Higher Polygenic Risk Scores Research Articles

Coronary artery disease polygenic risk score in patients undergoing coronary angiography and risk of future revascularization

Abstract Background Coronary artery disease (CAD) polygenic risk score (PRS) is a strong predictor of incident CAD. The role of CAD PRS in patients with known or suspected CAD already presenting for invasive coronary angiography remains poorly understood. Purpose We aimed to (i) study the association between CAD PRS and coronary angiography traits, and (ii) determine whether CAD PRS can predict risk of future revascularization after an initial coronary angiogram. Methods Patients who underwent coronary angiography at a single hospital and were part of its biobank were included in the study. Participants were classified into 3 risk groups based on CAD PRS distribution–low (0-20%), intermediate (21-80%), and high (81-100%)–computed from a recently reported PRS comprised of 1,296,172 variants (GPSMult, PGS003725). Revascularization was defined as a composite of coronary artery bypass graft and percutaneous coronary intervention with a 3-month blocking window after the initial angiogram. Associations between coronary stenosis severity and burden, and CAD PRS were assessed using multinomial logistic regression adjusted for age, sex, and genetic ancestry. The cumulative incidence of revascularization was tested using Fine-Gray regression accounting for competing risk of all-cause mortality and compared across CAD PRS strata by log-rank test. Results Among 3,518 participants (29.90% female, mean age 63.29±12.14 years), 2,568 (73%) had angiographic evidence of CAD – 340 (13.24%) mild, 346 (13.47%) moderate, and 1,882 (73.29%) severe. Out of those with CAD, 844 (32.87%) presented with acute coronary syndromes (ACS) and 1,724 (67.13%) with stable CAD. CAD PRS was strongly associated with angiographic presence of CAD (OR 2.62, 95%CI 2.08-3.29) and this did not differ among patients presenting with ACS vs. stable CAD (Fig1A). The association was weakest for mild CAD (OR 1.14, 95%CI 0.77-1.68) and strongest for severe CAD (OR 3.04, 95%CI 2.40-3.84). Besides severity, CAD PRS was also strongly associated with angiographic burden of CAD with the strongest association observed for presence of left main coronary stenosis (OR 2.63, 95%CI 1.86-3.73). Each standard deviation increase in CAD PRS was associated with a 10-point increase in the Gensini score, a continuous measure of angiographic burden of CAD (p<2e-16) (Fig1B). Over a mean follow-up period of 9.26±5.81 years, 659 (18.73%) patients required revascularization at a mean period of 5.31±4.69 years. Risk of revascularization varied dramatically by CAD PRS; HR was 1.64 (95%CI 1.28-2.10, p=8.7e-5) for high vs. low CAD PRS (Fig2). CAD PRS remained predictive of future revascularization even after adjusting for the angiographic burden of CAD at baseline (HR 1.41, 95%CI 1.09-1.82, p=7.9e-3). Conclusion CAD PRS is strongly associated with severity and burden of CAD assessed on coronary angiography and is predictive of future risk of revascularization even after accounting for baseline disease burden.Figure 1.CAD PRS and angiographic traitsFigure 2.CAD PRS and revascularization

Socioeconomic deprivation and atrial fibrillation risk: an observational and gene-environment interaction analysis

Abstract Background The association between socioeconomic deprivation and incident atrial fibrillation (AF) is debated, along with limited evidence on how genetic predisposition to AF interacts with socioeconomic deprivation and AF risk. Purpose To evaluate the association and gene-environmental interaction between socioeconomic deprivation and the risk of incident AF. Methods From the UK Biobank prospective cohort, we selected participants who were free from previous AF. Participants with missing values and those who did not pass the genetic quality control were excluded. As an indicator of socioeconomic deprivation, we utilised the indices of multiple deprivation (IMD), which is calculated from scores of multiple socioeconomic factors, including crime, education, employment, health, housing, income, and living environment. Participants were divided into 3 groups by IMD; the top 20% as high IMD (most deprived), the bottom 20% as low IMD, and 20-80% as mid IMD. Using a polygenic risk score (PRS) for AF generated using a Bayesian approach applied to external genome-wide association study data, the interaction between genetic risk and socioeconomic deprivation was assessed. The primary endpoint was incident AF during a median of 13.7 years of follow-up. Results A total of 377,386 (aged 56.5±8.1 years, 45.2% male) were analysed. The high IMD group (n=85,108) was younger and had a higher proportion of comorbidities than the mid or low-IMD groups. An increase in IMD as a continuous variable was significantly associated with an increased risk of incident AF. The high IMD group showed a significantly increased risk of AF (multivariable-adjusted hazard ratio [aHR]=1.12, 95% confidence interval=1.07-1.17, P<0.001) compared with the low IMD group (incidence rate 7.7 vs. 4.8/1,000 person-year). All components of IMD except housing score significantly increased the risk of incident AF (aHR ranged from 1.07 to 1.15). Within each IMD group, higher AF PRS groups were significantly associated with an increased risk of incident AF with the low AF PRS group as a reference, showing aHRs of 1.50 for mid-PRS and 2.57 for high-PRS in the low IMD group, 1.60 and 2.65 in the mid-IMD group, and 1.55 and 2.33 in the high IMD group, respectively (all P<0.001). The impact of socioeconomic deprivation was attenuated in participants with high AF PRS (P for interaction=0.042), mainly driven by the interaction effect of crime (P for interaction [Pi]=0.005), employment deprivation (Pi=0.005), and health deprivation scores (Pi=0.043). Conclusion Socioeconomically deprived individuals had a significantly higher risk of AF, and the effect was partially modified by genetic predisposition to AF. A personalised approach to applying AF screening for high-risk individuals may be more efficacious. Legal measures and policies to enhance public health by alleviating socioeconomic inequalities are needed to mitigate AF risk and improve cardiovascular health outcomes.

Interplay between family History and polygenic risk for coronary heart disease: a cohort study among over 60 thousand individuals

Abstract Background The degree to which background genetic risk adds to self-report of family history of coronary heart disease (CHD) remains an important question. Methods We utilized data from the multiethnic Genetic Epidemiology Resource in Adult Health and Aging (GERA) cohort of 60,070 Kaiser Permanente of Northern California (KPNC) members (mean ± SD age=59 ± 9 years; 67% female; 18% non-white). We characterized the cohort at baseline in 2003-2007. Excluding those with missing self-report of family history of CHD (n=1,718) resulted in a final sample of 61,352. We stratified the cohort into not having (n=42,866; 70%) and having (n=18,486; 30%) self-reported family history of CHD and then (within stratum of family history of CHD) by three groups of CHD polygenic risk (low: quintile 1; intermediate: quintiles 2, 3 and 4 combined; and high: quintile 5) using a validated 12-SNP polygenic risk score (PRS) for CHD (CARDIO inCode-Score®). Incident CHD was based on ICD-9/10 codes for angina pectoris, myocardial infarction, revascularization procedures or CHD death (n=3,040) through 12/31/2022; mean follow-up was 14.5 years. Results Age-adjusted CHD incidence rates per 10,000 person years were estimated using Poisson regression (accounting for death and health plan disenrollment) by absence/presence of family history of CHD and polygenic risk groups. As shown in the Figure, polygenic risk provided additional risk stratification within categories of family history. The hazard ratio of high PRS (vs low PRS) adjusted for age, sex, 10 principal components of ancestry, smoking, body mass index, diabetes, hypertension, total cholesterol/HDL ratio and cholesterol lowering therapy was 1.62 (95% CI, 1.39-1.87; p<0.001) in those with no family history of CHD, and 1.66 (95% CI, 1.37-2.00; p<0.001) in those with family history of CHD (p-interaction PRS continuous*family history of CHD=0.93). Conclusions Our results show that polygenic risk predicts future CHD regardless of the presence of family history of CHD. Thus, it is not enough to rely of family history to fully characterize potential genetic burden. These data are therefore important for the future of precision medicine.

Plasma proteomic and polygenic profiling improve risk stratification and personalized screening for colorectal cancer

This study aims to identify colorectal cancer (CRC)-related proteomic profiles and develop a prediction model for CRC onset by integrating proteomic profiles with genetic and non-genetic factors (QCancer-15) to improve the risk stratification and estimate of personalized initial screening age. Here, using a two-stage strategy, we prioritize 15 protein biomarkers as predictors to construct a protein risk score (ProS). The risk prediction model integrating proteomic profiles with polygenic risk score (PRS) and QCancer-15 risk score (QCancer-S) shows improved performance (C-statistic: 0.79 vs. 0.71, P = 4.94E–03 in training cohort; 0.75 vs 0.69, P = 5.49E–04 in validation cohort) and net benefit than QCancer-S alone. The combined model markedly stratifies the risk of CRC onset. Participants with high ProS, PRS, or combined risk score are proposed to start screening at age 46, 41, or before 40 years old. In this work, the integration of blood proteomics with PRS and QCancer-15 demonstrates improved performance for risk stratification and clinical implication for the derivation of risk-adapted starting ages of CRC screening, which may contribute to the decision-making process for CRC screening.

Joint exposure to multiple air pollutants, genetic risk, and incident psoriasis: a large-scale prospective cohort study.

Air pollution and genetic risk have been found to contribute to both onset and development of psoriasis. However, the extent to which genetic susceptibility modifies the effects of air pollutants on the risk of incident psoriasis remains unknown. Our study aimed to assess the association between joint exposure to multiple air pollutants and the risk of psoriasis and the modification by the genetic susceptibility. This prospective study included 451,064 participants with complete air pollution data and free of psoriasis at baseline from the UK Biobank. All participants were enrolled from 2006 to 2010 and followed up to 2022. The air pollution score (APS) was calculated to assess the joint exposure to multiple air pollutants, including particulate matter (PM) with diameters ≤ 2.5 μm (PM2.5), between 2.5 and 10 μm (PM2.5-10), and ≤ 10 μm (PM10), as well as nitrogen dioxide (NO2) and nitrogen oxides (NOx). To evaluate the genetic risk, the polygenic risk score (PRS) for psoriasis was constructed. The Cox proportional hazard models were used to assess the association of air pollution and genetic susceptibility with the risk of psoriasis. Stratified analyses were conducted based on the individual characteristics. During a median follow-up of 13.79 years, 4414 psoriasis events were recorded. The hazard ratios (HRs) [95% confidence intervals (CIs)] for psoriasis were 1.036 (0.936-1.147), 1.091 (0.987-1.206), 1.159 (1.048-1.283), and 1.163 (1.052-1.286) in higher quintile groups compared with the lowest quintile of APS (P trend <0.05). When considering genetic susceptibility, participants with high PRS and high APS had the greatest risk of incident psoriasis [HR (95% CI): 1.962 (1.630-2.362)] than those with low PRS and low APS. The HRs (95% CIs) for PM2.5-10, NOx, PM2.5 absorbance, PM2.5, NO2, and PM10 in the group with high exposure level and genetic risk were 1.831 (1.537-2.181), 1.722 (1.431-2.073), 1.698 (1.416-2.037), 1.619 (1.353-1.938), 1.504 (1.252-1.806), and 1.425 (1.192-1.704), respectively. Long-term exposure to various air pollutants is positively associated with an increased risk of incident psoriasis, particularly in individuals with high genetic risk. More comprehensive measures are needed to reduce the air pollution levels for better prevention of psoriasis.

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.

Genetic Susceptibility to Hidradenitis Suppurativa and Predisposition to Cardiometabolic Disease.

Hidradenitis suppurativa (HS) is associated with an increased prevalence of cardiovascular diseases compared with the general population. Any association between polygenic risk for HS, risk of incident cardiometabolic outcomes, and the plasma proteome is unclear. To investigate the genetic correlation between HS and cardiometabolic disease. This cohort study used a polygenic risk score (PRS) for HS to examine the risks of coronary artery disease (CAD) and diabetes and identify changes in the plasma proteome in individuals of European ancestry from the UK Biobank. Participants were enrolled from January 1, 2006, to December 31, 2010. End of follow-up was January 1, 2023. Correlations were assessed between HS susceptibility and cardiometabolic traits using linkage disequilibrium score regression. Odds ratios were assessed in logistic regressions. The risk of incident CAD and diabetes was estimated in cause-specific survival models designed as time-to-event analyses. The PRS for HS. Main outcomes were CAD and diabetes diagnosis measured by logistic regressions and incident disease measured by Cox proportional hazards regression models adjusted for sex, age, body mass index, and smoking status. The study included 391 481 individuals (median [IQR] age, 58 [51-64] years; 209 235 [53%] female). Genetic variants for HS correlated significantly with variants associated with CAD, diabetes, and plasma levels of high-density lipoprotein cholesterol, triglycerides, and C-reactive protein. Compared with the low-risk group, a high PRS for HS (≥75th percentile) conferred odds ratios of 1.09 (95% CI, 1.06-1.12; P < .001) for CAD and 1.13 (95% CI, 1.10-1.17; P < .001) for diabetes. Estimates remained consistent when examining only incident CAD and diabetes. The PRS for HS was significantly associated with altered expression of 58 plasma proteins. Integrating this proteomic profile and the PRS for HS in a machine learning model improved prediction of CAD and diabetes compared with a reference model based on sex, age, and body mass index. These findings suggest that a high genetic risk of HS is associated with increased risk of subsequent CAD and diabetes and altered composition of the plasma proteome. Additional investigation into the identified proteins and their potential roles as drug targets is warranted.

Association of Polygenic Risk Score With Lifetime Risk of Developing Multiple Sclerosis in a Population-Based Birth-Year Cohort.

More than 200 genetic variants have been associated with multiple sclerosis (MS) susceptibility. However, it is unclear to what extent genetic factors influence lifetime risk of MS. Using a population-based birth-year cohort, we investigate the effect of genetics on lifetime risk of MS. In the Project Y study, we tracked down almost all persons with MS (pwMS) from birth year 1966 in the Netherlands. As control participants, we included non-MS participants from the Project Y cohort (born 1965-1967 in the Netherlands) and non-MS participants from the Amsterdam Dementia Cohort born between 1963 and 1969. Genetic variants associated with MS were determined in pwMS and control participants using genotyping or imputation methods. Polygenic risk scores (PRSs) based on variants and weights from the largest genetic study in MS were calculated for each participant and assigned into deciles based on the PRS distribution in the control participants. We examined the lifetime risk for each decile and the association between PRS and MS disease variables, including age at onset and time to secondary progression. MS-PRS was calculated for 285 pwMS (mean age 53.0 ± 0.9 years, 72.3% female) and 267 control participants (mean age 51.8 ± 3.2 years, 58.1% female). Based on the lifetime risk estimation, we observed that 1:2,739 of the women with the lowest 30% genetic risk developed MS, whereas 1:92 of the women with the top 10% highest risk developed MS. For men, only 1:7,900 developed MS in the lowest 30% genetic risk group, compared with 1:293 men with the top 10% genetic risk. The PRS was not significantly associated with age at onset and time to secondary progression in both sexes. Our results show that the lifetime risk of MS is strongly influenced by genetic factors. Our findings have the potential to support diagnostic certainty in individuals with suspected MS: a high PRS could strengthen a diagnosis, but especially a PRS from the lowest tail of the PRS distribution should be considered a red flag and could prevent misdiagnosing conditions that mimic MS.

Exposure to Air Pollutants and Myocardial Infarction Incidence: A UK Biobank Study Exploring Gene-Environment Interaction.

Unraveling gene-environment interaction can provide a novel insight into early disease prevention. Nevertheless, current understanding of the interplay between genetic predisposition and air pollution in relation to myocardial infarction (MI) risk remains limited. Furthermore, the potential long-term influence of air pollutants on MI incidence risk warrants more conclusive evidence in a community population. We investigated interactions between genetic predisposition and exposure to air pollutants on MI incidence. This study incorporated a sample of 456,354 UK Biobank participants and annual mean air pollution (, , , and ) from the UK Department for Environment, Food and Rural Affairs (2006-2021). The Cox proportional hazards model was employed to explore MI incidence after chronic air pollutants exposure. By quantifying genetic risk through the calculation of polygenic risk score (PRS), this study further examined the interactions between genetic risk and exposure to air pollutants in the development of MI on both additive and multiplicative scales. Among 456,354 participants, 9,114 incident MI events were observed during a median follow-up of 12.08 y. Chronic exposure to air pollutants was linked with an increased risk of MI occurrence. Specifically, the hazard ratios (per interquartile range) were 1.12 (95% CI: 1.10, 1.13) for , 1.20 (95% CI: 1.19, 1.22) for , 1.13 (95% CI: 1.12, 1.15) for , and 1.12 (95% CI: 1.11, 1.13) for . In terms of the joint effects, participants with high PRS and high level of air pollution exposure exhibited the greatest risk of MI among all study participants ( to 324%). Remarkably, both multiplicative and additive interactions were detected in the ambient air pollutants exposure and genetic risk on the incidence of MI. There were interactions between exposure to ambient air pollutants and genetic susceptibility on the risk of MI onset. Moreover, the joint effects of these two exposures were greater than the effect of each factor alone. https://doi.org/10.1289/EHP14291.

Circulating ketone bodies, genetic susceptibility, with left atrial structure, function and atrial fibrillation: A prospective study from UK Biobank

BackgroundKetone bodies (KB) are important cardiac metabolic energy source. Metabolic remodeling has been recently pointed to play an important role in the pathological process of atrial fibrillation (AF). ObjectiveTo evaluate the associations between circulating KB levels with incident AF risk in the general population. MethodsWe studied 237,163 participants (mean age, 56.5 years; 55% women) from the UK Biobank who were free of AF at baseline and had data about circulating β-hydroxybutyrate (β-OHB), acetoacetate, and acetone. The associations between KB with new-onset AF were evaluated by Cox regression in the general population and across three genetic risk groups [low, moderate, and high polygenic risk score of AF]. ResultsDuring a median follow-up of 14.8 years, 16,638 (7.0%) participants developed AF. There was a U-shaped association between total KB and β-OHB with incident AF, with nadirs at 60.6 and 40.8 μmol/L, respectively (P non-linear <0.05), whereas a positive association between acetoacetate and acetone with AF was observed (P overall <0.001, P non-linear >0.05). Consistently, a U-shaped association was observed between total KB and β-OHB with left atrial (LA) volume parameters, including LA maximum volume (LAVmax), LA minimum volume (LAVmin), and their body surface area-indexed counterparts, and an inverted U-shaped association was observed for LA ejection fraction (all P non-linear <0.05). The association between KB with AF was greater among individuals with low genetic risk (Pinteraction <0.05), while the highest AF risk was for those at high genetic risk with high KB levels. Significant mediation effects of inflammatory markers on the associations between KB and AF were identified. ConclusionsThere was a U-shaped association between circulating total KB and β-OHB with incident AF, as well as a positive association between acetoacetate and acetone level with AF risk in the general population.

Associations of combined accelerated biological aging and genetic susceptibility with incident dementia: a prospective study in the UK Biobank

BackgroundAccelerated biological aging has been verified to be a critical risk factor for a number of age-related diseases, but its role in dementia remained unclear. Whether it modified the effects of genetic factors was also unknown. This study evaluated the associations between accelerated biological aging and dementia and the moderating role of accelerated biological aging in the genetic susceptibility to the disease.MethodsWe included 200,731 participants in the UK biobank. Nine clinical blood biomarkers and chronological age were used to calculate Phenotypic age acceleration (PhenoAgeAccel), which is a novel indicator for accelerated biological aging. The associations of PhenoAgeAccel with dementia, both young-onset and late-onset dementia, were assessed by Cox proportional hazard models. Apolipoprotein E (APOE) alleles and polygenic risk scores (PRS) were used to evaluate the genetic risk of dementia. The interactions between genetic susceptibility and biological aging were tested on both multiplicative and additive scales.ResultsThese findings showed individuals who were in the highest quartile of PhenoAgeAccel had a higher risk with incidence of dementia compared to individuals in the lowest quartile of PhenoAgeAccel (HR: 1.145 (95% CI: 1.050, 1.249)). Individuals with biologically older had a higher risk of dementia than individuals with biologically younger (HR: 1.069 (95% CI: 1.004, 1.138)). Furthermore, compared to individuals with biologically younger and low APOE ε4-related genetic risk, individuals with biologically younger and high APOE ε4-related genetic risk (HR:3.048 (95% CI: 2.811, 3.305)) had a higher risk of dementia than individuals with biologically older and high APOE ε4-related genetic risk (HR: 2.765 (95% CI: 2.523, 3.029)). Meanwhile, referring to low dementia PRS and biologically younger, the risk of dementia increased by 72.7% (HR: 1.727 (95% CI: 1.538, 1.939) in the biologically younger and high PRS group and 58.7% (HR: 1.587 (95% CI: 1.404, 1.793) in the biologically older and high PRS group, respectively. The negative interactions between PhenoAgeAccel with APOE ε4 and PRS were also tested on the additive scale.ConclusionsAccelerated biological aging could bring the extra risk of dementia but attenuate the effects of genetic risk on dementia. These findings provide insights for precise prevention and intervention of dementia.

High Polygenic Risk Scores Positively Associated with Gastric Cancer Risk Interact with Coffee and Polyphenol Intake and Smoking Status in Korean Adults.

This study investigated the relationship between single nucleotide polymorphisms (SNPs) and gastric cancer (GC) risk, while also examining the interaction of genetic factors with lifestyle variables including the nutrient and bioactive compound intake in Korean adults of a large hospital-based cohort. We conducted a genome-wide association study (GWAS) comparing GC patients (n = 312) with healthy controls without cancers (n = 47,994) to identify relevant genetic variants. Generalized multifactor dimensionality reduction (GMDR) was employed to detect SNP interactions between diets and lifestyles. We utilized polygenic risk scores (PRSs) to assess individuals' GC risk based on multiple SNP loci. Among the selected SNPs, since SEMA3C_rs1527482 was a missense mutation, bioactive compounds which decrease the binding energy were found with its wild and mutated proteins by molecular docking analysis. Individuals with high PRSs exhibited a 4.12-fold increased risk of GC compared to those with low PRSs. Additional factors associated with elevated GC risk included a low white blood cell count (OR = 5.13), smoking (OR = 3.83), and low coffee consumption (OR = 6.30). The SEMA3C_rs1527482 variant showed a positive correlation with GC risk. Molecular docking analyses suggested that certain polyphenols, including theaflavate, rugosin E, vitisifuran B, and plantacyanin, reduced the binding free energy in both wild-type and mutated SEMA3C_rs1527482. However, some polyphenols exhibited differential binding energies between its wild and mutated forms, suggesting they might modulate wild and mutated proteins differently. High PRSs and SEMA3C_rs1527482 interact with immune function, coffee intake, polyphenol consumption, and smoking status to influence GC risk. These findings could contribute to developing personalized nutrition and lifestyle interventions to reduce GC risk.

Prenatal exposure to per- and polyfluoroalkyl substances, genetic factors, and autistic traits: Evidence from the Shanghai birth cohort

The epidemiological evidence regarding prenatal PFAS exposure and its interaction with genetic factors on the autistic traits risk is unclear. This study included 1610 mother-child pairs from the Shanghai Birth Cohort (SBC). Ten PFAS were quantified in blood serum collected in the first trimester. Child autistic traits were evaluated at age 4 using a Chinese version of the social responsiveness scale-short form (SRS-SF). We calculated the polygenic risk score (PRS) to evaluate the cumulative genetic effects of autism. Additive interaction models were established to explore whether genetic susceptibility modified the effects of prenatal PFAS exposure. After adjusting for confounders, we found prenatal PFOA exposure was associated with an increased risk of autistic traits in children (OR, 3.05; 95 % CI, 1.14–7.58), and the increased risk associated with PFOA was mitigated among women who reported pre-pregnancy folic acid supplementation. Additionally, an increased risk of autistic traits was observed in children with higher levels of prenatal PFHxS exposure and a high PRS (p for interaction = 0.021). Our findings suggest prenatal PFAS exposure may increase the risk of autistic traits in children, especially in those with a high genetic risk. Further research is warranted to confirm this association and explore the underlying mechanisms.

Intergenerational continuation of parent-child separation and 1-year telomere length attrition among mother-offspring dyads in rural China: The moderating effects of resilience

BackgroundAlthough stressor exposure early in life was known risk factor for telomere length (TL) attrition, limited literature explored it across generations. Furthermore, the effects of resilience have rarely been examined. Here, we examined whether the effects of intergenerational parent-child separation on offspring 1-year TL attrition vary by the levels of resilience. MethodIn a sample of 342 mother-child dyads living in rural China, the intergenerational continuation of parent-child separation was defined as the two generations both experiencing parent-child separation from both parents for >6 months a year early in life assessed by the parent-reported questionnaire, whereas intergenerational discontinuity refers to parent-child separation exposed in one generation only. TL was measured at baseline (from June to November 2021) and 1-year later with children's buccal mucosa swabs, with resilience polygenic risk scores (PRS) evaluated based on 4 single-nucleotide variations in 4 resilience-related genes (OXTR, FKBP5, NPY, and TNF-α). ResultsAmong 342 mother-offspring dyads, 35 (10.2 %) experienced intergenerational continuation of parent-child separation, and 139 (40.6 %) were identified as discontinuous. Remarkably, a 0.12-point reduction in TL attrition was only associated with intergenerational continuation of parent-child separation (95 % CI: 0.04, 0.21, P < 0.01) but not discontinuity. Importantly, the association between intergenerational continuation of parent-child separation with accelerated TL attrition disappeared in offspring with high resilience PRS (β = 0.07, 95%CI: −0.06, 0.21). ConclusionOur findings highlight the importance of breaking the intergenerational cycle of parent-child separation and the moderating effects of resilience on TL attrition for children exposed to adversity.

Family history and genetic risk score combined to guide cancer risk stratification: A prospective cohort study.

Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.

Anemia, blood cell indices, genetic correlations, and brain structures: A comprehensive analysis of roles in Parkinson's disease risk

IntroductionAnemia may contribute significantly to the onset of Parkinson's disease (PD). Current research on the association between anemia and PD risk is inconclusive, and the relationships between anemia-related blood cell indices and PD incidence require further clarification. This study aims to investigate the relationships between anemia, blood cell indicators, and PD risk using a thorough prospective cohort study. MethodsWe used data from the UK Biobank, a prospective cohort study of 502,649 participants, and ultimately, 365,982 participants were included in the analysis. Cox proportional hazards models were utilized to adjust for confounding factors, aiming to thoroughly explore the associations between anemia and blood cell indices with the risk of incident PD. The interaction between anemia and Polygenic Risk Score (PRS) for PD was also examined. Linear regression and mediation analyses assessed potential mechanisms driven by brain structures, including grey matter volume. ResultsDuring a median follow-up of 14.24 years, 2513 participants were diagnosed with PD. Anemia considerably increased PD risk (hazard ratio [HR] 1.98, 95 % confidence interval [CI]: 1.81–2.18, P < 0.001) after adjustments. Those with high PRS for anemia had an 83 % higher PD incidence compared to low PRS participants. Sensitivity analyses confirmed result robustness. Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. Furthermore, mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD risk. ConclusionIn summary, we consider there to be a substantial correlation between anemia and increased PD risk.

Life's Essential 8, genetic susceptibility, and risk of incident pancreatic cancer: A prospective cohort study.

The association between the American Heart Association (AHA) Life's Essential 8 (LE8) and the risk of pancreatic cancer (PC) remains unclear. Our goal was to assess the relationships between LE8, genetic susceptibility, and PC risk. This cohort consisted of 234,102 participants from the UK Biobank. The components of LE8 include diet, nicotine exposure, sleep, physical activity, blood glucose, body mass index, blood lipids, and blood pressure. LE8 is classified into three categories: low cardiovascular health (CVH), moderate CVH, and high CVH. Measurements were made using Cox proportional risk models to estimate impact of associations between LE8, genetic susceptibility, and incidence of PC in participants. Compared to participants with low LE8 scores, those with moderate and high LE8 scores had a 53% (HR, 0.47; 95% CI, 0.39-0.57) and 70% (HR, 0.30; 95% CI, 0.22-0.41) lower risk of developing PC, respectively. Interestingly, among individuals with high genetic risk, high LE8 scores were associated with greater benefits (HR, 0.24; 95% CI, 0.15-0.40), whereas the protective effect was weaker among those with low genetic risk (HR, 0.40; 95% CI, 0.21-0.75). Participants with a high LE8 score and a low polygenic risk score (PRS) had the lowest risk of PC (HR, 0.19; 95% CI: 0.11-0.33). Furthermore, we observed a significant additive interaction between LE8 and PRS. A higher LE8 score is associated with a lower risk of PC, especially for participants with a high PRS. These findings have important implications for participants most genetically predisposed to PC and for targeted strategies for PC prevention.

Evaluating the cost-effectiveness of polygenic risk score-stratified screening for abdominal aortic aneurysm

As the heritability of abdominal aortic aneurysm (AAA) is high and AAA partially shares genetic architecture with other cardiovascular diseases, genetic information could help inform AAA screening strategies. Exploiting pleiotropy and meta-analysing summary data from large studies, we construct a polygenic risk score (PRS) for AAA. Leveraging related traits improves PRS performance (R2) by 22.7%, relative to using AAA alone. Compared with the low PRS tertile, intermediate and high tertiles have hazard ratios for AAA of 2.13 (95%CI 1.61, 2.82) and 3.70 (95%CI 2.86, 4.80) respectively, adjusted for clinical risk factors. Using simulation modelling, we compare PRS- and smoking-stratified screening with inviting men at age 65 and not inviting women (current UK strategy). In a futuristic scenario where genomic information is available, our modelling suggests inviting male current smokers with high PRS earlier than 65 and screening female smokers with high/intermediate PRS at 65 and 70 respectively, may improve cost-effectiveness.

Genomic insights into mRNA COVID-19 vaccines efficacy: Linking genetic polymorphisms to waning immunity

ABSTRACT Genetic polymorphisms have been linked to the differential waning of vaccine-induced immunity against COVID-19 following vaccination. Despite this, evidence on the mechanisms behind this waning and its implications for vaccination policy remains limited. We hypothesize that specific gene variants may modulate the development of vaccine-initiated immunity, leading to impaired immune function. This study investigates genetic determinants influencing the sustainability of immunity post-mRNA vaccination through a genome-wide association study (GWAS). Utilizing a hospital-based, test negative case-control design, we enrolled 1,119 participants from the Taiwan Precision Medicine Initiative (TPMI) cohort, all of whom completed a full mRNA COVID-19 vaccination regimen and underwent PCR testing during the Omicron outbreak. Participants were classified into breakthrough and protected groups based on PCR results. Genetic samples were analyzed using SNP arrays with rigorous quality control. Cox regression identified significant single nucleotide polymorphisms (SNPs) associated with breakthrough infections, affecting 743 genes involved in processes such as antigenic protein translation, B cell activation, and T cell function. Key genes identified include CD247, TRPV1, MYH9, CCL16, and RPTOR, which are vital for immune responses. Polygenic risk score (PRS) analysis revealed that individuals with higher PRS are at greater risk of breakthrough infections post-vaccination, demonstrating a high predictability (AUC = 0.787) in validating population. This finding confirms the significant influence of genetic variations on the durability of immune responses and vaccine effectiveness. This study highlights the importance of considering genetic polymorphisms in evaluating vaccine-induced immunity and proposes potential personalized vaccination strategies by tailoring regimens to individual genetic profiles.

Cardiovascular health and cancer mortality: evidence from US NHANES and UK Biobank cohort studies

BackgroundThe American Heart Association recently introduced a novel cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the relationship between LE8 and cancer mortality risk remains uncertain.MethodsWe investigated 17,076 participants from US National Health and Nutrition Examination Survey (US NHANES) and 272,727 participants from UK Biobank, all free of cancer at baseline. The CVH score, based on LE8 metrics, incorporates four health behaviors (diet, physical activity, smoking, and sleep) and four health factors (body mass index, lipid, blood glucose, and blood pressure). Self-reported questionnaires assessed health behaviors. Primary outcomes were mortality rates for total cancer and its subtypes. The association between CVH score (continuous and categorical variable) and outcomes was examined using Cox model with adjustments. Cancer subtypes-related polygenic risk score (PRS) was constructed to evaluate its interactions with CVH on cancer death risk.ResultsOver 141,526 person-years in US NHANES, 424 cancer-related deaths occurred, and in UK Biobank, 8,872 cancer deaths were documented during 3,690,893 person-years. High CVH was associated with reduced overall cancer mortality compared to low CVH (HR 0.58, 95% CI 0.37–0.91 in US NHANES; 0.51, 0.46–0.57 in UK Biobank). Each one-standard deviation increase in CVH score was linked to a 19% decrease in cancer mortality (HR: 0.81; 95% CI: 0.73–0.91) in US NHANES and a 19% decrease (HR: 0.81; 95% CI: 0.79–0.83) in UK Biobank. Adhering to ideal CVH was linearly associated with decreased risks of death from lung, bladder, liver, kidney, esophageal, breast, colorectal, pancreatic, and gastric cancers in UK Biobank. Furthermore, integrating genetic data revealed individuals with low PRS and high CVH exhibited the lowest mortality from eight cancers (HRs ranged from 0.36 to 0.57) compared to those with high PRS and low CVH. No significant modification of the association between CVH and mortality risk for eight cancers by genetic predisposition was observed. Subgroup analyses showed a more pronounced protective association for overall cancer mortality among younger participants and those with lower socio-economic status.ConclusionsMaintaining optimal CVH is associated with a substantial reduction in the risk of overall cancer mortality. Adherence to ideal CVH correlates linearly with decreased mortality risk across multiple cancer subtypes. Individuals with both ideal CVH and high genetic predisposition demonstrated significant health benefits. These findings support adopting ideal CVH as an intervention strategy to mitigate cancer mortality risk and promote healthy aging.