Predictive value of polygenic risk score for prostate cancer incidence and prognosis in the Han Chinese.

Although prostate cancer is a common occurrence among males, the relationship between existing risk prediction models remains unclear. The objective of this hospital-based retrospective study is to investigate the impact of polygenic risk scores (PRSs) on the incidence and prognosis of prostate cancer in the Han Chinese population. A total of 24,778 male participants including 903 patients with prostate cancer at Taichung Veterans General Hospital were enrolled in the study. PRS was calculated using 269 single nucleotide polymorphisms and their corresponding effect sizes from the polygenic score catalog. The association between PRS and the risk prostate cancer was evaluated using Cox proportional hazards regression model. Among the 24,778 participants, 903 were diagnosed with prostate cancer. The risk of prostate cancer was significantly higher in the highest quartile of PRS distribution compared to the lowest (hazard ratio = 4.770, 95% CI = 3.999-5.689, p < 0.0001), with statistical significance across all age groups. Patients in the highest quartile were diagnosed with prostate cancer at a younger age (66.8 ± 8.3 vs. 69.5 ± 8.8, p = 0.002). Subgroup analysis of patients with localized or stage 4 prostate cancer showed no significant differences in biochemical failure or overall survival. This hospital-based cohort study observed that a higher PRS was associated with increased susceptibility to prostate cancer and younger age of diagnosis. However, PRS was not found to be a significant predictor of disease stage and prognosis. These findings suggest that PRS could serve as a useful tool in prostate cancer risk assessment.

Descriptives and genetic correlates of eating disorder diagnostic transitions and presumed remission in the Danish registry.

Objective: Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort. Methods: The sample compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models. Results: A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite. Conclusions: The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.

What do women want to see in a personalized breast cancer risk report? A qualitative study of Asian women of two countries.

A breast cancer risk assessment tool for Asian populations, incorporating Polygenic Risk Score and Gail Model algorithm, has been established and validated. However, effective methods for delivering personalized risk information remain underexplored. This study aims to identify and develop effective methods for conveying breast cancer risk information to Asian women. Through ten focus group discussions with 32 women in Indonesia and Singapore, we explored preferences for the presentation of risk information. Participants favored comprehensive reports featuring actionable steps, simplified language, non-intimidating visuals, and personalized risk reduction recommendations. Singaporean participants, more aware of breast cancer prevention, showed a lower likelihood of seeking follow-ups upon receiving low-risk results compared to Indonesians. Overall, participants found the reports useful and advocated for similar approaches in other disease assessments. Balancing content and complexity in reports is crucial, highlighting the need for improved patient understanding and engagement with healthcare providers. Future studies could explore physicians' roles in delivering personalized risk assessments for breast cancer prevention.

Dynamics of Cognitive Impairment in MCI Patients over a Three-Year Period: The Informative Role of Blood Biomarkers, Neuroimaging, and Genetic Factors.

Given the high growth rates of cognitive decline among the elderly population and the lack of effective etiological treatments, early diagnosis of cognitive impairment progression is an imperative task for modern science and medicine. It is of particular interest to identify predictors of an unfavorable subsequent course of cognitive disorders, specifically, rapid progression. Our study assessed the informative role of various risk factors on the dynamics of cognitive impairment among mild cognitive impairment (MCI) patients. The study included patients with MCI (N = 338) who underwent neuropsychological assessment, magnetic resonance imaging (MRI) examination, blood sampling for general and biochemical analysis, APOE genotyping, and polygenic risk score (PRS) evaluation. The APOE ε4/ε4 genotype was found to be associated with a diminished overall cognitive scores initial assessment and negative cognitive dynamics. No associations were found between cognitive changes and the PRS. The progression of cognitive impairment was associated with the width of the third ventricle and hematological parameters, specifically, hematocrit and erythrocyte levels. The absence of significant associations between the dynamics of cognitive decline and PRS over three years can be attributed to the provided suitable medical care for the prevention of cognitive impairment. Adding other risk factors and their inclusion in panels assessing the risk of progression of cognitive impairment should be considered.

Identification of Sweetness Preference-Related Single-Nucleotide Polymorphisms for Polygenic Risk Scores Associated with Obesity.

Our study aimed to identify sweetness preference-associated single-nucleotide polymorphisms (SNPs), characterize the related genetic loci, and develop SNP-based polygenic risk scores (PRS) to analyze their associations with obesity. For genotyping, we utilized a pooled genome-wide association study (GWAS) dataset of 18,499 females and 10,878 males. We conducted genome-wide association analyses, functional annotation, and employed the weighted method to calculate the levels of PRS from 677 sweetness preference-related SNPs. We used Cox proportional hazards modeling with time-varying covariates to estimate age-adjusted and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for obesity incidence. We also tested the correlation between PRS and environmental factors, including smoking and dietary components, on obesity. Our results showed that in males, the TT genotype of rs4861982 significantly increased obesity risk compared to the GG genotype in the Health Professionals Follow-up Study (HPFS) cohort (HR = 1.565; 95% CI, 1.122-2.184; p = 0.008) and in the pooled analysis (HR = 1.259; 95% CI, 1.030-1.540; p = 0.025). Protein tyrosine phosphatase receptor type O (PTPRO) was identified as strongly associated with sweetness preference, indicating a positive correlation between sweetness preference and obesity risk. Moreover, each 10 pack-year increment in smoking was significantly associated with an increased risk of obesity in the HPFS cohort (HR = 1.024; 95% CI, 1.000-1.048) in males but not in females. In conclusion, significant associations between rs4861982, sweetness preference, and obesity were identified, particularly among males, where environmental factors like smoking are also correlated with obesity risk.

Genetic overlap between schizophrenia spectrum disorders and Alzheimer's disease: Current evidence and future directions - An integrative review.

Schizophrenia and Alzheimer's disease (AD) are distinct neurodegenerative disorders characterized by progressive cognitive deficits and structural alterations in the brain. Schizophrenia typically emerges in adolescence or early adulthood with symptoms such as hallucinations, delusions, and cognitive impairments, whereas AD primarily affects elderly individuals, causing progressive memory loss, cognitive decline, and behavioral changes. Delusional disorder, which often emerges later in life, shares some features with schizophrenia and is considered a schizophrenia spectrum disorder. Patients with schizophrenia or delusional disorder, particularly women and those aged 65 years or older, have an increased risk of developing AD later in life. In contrast, approximately 30 % of AD patients exhibit psychotic symptoms, which accelerate cognitive decline and worsen health outcomes. This integrative review explored the genetic overlap between schizophrenia spectrum disorders and AD to identify potential shared genetic factors. The genetic correlations between schizophrenia and AD were weak but positive (rg=0.03-0.10). Polygenic risk scores (PRSs) for schizophrenia and AD indicate some genetic predisposition, although findings are inconsistent among studies; e.g., PRS-schizophrenia or PRS-AD were associated with the risk of developing psychosis in patients with AD. A higher PRS for various developmental and psychiatric disorders was correlated with an earlier age at onset of schizophrenia. Research gaps include the need for studies on the impacts of PRS-AD on the risk of schizophrenia, genetic correlations between later-onset delusional disorder and AD, and genetic relationships between AD and late-onset schizophrenia (LOS) with a greater risk of progressing to AD. Further investigation into these genetic overlaps is crucial to enhance prevention, treatment, and prognosis for affected patients.

Integrating Multi-Organ Imaging-Derived Phenotypes and Genomic Information for Predicting the Occurrence of Common Diseases.

As medical imaging technologies advance, these tools are playing a more and more important role in assisting clinical disease diagnosis. The fusion of biomedical imaging and multi-modal information is profound, as it significantly enhances diagnostic precision and comprehensiveness. Integrating multi-organ imaging with genomic information can significantly enhance the accuracy of disease prediction because many diseases involve both environmental and genetic determinants. In the present study, we focused on the fusion of imaging-derived phenotypes (IDPs) and polygenic risk score (PRS) of diseases from different organs including the brain, heart, lung, liver, spleen, pancreas, and kidney for the prediction of the occurrence of nine common diseases, namely atrial fibrillation, heart failure (HF), hypertension, myocardial infarction, asthma, type 2 diabetes, chronic kidney disease, coronary artery disease (CAD), and chronic obstructive pulmonary disease, in the UK Biobank (UKBB) dataset. For each disease, three prediction models were developed utilizing imaging features, genomic data, and a fusion of both, respectively, and their performances were compared. The results indicated that for seven diseases, the model integrating both imaging and genomic data achieved superior predictive performance compared to models that used only imaging features or only genomic data. For instance, the Area Under Curve (AUC) of HF risk prediction was increased from 0.68 ± 0.15 to 0.79 ± 0.12, and the AUC of CAD diagnosis was increased from 0.76 ± 0.05 to 0.81 ± 0.06.

Comparing Ancestry Standardization Approaches for a Transancestry Colorectal Cancer Polygenic Risk Score.

Colorectal cancer (CRC) is a complex disease with monogenic, polygenic and environmental risk factors. Polygenic risk scores (PRSs) aim to identify high polygenic risk individuals. Due to differences in genetic background, PRS distributions vary by ancestry, necessitating standardization. We compared four post-hoc methods using the All of Us Research Program Whole Genome Sequence data for a transancestry CRC PRS. We contrasted results from linear models trained on A. the entire data or an ancestrally diverse subset AND B. covariates including principal components of ancestry or admixture. Standardization with the training subset also adjusted the variance. All methods performed similarly within ancestry, OR (95% C.I.) per s.d. change in PRS: African 1.5 (1.02, 2.08), Admixed American 2.2 (1.27, 3.85), European 1.6 (1.43, 1.89), and Middle Eastern 1.1 (0.71, 1.63). Using admixture and an ancestrally diverse training set provided distributions closest to standard Normal. Training a model on ancestrally diverse participants, adjusting both the mean and variance using admixture as covariates, created standard Normal z-scores, which can be used to identify patients at high polygenic risk. These scores can be incorporated into comprehensive risk calculation including other known risk factors, allowing for more precise risk estimates.

Sleep pattern, genetic risk, and the risk of incident rheumatoid arthritis: A cohort study.

OBJECTIVE: To investigate the associations of sleep behaviors with the risk of rheumatoid arthritis, and whether the associations differ among individuals with low, intermediate, or high genetic risk. METHODS: We included participants who were free of rheumatoid arthritis at baseline based the UK Biobank. We evaluated the associations of five sleep behaviors with the risk of rheumatoid arthritis using Cox proportional hazard regression models. We then generated a sleep risk score which combined five sleep behaviors and assessed its association with the risk of rheumatoid arthritis. We finally generated a genetic risk score and examined the joint effects of sleep patterns and genetic susceptibility on the risk of rheumatoid arthritis. RESULTS: Of the 375,133 participants at baseline, 4913 incident rheumatoid arthritis cases were identified over a median follow-up of 11.73years. We found that insomnia and daytime sleepiness were associated with a 33% and a 38% increased risk of rheumatoid arthritis. A U-shaped association was observed between sleep duration and the risk of rheumatoid arthritis, with a 29% higher risk for those with short sleep and a 30% higher risk for those with long sleep. Participants with unfavorable sleep patterns had a 63% increased risk of rheumatoid arthritis compared with those with favorable sleep patterns. Participants with unfavorable sleep patterns and high genetic risk showed the highest risk of rheumatoid arthritis although no statistically significant multiplicative or additive interaction was found. CONCLUSIONS: Our study suggested that insomnia, daytime sleepiness, and short or long sleep duration, as well as sleep risk score were associated with an increased risk of rheumatoid arthritis.

Predicting Lung Cancer in Korean Never-Smokers With Polygenic Risk Scores.

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer and these loci have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs); PRSs were calculated using a pruning-thresholding-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23) using the 40%-60% percentile group as the reference, and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong's test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

Associations of dinitroaniline herbicide exposure, genetic susceptibility, and lifestyle with glucose dysregulation: A gene-environment interaction study from the Wuhan-Zhuhai cohort.

OBJECTIVE: To assess the association of dinitroaniline herbicides as well as their interactions with genetic susceptibility and lifestyle with glucose dysregulation. METHODS: A total of 4310 Chinese urban adults from the baseline of the Wuhan-Zhuhai Cohort were included in the cross-sectional study. A follow-up panel from the cohort was included in the longitudinal study, including 158 participants with 432 observations. Glucose dysregulation, including fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (HOMA-IR), type 2 diabetes mellitus (T2DM), and impaired fasting glucose (IFG) were assessed. Serum dinitroaniline herbicides including benfluralin, trifluralin, and pendimethalin were measured. T2DM-related polygenic risk score (PRS) and healthy life scores were constructed. RESULTS: Cross-sectionally, each 2-fold increase in serum benfluralin was associated with a 1.12%, 2.03%, and 9% increase in FPG, HOMA-IR, and IFG risk, respectively. Each 2-fold increase in serum trifluralin was associated with a 0.70% increase in FPG. Each 2-fold increase in serum pendimethalin was associated with a 2.53% and 24% increase in FPG and IFG risk, respectively (all P < 0.05). Positive associations were found between the dinitroaniline herbicide mixture and glucose dysregulation. Longitudinally, serum benfluralin and pendimethalin were associated with the annual increases in FPG and HOMA-IR (P < 0.05). Joint and interaction effect analysis showed that compared with participants with high benfluralin/trifluralin/pendimethalin, high PRS, and unhealthy lifestyle, those with low benfluralin/trifluralin/pendimethalin, low PRS, and healthy lifestyle showed the greatest declines in FPG, i.e., -15.46%, -13.58%, and -10.51% changes, respectively; and the greatest reductions in IFG risks, i.e., 75%, 61%, and 73% reductions, respectively (all P < 0.05). CONCLUSIONS: This study highlighted the importance of controlling dinitroaniline herbicide exposure and following healthy lifestyles in glucose dysregulation prevention, especially among individuals with high genetic risk of T2DM.

Germline polygenic risk scores are associated with immune gene expression signature and immune cell infiltration in breast cancer.

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME. We derived 154 immune traits from bulk gene expression profiles of 764 breast tumors and 598 adjacent normal tissue samples from 825 individuals with breast cancer in the Nurses' Health Study (NHS) and NHSII. Immunohistochemical staining of four immune cell markers were available for a subset of 205 individuals. Germline PRSs were calculated for 16 different traits including breast cancer, autoimmune diseases, type 2 diabetes, ages at menarche and menopause, body mass index (BMI), BMI-adjusted waist-to-hip ratio, alcohol intake, and tobacco smoking. Overall, we identified 44 associations between germline PRSs and immune traits at false discovery rate q < 0.25, including 3 associations with q < 0.05. We observed consistent inverse associations of inflammatory bowel disease (IBD) and Crohn disease (CD) PRSs with interferon signaling and STAT1 scores in breast tumor and adjacent normal tissue; these associations were replicated in a Norwegian cohort. Inverse associations were also consistently observed for IBD PRS and B cell abundance in normal tissue. We also observed positive associations between CD PRS and endothelial cell abundance in tumor. Our findings suggest that the genetic mechanisms that influence immune-related diseases are also associated with TIME in breast cancer.

Genetic Risk, Lifestyle Adherence, and Risk of Developing Hyperuricaemia in a Japanese Population.

OBJECTIVE: To investigate the inter-relationships among genetic risk, healthy lifestyle adherence, and hyperuricaemia susceptibility. METHODS: This prospective cohort study was conducted with 7,241 hyperuricaemia-free individuals aged ≥ 20 years from the Tohoku Medical Megabank Community-based cohort study. A comprehensive lifestyle score included body mass index, smoking, drinking, and physical activity, and a polygenic risk score (PRS) was constructed based on uric acid loci from a previous genome-wide association study meta-analysis. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and hyperuricaemia incidence and calculate the area under the receiver operating characteristic curve (AUROC). Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dl or a self-reported history of hyperuricaemia. RESULTS: Of the 7,241 adults (80.7% females; mean [SD] age: 57.7 [12.6] years), 217 (3.0%) developed hyperuricaemia during 3.5 years of follow-up. Genetic risk correlated with hyperuricaemia development (P for interaction = 0.287), and lifestyle risks were independently associated. Those with a high genetic risk and poor lifestyle had the highest risk (odds ratio: 5.34; 95% confidence interval [CI]: 2.61-12.10). Although not statistically significant, incorporating the PRS in the model with lifestyle information improved predictive ability (AUROC = 0.771, 95% CI: 0.736-0.806 for lifestyle; AUROC = 0.785, 95% CI: 0.751-0.819 for lifestyle and PRS; p = 0.07). CONCLUSION: : A healthy lifestyle to prevent hyperuricaemia, irrespective of genetic risk, may mitigate the genetic risk. Genetic risk may complement lifestyle factors in identifying individuals at a heightened hyperuricaemia risk.

Associations of Polygenic Risk for Depression, Traditional Chinese Medicine Constitution, and Depression: A Population-Based Study in Taiwan.

To comprehensively investigate the risk factors associated with depression, traditional Chinese medicine constitution (TCMC) has been found to be related to depression. However, the underlying mechanism remains unclear. This study examined the association between the concept of unbalanced TCMCs and major depressive disorder (MDD), investigated the overlapping polygenic risks between unbalanced TCMC and MDD, and performed a mediation test to establish potential pathways. In total, 11,030 individuals were recruited from the Taiwan Biobank, and the polygenic risk score (PRS) for MDD for each participant was calculated using the data from the Psychiatric Genomics Consortium. Unbalanced TCMC were classified as yang-deficiency, yin-deficiency, and stasis. The MDD PRS was associated with yang-deficiency odds ratio [OR] per standard deviation increase in standardized (PRS = 1.07, p = 0.0080), yin-deficiency (OR = 1.07, p = 0.0030), and stasis constitution (OR = 1.06, p = 0.0331). Yang-deficiency (OR = 2.07, p < 0.0001) and stasis constitutions (OR = 1.65, p = 0.0015) were associated with an increased risk of MDD. A higher number of unbalanced constitutions was associated with MDD (p < 0.0001). The effect of MDD PRS on MDD was partly mediated by yang-deficiency (10.21%) and stasis (8.41%) constitutions. This study provides evidence for the shared polygenic risk mechanism underlying depression and TCMC and the potential mediating role of TCMC in the polygenic liability for MDD.

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.

Alzheimer's disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults.

Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE-ɛ4, APOE-ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of APOE-ɛ4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ɛ4 status. APOE-ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ɛ4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ɛ4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ɛ4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ɛ2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.

EAT-Lancet Diet Pattern, Genetic Predisposition, Inflammatory Biomarkers, and Risk of Lung Cancer Incidence and Mortality.

SCOPE: The association between a planetary and sustainable EAT-Lancet diet and lung cancer remains inconclusive, with limited exploration of the role of genetic susceptibility and inflammation. METHODS AND RESULTS: The study includes 175 214 cancer-free participants in the UK Biobank. Fourteen food components are collected from a 24-h dietary recall questionnaire. A polygenic risk score is constructed through capturing the overall risk variants for lung cancer. Sixteen inflammatory biomarkers are assayed in blood samples. Participants with the highest EAT-Lancet diet scores (≥12) have a lower risk of lung cancer incidence (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.51-0.80) and mortality (HR = 0.65, 95% CI: 0.48-0.88), compared to those with the lowest EAT-Lancet diet scores (≤8). Interestingly, there is a significantly protective trend against both lung adenocarcinoma and lung squamous cell carcinoma with higher EAT-Lancet diet scores. Despite no significant interactions, a risk reduction trend for lung cancer is observed with increasing EAT-Lancet diet scores and decreasing genetic risk. Ten inflammatory biomarkers partially mediate the association between the EAT-Lancet diet and lung cancer risk. CONCLUSION: The study depicts a lower risk of lung cancer conferred by the EAT-Lancet diet associated with lower inflammation levels among individuals with diverse genetic predispositions.

Genome-wide association study and polygenic risk score analysis for schizophrenia in a Korean population.

Although large-scale genome-wide association studies (GWASs) have revealed the genetic architecture of schizophrenia, these studies have mainly focused on populations of European ancestry. This study aimed to identify common genetic variants associated with schizophrenia in the Korean population and evaluate the performance of polygenic risk scores (PRSs) derived from large-scale GWASs across ancestries. In the Korean psychiatric GWAS project (KPGP), seven academic institutes and their affiliated hospitals across South Korea recruited a cohort of 1670 patients with DSM-IV-defined schizophrenia and 2271 healthy controls. A total of 6690,822 SNPs were tested for association with schizophrenia. We identified one previously unreported genome-wide significant locus rs2423464 (P = 2.83 × 10-11; odds ratio = 1.65; 95 % confidence interval = 1.43-1.91, minor allele frequency = 0.126). This variant was also associated with increased lysosomal-associated membrane protein family member 5 (LAMP5) gene expression. The PRS derived from the meta-analysis results of East Asian and European GWASs explained a larger proportion of the phenotypic variance in the Korean schizophrenia sample than the PRS of an East Asian or European GWAS. (R2 = 0.073 for meta-analysis; 0.028 for East Asian GWAS; 0.037 for European GWAS). GWASs involving diverse ethnic groups will expand our understanding of the genetic architecture of schizophrenia.