofold after adjusting for MI-related covariates (p < 0.001). The PRS interacted with moderate fat intake (>15 energy percent), alcohol consumption (<30 g/day), and non-smoking, reducing MI risk in participants with a high PRS. MI was negatively correlated with the consumption of olive oil, sesame oil, and perilla oil used for cooking (rg = -0.364). MI risk was associated with storkhead box 1 (STOX1) and vacuolar protein sorting-associated protein 26A (VPS26A) in atrial and ventricular cardiomyocytes and fibroblasts. This study identified novel genetic variants and gene expression patterns associated with MI risk, influenced by their interaction with fat and alcohol intake, and smoking status. Our findings provide insights for developing personalized prevention and treatment strategies targeting this complex clinical presentation of MI.

The Joint Contribution of Childhood Exposure to Parental Smoking and Genetic Susceptibility to Smoking to Epigenetic Age Acceleration in Late Adulthood: The Health and Retirement Study

The impact of childhood exposure to parental smoking on epigenetic age acceleration (EAA) in later life has not been thoroughly investigated. This study investigates the relationship while considering genetic susceptibility to smoking. We analyzed data from 3102 participants in the Health and Retirement Study (HRS) who also participated in the 2016 Venous Blood Study and the 2015–2017 Life History Mail Survey. Self-reported measures included childhood parental smoking exposure and smoking status in late adulthood. We utilized five epigenetic clocks—HorvathAA, HannumAA, GrimAA, PhenoAA, and DunedinAA—and assessed genetic susceptibility with a polygenic risk score (PRS) for smoking initiation, categorized into tertiles. We regressed the clocks against chronological age to derive EAA residuals. Associations between childhood exposure and EAA were examined in the overall sample and by PRS tertiles, stratified by race. The model controlled for age, sex, education, smoking, alcohol consumption, body mass index, and CESD scores. Significant associations were found between childhood exposure to parental smoking and the EAA measured by GrimAA (β = 0.98; p &lt; 0.001) and DunedinAA (β = 0.01; p = 0.002) among White participants, with stronger effects in those with a high PRS. Similar patterns were observed in Black participants, highlighting the importance of preventing secondhand smoke exposure in children.

Accelerated biological aging, healthy behaviors, and genetic susceptibility with incidence of stroke and its subtypes: A prospective cohort study.

Stroke risk increases with chronological age, but the relationship with biological age (BA) acceleration is poorly understood. We aimed to examine the association between BA acceleration and incident stroke and its subtypes, explore the modifying effects on genetic susceptibility, and assess how BA acceleration mediates the effect of behavior score. We studied 253,932 UK Biobank participants and computed two BA measures (Klemera-Doubal Method [KDM], Phenotypic Age [PhenoAge]), with BA acceleration calculated by regressing BA on chronological age. The polygenic risk score (PRS) was derived from 87 genetic loci. The behaviors score was based on diet, physical activity, tobacco/nicotine, sleep, and BMI. During a median follow-up of 13.6 years, 5460 strokes, 4337 ischemic stroke (IS), 951 intracerebral hemorrhage (ICH), and 553 subarachnoid hemorrhage (SAH) cases were documented. Adjusting for confounding factors, each standard deviation increase in BA acceleration was associated with higher stroke risk: for KDM-BA acceleration, stroke (HR = 1.28, 95% CI = 1.25-1.32), IS (1.32, 1.28-1.36), ICH (1.15, 1.08-1.23), and SAH (1.16, 1.07-1.27); for PhenoAge acceleration, stroke (1.22, 1.19-1.25), IS (1.26, 1.22-1.29), ICH (1.08, 1.02-1.16), and SAH (1.08, 1.00-1.18). Compared to participants with the lowest PRS and BA acceleration, those with the highest PRS and BA acceleration had the highest stroke risk (KDM-BA acceleration: 2.19, 1.85-2.59; PhenoAge acceleration: 2.03, 1.69-2.42). Additionally, there was an additive interaction between KDM-BA acceleration and PRS. The mediation proportion of BA acceleration in associations of behaviors score with incident stroke and its subtypes ranged from 15.84% to 33.08%. BA acceleration may raise stroke risk, especially in those with high genetic risk. Maintaining healthy behaviors may help mitigate this risk.

Pancreatitis polygenic risk score is independently associated with all-cause acute pancreatitis risk in the UK Biobank.

Acute pancreatitis (AP) is a complex disease most commonly caused by gallstones, alcohol intake, or hypertriglyceridemia. Even in subjects with hypertriglyceridemia, the risk of AP is heterogeneous. Identifying individuals with a high genetic susceptibility to AP could contribute to a better risk stratification in the clinic. This study aimed to determine if a weighted polygenic risk score (PRS) of common variants in pancreatitis susceptibility genes can independently predict all-cause AP incidence in the general population. A weighted PRS was calculated for 484932 individuals from the UK Biobank, including 3346 individuals who developed AP during follow-up. The PRS included eight single nucleotide polymorphisms in known pancreatitis susceptibility genes. Individuals with a pancreatitis PRS above the 90th percentile had a 1.21-fold (1.03-1.43; P=0.02) increased risk of AP compared with those with a pancreatitis PRS below the 90th percentile. When comparing individuals in the third tertile versus the first tertile, the risk of AP was 1.13-fold (1.00-1.28; P=0.06) higher. Individuals with both a high triglyceride (TG) level and a high pancreatitis PRS (third tertile) had a 2.31-fold (1.83-2.93; P=3.4×10-12) increased risk of AP compared with those with a low pancreatitis PRS and a low TG level (first tertile). Overall, the association between pancreatitis PRS and incident AP was independent of baseline TG level. Results of this study suggest that the accumulation of common variants in pancreatitis susceptibility genes is associated with all-cause AP incidence. Pancreatitis PRS could help clinicians identify patients who may be at higher risk of AP and who may benefit from more aggressive treatment.

Predictive Power of Polygenic Risk Scores for Intraocular Pressure or Vertical Cup-Disc Ratio

Early detection of glaucoma is essential to timely monitoring and treatment, and primary open-angle glaucoma risk can be assessed by measuring intraocular pressure (IOP) or optic nerve head vertical cup-disc ratio (VCDR). Polygenic risk scores (PRSs) could provide a link between genetic effects estimated from genome-wide association studies (GWASs) and clinical applications to provide estimates of an individual's genetic risk by combining many identified variants into a score. To construct IOP and VCDR PRSs with clinically relevant predictive power. This genetic association study evaluated the PRSs for 6959 of 51 338 individuals in the Canadian Longitudinal Study on Aging (CLSA; 2010 to 2015 with data from 11 centers in Canada) and 4960 of 5107 individuals the community-based Busselton Healthy Aging Study (BHAS; 2010 to 2015 in Busselton, Western Australia) with an artificial intelligence grading approach used to obtain precise VCDR estimates for the CLSA dataset. Data for approximately 500 000 individuals in UK Biobank from 2006 to 2010 were used to validate the power of the PRS. Data were analyzed from June to November 2023. IOP and VCDR PRSs and phenotypic variance (R2) explained by each PRS. Participants in CLSA were aged 45 to 85 years; those in BHAS, 46 to 64 years; and those in UK Biobank, 40 to 69 years. The VCDR PRS explained 22.0% (95% CI, 20.1-23.9) and 19.7% (95% CI, 16.3-23.3) of the phenotypic variance in VCDR in CLSA and BHAS, respectively, while the IOP PRS explained 12.9% (95% CI, 11.3-14.6) and 9.6% (95% CI, 8.1-11.2) of phenotypic variance in CLSA and BHAS IOP measurements. The VCDR PRS variance explained 5.2% (95% CI, 3.6-7.1), 12.1% (95% CI, 7.5-17.5), and 14.3% (95% CI, 9.3-19.9), and the IOP PRS variance explained 2.3% (95% CI, 1.5-3.3), 3.2% (95% CI, 1.3-5.8), and 7.5% (95% CI, 6.2-8.9) (P < .001) across African, East Asian, and South Asian populations, respectively. VCDR and IOP PRSs derived using a large recently published multitrait GWAS exhibited validity across independent cohorts. The findings suggest that an IOP PRS has the potential to identify individuals who may benefit from more intensive IOP-lowering treatments, which could be crucial in managing glaucoma risk more effectively. Individuals with a high VCDR PRS may be at risk of developing glaucoma even if their IOP measures fall within the normal range, suggesting that these PRSs could help in early detection and intervention, particularly among those who might otherwise be considered at low risk based on IOP alone.

Abstract 4137717: Atrial Fibrillation in Valvular Heart Disease: Assessing the Impact of Genetics in the UK Biobank

Background: Atrial fibrillation (AF) in valvular heart disease (VHD) is typically linked to pressure or volume overload resulting in atrial remodeling. However, the independent contribution of genetics to AF in VHD beyond abnormal hemodynamics and other risk factors remains unclear. Objective: To study the role of a previously developed Polygenic Risk Score (PRS) for AF in predicting AF across different VHDs in the UK Biobank cohort. Methods: We analyzed UK Biobank data between 2000 and 2022. ICD codes were used to define incident AF and VHD status, including mitral valve (MV) disease [prolapse (MVP), regurgitation (MR) and stenosis (MS)] and aortic (AV) disease [stenosis (AS) and regurgitation (AR)]. Prior AF was excluded. Participants were divided into quintiles based on the PRS: the top quintile was defined as high genetic AF risk, second through fourth as intermediate genetic risk, and bottom quintile as low genetic risk. Results: Among 452841 participants with available PRS, 2238 had at least one VHD (385 MVP, 1058 MR, 81 MS, 421 AR, and 509 AS). AF incidence was 9.9%, 13.6%, and 19% in the low, intermediate and high genetic risk groups respectively, compared to 1.4%, 2.8%, and 5.7% in the general population (all p&lt;0.05) - Figure 1A . Cox regression models adjusted for cardiovascular risk factors showed different genetic effects on AF across VHD types. Censoring patients at death, including valve intervention as a time-dependent variable, and excluding AF within 30 days post-intervention, PRS independently predicted AF in MV disease (hazard ratio [HR] 1.7, p=0.03 for the intermediate risk/mid PRS; HR 2.3, p=0.002 for the high risk PRS), particularly in those with MVP (HR 3.1, p=0.03 for the high PRS). However, in those with AV disease, PRS was not significantly associated with AF (p=0.93 and p=0.07) - Figure 1B. Conclusion: In patients with VHD, AF PRS is significantly associated with an increased risk of developing AF. However, the genetic impact varies across different VHD. In AV disease, there is a minimal genetic contribution, and the elevated AF risk may be predominantly due to pressure or volume overload. In contrast, in MV disease, particularly in MVP, there is a substantial genetic influence on AF risk.