A review of the advances in understanding the genetic basis of spondylarthritis and emerging clinical benefit.

Spondyloarthropathies (SpA), including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), have been shown to have a substantial genetic predisposition based on heritability estimates derived from family studies and genome-wide association studies (GWAS). GWAS have uncovered numerous genetic loci associated with susceptibility to SpA, with significant associations to human leukocyte antigen (HLA) genes, which are major genetic risk factors for both AS and PsA. Specific loci differentiating PsA from cutaneous-only psoriasis have been identified, though these remain limited. Further research with larger sample sizes is necessary to identify more PsA-specific genetic markers. Current research focuses on translating these genetic insights into clinical applications. For example, polygenic risk scores are showing promise for the classification of disease risk and diagnosis and future research should focus on refining these risk assessment tools to improve clinical outcomes for individuals with SpA. Addressing these challenges will help integrate genetic testing into patients care and impact clinical practice.

Associations between dietary one-carbon metabolism nutrients, genetic risk, with Alzheimer's disease: a prospective cohort study.

BACKGROUND: The associations between one-carbon metabolism (OCM) nutrients (methionine, folate, vitamin B6, and vitamin B12) and Alzheimer's disease (AD) remains inconclusive. OBJECTIVES: This study aims to investigate the association of dietary OCM nutrients with the subsequent risk of AD, and further assessed whether participants with a high genetic risk for AD might benefit from dietary OCM nutrients. METHODS: We analyzed data from 192,214 participants who completed at least one 24-hour dietary questionnaire and had no previous history of AD based on the UK Biobank. Nutrients intake was calculated using McCance and Widdowson's The Composition of Food and USDA's Food and Nutrient Database for Dietary Studies. Cox proportional models with restricted cubic splines were applied to explore the associations. RESULTS: Over a median follow-up of 13.35 years, 959 cases of AD (41 early-onset cases and 918 late-onset cases) were identified. Compared to those in the low-intake OCM group (quartile 1), participants in the high-intake OCM group (quartile 4) had a reduced risk of developing AD. The corresponding hazard ratios (HRs) and 95% CI for methionine, folate, vitamin B6, and vitamin B12 intake were 0.66 (0.54, 0.80), 0.71 (0.58, 0.87), 0.71 (0.59, 0.87), and 0.77 (0.64, 0.93), respectively. Similar associations were observed in late-onset AD. In early-onset AD, high methionine and vitamin B12 intake were associated with a 70% (HR = 0.30, 95% CI: 0.10, 0.86) and 71% (HR = 0.29, 95% CI: 0.09, 0.96) reduction in risk, respectively. Participants with low genetic risk and high OCM nutrients intake had a >75% reduced AD risk compared to high-risk, low-intake participants. CONCLUSIONS: In this prospective cohort study, we found that higher intake of OCM nutrients is associated with a reduced risk of AD. Participants with a high genetic risk of AD are more likely to benefit from dietary OCM nutrients intake.

Role of Selected Genetic Polymorphisms in the Development of Rheumatoid Arthritis in a British White Population.

BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease that negatively affects synovial joints, leading to the deterioration of movement and mobility of patients. This chronic disease is considered to have a strong genetic inheritance, with genome-wide association studies (GWAS) highlighting many genetic loci associated with the disease. Moreover, numerous confounding and non-genetic factors also contribute to the risk of the disease. AIMS: This study investigates the association of selected genetic polymorphisms with rheumatoid arthritis risk and develops a polygenic risk score (PRS) based on selected genes. METHODS: A case-control study recruited fully consenting participants from the East Midlands region of the UK. DNA samples were genotyped for a range of polymorphisms and genetic associations were calculated under several inheritance models. PRS was calculated at crude (unweighted) and weighted levels, and its associations with clinical parameters were determined. RESULTS: There were significant associations with the risk of RA at six genetic markers and their associated risk alleles (TNRF2*G, TRAF1*A, PTPN22*T, HLA-DRB1*G, TNFα*A, and IL4-590*T). The TTG haplotype at the VDR locus increased the risk of RA with an OR of 3.05 (CI 1.33-6.98, p = 0.009). The GA haplotype of HLADRB1-TNFα-308 was a significant contributor to the risk of RA in this population (OR = 2.77, CI 1.23-6.28, p = 0.01), although linkage disequilibrium was low. The polygenic risk score was significantly higher in cases over controls in both unweighted (mean difference = 1.48, t285 = 5.387, p < 0.001) and weighted (mean difference = 2.75, t285 = 6.437, p < 0.001) results. CONCLUSION: Several genetic loci contribute to the increased risk of RA in the British White sample. The PRS is significantly higher in those with RA and can be used for clinical applications and personalised prevention of disease.

Red and Processed Meat Intake, Polygenic Risk and the Prevalence of Colorectal Neoplasms: Results from a Screening Colonoscopy Population.

High red and processed meat intake and genetic predisposition are risk factors of colorectal cancer (CRC). However, evidence of their independent and joint associations on the risk of colorectal neoplasms is limited. We assessed these associations among 4774 men and women undergoing screening colonoscopy. Polygenic risk scores (PRSs) were calculated based on 140 loci related to CRC. We used multiple logistic regression models to evaluate the associations of red and processed meat intake and PRS with the risk of colorectal neoplasms. Adjusted odds ratios (aORs) were translated to genetic risk equivalents (GREs) to compare the strength of the associations with colorectal neoplasm risk of both factors. Compared to ≤1 time/week, processed meat intake >1 time/week was associated with a significantly increased risk of colorectal neoplasm [aOR (95% CI): 1.28 (1.12-1.46)]. This risk increase was equivalent to the risk increase associated with a 19 percentile higher PRS. The association of red meat intake with colorectal neoplasm was weaker and did not reach statistical significance. High processed meat intake and PRS contribute to colorectal neoplasm risk independently. Limiting processed meat intake may offset a substantial proportion of the genetically increased risk of colorectal neoplasms.

Interplay between polygenic risk score and solar insolation: Implication for systemic lupus erythematosus diagnosis and pathogenesis.

OBJECTIVES: This research elucidates the correlation between solar radiation insolation, polygenic risk score (PRS), and systemic lupus erythematosus (SLE) diagnosis, utilizing genomic, environmental, and clinical data. METHODS: We included 1,800 SLE participants and 1,800 controls from the Taiwan Precision Medicine Initiative, genotyped via the Affymetrix Genome-Wide TWB 2.0 SNP Array. The study employed a SLE-PRS tailored for individuals of Taiwanese ancestry, comprising 27 single nucleotide polymorphisms (SNPs). QGIS computed solar radiation insolation from participants' residences. We employed logistic regression to investigate the associations between SLE-PRS, solar insolation susceptibility, and SLE. Additive and multiplicative interactions were utilized to assess the interactions between solar insolation and SLE-PRS regarding the risk of SLE. RESULTS: SLE patients showed decreased solar insolation (p < 0.001). The highest decile of SLE-PRS exhibited a statistically significant lower solar insolation 1, 3, 6, and 12 months prior to diagnosis as compared to the lowest decile. Specifically, there were significant differences observed at 1 and 12 months (p = 0.025 and p = 0.004, respectively). It suggests that higher SLE-PRS correlated with reduced solar insolation tolerance. We observed an increase in SLE risk across ascending SLE-PRS percentiles exclusively in the high solar insolation group, not in the low solar insolation group. However, the interaction effect of SLE-PRS and solar insolation on SLE risk is not statistically significant. Compared to the lowest decile, the highest SLE-PRS decile showed a 10.98-fold increase in SLE risk (95 % CI, 3.773-31.952, p < 0.001). High SLE-PRS scores in conjunction with high solar insolation contribute to SLE incidence. CONCLUSIONS: Our study unveils the intertwined nature of UV insolation and polygenic risks in SLE. Future studies should explore the preventative potential of robust solar radiation protection for high-risk individuals before the disease onset.

The HUNT lung-SNP model: genetic variants plus clinical variables improve lung cancer risk assessment over clinical models.

PURPOSE: The HUNT Lung Cancer Model (HUNT LCM) predicts individualized 6-year lung cancer (LC) risk among individuals who ever smoked cigarettes with high precision based on eight clinical variables. Can the performance be improved by adding genetic information? METHODS: A polygenic model was developed in the prospective Norwegian HUNT2 study with clinical and genotype data of individuals who ever smoked cigarettes (n = 30749, median follow up 15.26 years) where 160 LC were diagnosed within six years. It included the variables of the original HUNT LCM plus 22 single nucleotide polymorphisms (SNPs) highly associated with LC. External validation was performed in the prospective Norwegian Tromsø Study (n = 2663). RESULTS: The novel HUNT Lung-SNP model significantly improved risk ranking of individuals over the HUNT LCM in both HUNT2 (p < 0.001) and Tromsø (p < 0.05) cohorts. Furthermore, detection rate (number of participants selected to detect one LC case) was significantly better for the HUNT Lung-SNP vs. HUNT LCM in both cohorts (42 vs. 48, p = 0.003 and 11 vs. 14, p = 0.025, respectively) as well as versus the NLST, NELSON and 2021 USPSTF criteria. The area under the receiver operating characteristic curve (AUC) was higher for the HUNT Lung-SNP in both cohorts, but significant only in HUNT2 (AUC 0.875 vs. 0.844, p < 0.001). However, the integrated discrimination improvement index (IDI) indicates a significant improvement of LC risk stratification by the HUNT Lung-SNP in both cohorts (IDI 0.019, p < 0.001 (HUNT2) and 0.013, p < 0.001 (Tromsø)). CONCLUSION: The HUNT Lung-SNP model could have a clinical impact on LC screening and has the potential to replace the HUNT LCM as well as the NLST, NELSON and 2021 USPSTF criteria in a screening setting. However, the model should be further validated in other populations and evaluated in a prospective trial setting.

Association of prescription data with clinical manifestations and polygenic risk scores in patients with bipolar I disorder: An exploratory study.

BACKGROUND: We assessed the association of prescription data with clinical manifestations and polygenic risk scores (PRS) in patients with bipolar I disorder. METHODS: We enrolled 1471 individuals with BID and divided them into several groups according to treatment options and clinical manifestations. BD-PRS of each patient was calculated using the Psychiatric Genomics Consortium data. Data on single nucleotide polymorphisms, clinical manifestations, and prescriptions were extracted from BiGS. RESULTS: Chronicity, suicidality, substance misuse, mixed symptoms, and deterioration of life functioning were significantly more severe in the group that was not prescribed any mood stabilizers (MS). Chronicity, psychotic symptoms, suicidality, and deterioration of life functioning were significantly severe in the group that received two or more antipsychotics (APs). BD-PRS between the group with AP(s) only and that with other treatment options significantly differed. BD-PRS of the group with AP(s) only was significantly lower than that with other treatment options. Our linear regression results showed that high severity of particular clinical aspects, lower BD-PRS, and prescriptions with fewer MSs or more APs were independently associated with poor life functioning. LIMITATIONS: This study had a cross-sectional design, without differentiating the bipolar phase, which could influence our results. CONCLUSIONS: Poor life functioning in patients with BID was associated with a high severity of particular clinical aspects, BD-PRS, and prescriptions including fewer MSs or more APs. BD-PRS was significantly higher in the group receiving only AP(s) than that in the groups receiving other drugs.

Distinct Longitudinal Brain White Matter Microstructure Changes and Associated Polygenic Risk of Common Psychiatric Disorders and Alzheimer's Disease in the UK Biobank.

Background: During the course of adulthood and aging, white matter (WM) structure and organization are characterized by slow degradation processes such as demyelination and shrinkage. An acceleration of such aging processes has been linked to the development of a range of diseases. Thus, an accurate description of healthy brain maturation, particularly in terms of WM features, is fundamental to the understanding of aging. Methods: We used longitudinal diffusion magnetic resonance imaging to provide an overview of WM changes at different spatial and temporal scales in the UK Biobank (UKB) (n = 2678; agescan 1 = 62.38 ± 7.23 years; agescan 2 = 64.81 ± 7.1 years). To examine the genetic overlap between WM structure and common clinical conditions, we tested the associations between WM structure and polygenic risk scores for the most common neurodegenerative disorder, Alzheimer's disease, and common psychiatric disorders (unipolar and bipolar depression, anxiety, obsessive-compulsive disorder, autism, schizophrenia, attention-deficit/hyperactivity disorder) in longitudinal (n = 2329) and cross-sectional (n = 31,056) UKB validation data. Results: Our findings indicate spatially distributed WM changes across the brain, as well as distributed associations of polygenic risk scores with WM. Importantly, brain longitudinal changes reflected genetic risk for disorder development better than the utilized cross-sectional measures, with regional differences giving more specific insights into gene-brain change associations than global averages. Conclusions: We extend recent findings by providing a detailed overview of WM microstructure degeneration on different spatial levels, helping to understand fundamental brain aging processes. Further longitudinal research is warranted to examine aging-related gene-brain associations.

In their study, Korbmacher et al. benchmark healthy aging processes in the brain's white matter. Findings of degrading white matter at higher ages were consistent with recent cross-sectional and longitudinal findings, particularly outlining changes in ventricle-near and cerebellar white matter. Degenerative processes were also found to accelerate at a higher age. Finally, the polygenic risk to develop psychiatric and neurodegenerative disorders was weakly associated with the white matter change in the otherwise healthily aging participants.

Genetic Polymorphisms and Genetic Risk Scores Contribute to the Risk of Coronary Artery Disease (CAD) in a North Indian Population.

Coronary artery disease (CAD) is the leading cause of death in India. Many genetic polymorphisms play a role in regulating oxidative stress, blood pressure and lipid metabolism, contributing to the pathophysiology of CAD. This study examined the association between ten polymorphisms and CAD in the Jat Sikh population from Northern India, also considering polygenic risk scores. This study included 177 CAD cases and 175 healthy controls. The genetic information of GSTM1 (rs366631), GSTT1 (rs17856199), ACE (rs4646994), AGT M235T (rs699), AGT T174M (rs4762), AGTR1 A1166C (rs5186), APOA5 (rs3135506), APOC3 (rs5128), APOE (rs7412) and APOE (rs429358) and clinical information was collated. Statistical analyses were performed using SPSS version 27.0 and SNPstats. Significant independent associations were found for GST*M1, GST*T1, ACE, AGT M235T, AGT T174M, AGTR1 A1166C and APOA5 polymorphisms and CAD risk (all p < 0.05). The AGT CT haplotype was significantly associated with a higher CAD risk, even after controlling for covariates (adjusted OR = 3.93, 95% CI [2.39-6.48], p < 0.0001). The APOA5/C3 CC haplotype was also significantly associated with CAD (adjusted OR = 1.86, 95% CI [1.14-3.03], p < 0.05). A higher polygenic risk score was associated with increased CAD risk (adjusted OR = 1.98, 95% CI [1.68-2.34], p < 0.001). Seven polymorphisms were independently associated with an increase in the risk of CAD in this North Indian population. A considerable risk association of AGT, APOA5/C3 haplotypes and higher genetic risk scores is documented, which may have implications for clinical and public health applications.

Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson's disease.

Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson's disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from a small cohort of post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes (ODCs) and oligodendrocyte precursor cells (OPCs) with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria. In an independent PD cohort with clinical measures (681 cases and 549 controls), polygenic risk scores derived from the dysregulated genes significantly predicted Montreal Cognitive Assessment (MoCA)-, and Beck Depression Inventory-II (BDI-II)-scores but not motor impairment (UPDRS-III). We extended our analysis of clinical outcome prediction by incorporating differentially expressed genes from three separate datasets that were previously published by different laboratories. In the first dataset from the anterior cingulate cortex, we identified an association between ODCs and BDI-II. In the second dataset obtained from the substantia nigra (SN), OPCs displayed an association with UPDRS-III. In the third dataset from the SN region, a distinct subtype of OPCs, labeled OPC_ADM, exhibited an association with UPDRS-III. Intriguingly, the OPC_ADM cluster also demonstrated a significant increase in PD samples. These results suggest that by expanding our focus to glial cells, we can uncover region-specific molecular pathways associated with PD symptoms.

DeepRisk: A deep learning approach for genome-wide assessment of common disease risk.

The potential for being able to identify individuals at high disease risk solely based on genotype data has garnered significant interest. Although widely applied, traditional polygenic risk scoring methods fall short, as they are built on additive models that fail to capture the intricate associations among single nucleotide polymorphisms (SNPs). This presents a limitation, as genetic diseases often arise from complex interactions between multiple SNPs. To address this challenge, we developed DeepRisk, a biological knowledge-driven deep learning method for modeling these complex, nonlinear associations among SNPs, to provide a more effective method for scoring the risk of common diseases with genome-wide genotype data. Evaluations demonstrated that DeepRisk outperforms existing PRS-based methods in identifying individuals at high risk for four common diseases: Alzheimer's disease, inflammatory bowel disease, type 2 diabetes, and breast cancer.

The importance of functional genomics studies in precision rheumatology.

Rheumatic diseases, those that affect the musculoskeletal system, cause significant morbidity. Among risk factors of these diseases is a significant genetic component. Recent advances in high-throughput omics techniques now allow a comprehensive profiling of patients at a genetic level through genome-wide association studies. Without functional interpretation of variants identified through these studies, clinical insight remains limited. Strategies include statistical fine-mapping that refine the list of variants in loci associated with disease, whilst colocalization techniques attempt to attribute function to variants that overlap a genetically active chromatin annotation. Functional validation using genome editing techniques can be used to further refine genetic signals and identify key pathways in cell types relevant to rheumatic disease biology. Insight gained from the combination of genetic studies and functional validation can be used to improve precision medicine in rheumatic diseases by allowing risk prediction and drug repositioning.

No evidence that ACE2 or TMPRSS2 drive population disparity in COVID risks.

Early in the SARS-CoV2 pandemic, in this journal, Hou et al. (BMC Med 18:216, 2020) interpreted public genotype data, run through functional prediction tools, as suggesting that members of particular human populations carry potentially COVID-risk-increasing variants in genes ACE2 and TMPRSS2 far more often than do members of other populations. Beyond resting on predictions rather than clinical outcomes, and focusing on variants too rare to typify population members even jointly, their claim mistook a well known artifact (that large samples reveal more of a population's variants than do small samples) as if showing real and congruent population differences for the two genes, rather than lopsided population sampling in their shared source data. We explain that artifact, and contrast it with empirical findings, now ample, that other loci shape personal COVID risks far more significantly than do ACE2 and TMPRSS2-and that variation in ACE2 and TMPRSS2 per se unlikely exacerbates any net population disparity in the effects of such more risk-informative loci.

CLUSTERS OF PARENTAL SOCIOECONOMIC STATUS IN EARLY CHILDHOOD AND INHERITED RISK FOR CEREBROVASCULAR DISEASE UNTIL MID-LIFE - NORTHERN FINLAND BIRTH COHORT 1966.

BACKGROUND AND AIMS: The incidence of cerebrovascular disease (CVD) is rising among young adults (<55 years). The risk for CVD starts to form in early childhood and is comprised of genetic and environmental risk factors. The aim of this study is to investigate the relationship between early family socioeconomic status (SES), inherited risk, and CVD until midlife. METHODS: In the Northern Finland Birth Cohort 1966 of 12,058 children, individuals were followed from gestational period up to 54 years. We used previously published early family SES clusters, based on latent class analysis of a wide set of prenatally collected variables. We investigated inherited risk with polygenic risk score (PRS) and parental CVDs during follow-up. The associations of the five distinct clusters, inherited risk, and consequent risk for various types of CVDs until middle age were analysed with Cox regression. All analyses were conducted first in the whole sample and then stratified by sex as is recommended in cardiovascular studies. RESULTS: During the follow-up of 586,943 person-years, 512 CVDs occurred. No clear association between SES clusters and CVD were found. Higher PRS associated with any CVD (HR per 1 SD increase 1.15; 95%CI 1.02-1.31), and ischemic CVD (HR 1.21; 1.05-1.40). We found no combined associations of early family SES and inherited risk for CVD. CONCLUSIONS: Inherited risk was associated with the risk for CVD in mid-life in Finnish population. We found no clear connection with early family SES and CVD. Being born to a specific SES group did not increase the effect of inherited risk.

Polygenic Risk Score (PRS) Combined with NGS Panel Testing Increases Accuracy in Hereditary Breast Cancer Risk Estimation.

Breast cancer (BC) is the most prominent tumor type among women, accounting for 32% of newly diagnosed cancer cases. BC risk factors include inherited germline pathogenic gene variants and family history of disease. However, the etiology of the disease remains occult in most cases. Therefore, in the absence of high-risk factors, a polygenic basis has been suggested to contribute to susceptibility. This information is utilized to calculate the Polygenic Risk Score (PRS) which is indicative of BC risk. This study aimed to evaluate retrospectively the clinical usefulness of PRS integration in BC risk calculation, utilizing a group of patients who have already been diagnosed with BC. The study comprised 105 breast cancer patients with hereditary genetic analysis results obtained by NGS. The selection included all testing results: high-risk gene-positive, intermediate/low-risk gene-positive, and negative. PRS results were obtained from an external laboratory (Allelica). PRS-based BC risk was computed both with and without considering additional risk factors, including gene status and family history. A significantly different PRS percentile distribution consistent with higher BC risk was observed in our cohort compared to the general population. Higher PRS-based BC risks were detected in younger patients and in those with FH of cancers. Among patients with a pathogenic germline variant detected, reduced PRS values were observed, while the BC risk was mainly determined by a monogenic etiology. Upon comprehensive analysis encompassing FH, gene status, and PRS, it was determined that 41.90% (44/105) of the patients demonstrated an elevated susceptibility for BC. Moreover, 63.63% of the patients with FH of BC and without an inherited pathogenic genetic variant detected showed increased BC risk by incorporating the PRS result. Our results indicate a major utility of PRS calculation in women with FH in the absence of a monogenic etiology detected by NGS. By combining high-risk strategies, such as inherited disease analysis, with low-risk screening strategies, such as FH and PRS, breast cancer risk stratification can be improved. This would facilitate the development of more effective preventive measures and optimize the allocation of healthcare resources.

Association of healthy lifestyle factors and genetic liability with bipolar disorder: Findings from the UK Biobank.

BACKGROUND: The interplay between genetic and lifestyle factors in the development of bipolar disorder (BD) remains unclear. METHODS: A cohort study was carried out on 365,517 participants from the UK Biobank. Lifestyle scores, based on smoking, physical activity, diet, alcohol consumption, sedentary behavior, sleep duration, and social contact, were grouped as favorable (scores 6-7), intermediate (scores 4-5), or unfavorable (scores 0-3). The BD polygenic risk score (PRS) was also categorized into high, intermediate, and low-risk groups using PRS tertiles. Cox regression models determined hazard ratios (HRs) and 95 % confidence intervals (CIs) for BD. RESULTS: During the 12.9-year follow-up, 529 individuals developed BD. Comparing those with favorable lifestyles to those with unfavorable participants, the HR of developing BD was 3.28 (95 % CI, 2.76-3.89). Similarly, individuals with a high PRS had a risk of 3.20 (95 % CI, 2.83-3.63) compared to those with a low PRS. Notably, individuals with both a high PRS and an unfavorable lifestyle had a significantly higher risk of BD (HR = 6.31, 95 % CI, 4.14-9.63) compared to those with a low PRS and a favorable lifestyle. Additionally, the interaction between PRS and lifestyle contributed an additional risk, with a relative excess risk of 1.74 (95 % CI, 0.40-3.07) and an attributable proportion due to the interaction of 0.37 (95 % CI, 0.16-0.58). CONCLUSIONS: Our findings suggest that genetic liability for BD, measured as PRS, and lifestyle have an additive effect on the risk of developing BD. A favorable lifestyle was associated with a reduced risk of developing BD.

Impact of hyperuricemia on CKD risk beyond genetic predisposition in a population-based cohort study.

The bidirectional effect of hyperuricemia on chronic kidney disease (CKD) underscores the importance of hyperuricemia as a risk factor for CKD. We evaluated the effect of hyperuricemia on the presence and development of CKD after considering genetic background by calculating polygenic risk scores (PRSs). We employed genome-wide association study summary statistics-excluding the United Kingdom Biobank (UKB) datasets among published CKD Gen Consortium papers-to calculate the PRSs for CKD in white background subjects. To validate PRS performance, we divided the UKB into two datasets to validate and test the data. We used logistic regression analysis to evaluate the association between hyperuricemia and CKD, and performed Kaplan-Meier survival analysis exclusively for subjects with available follow-up data. In total, 438,253 clinical data and 4,307,940 single nucleotide polymorphisms from 459,155 samples were included. We observed a significant positive association between PRS and CKD and the presence and development of CKD. Hyperuricemia significantly increased CKD risk (adjusted odds ratio 1.55, 95% confidence interval 1.48-1.61). The impact of hyperuricemia on CKD was maintained irrespective of PRS range. In addition, negative interaction between hyperuricemia and PRS for CKD was found. Survival analysis indicates that the presence of hyperuricemia significantly increased the risk of CKD development. The PRS for CKD thoroughly reflects the risk of CKD development. Hyperuricemia is a significant indicator of CKD risk, even after incorporating the genetic risk score for CKD. Irrespective of genetic risk, patients with a prospective risk of developing CKD require uric acid monitoring and management.

Colorectal Cancer Polygenic Risk Score Is Associated With Screening Colonoscopy Findings but Not Follow-Up Outcomes.

Background and Aims: Colorectal cancer (CRC) polygenic risk scores (PRS) may help personalize CRC prevention strategies. We investigated whether an existing PRS was associated with advanced neoplasia (AN) in a population undergoing screening and follow-up colonoscopy. Methods: We evaluated 10-year outcomes in the Cooperative Studies Program #380 screening colonoscopy cohort, which includes a biorepository of selected individuals with baseline AN (defined as CRC or adenoma ≥10 mm or villous histology, or high-grade dysplasia) and matched individuals without AN. A PRS was constructed from 136 prespecified CRC-risk single nucleotide polymorphisms. Multivariate logistic regression was used to evaluate the PRS for associations with AN prevalence at baseline screening colonoscopy or incident AN in participants with at least one follow-up colonoscopy. Results: The PRS was associated with AN risk at baseline screening colonoscopy (P = .004). Participants in the lowest PRS quintile had more than a 70% decreased risk of AN at baseline (odds ratio 0.29, 95% confidence interval 0.14-0.58; P < .001) compared to participants with a PRS in the middle quintile. Using a PRS cut-off of more than the first quintile to indicate need for colonoscopy as primary screening, the sensitivity for detecting AN at baseline is 91.8%. We did not observe a relationship between the PRS and incident AN during follow-up (P = .28). Conclusion: A PRS could identify individuals at low risk for prevalent AN. Ongoing work will determine whether this PRS can identify a subset of individuals at sufficiently low risk who could safely delay or be reassured about noninvasive screening. Otherwise, more research is needed to augment these genetic tools to predict incident AN during long-term follow-up.

Fast and scalable ensemble learning method for versatile polygenic risk prediction.

Polygenic risk scores (PRS) enhance population risk stratification and advance personalized medicine, but existing methods face several limitations, encompassing issues related to computational burden, predictive accuracy, and adaptability to a wide range of genetic architectures. To address these issues, we propose Aggregated L0Learn using Summary-level data (ALL-Sum), a fast and scalable ensemble learning method for computing PRS using summary statistics from genome-wide association studies (GWAS). ALL-Sum leverages a L0L2 penalized regression and ensemble learning across tuning parameters to flexibly model traits with diverse genetic architectures. In extensive large-scale simulations across a wide range of polygenicity and GWAS sample sizes, ALL-Sum consistently outperformed popular alternative methods in terms of prediction accuracy, runtime, and memory usage by 10%, 20-fold, and threefold, respectively, and demonstrated robustness to diverse genetic architectures. We validated the performance of ALL-Sum in real data analysis of 11 complex traits using GWAS summary statistics from nine data sources, including the Global Lipids Genetics Consortium, Breast Cancer Association Consortium, and FinnGen Biobank, with validation in the UK Biobank. Our results show that on average, ALL-Sum obtained PRS with 25% higher accuracy on average, with 15 times faster computation and half the memory than the current state-of-the-art methods, and had robust performance across a wide range of traits and diseases. Furthermore, our method demonstrates stable prediction when using linkage disequilibrium computed from different data sources. ALL-Sum is available as a user-friendly R software package with publicly available reference data for streamlined analysis.

Traumatic Brain Injury and Genetic Risk for Alzheimer's Disease Impact Cerebrospinal Fluid ß-Amyloid Levels in Vietnam War Veterans.

Traumatic brain injuries (TBIs) may increase the risk for Alzheimer's disease (AD) and its neuropathological correlates, although the mechanisms of this relationship are unclear. The current study examined the synergistic effects of TBI and genetic risk for AD on ß-amyloid (Aß) levels among Vietnam War Veterans. We hypothesized that the combination of TBI and higher polygenic risk score (PRS) for AD would be associated with lower cerebrospinal fluid (CSF) Aß42/40. Data were obtained from the Department of Defense Alzheimer's Disease Neuroimaging Initiative. Participants included Vietnam War Veterans without dementia who identified as White non-Hispanic/Latino and had available demographic, clinical assessment, genetic, and CSF biomarker data. Lifetime TBI history was assessed using The Ohio State University TBI Identification Method. Participants were categorized into those with and without TBI. Among those with a prior TBI, injury severity was defined as either mild or moderate/severe. CSF Aß42/40 ratios were calculated. Genetic propensity for AD was assessed using PRSs. Hierarchical linear regression models examined the interactive effects of TBI and PRS for AD on Aß42/40. Exploratory analyses examined the interaction between TBI severity and PRS. The final sample included 88 male Vietnam War Veterans who identified as White non-Hispanic/Latino (M age = 68.3 years), 49 of whom reported a prior TBI. There was a significant interaction between TBI and PRS, such that individuals with TBI and higher PRS for AD had lower Aß42/40 (B = -0.45, 95% CI: -0.86 to -0.05, p = 0.03). This relationship may be stronger with increasing TBI severity (p = 0.05). Overall, TBI was associated with lower Aß42/40, indicating greater amyloid deposition in the brain, in the context of greater polygenic risk for AD. These findings highlight who may be at increased risk for AD neuropathology following TBI.