Individual Genetic Risk Research Articles

Ethnic differences of genetic risk and smoking in lung cancer: two prospective cohort studies.

The role of genetic background underlying the disparity of relative risk of smoking and lung cancer between European populations and East Asians remains unclear. To assess the role of ethnic differences in genetic factors associated with smoking-related risk of lung cancer, we first constructed ethnic-specific polygenic risk scores (PRSs) to quantify individual genetic risk of lung cancer in Chinese and European populations. Then, we compared genetic risk and smoking as well as their interactions on lung cancer between two cohorts, including the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). We also evaluated the absolute risk reduction over a 5-year period. Differences in compositions and association effects were observed between the Chinese-specific PRSs and European-specific PRSs, especially for smoking-related loci. The PRSs were consistently associated with lung cancer risk, but stronger associations were observed in smokers of the UKB [hazard ratio (HR) 1.26 vs 1.15, P = 0.028]. A significant interaction between genetic risk and smoking on lung cancer was observed in the UKB (RERI, 11.39 (95% CI, 7.01-17.94)], but not in the CKB. Obvious higher absolute risk was observed in nonsmokers of the CKB, and a greater absolute risk reduction was found in the UKB (10.95 vs 7.12 per 1000 person-years, P <0.001) by comparing heavy smokers with nonsmokers, especially for those at high genetic risk. Ethnic differences in genetic factors and the high incidence of lung cancer in nonsmokers of East Asian ethnicity were involved in the disparity of smoking-related risk of lung cancer.

The Relationship Between Antisocial Personality Disorder and Criminology: Acquired Factors and Genetic Influences

This study looks at the interaction of internal and external factors in the process of antisocial personality disorder (ASPD) and criminal conduct. It reveals the major contributions of both genetic and acquired factors using data from longitudinal twin studies, neuroimaging research, and gene-environment interaction studies. Environmental variables, such as bad childhood experiences, community hardship, and exposure to violence, also play important roles in antisocial behavior variance. The complicated interaction between genetic predispositions and environmental conditions emphasizes the need of understanding these components' dynamic character throughout an individual's development. With further knowledge, it will be feasible to build complete, individualized therapies that target both genetic and environmental aspects in the emergence and maintenance of antisocial behavior. Furthermore, this review emphasizes the importance of early intervention and prevention strategies that take an individual's unique genetic and environmental risk factors into account, ultimately contributing to a more effective approach in reducing the prevalence of ASPD and criminal behavior in society.

Individual Risk Assessment for Population Living on the Territories Long-Term Polluted by Organochlorine Pesticides

The long-term storage of unutilized pesticides raised new problems of long-term environmental contamination. The study presents the results of surveying 151 individuals in 7 villages living close to pesticide-contaminated localities. All individuals have been surveyed concerning their consumption habits and lifestyle characteristics. An assessment of the general exposure risks of the local population was carried out using the analysis of pollutants in food products and the average levels of their consumption in the region. The cohort risk evaluation revealed that the greatest risk was associated with the regular consumption of cucumbers, pears, bell peppers, meat, and milk. The new model to estimate individual risks of long-term pesticide pollution was proposed as a calculation of the combined action of 9 risk factors, including individual genotypes, age, lifestyle, and personal pesticide consumption rates. The analysis of the predictive ability of this model showed that the final score for individual health risks corresponded to the development of chronic diseases. A high level of chromosomal aberrations was evidenced for individual genetic risk manifestations. The combined influence of all risk factors revealed contributions of 24.7% for health status and 14.2% for genetic status, while other impacts go to all unaccounted factors.

Current Understanding of the Effects of Sun Exposure on Skin Tanning: Mechanisms, Risks, and Protective Strategies

UV radiation (UV) is designated as a "comprehensive carcinogen" due to its dual nature as a mutagen and a non-specific damaging agent, exhibiting properties of both a tumor initiator and a tumor promoter. UV radiation is the foremost modifiable risk factor for skin cancer and various other environmentally-influenced skin disorders. Nevertheless, UV radiation also plays a beneficial role in human health by facilitating the natural synthesis of vitamin D and endorphins in the skin. Consequently, UV radiation exhibits complex and diverse effects on human health. However, excessive exposure to UV radiation poses significant health risks, including skin atrophy, pigmentary alterations, wrinkling, and malignancy. Epidemiological and molecular evidence establish a clear link between UV radiation and the three most prevalent types of skin cancer: basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, collectively impacting over a million Americans each year. Furthermore, genetic factors contribute to the susceptibility of UV-mediated skin diseases. Notably, specific variations in the melanocortin 1 receptor (MC1R) gene are associated with skin fairness, UV sensitivity, and heightened cancer risk. In light of these findings, our research aims to develop innovative UV-protective strategies by comprehensively understanding the molecular events that occur following UV exposure, with a specific focus on epidermal melanization and the pivotal role played by the MC1R in maintaining the integrity of the genome. By leveraging this knowledge, we endeavor to devise pharmaceutical interventions that can effectively mitigate the detrimental effects of UV radiation on the skin, reduce the risk of skin cancer, and enhance skin health. Such advancements will not only contribute to safeguarding individuals from the harmful consequences of excessive UV exposure but also pave the way for novel approaches in the field of dermatology and personalized medicine, tailored to the individual's genetic makeup and specific risk factors.

Genetic impact on the association of sleep patterns and chronic kidney disease: A prospective cohort study of 157,175 UK Biobank participants

ObjectivesThe association between sleep pattern and chronic kidney disease (CKD) incidence, and whether the association is dependent on the genetic backgrounds has not been addressed. We sought to investigate the association of multidimensional sleep pattern with CKD in consideration of genetic polymorphisms. MethodsIn this prospective cohort study of 157,175 participants from the UK Biobank, sleep patterns were derived by multiple correspondence analysis (MCA) and k-means clustering of individual sleep traits (sleep duration, insomnia, chronotype, daytime sleepiness, snoring, and night shift status). Cox proportional hazard regression was used to estimate the association between sleep patterns and CKD incidence. Gene-environment-wide interaction study (GEWIS) was performed to detect whether gene polymorphisms were modifiers on this association. ResultsCompared with “healthy sleep” pattern, increased CKD incidence was observed in the clusters with “long sleep duration” (hazard ratios (HR) 1.42, 95% confidence intervals (CI), 1.18–1.72) and “night shift” (HR 1.23, 95% CI, 1.05–1.45) patterns, but not with the “short sleep duration” pattern. By GEWIS, we identified 167 SNPs as suggestive effect modifiers that interacted with unhealthy sleep patterns and affected the risk of CKD. ConclusionsUnhealthy sleep patterns, with features of long sleep duration and night shift, may increase the risk of CKD. The study highlights the interaction of sleep and individual genetic risk to affect health outcomes.

Association of Combined Exposure to Ambient Air Pollutants, Genetic Risk, and Incident Rheumatoid Arthritis: A Prospective Cohort Study in the UK Biobank.

Evidence for a potential link between air pollution and rheumatoid arthritis (RA) is inconsistent, and the modified effect of genetic susceptibility on the relationship between air pollution and RA has not been well studied. Using a general population cohort from the UK Biobank, this study aimed to investigate the associations between various air pollutants and the risk of incident RA and to further estimate the impact of combined exposure to ambient air pollutants on the risk of developing RA under the modification effect of genetic predisposition. A total of 342,973 participants with completed genotyping data and who were free of RA at baseline were included in the study. An air pollution score was constructed by summing the concentrations of each pollutant weighted by the regression coefficients with RA from single-pollutant models to assess the combined effect of air pollutants, including particulate matter (PM) with diameters (), between 2.5 and (), and (), as well as nitrogen dioxide () and nitrogen oxides (). In addition, the polygenic risk score (PRS) of RA was calculated to characterize individual genetic risk. The Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of associations of single air pollutant, air pollution score, or PRS with incident RA. During a median follow-up time of 8.1 y, 2,034 incident events of RA were recorded. The HRs (95% CIs) of incident RA per interquartile range increment in , , , , and were 1.07 (1.01, 1.13), 1.00 (0.96, 1.04), 1.01 (0.96, 1.07), 1.03 (0.98, 1.09), and 1.07 (1.02, 1.12), respectively. We also found a positive exposure-response relationship between air pollution score and RA risk (). The HR (95% CI) of incident RA was 1.14 (1.00, 1.29) in the highest quartile group compared with the lowest quartile group of the air pollution score. Furthermore, the results of the combined effect of air pollution score and PRS on the RA risk showed that the risk of RA incidence in the highest genetic risk and air pollution score group was almost twice that of the lowest genetic risk and air pollution score group [incidence rate (IR) per 100,000 person-years: 98.46 vs. 51.19, and 1.73 (95% CI: 1.39, 2.17) vs. 1 (reference)], although no statistically significant interaction between the air pollution and genetic risk for incident RA was found (). The results revealed that long-term combined exposure to ambient air pollutants might increase the risk of RA, particularly in those with high genetic risk. https://doi.org/10.1289/EHP10710.

Pathway-Specific Polygenic Risk Scores Identify Obstructive Sleep Apnea-Related Pathways Differentially Moderating Genetic Susceptibility to Coronary Artery Disease.

Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia, may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (eg, inflammatory) and protective (eg, increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner. We selected a cross-sectional sample of 471 877 participants from the UK Biobank, with 4974 ascertained to have OSA, 25 988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics), annotated to specific genes and pathways using functional genomics databases. Based on prior evidence of involvement with intermittent hypoxia and CAD, we tested pathway-specific polygenic risk scores for the HIF1 (hypoxia-inducible factor 1), VEGF (vascular endothelial growth factor), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and TNF (tumor necrosis factor) signaling pathways. In a multivariable-adjusted logistic generalized additive model, elevated pathway-specific polygenic risk scores for the Kyoto Encyclopedia of Genes and Genomes VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds ratio 0.86, P=6×10-4). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA. We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner. These results provide evidence that gene-by-environment interaction influences CAD risk in certain pathways among people with OSA, an effect that is not well-captured by the genome-wide PRS. This invites further study of how OSA interacts with genetic risk at the molecular level and suggests eventual personalization of OSA treatment to reduce CAD risk according to individual pathway-specific genetic risk profiles.

Optimisation of individual cardiovascular risk assessment in a German coronary artery disease cohort using a commercial test for genetic polymorphisms – a pilot study

Background and aims Assessment of cardiovascular risk using established risk scores such as ESC SCORE2 or PROCAM insufficiently emphasise the role of genetic factors. We hypothesise that commercially available genetic assays may provide additional information on hereditary cardiovascular risk in a timely and cost-efficient manner. Methods In a cohort of 51 patients treated for coronary artery disease (CAD) at University Hospital Heidelberg, Germany, a subgroup of patients with “unstable” CAD (i.e. recurrent acute coronary syndrome) was identified and compared to patients with “stable” disease (i.e. chronic coronary syndrome). Gene array analysis using a commercial assay for 15 potentially pathogenic polymorphisms revealed our cohort’s genetic risk profile regarding atherosclerotic/thromboembolic events. Improvement of cardiovascular risk assessment based on established risk scores was analysed using net reclassification, logistic regression and receiver operating characteristic (ROC) analysis. Results Discriminatory capacity of traditional risk scores such as SCORE2 or PROCAM with regard to stable and unstable CAD groups was poor (ROC AUC <0.5). Patients with “unstable” CAD exhibited a significantly increased frequency of pathogenic eNOS 894 T and MTHFR 1298 C polymorphisms compared to “stable” CAD patients, and information on these polymorphisms individually as well as combinations with additional polymorphisms included in the assay such as ACE D/D or PAI-1 5 G variants markedly improved risk prediction compared to SCORE2/PROCAM alone (ROC AUC ≥0.75). Conclusion Commercially available assays for genetic polymorphisms may provide valuable information on individual genetic cardiovascular risk, potentially guiding future primary and/or secondary preventative therapies for coronary artery disease.

Impaired kidney function biomarkers and risk of severe COVID-19: Analysis of population-based cohort data.

BackgroundPatients with impaired kidney function were found at a high risk of COVID‐19 hospitalization and mortality in many observational, cross‐sectional, and hospital‐based studies, but evidence from large‐scale prospective cohorts has been lacking. We aimed to examine the association of kidney function‐related biomarkers and their genetic predisposition with the risk of developing severe COVID‐19 in population‐based data.MethodsWe analyzed data from UK Biobank to examine the prospective association of abnormal kidney function biomarkers with severe COVID‐19, defined by laboratory‐confirmed COVID‐19 hospitalizations. Using genotype data, we constructed polygenic risk scores (PRS) to represent an individual's overall genetic risk for these biomarkers. We also identified tipping points where the risk of severe COVID‐19 began to increase significantly for each biomarker.ResultsOf the 502,506 adults, 1650 (0.32%) were identified as severe COVID‐19, before August 12, 2020. High levels of cystatin C (OR: 1.3; 95% CI: 1.2–1.5; FDR = 1.5 × 10−5), serum creatinine (OR: 1.7; 95% CI: 1.3–2.1; p = 3.5 × 10−4; FDR = 3.5 × 10−4), microalbuminuria (OR: 1.4; 95% CI: 1.2–1.6; FDR = 4 × 10−4), and UACR (urinary albumin creatinine ratio; OR: 1.4; 95% CI: 1.2–1.6; p = 3.5 × 10−4; FDR = 3.5 × 10−4) were found significantly associated with severe COVID‐19. Individuals with top 10% of PRS for elevated cystatin C, urate, and microalbuminuria had 28% to 43% higher risks of severe COVID‐19 than individuals with bottom 30% PRS (p < 0.05). Tipping‐point analyses further supported that severe COVID‐19 could occur even when the values of cystatin C, urate (male), and microalbuminuria were within their normal value ranges (OR >1.1, p < 0.05).ConclusionsFindings from this study might point to new directions for clinicians and policymakers in optimizing risk‐stratification among patients based on polygenic risk estimation and tipping points of kidney function markers. Our results call for further investigation to develop a better strategy to prevent severe COVID‐19 outcomes among patients with genetic predisposition to impaired kidney function. These findings could provide a new tool for clinicians and policymakers in the future especially if we need to live with COVID‐19 for a long time.

Does APOE ɛ4 Status Change How 24-Hour Time-Use Composition Is Associated with Cognitive Function? An Exploratory Analysis Among Middle-to-Older Adults.

The 24 h time-use composition of physical activity, sedentary behavior, and sleep is linked to cognitive function in adults and may contribute to future dementia risk. However, the impact of reallocating time between behaviors may differ depending on an individual's genetic dementia risk. To explore if there is an interaction between 24 h time-use composition and genetic dementia risk in relation to cognitive function, and to simulate how time-reallocations are associated with cognitive function across different levels of genetic dementia risk. Cross-sectional global cognition, executive function, genetic dementia risk (at least one apolipoprotein (APOE) ɛ4 allele versus none) and 7 days of 24 h accelerometry (average daily time-use composition of moderate-to-vigorous physical activity (MVPA), light physical activity, sedentary behavior, sleep) were collected from 82 adults (65.6±7.5 years, 49 females). Linear regression was used to explore the relationship between time-use composition and cognitive measures, testing for interaction between APOE ɛ4 status and time-use composition. The models were used to simulate time reallocations in both APOE ɛ4 status groups. The 24 h time-use composition was associated with global cognition (F = 2.4, p = 0.02) and executive function (F = 2.6, p = 0.01). For both measures, the association differed according to genetic risk (interactions p < 0.001). In both APOE groups, reallocating time to MVPA was beneficially associated with measures of cognitive function, but associations were larger among those with at least one APOE ɛ4 allele. Genetic dementia risk may impact the effectiveness of activity interventions. Increasing MVPA may provide greater benefits among those with higher genetic dementia risk.

MicroRNA Processing Pathway-Based Polygenic Score for Clear Cell Renal Cell Carcinoma in the Volga-Ural Region Populations of Eurasian Continent.

The polygenic scores (PGSs) are developed to help clinicians in distinguishing individuals at high risk of developing disease outcomes from the general population. Clear cell renal cell carcinoma (ccRCC) is a complex disorder that involves numerous biological pathways, one of the most important of which is responsible for the microRNA biogenesis machinery. Here, we defined the biological-pathway-specific PGS in a case-control study of ccRCC in the Volga-Ural region of the Eurasia continent. We evaluated 28 DNA SNP variants, located in microRNA biogenesis genes, in 464 individuals with clinically diagnosed ccRCC and 1042 individuals without the disease. Individual genetic risks were defined using the SNP-variant effects derived from the ccRCC association analysis. The final weighted and unweighted PGS models were based on 21 SNPs, and 7 SNPs were excluded due to high LD. In our dataset, microRNA-machinery-weighted PGS revealed 1.69-fold higher odds (95% CI [1.51–1.91]) for ccRCC risk in individuals with ccRCC compared with controls with a p-value of 2.0 × 10−16. The microRNA biogenesis pathway weighted PGS predicted the risk of ccRCC with an area under the curve (AUC) = 0.642 (95%nCI [0.61–0.67]). Our findings indicate that DNA variants of microRNA machinery genes modulate the risk of ccRCC in Volga-Ural populations. Moreover, larger powerful genome-wide association studies are needed to reveal a wider range of genetic variants affecting microRNA processing. Biological-pathway-based PGSs will advance the development of innovative screening systems for future stratified medicine approaches in ccRCC.

Importance of Including Non-European Populations in Large Human Genetic Studies to Enhance Precision Medicine.

One goal of genomic medicine is to uncover an individual's genetic risk for disease, which generally requires data connecting genotype to phenotype, as done in genome-wide association studies (GWAS). While there may be clinical promise to employing prediction tools such as polygenic risk scores (PRS), it currently stands that individuals of non-European ancestry may not reap the benefits of genomic medicine because of underrepresentation in large-scale genetics studies. Here, we discuss why this inequity poses a problem for genomic medicine and the reasons for the low transferability of PRS across populations. We also survey the ancestry representation of published GWAS and investigate how estimates of ancestry diversity in GWASparticipants might be biased. We highlight the importance of expanding genetic research in Africa, one of the most underrepresented regions in human genomics research, and discuss issues of ethics, resources, and technology for equitable advancement of genomic medicine.

Assessing Breast Cancer Risks to Improve Care for an Increased-Risk Population within Eastern North Carolina.

BACKGROUND The average lifetime risk of breast cancer for an American woman is 12.5%, but individual risks vary significantly. Risk modeling is a standard of care for breast cancer screening and prevention with recommended tools to stratify individual risks based on age, family history, breast density, and a host of other known risk factors. Because of a lack of resources rurally, we have not consistently met this standard of care within all of North Carolina.METHODS We implemented a quality improvement project to assess the risk for breast cancer by gathering data on community risks. We implemented an evidence-based tool (Tyrer-Cuzick) for quantifying risk within a mostly rural population of Eastern North Carolina and developed customized services for women meeting elevated-risk definition. These services included additional imaging for elevated-risk women and a risk-reduction program. We also assessed genetic risks for hereditary breast and ovarian cancer in our at-risk population using National Comprehensive Cancer Network (NCCN) guidelines based on family history and added local genetics extenders to help test more women. We analyzed data regularly using Plan-Do-Study-Act methods to improve outcomes over 1 year.RESULTS We screened a population of 4500 women at a community hospital over a 1-year period for their individual lifetime cancer risk and genetic risk. Breast cancer risk was quantitated at the time of mammography, and women were stratified into 3 groups for risk management. Within our screening population, 6.3% of women were at high risk (defined by a lifetime breast cancer risk greater than or equal to 20%) and another 8.1% were above-average risk (defined by a lifetime breast cancer risk of 15%-20%). These women (14.4%) could potentially benefit from additional risk-management strategies. Additionally, 20% of all unaffected women within a typical screening population of Eastern North Carolina met NCCN guidelines for hereditary breast cancer and ovarian cancer testing independent of their cancer risk score. Using a model of targeted intervention within a population with elevated risks can be helpful in improving outcomes.LIMITATIONS This population within Eastern North Carolina is mostly rural and represents a potentially biased population, as it involves older women undergoing annual mammography. It may not be broadly applicable to the entire population based on age, geography, and other risks.CONCLUSIONS This model for improving cancer risk assessment and testing at a small community hospital in Eastern North Carolina was successful and addressed a community need. We discovered a high rate of increased-risk women who can benefit from individualized risk management, and a higher percentage of women who potentially benefit from genetic testing. These higher cumulative risks may in part explain some of the disparities seen for breast-cancer-specific outcomes in some parts of the state.

Expert Consensus on the Use of Prognostic Gene Expression Profiling Tests for the Management of Cutaneous Melanoma: Consensus from the Skin Cancer Prevention Working Group.

BackgroundPrognostic assessment of cutaneous melanoma relies on historical, clinicopathological, and phenotypic risk factors according to American Joint Committee on Cancer(AJCC) and National Comprehensive Cancer Network (NCCN) guidelines but may not account for a patient’s individual additional genetic risk factors.ObjectiveTo review the available literature regarding commercially available gene expression profile (GEP) tests and their use in the management of cutaneous melanoma.MethodsA literature search was conducted for original, English-language studies or meta-analyses published between 2010 and 2021 on commercially available GEP tests in cutaneous melanoma prognosis, clinical decision-making regarding sentinel lymph node biopsy, and real-world efficacy. After the literature review, the Skin Cancer Prevention Working Group, an expert panel of dermatologists with specialized training in melanoma and non-melanoma skin cancer diagnosis and management, utilized a modified Delphi technique to develop consensus statements regarding prognostic gene expression profile tests. Statements were only adopted with a supermajority vote of > 80%.ResultsThe initial search identified 1064 studies/meta-analyses that met the search criteria. Of these, we included 21 original articles and meta-analyses that studied the 31-GEP test (DecisionDx-Melanoma; Castle Biosciences, Inc.), five original articles that studied the 11-GEP test (Melagenix; NeraCare GmbH), and four original articles that studied the 8-GEP test with clinicopathological factors (Merlin; 8-GEP + CP; SkylineDx B.V.) in this review. Six statements received supermajority approval and were adopted by the panel.ConclusionGEP tests provide additional, reproducible information for dermatologists to consider within the larger framework of the eighth edition of the AJCC and NCCN cutaneous melanoma guidelines when counseling regarding prognosis and when considering a sentinel lymph node biopsy.

Unsuppressed Striatal Activity and Genetic Risk for Schizophrenia Associated With Individual Cognitive Performance Under Social Competition.

Social competition affects human behaviors by inducing psychosocial stress. The neural and genetic mechanisms of individual differences of cognitive-behavioral response to stressful situations in a competitive context remain unknown. We hypothesized that variation in stress-related brain activation and genetic heterogeneity associated with psychiatric disorders may play roles towards individually differential responses under stress. A total of 419 healthy subjects and 66 patients with schizophrenia were examined functional magnetic resonance imaging during working memory task including social competition stressors. We explored the correlation between stress-induced brain activity and individual working memory performance. The partial least squares regression was performed to examine the genetic correlates between stress-related activity and gene expression data from Allen Human Brain Atlas. Polygenic risk score (PRS) was used to assess individual genetic risk for schizophrenia. Greater suppression of bilateral striatal activity was associated with better behavioral improvement in working memory manipulation under social competition (left: rPearson = -0.245, P = 4.0 × 10-6, right: rPearson = -0.234, P = 1.0 × 10-5). Genes transcriptionally related to stress-induced activation were linked to genetic risk for schizophrenia (PFDR < 0.005). Participants with decreased accuracy under social competition exhibited higher PRS of schizophrenia (t = 2.328, P = .021). Patients with schizophrenia showed less suppressed striatal activity under social stress (F = 13.493, P = 3.5 × 10-4). Striatal activity change and genetic risk for schizophrenia might play a role in the individually behavioral difference in working memory manipulation under stress.

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

The role of environmental exposures and gene-environment interactions in the etiology of systemic lupus erythematous.

Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease, whose etiology includes both genetic and environmental factors. Individual genetic risk factors likely only account for about one-third of observed heritability among individuals with a family history of SLE. A large portion of the remaining risk may be attributable to environmental exposures and gene-environment interactions. This review focuses on SLE risk associated with environmental factors, ranging from chemical and physical environmental exposures to lifestyle behaviors, with the weight of evidence supporting positive associations between SLE and occupational exposure to crystalline silica, current smoking, and exogenous estrogens (e.g., oral contraceptives and postmenopausal hormones). Other risk factors may include lifestyle behaviors (e.g., dietary intake and sleep) and other exposures (e.g., ultraviolet [UV] radiation, air pollution, solvents, pesticides, vaccines and medications, and infections). Alcohol use may be associated with decreased SLE risk. We also describe the more limited body of knowledge on gene-environment interactions and SLE risk, including IL-10, ESR1, IL-33, ITGAM, and NAT2 and observed interactions with smoking, UV exposure, and alcohol. Understanding genetic and environmental risk factors for SLE, and how they may interact, can help to elucidate SLE pathogenesis and its clinical heterogeneity. Ultimately, this knowledge may facilitate the development of preventive interventions that address modifiable risk factors in susceptible individuals and vulnerable populations.

Utility of Polygenic Risk Scoring to Predict Cognitive Impairment as Measured by Preclinical Alzheimer Cognitive Composite Score.

The utility of Polygenic Risk Scores (PRS) is gaining increasing attention for generating an individual genetic risk profile to predict subsequent likelihood of future onset of Alzheimer's disease (AD), especially those carry two copies of the APOE E3 allele, currently considered at neutral risk in all populations studied. To access the performance of PRS in predicting individuals whilst pre-symptomatic or with mild cognitive impairment who are at greatest risk of progression of cognitive impairment due to Alzheimer's Disease from the Alzheimer's Disease Neuroimaging Initiative (ADNI) as measured by the Preclinical Alzheimer Cognitive Composite (PACC) score profile. Design: A longitudinal analysis of data from the ADNI study conducted across over 50 sites in the US and Canada. Multi-centre genetics study. 594 subjects either APOE E3 homozygotes or APOE E3/E4 heterozygotes who upon entry to the study were diagnosed as cognitively normal or with mild cognitive impairment. Use of genotyping and/or whole genome sequencing data to calculate polygenic risk scores and assess its ability to predict subsequent cognitive decline as measured by PACC over 5 years. Results: Assessing both cognitively normal and mild cognitive impaired subjects using a PRS threshold of greater than 0.6, the high genetic risk participant group declined more than the low risk group over 5 years as measured by PACC score (PACC score reduced by time). Our findings have shown that polygenic risk score provides a promising tool to identify those with higher risk to decline over 5 years regardless of their APOE alleles according to modified PACC profile, especially its ability to identify APOE3/E3 cognitively normal individuals who are at most risk for early cognitive decline. This genotype accounts for approximately 60% of the general population and 35% of the AD population but currently would not be considered at higher risk without access to expensive or invasive biomarker testing.

Vascular burden and genetic risk in association with cognitive performance and dementia in a population-based study.

Vascular risk factors may influence cognitive function and thus represent possible targets for preventive approaches against dementia. Yet it remains unknown, if they associate with cognition independently of the individual genetic risk for dementia. In a population-based study of 1172 community-dwelling individuals aged ≥65 years in Greece, we constructed a vascular burden score (VBS; based on presence of hypertension, diabetes, hyperlipidemia, heart disease, and cerebrovascular disease, range 0-5) and a polygenic risk score (PRS) for clinically-diagnosed Alzheimer's disease (AD) based on 23 genetic variants. We then explored in joint models the associations of the PRS for AD and VBS with global cognitive performance, cognitive performance across multiple cognitive domains, and odds of dementia. The mean age of study participants was 73.9±5.2 years (57.1% females). Both the PRS for AD and VBS were associated with worse global cognitive performance (beta per-SD-increment in PRS: -0.06, 95%CI: -0.10 to -0.02, beta per-point-increment in VBS: -0.05, 95%CI: -0.09 to -0.02), worse performance across individual cognitive domains (memory, executive function, attention, language, visuospatial ability), and higher odds of dementia (OR per-SD increment in PRS: 1.56, 95%CI: 1.17-2.09, OR per-point increment in VBS: 1.38, 95%CI: 1.05-1.81). There was no evidence of an interaction between the two scores. Higher VBS was associated with worse cognitive performance equally across tertiles of the PRS for AD, even among individuals at the highest tertile. Both genetic risk and vascular burden are independently and additively associated with worse cognitive performance and higher odds of dementia.

In vitro modeling of the complex retinal condition age-related macular degeneration

Aim: To model a complex retinal disease such as age-related macular degeneration (AMD) in vitro, we aimed to combine genetic and environmental risk factors in a retinal pigment epithelium (RPE) cell culture model generated via induced pluripotent stem cells (iPSCs) from subjects with an extremely high and an extremely low genetic disease risk. As an external stimulus, we chose defined oxidative stress conditions. Methods: Patients were genotyped for known AMD-associated genetic variants and their individual genetic risk score (GRS) was calculated defining individual iPSC-RPE cell lines which reflect the extreme ends of the genetic risk for AMD. Sodium iodate (NaIO3, SI) was used to induce oxidative stress and cellular responses were followed by analyzing nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation by mRNA and protein expression. Results: We present a collection of eight iPSC-RPE cell lines, with four each harboring an extreme low or an extreme high GRS for AMD. RPE identity was verified structurally and functionally. We found that 24 and 72 h of SI treatment induced a significant upregulation of NRF2 response genes HMOX1 and NQO1, without showing cytotoxic effects or negatively influencing RPE cell integrity. High- vs. low-risk cell lines revealed similar first line defenses in oxidative stress response mediated through the NRF2 pathway. Conclusion: Delineating the NRF2-mediated oxidative stress response was sought in iPSC-RPE cell lines with maximally divergent genetic AMD risk profiles. Under the specific stress conditions chosen, our data indicate that genetic predisposition to AMD may not exert a major influence on the NRF2 signaling pathway.