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Background Context: Degenerative cervical myelopathy (DCM) is a progressive spinal condition that can lead to severe neurological dysfunction. Despite its degenerative pathophysiology, family history has shown to be a largely important factor in incidence and progression, suggesting that inherent genetic predisposition may play a role in pathophysiology., Purpose: To determine the tissue-specific, functional genetic basis of hereditary predisposition to cervical myelopathy., Study Design: Retrospective case-control study using patient genetics and matched EHR from the Mount Sinai BioMe Biobank., Methods: In a large, diverse, urban biobank of 32,031 individuals, with 558 individuals with cervical myopathy, we applied transcriptomic imputation to identify genetically regulated gene expression signatures associated with DCM. We performed drug-repurposing analysis using the CMAP database to identify candidate therapeutic interventions to reverse the cervical myelopathy-associated gene signature., Results: We identified 16 genes significantly associated with DCM across five different tissues, suggesting tissue-specific manifestations of inherited genetic risk (upregulated: HES6, PI16, TMEM183A, BDH2, LINC00937, CLEC4D, USP43, SPATA1; downregulated: TTC12, CDK5, PAFAH1B2, RCSD1, KLHL29, PTPRG, RP11-620J15.3, C1RL). Drug repurposing identified 22 compounds with the potential to reverse the DCM-associated signature, suggesting points of therapeutic intervention., Conclusions: The inherited genetic risk for cervical myelopathy is functionally associated with genes involved in tissue-specific nociceptive and proliferative processes. These signatures may be reversed by candidate therapeutics with nociceptive, calcium channel modulating, and antiproliferative effects., Clinical Significance: Understanding the genetic basis of DCM provides critical insights into the hereditary factors contributing to the disease, allowing for more personalized and targeted therapeutic approaches. The identification of candidate drugs through transcriptomic imputation and drug repurposing analysis offers potential new treatments that could significantly improve patient outcomes and quality of life by addressing the underlying genetic mechanisms of DCM., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Latines suffer from breast cancer (BC), due to elevated biological and social determinants of health (SDOH) risks. This study compares the effects of different strategies on uptake of cancer genetic services, specifically hereditary cancer risk assessment, genetic counseling, and genetic testing, and risk-based BC care., Design/methods: In Chicago, Illinois, Aim 1 participants are recruited from a federally qualified health center (FQHC) and community venues. For Aim 1, eligible participants: (1) are female; (2) are Latine; (3) are 30+ years old; (4) have personal or family history of BC or cancers with shared hereditary mutations; (5) have at least one SDOH risk; and (6) have not received any cancer genetic services. Participants are randomly assigned to different study arms. Both arms include phone-based sessions, FQHC-based navigation for SDOH, and low- or no-cost cancer genetic services. The educate sessions focus on risk assessment and prevention. The empower sessions focus on risk assessment and equip participants with the skills to share information about FQHC-based cancer genetic services. For Aim 2, eligible participants are: (1) female; (2) network members of Aim 1 participants; and (3) eligible for BC screening based on guidelines recommended by the American Cancer Society (ACS). Primary outcomes include uptake of any cancer genetic services. Analyses will also explore intervention differences by neighborhood context., Discussion: This is one of the first trials focused on Latines' participation in cancer genetic services and risk-based BC care within the context of SDOH - which has major implications for equity in precision cancer prevention., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Type 1 diabetes is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of haematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between type 1 diabetes, CAD and leukocyte counts., Methods: Genome-wide association study summary statistics were used to perform pairwise linkage disequilibrium score regression and heritability estimation from summary statistics (ρ-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomisation to estimate the causal relationships between leukocyte counts (335,855 healthy individuals), type 1 diabetes (18,942 cases, 501,638 control individuals) and CAD (122,733 cases, 424,528 control individuals). A latent causal variable (LCV) model was performed to estimate the genetic causality proportion of the genetic correlation between type 1 diabetes and CAD., Results: There was significant genome-wide genetic correlation (r g ) between type 1 diabetes and CAD (r g =0.088, p=8.60 × 10 -3 ) and both diseases shared significant genome-wide genetic determinants with eosinophil count (r g for type 1 diabetes [r g(T1D) ]=0.093, p=7.20 × 10 -3 , r g for CAD [r g(CAD) ]=0.092, p=3.68 × 10 -6 ) and lymphocyte count (r g(T1D) =-0.052, p=2.76 × 10 -2 , r g(CAD) =0.176, p=1.82 × 10 -15 ). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, type 1 diabetes and/or CAD. Cis-genetic regulation of the expression levels of genes within shared loci between type 1 diabetes and CAD was associated with both diseases as well as leukocyte counts, including SH2B3, CTSH, MORF4L1, CTRB1, CTRB2, CFDP1 and IFIH1. Genetically predicted lymphocyte, neutrophil and eosinophil counts were associated with type 1 diabetes and CAD (lymphocyte OR for type 1 diabetes [OR T1D ]=0.67, p=2.02 -19 , OR CAD =1.09, p=2.67 × 10 -6 ; neutrophil OR T1D =0.82, p=5.63 × 10 -5 , OR CAD =1.17, p=5.02 × 10 -14 ; and eosinophil OR T1D =1.67, p=5.45 × 10 -25 , OR CAD =1.07, p=2.03 × 10 -4 . The genetic causality proportion between type 1 diabetes and CAD was 0.36 ± 0.16 (p LCV =1.30 × 10 -2 ), suggesting a possible intermediary causal variable., Conclusions/interpretation: This study sheds light on shared genetic mechanisms underlying type 1 diabetes and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts and identifies cellular and molecular targets for further investigation for disease prediction and potential drug discovery., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Genetic risks can accelerate ageing, yet better quality sleep may slow down it. We thus examined the interaction and combined effects of genetic predisposition and sleep quality on the risk of accelerate aging., Methods: This study included 407,027 participants from the UK Biobank. Sleep index of each participant was retrieved from the following seven sleep behaviors: snoring, chronotype, daytime sleepiness, sleep duration, insomnia, nap and difficulties in getting up. The biological age (PhenoAge) were estimated by corresponding algorithms based on clinical traits, and their residual discrepancies with chronological age were defined as the age accelerations (PhenoAgeaccel). We explored the interaction and combined effects of genetic risk and sleep quality on accelerated ageing by constructing a linear model., Results: Compared with participants in low sleep quality group, those in medium and high sleep quality group decreased 0.727 (95%CI, 0.653 to 0.801) and 1.056 (95%CI, 0.982 to 1.130) years of PhenoAgeaccel, respectively. Compared with participants in low genetic risk group, those in medium and high genetic risk group increased 0.833 (95%CI, 0.792 to 0.874) and 1.543 (95%CI, 1.494 to 1.592) years of PhenoAgeaccel, respectively. There was interaction between the genetic risk and sleep quality (P-interaction<0.001). For combined effect, compared to the group with high sleep quality and lower genetic risk, people with low sleep quality and high genetic risk had 2.747 (95%CI, 2.602 to 2.892) years higher PhenoAgeaccel., Conclusion: Our findings elucidate that better sleep quality could lessen accelerated biological ageing especially among population with high genetic risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This cross-sectional study explores the impact of FTO gene single nucleotide polymorphisms (SNPs) rs9939609 and rs1421085 on dietary habits contributing to obesity risk in Thai adults. The study enrolled 384 participants from Bangkok, categorized as non-obese (BMI < 25 kg/m 2 ) or obese (BMI ≥ 25 kg/m 2 ) based on WHO Asia Pacific Guidelines. Genotyping for FTO variants was performed using DNA from blood samples. While both SNPs adhered to Hardy-Weinberg equilibrium, the association between risk alleles and anthropometric measurements was not statistically significant. However, risk allele carriers showed significantly higher intakes of sugar and saturated fat compared to homozygous dominant individuals. In the obese group, the odds ratio for high-sugar intake was 2.22 (95% CI 1.13-4.37, p = 0.021) for rs9939609 risk allele carriers. For high-saturated fat intake, the odds ratio was 1.86 (95% CI 1.02-3.40, p = 0.041). Similar associations were observed for rs1421085. Risk allele carriers also exhibited significantly higher leptin levels (p < 0.043) and a positive correlation with myeloperoxidase levels (p < 0.038). These findings highlight the complex relationship between FTO risk alleles, increased consumption of sugar and saturated fat, and obesity-related parameters. The insights emphasize the importance of considering both genetic and dietary factors in obesity prevention strategies., (© 2024. The Author(s).)

Background: Obesity has become a significant global health issue. This multifaceted condition is influenced by genetic, environmental, and lifestyle factors, significantly influenced by nutrition. Aim : The study's objective is to elucidate the relationship between obesity-related genes, nutrient intake, and the development of obesity and the importance of other metabolic diseases. Methods : A comprehensive literature review spanning the past two decades was conducted to analyze the contributions of genetic variants-including FTO , MC4R , and LEPR -and their associations with dietary habits, highlighting how specific nutrients affect gene expression and obesity risk and how the coexistence of metabolic diseases such as type 2 diabetes and osteoporosis may modulate these factors. Moreover, the role of epigenetic factors, such as dietary patterns that encourage the development of obesity, was explored. Discussion and Conclusions : By understanding the intricate relationships among genetics, nutrients, and obesity development, this study highlights the importance of personalized dietary strategies in managing obesity. Overall, an integrated approach that considers genetic predispositions alongside environmental influences is essential for developing effective prevention and treatment methodologies, ultimately contributing to better health outcomes in diverse populations.

Background: Ketone bodies (KB) are important cardiac metabolic energy source. Metabolic remodeling has been recently pointed to play an important role in the pathological process of atrial fibrillation (AF)., Objective: To evaluate the associations between circulating KB levels with incident AF risk in the general population., Methods: We studied 237,163 participants (mean age, 56.5 years; 55% women) from the UK Biobank who were free of AF at baseline and had data about circulating β-hydroxybutyrate (β-OHB), acetoacetate, and acetone. The associations between KB with new-onset AF were evaluated by Cox regression in the general population and across three genetic risk groups [low, moderate, and high polygenic risk score of AF]., Results: During a median follow-up of 14.8 years, 16,638 (7.0%) participants developed AF. There was a U-shaped association between total KB and β-OHB with incident AF, with nadirs at 60.6 and 40.8 μmol/L, respectively (P non-linear <0.05), whereas a positive association between acetoacetate and acetone with AF was observed (P overall <0.001, P non-linear >0.05). Consistently, a U-shaped association was observed between total KB and β-OHB with left atrial (LA) volume parameters, including LA maximum volume (LAVmax), LA minimum volume (LAVmin), and their body surface area-indexed counterparts, and an inverted U-shaped association was observed for LA ejection fraction (all P non-linear <0.05). The association between KB with AF was greater among individuals with low genetic risk (P interaction <0.05), while the highest AF risk was for those at high genetic risk with high KB levels. Significant mediation effects of inflammatory markers on the associations between KB and AF were identified., Conclusions: There was a U-shaped association between circulating total KB and β-OHB with incident AF, as well as a positive association between acetoacetate and acetone level with AF risk in the general population., (Copyright © 2024. Published by Elsevier Inc.)

Background: The Apolipoprotein E (APOE) ε4 allele, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) are well-established risk factors for dementia. Relationships between APOE and incidence of T2DM and CVD are not fully understood but may shed light on the mechanisms underlying dementia pathogenesis., Methods: Postmenopausal women (N=6,795) from the Women's Health Initiative hormone therapy clinical trial with APOE genotyping and no prior diagnosis of T2DM or CVD were included. We examined associations of APOE status (APOE2+ [ε2/ε2, ε2/ε3], APOE3 [ε3/ε3], and APOE4+ [ε4/ε4, ε3/ε4] carriers) with incidence of T2DM, coronary heart disease (CHD), stroke, and total CVD events using Cox regression. CVD outcomes were examined in baseline non-statin users and adjusted for statin initiation over follow-up to account for possible confounding by statins., Results: Among all participants (mean age 66.7±6.5 years, 100% non-Hispanic white), 451 (6.6%) were using statins at baseline. Over the follow-up (mean 14.9 and 16.0 years for T2DM and CVD, respectively), 1,564 participants developed T2DM and 1,578 developed CVD. T2DM incidence did not differ significantly by APOE status (ps≥0.09). Among non-statin users, APOE4+ had higher incidence of total CVD (hazard ratio [95% confidence interval]=1.18 [1.02-1.38], p=0.03) compared to APOE3 carriers, but risks for CHD (1.09 [0.87-1.36], p=0.47) and stroke (1.14 [0.91-1.44], p=0.27) were not significantly elevated when examined individually. CVD outcomes did not differ between APOE2+ and APOE3 carriers (ps≥0.11)., Conclusions: T2DM risk did not differ by APOE status among postmenopausal women, but APOE4+ carriers not using statins had an increased risk of total CVD events., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Single Nucleotide polymorphisms (SNPs) in MMP8 and MMP9 have been widely associated with breast cancer risk in different ethnicities with inconsistent results. There is no such study conducted so far in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. Therefore, this study was conducted to check MMP8 (rs11225395) and MMP9 (rs3787268) polymorphism with breast cancer risk in the selected population., Methods: This study, consisting of 300 breast cancer patients and 168 gender and age-matched healthy controls was subjected to confirm MMP8 and MMP9 polymorphisms. Clinicopathological data and blood samples were taken from all the participants. DNA was extracted and SNPs were confirmed using the T-ARMS-PCR protocol., Results: Based on our study results, significant associations were observed between the MMP8 rs11225395 risk allele (G) and increased breast cancer risk, with the G allele frequency higher in patients (65%) compared to controls (51%) (OR = 1.752, 95% CI = 1.423-3.662, p = 0.002). Genotypes GG (OR = 4.218, p = 0.005) and AG (OR = 7.286, p = 0.0001) of MMP8 rs11225395 were also significantly associated with elevated breast cancer risk. Similarly, MMP9 rs3787268 exhibited a higher frequency of the risk allele (A) in breast cancer cases (81%) compared to controls (41%), correlating strongly with increased risk (OR = 6.320, p = 0.0001). Genotypes AA (OR = 14.500, p = 0.0001) and AG (OR = 2.429, p = 0.077) of MMP9 rs3787268 containing the risk allele showed significant associations with heightened breast cancer risk. Subgroup analyses based on age, disease progression, tumor size, and grade revealed noteworthy associations for both MMP8 rs11225395 and MMP9 rs3787268. MMP8 rs11225395 genotypes displayed significant correlations with age (p = 0.066), disease progression (p = 0.0001), larger tumor size (p = 0.005), and higher tumor grade (p = 0.006). Similarly, MMP9 rs3787268 genotypes were significantly associated with age (p = 0.001), disease progression (p = 0.010), larger tumor size (p = 0.018), and higher tumor grade (p = 0.037). Logistic regression analyses further underscored these genetic variants' potential role as biomarkers in breast cancer, particularly in relation to specific hormone receptor statuses such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) positivity., Conclusion: The results revealed significant associations between the mutant alleles and genotypes of MMP8 (rs11225395) and MMP9 (rs3787268) with increased breast cancer risk in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. However, more investigation will be required on large data sets to confirm the selected SNPs and other SNPs in the selected and other related genes with the risk of breast cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Pancreatic cancer (PC) has one of the highest mortality to incidence ratio of all cancers. Early identification of at-risk individuals should permit early diagnosis. Genome-wide association studies showed the association of several genetic variants with PC risk in multi-ethnic populations. Our objective was to examine the association of these genetic variants with PC in a population sample from Kuwait., Methods: DNA samples from 103 pancreatic ductal adenocarcinoma (PDAC) specimens and 132 healthy controls were used for genotyping ABO rs505922, BCAR1 rs7190458, LINC-PINT rs6971499, HNF1B rs4795218, VDR rs2228570 rs731236, and PRSS1 rs111033565 rs111033568 rs387906698 and rs267606982 using TaqMan genotyping assays, and VDR expression was performed by immunocytochemistry., Results: ABO rs505922C and VDR rs2228570A were associated with PDAC risk (odds ratio (OR): 1.55, 95% confidence interval (CI): 1.07 - 2.24, P = 0.027; OR: 1.64, 95% CI: 1.09 - 2.48, P = 0.024; respectively). An unweighted polygenic risk score ( ABO rs505922, BCAR1 rs7190458, LINC-PINT rs6971499, and HNF1B rs4795218) was significantly associated with PDAC risk (β: -0.11, 95% CI: -0.15 to -0.05, P < 0.001). VDR expression was downregulated or absent in most PDAC specimens regardless of VDR haplotype., Conclusion: ABO rs505922C and VDR rs2228570A are PDAC genetic risk factors in our population. Ethnicity influences the association of reported genetic PDAC risk factors and should be adjusted for when performing PDAC genetic risk estimations. Investigation of these genetic risk factors in other ethnic populations is a necessity to evaluate their PDAC risk prediction potential., Competing Interests: The authors have no conflict of interest to declare that are relevant to the content of this article., (Copyright 2024, Al-Qahtani et al.)

Background: Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD., Method: This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk., Results: During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27-6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals., Conclusion: Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk., Competing Interests: Declaration of competing interest The authors declared that no competing interests exist., (Copyright © 2024. Published by Elsevier B.V.)

evidence from animal experiments indicates that anthocyanin supplements can contribute to intestinal health. Nevertheless, no evidence has linked dietary anthocyanins to the prevention potential against inflammatory bowel disease (IBD) in humans. We leveraged data from 188,044 IBD-free individuals (mean age 59 years; 55.2% females) from the prospective cohort UK Biobank. The anthocyanin intake was estimated using dietary information from validated 24 h dietary recalls. Incident IBD was ascertained via national health-related records. Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) was estimated by polygenic risk scores and further categorized into low- and high-risk groups by median value. The Cox proportional regression model was applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). During the mean follow-up of 9.7 years, we documented 255 CD and 606 UC. We found that compared with participants with the lowest quartiles of anthocyanin intake, those in the highest quartiles were associated with 24% (95% CI 6%-38%, p = 0.012; p-trend = 0.003) and 35% (95% CI 16%-49%, p = 0.001; p-trend < 0.001) reduced risk of IBD and UC, respectively. The inverse associations were stronger (p-interaction = 0.022) among individuals with a high genetic risk of UC. We did not observe a significant association between anthocyanin intake and CD (p-trend = 0.536). Higher dietary anthocyanin intake was associated with reduced risk of IBD and UC, but not CD. Genetic factors may modify the influence of dietary anthocyanin on UC susceptibility, and possible mechanisms need to be further elucidated in the future., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Background: Limited epidemiological evidence exists concerning the impact of healthy dietary patterns on reducing the risk of cholelithiasis. We aimed to examine the association of seven established dietary patterns with subsequent cholelithiasis risk and whether this association was modified by genetic risk., Methods: We conducted a prospective cohort study from the UK Biobank, including 155,323 participants initially free of cholelithiasis and cholecystectomy. Dietary patterns were assessed using a validated food frequency questionnaire (Oxford WebQ), covering Mediterranean Diet Score (MED), alternate Mediterranean Diet Score(aMED), overall Plant-based Diet Index (PDI), healthy Plant-based Diet Index (hPDI), unhealthy Plant-based Diet Index (uPDI), Healthy Eating Index 2015 (HEI-2015) and EAT-lancet Score. Genetic risk was quantified and stratified by a polygenic risk score (PRS) incorporating 13 known cholelithiasis-associated loci. Cox proportional hazards regression was employed to estimate the association between dietary patterns, PRS, and cholelithiasis incidence, adjusting for potential confounders., Results: During a median follow-up of 13.3 years, 5,056 cases of cholelithiasis were identified. After adjusting for potential confounders, adherence to aMED and HEI-2015 dietary patterns reduced cholelithiasis risk by 10% (HR: 0.90; 95%CI: 0.83-0.98) and 11% (HR: 0.89; 95%CI: 0.82-0.96), respectively. A significant decrease in cholelithiasis risk was observed across PRS quintiles, low PRS was associated with a 16% reduced risk (HR: 0.84; 95%CI: 0.77-0.92). Participants with both high dietary scores and low genetic risk had the lowest cholelithiasis risk, with an HR of 0.76 (95%CI: 0.64-0.91) for aMED and 0.73 (95%CI: 0.61-0.88) for HEI-2015., Conclusion: Higher adherence to aMED and HEI-2015 might significantly decrease the risk of cholelithiasis, irrespective of genetic risk. Our results highlighted the potential of diet intervention for cholelithiasis prevention in the general population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jin, Mi, He, Zhong, Jin, Liu, Dong, Lin, Yue, Xia, He, Yuan and Meng.)

Multiple scientific studies, mostly performed within European populations, have unraveled many of the genetic factors associated with Alzheimer's disease (AD) and Parkinson's disease (PD) etiologies, improving our understanding of the molecular pathways implicated in the pathogenesis of these conditions. However, there is increasing evidence that the genetic architecture of these diseases differs across ancestral populations. This raises concerns about the efficacy of therapeutic interventions crafted around genetic targets prevalent only in European ancestry populations. Such interventions neglect potentially distinctive etiological profiles, including Latino, Black/African American, and East Asian populations. In the current study, we explore Population Attributable Risk (PAR) in AD and PD etiologies and assess the proportion of disease attributed to specific genetic factors across diverse populations. Leveraging data from genome-wide association studies across four ancestries, we explore distinct and universal therapeutic targets across diverse populations. Multi-ancestral genetics research is critical to the development of successful therapeutics and treatments for neurodegenerative diseases. By offering insights into genetic disparities, we aim to inform more inclusive and effective therapeutic strategies, advancing personalized healthcare., Competing Interests: Conflicts of interest: L.J., H.I, M.B.M, and M.A.N.’s participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board at Clover Therapeutics and is an advisor and scientific founder at Neuron23 Inc.

Uveal melanoma (UM) and nonacral cutaneous melanoma (CM) are distinct entities with varied genetic landscapes despite both arising from melanocytes. There are, however, similarities in that they most frequently affect people of European ancestry, and high penetrance germline variants in BAP1, POT1 and CDKN2A have been shown to predispose to both UM and CM. This study aims to further explore germline variants in patients affected by both UM and CM, shedding light on the underlying genetic mechanism causing these diseases. Using exome sequencing we analysed germline DNA samples from a cohort of 83 Australian patients diagnosed with both UM and CM. Eight (10%) patients were identified that carried pathogenic mutations in known melanoma predisposition genes POT1, MITF, OCA2, SLC45A2 and TYR. Three (4%) patients carried pathogenic variants in genes previously linked with other cancer syndromes (ATR, BRIP1 and MSH6) and another three cases carried monoallelic pathogenic variants in recessive cancer genes (xeroderma pigmentosum and Fanconi anaemia), indicating that reduced penetrance of phenotype in these individuals may contribute to the development of both UM and CM. These findings highlight the need for further studies characterising the role of these genes in melanoma susceptibility., (© 2024 The Author(s). Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

First-person representations of illness have been studied as key to the cultural fabric disrupting dominant practices of ill health or disease regimes. However, the role that digital platforms play in shaping this fabric in contemporary societies has been mostly overlooked. We address this gap by investigating how mainstream social media, as mundane spaces modelled by corporate-driven techno-commercial structures, frame specific forms of visuality or ways to see ill health. We reflect on how these forms of visuality relate to existing disease regimes. The article presents an investigation of popular images of BReast CAncer (BRCA) hereditary cancer syndromes posted on Instagram, Twitter (now X) or Facebook over the course of 12 months. By combining cultural analytics, visual network analysis and interpretive techniques, we explore the emergence of platform-specific visual vernaculars and the visual genres of ill health emerging from these vernaculars. Our analysis suggests that, in the context of BRCA hereditary cancer syndromes, popular social media images primarily exacerbate existing racialised and gendered practices. Where alternative views emerge, in their being shaped by platforms' attention economies, they often operate in what we define as a 'liminal space' of imagination - one that hints at renewed, but not necessarily disruptive and certainly not radical ways to imagine ill health., (© 2024 The Author(s). Sociology of Health & Illness published by John Wiley & Sons Ltd on behalf of Foundation for the Sociology of Health & Illness.)

Background: Both body mass index (BMI) and genetic factors independently contribute to cardiovascular disease (CVD). However, it is unclear whether genetic risk modifies the association between BMI and the risk of incident CVD. This study aimed to investigate whether BMI categories and genetic risk jointly and interactively contribute to incident CVD events, including hypertension (HTN), atrial fibrillation (AF), coronary heart disease (CHD), stroke, and heart failure (HF)., Methods: A total of 496,851 participants from the UK Biobank with one or more new-onset CVD events were included in the analyses. BMI was categorized as normal weight (< 25.0 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ), and obesity (≥ 30.0 kg/m 2 ). Genetic risk for each outcome was defined as low (lowest tertile), intermediate (second tertile), and high (highest tertile) using polygenic risk score. The joint associations of BMI categories and genetic risk with incident CVD were investigated using Cox proportional hazard models. Additionally, additive interactions were evaluated., Results: Among the 496,851 participants, 270,726 (54.5%) were female, with a mean (SD) age was 56.5 (8.1) years. Over a median follow-up (IQR) of 12.4 (11.5-13.1) years, 102,131 (22.9%) participants developed HTN, 26,301 (5.4%) developed AF, 32,222 (6.9%) developed CHD, 10,684 (2.2%) developed stroke, and 13,304 (2.7%) developed HF. Compared with the normal weight with low genetic risk, the obesity with high genetic risk had the highest risk of CVD: HTN (HR: 3.96; 95%CI: 3.84-4.09), AF (HR: 3.60; 95%CI: 3.38-3.83), CHD (HR: 2.76; 95%CI: 2.61-2.91), stroke (HR: 1.44; 95%CI: 1.31-1.57), and HF (HR: 2.47; 95%CI: 2.27-2.69). There were significant additive interactions between BMI categories and genetic risk for HTN, AF, and CHD, with relative excess risk of 0.53 (95%CI: 0.43-0.62), 0.67 (95%CI: 0.51-0.83), and 0.37 (95%CI: 0.25-0.49), respectively., Conclusions: BMI and genetic factors jointly and interactively contribute to incident CVD, especially among participants with high genetic risk. These findings have public health implications for identifying populations more likely to have cardiovascular benefit from weight loss interventions., (© 2024. The Author(s).)

The extent to which parents experience guilt related to their child's health may depend on their perceptions of their contribution to these outcomes. The impact of the child's "other" biological parent's (OBP) contribution to child health on guilt responses is understudied. Some models posit a diffusion-of-responsibility process, while others favor a heightened-risk-heightened-guilt model. The present study examines how perceived OBP contribution to child risk affects guilt among a sample of parents with self-reported overweight. Parents who perceived their child's OBP to also have overweight experienced more guilt for passing down genetic and family environment-based obesity risk to their child, which suggests that perceptions of shared risk contribution promote guilt-related outcomes. Additionally, risk information endorsing a gene-environment interaction liability framing was the most responsive to OBP weight status. These results support a heightened-risk-heightened-guilt process. Future work should consider guilt when developing child health interventions to avoid undesirable emotional outcomes among parents., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Cross-sectional evidence has shown that frailty is highly prevalent in patients with chronic kidney disease (CKD). However, there is limited evidence of the longitudinal associations between frailty, genetic predisposition to CKD, and the risk of CKD in the general population. Therefore, this study aimed to examine such associations among participants in the UK Biobank., Study Design: This is a prospective cohort study included 370,965 middle-aged and older adults from the UK Biobank. Physical frailty was assessed using a modified version of the Fried phenotype classification. A weighted genetic risk score was built using 263 variants associated with estimated glomerular filtration rate., Main Outcome Measures: Incident CKD was identified from hospital inpatient records., Results: Over a median follow-up of 12.3 years, we documented a total of 11,121 incident CKD cases. Time-dependent Cox proportional hazards regression models indicated that individuals with frailty (hazard ratio [HR]: 1.94, 95 % confidence interval [CI]: 1.81-2.08) and pre-frailty (HR: 1.27, 95 % CI: 1.22-1.33) had an increased risk of developing CKD, compared with non-frail individuals. No significant interaction between frailty and genetic risk score was observed (P for interaction = 0.41). The highest risk was observed among the individuals with high genetic risk and frailty (HR: 2.31, 95 % CI: 2.00-2.68)., Conclusion: Our results demonstrated that frailty and pre-frailty were associated with increased risk of incident CKD in middle-age and older adults, regardless of genetic risk of CKD. Our study underscores the importance of frailty screening and intervention as a potential strategy to prevent CKD. Future clinical trials are needed to validate our findings., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Unhealthy sleep behaviors are associated with higher risks of osteoporosis (OP), while prospective evidence is limited. This study aimed to prospectively investigate this association, quantify the attributable burden of OP incidence reduction due to unhealthy sleep behaviors, and explore potential modifications by genetic risk factors., Methods: This longitudinal cohort study was conducted utilizing data from the UK Biobank, comprising 293,164 participants initially free of OP and with requisite sleep behaviors data at baseline. We followed the participants after recruitment until November 30, 2022, to ascertain incident OP. We assessed the associations of five sleep behaviors including sleep duration, chronotype, insomnia, daytime napping, and morning wake-up difficulties, as well as sleep behavior patterns identified based on the above sleep behaviors, with the risk of OP, using Cox models adjusted for multiple confounders. The analyses were then performed separately among individuals with different OP susceptibility, indexed by standard polygenetic risk scores(PRS) for OP. Our secondary outcome was OP with pathologic fracture. Subgroup and sensitivity analyses were performed. Additionally, attributable risk percent in the exposed population (AR%) and population attributable fraction (PAF) of sleep behaviors were calculated., Results: Over a median follow-up of 13.7 years, 8253 new-onset OP cases were documented. Unhealthy sleep behaviors, such as long or short sleep duration, insomnia, daytime napping, morning wake-up difficulties, and unhealthy sleep patterns, were associated with elevated risks of OP (HRs ranging from 1.14 to 1.46, all P-value <0.001) compared to healthy sleep behaviors. Similar associations were observed for OP with pathologic fractures. Insomnia exhibited the largest AR% of 39.98 % (95%CI: 36.46, 43.31) and PAF of 33.25 % (95%CI: 30.00, 36.34) among healthy sleep patterns and components. A statistically significant multiplicative interaction was noted between sleep behaviors and OP PRS on OP risk (all P-interaction <0.001)., Conclusions: Four unhealthy sleep behaviors and sleep behavior patterns were associated to increased OP risk, with insomnia contributing the most to OP incidence, while genetic risk for OP modified this association. These findings underscore the crucial role of adhering to healthy sleep behaviors for effective OP prevention., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Telomere length (TL) is a biomarker of genomic aging. The evidence on the association between TL and air pollution was inconsistent. Besides, the modification effect of genetic susceptibility on the air pollution-TL association remains unknown., Objective: We aimed to evaluate the association of ambient air pollution with TL and further assess the modification effect of genetic susceptibility., Methods: 433,535 participants with complete data of TL and air pollutants in UK Biobank were included. Annual average exposure of NO 2 , NO x , PM 10 and PM 2.5 was estimated by applying land use regression models. Genetic risk score (GRS) was constructed using reported telomere-related SNPs. Leukocyte TL was measured by quantitative polymerase chain reaction (qPCR). Multivariable linear regression models were employed to conduct associational analyses., Results: Categorical exposure models and RCS models both indicated U-shaped (for NO 2 and NO x ) and L-shaped (for PM 10 and PM 2.5 ) correlations between air pollution and TL. In comparison to the lowest quartile, the 2nd and 3rd quartile of NO 2 (q2: -1.3% [-2.1%, -0.4%]; q3: -1.2% [-2.0%, -0.3%], NO x (q2: -1.3% [-2.1%, -0.5%]; q3: -1.4% [-2.2%, -0.5%]), PM 2.5 (q2: -0.8% [-1.7%, 0.0%]; q3: -1.3% [-2.2%, -0.5%]), and the third quartile of PM 10 (q3: -1.1% [-1.9%, -0.2%]) were inversely associated with TL. The highest quartile of NO 2 was positively correlated with TL (q4: 1.0% [0.0%, 2.0%]), whereas the negative correlation between the highest quartile of other pollutants and TL was also attenuated and no longer significant. In the genetic analyses, synergistic interactions were observed between the 4th quartile of three air pollutants (NO 2 , NO x , and PM 2.5 ) and genetic risk., Impact Statement: Our study for the first time revealed a non-linear trend for the association between air pollution and telomere length. The genetic analyses suggested synergistic interactions between air pollution and genetic risk on the air pollution-TL association. These findings may shed new light on air pollution's health effects, offer suggestions for identifying at-risk individuals, and provide hints regarding further investigation into gene-environment interactions., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: This study aimed to investigate the interplay between genetic susceptibility and socioeconomic disparities on psychiatric disorders., Methods: In this study, we utilized data from the UK Biobank to analyze the Generalized Anxiety Disorder (GAD)-7 scale (N = 74,425) and the Patient Health Questionnaire (PHQ)-9 (N = 74,101), along with the Index of Multiple Deprivation (IMD). The polygenic risk score (PRS) was calculated to assess the genetic risk associated with GAD-7/PHQ-9 scores, and the individuals were classified into low, medium, and high genetic risk groups according to tertiles of PRSs related to the GAD-7/PHQ-9. Linear regression models were used to explore the relationships between GAD-7/PHQ-9 scores and IMD scores in patients with different genetic susceptibilities., Results: Disadvantaged socioeconomic status was associated with the risk of anxiety and depression across all strata of genetic risk, and stronger associations were shown for individuals with greater genetic susceptibility. From low to high genetic risk, the risk of psychiatric disorders increased for the GAD-7 (β = 0.002 to 0.032) and PHQ-9 (β = 0.003 to 0.045) scores. In addition, strong associations of high genetic risk with anxiety (β = 0.875) and depression (β = 1.152) were detected in the IMD quartile 4 group compared with the least deprivation quartile group. Furthermore, income and employment were estimated to contribute strongly to anxiety (β employment  = 7.331, β income  = 4.492) and depression (β employment  = 9.951, β income  = 6.453) in the high genetic risk group., Conclusion: The results suggest that we should pay more attention to psychiatric disorders with high genetic susceptibility and try to improve their socioeconomic status to prevent the development of psychiatric disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The omnigenic model posits that genetic risk for traits with complex heritability involves cumulative effects of peripheral genes on mechanistic "core genes," suggesting that in a network of genes, those closer to clusters including core genes should have higher GWAS signals. In gene co-expression networks, we confirmed that GWAS signals accumulate in genes more connected to risk-enriched gene clusters, highlighting across-network risk convergence. This was strongest in adult psychiatric disorders, especially schizophrenia (SCZ), spanning 70% of network genes, suggestive of super-polygenic architecture. In snRNA-seq cell type networks, SCZ risk convergence was strongest in L2/L3 excitatory neurons. We prioritized genes most connected to SCZ-GWAS genes, which showed robust association to a CRISPRa measure of PGC3 regulation and were consistently identified across several brain regions. Several genes, including dopamine-associated ones, were prioritized specifically in the striatum. This strategy thus retrieves current drug targets and can be used to prioritize other potential drug targets., Competing Interests: Declaration of interests A.B. received consulting fees by Biogen and lecture fees by Otsuka, Janssen, and Lundbeck. D.R.W. serves on the scientific advisory boards of Sage Therapeutics and Pasithea Therapeutics. G.P. received lecture fees by Lundbeck., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study describes the experiences with the stigma attached to Machado-Joseph disease (MJD) in São Miguel Island, the Azores (Portugal). We draw on semi-structured interviews with persons with MJD, family members, healthcare professionals, and direct care providers recruited through the local patient's association (n = 28). Qualitative thematic analysis revealed three main themes: (i) the intense stigma associated with MJD in the past; (ii) the current tendency towards increased openness; and (iii) increased availability of information about MJD and support. The findings suggest that stigmatization was more frequent and intense in the past. Still, there is currently a decrease in the intensity of perceived stigma, accompanied by an increasing awareness about MJD within the community. The local patient's association is noted for playing a pivotal role in raising awareness about MJD in the community and fostering the confidence of individuals with MJD and their families to engage socially, which may help to reduce or mitigate feelings of stigma. This raises questions about whether the diminished stigma towards MJD in São Miguel results from heightened awareness about the condition, a decrease in the social acceptability of stigma, or a gradual internalization and normalization of stigma among individuals with MJD as a coping mechanism., (© 2024. The Author(s).)

Background: The associations between 1-carbon metabolism (OCM) nutrients (methionine, folate, vitamin B-6, and vitamin B-12) and Alzheimer disease (AD) remains inconclusive., Objectives: This study aimed to investigate the association of dietary OCM nutrients with subsequent risk of AD and further assess whether participants with 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-h 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 y, 959 cases of AD (41 early-onset cases and 918 late-onset cases) were identified. Compared with those in the low-intake OCM group (quartile 1), participants in the high-intake OCM group (quartile 4) had reduced risk of developing AD. The corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for methionine, folate, vitamin B-6, and vitamin B-12 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 B-12 intake were associated with 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 >75% reduced AD risk compared with high-risk, low-intake participants., Conclusions: In this prospective cohort study, we found that higher intake of OCM nutrients is associated with reduced risk of AD. Participants with high genetic risk of AD are more likely to benefit from dietary OCM nutrients intake., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

This study aimed to investigate the associations between carbohydrate intake and gout risk, along with interactions between genetic susceptibility and carbohydrates, and the mediating roles of biomarkers. We included 187,387 participants who were free of gout at baseline and completed at least one dietary assessment in the UK Biobank. Cox proportional hazard models were used to estimate the associations between carbohydrate intake and gout risk. Over a median follow-up of 11.69 years, 2548 incident cases of gout were recorded. Total carbohydrate intake was associated with a reduced gout risk (Q4 vs. Q1: HR 0.67, 95% CI 0.60-0.74), as were total sugars (0.89, 0.80-0.99), non-free sugars (0.70, 0.63-0.78), total starch (0.70, 0.63-0.78), refined grain starch (0.85, 0.76-0.95), wholegrain starch (0.73, 0.65-0.82), and fiber (0.72, 0.64-0.80), whereas free sugars (1.15, 1.04-1.28) were associated with an increased risk. Significant additive interactions were found between total carbohydrates and genetic risk, as well as between total starch and genetic risk. Serum urate was identified as a significant mediator in all associations between carbohydrate intake (total, different types, and sources) and gout risk. In conclusion, total carbohydrate and different types and sources of carbohydrate (excluding free sugars) intake were associated with a reduced risk of gout.

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.

Objectives: The association between physical activity and venous thromboembolism (VTE) remains unclear. Therefore, we investigated the prospective dose-response associations between accelerometer-measured intensity-specific physical activity and new-onset VTE, accounting for genetic risk., Methods: In total, 85,116 participants from the UK Biobank were included. Incident VTE was identified via linked hospital records and death registries. A weighted polygenic risk score (PRS) was used to quantifying genetic risk for VTE, with higher values indicating a high genetic risk. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of the associations., Results: Overall, 1,182 incident VTE cases were documented during a median follow-up of 6.18 years. In the overall study population, the participants in the highest quartiles of total volume of physical activity (0.60 [0.45, 0.79]), moderate-to-vigorous-intensity physical activity (0.66 [0.51, 0.86]), and light-intensity physical activity (0.66 [0.51, 0.85]) had lower adjusted HRs (95% CIs) for VTE than those of participants in the lowest quartiles. Both total volume of physical activity and light-intensity physical activity were negatively associated with VTE risk in participants with low, intermediate, and high PRS. However, moderate-to-vigorous-intensity physical activity was only protective against VTE in participants with low and intermediate PRS, with a significant interaction (P for interaction=0.02)., Conclusion: Higher levels of physical activity of any intensity were associated with a lower risk of new-onset VTE. However, the negative association between moderate-to-vigorous-intensity physical activity and new-onset VTE was significant only in participants with low and intermediate genetic predispositions to VTE., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Congenital heart disease (CHD) is the most prevalent congenital anomaly, but its underlying causes are still not fully understood. It is believed that multiple rare genetic mutations may contribute to the development of CHD., Methods: In this study, we aimed to identify novel genetic risk factors for CHD using an ENU-based dominant genetic screen in mice. We analyzed fetuses with malformed hearts and compared them to control littermates by whole exome or whole genome sequencing (WES/WGS). The differences in mutation rates between observed and expected values were tested using the Poisson and Binomial distribution. Additionally, we compared WES data from human CHD probands obtained from the Pediatric Cardiac Genomics Consortium with control subjects from the 1000 Genomes Project using Fisher's exact test to evaluate the burden of rare inherited damaging mutations in patients., Results: By screening 10,285 fetuses, we identified 1109 cases with various heart defects, with ventricular septal defects and bicuspid aortic valves being the most common types. WES/WGS analysis of 598 cases and 532 control littermates revealed a higher number of ENU-induced damaging mutations in cases compared to controls. GO term and KEGG pathway enrichment analysis showed that pathways related to cardiac contraction and neuronal development and functions were enriched in cases. Further analysis of 1457 human CHD probands and 2675 control subjects also revealed an enrichment of genes associated with muscle and nervous system development in patients. By combining the mice and human data, we identified a list of 101 candidate digenic genesets, from which each geneset was co-mutated in at least one mouse and two human probands with CHD but not in control mouse and control human subjects., Conclusions: Our findings suggest that gene mutations affecting early hemodynamic perturbations in the developing heart may play a significant role as a genetic risk factor for CHD. Further validation of the candidate gene set identified in this study could enhance our understanding of the complex genetics underlying CHD and potentially lead to the development of new diagnostic and therapeutic approaches., (© 2024. The Author(s).)

Background: LRRK2 variants have been associated with immune dysregulation as well as immune-related disorders such as IBD. A possible relationship between multiple sclerosis (MS) and LRRK2 PD has also been suggested. Further, neuropathologic studies of homozygous LRRK2 G2019S carriers with Parkinson's disease (PD) are rare, and there are no systematic reports of clinical features in those cases., Methods: We investigated the co-occurrence of PD and MS in our research cohort and report on two cases of MS in LRRK2 PD as well as neuropathological findings for one., Results: MS preceded PD in 1.4% (2/138) of participants with LRRK2 G2019S variants, and in none (0/638) with idiopathic PD ( p  = 0.03). One case with MS and PD was a LRRK2 G2019S homozygous carrier, and neuropathology showed evidence of substantia nigra pars compacta degeneration and pallor without Lewy deposition, as well as multiple white matter lesions consistent with MS-related demyelination., Discussion: The increased prevalence of MS in LRRK2 PD further supports an important role for immune function for LRRK2 PD. This co-occurrence, while rare, suggests that MS may be an expression of the LRRK2 G2019S variant that includes both MS and PD, with MS predating features diagnostic of PD. The neuropathology suggests that the MS-related effects occurred independent of synuclein deposition. Importantly, and in addition, the neuropathological results not only support the MS diagnosis, but provide further evidence that Lewy body pathology may be absent even in homozygote LRRK2 carriers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wise, Ortega, Raymond, Cervera, Thorn, Leaver, Russell, Bressman, Crary and Saunders-Pullman.)

Background: Substance use disorders (SUDs) have been consistently shown to exhibit moderate intergenerational continuity (1-3). While much research has examined genetic and social influences on addiction, less attention has been paid to clients' and lay persons' perceptions of genetic influences on the heritability of SUD (4) and implications for treatment., Methods: For this qualitative study, twenty-six structured Working Model of the Child Interviews (WMCI) were conducted with mothers receiving inpatient SUD treatment. These interviews were thematically analyzed for themes related to maternal perceptions around intergenerational transmission of substance use behaviours., Results: Findings show that over half of the mothers in this sample were preoccupied with their children's risk factors for addictions. Among this group, 29% spontaneously expressed concerns about their children's genetic risk for addiction, 54% shared worries about their children's propensity for addiction without mentioning the word gene or genetic. Additionally, 37% had challenges in even discussing their children's future when prompted. These concerns mapped onto internal working models of attachment in unexpected ways, with parents who were coded with balanced working models being more likely to discuss intergenerational risk factors and parents with disengaged working models displaying difficulties in discussing their child's future., Conclusion: This research suggests that the dominant discourse around the brain-disease model of addictions, in its effort to reduce stigma and self-blame, may have unintended downstream consequences for parents' mental models about their children's risks for future addiction. Parents receiving SUD treatment, and the staff who deliver it, may benefit from psychoeducation about the intergenerational transmission of SUD as part of treatment., (© 2024. The Author(s).)

Limited research has reported the association between MTNR1B gene polymorphisms and ischemic stroke (IS), and there is insufficient evidence on whether adopting a healthy lifestyle can mitigate genetic risks in this context. This study aimed to investigate the associations between MTNR1B gene variants (rs10830963 and rs1387153) and IS, examining the potential effect of gene-lifestyle interactions on IS risk. Conducted in northern China, this family-based cohort study involved 5116 initially IS-free subjects. Genotype data for rs10830963 and rs1387153 in MTNR1B were collected. Eight modifiable lifestyle factors, including body mass index (BMI), smoking, alcohol consumption, dietary habits, physical activity, sedentary time, sleep duration, and chronotype, were considered in calculating healthy lifestyle scores. Multilevel Cox models were used to examine the associations between MTNR1B variants and IS. Participants carrying the rs10830963-G and rs1387153-T alleles exhibited an elevated IS risk. Each additional rs10830963-G allele and rs1387153-T allele increased the IS risk by 36% (HR = 1.36, 95% CI, 1.12-1.65) and 32% (HR = 1.32, 95% CI, 1.09-1.60), respectively. Participants were stratified into low, medium, and high healthy lifestyle score groups (1537, 2188, and 1391 participants, respectively). Genetic-lifestyle interactions were observed for rs10830963 and rs1387153 (p for interaction < 0.001). Notably, as the healthy lifestyle score increased, the effect of MTNR1B gene variants on IS risk diminished (p for trend < 0.001). This study underscores the association between the MTNR1B gene and IS, emphasizing that adherence to a healthy lifestyle can mitigate the genetic predisposition to IS., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Gallstone disease (GD) is common but remains asymptomatic in most cases. However, gallstones can lead to complications like choledocholithiasis or gallbladder cancer. In this study, we analyse the common genetic risk factor for GD, the p.D19H variant in the sterol transporter ABCG8, in Polish patients with gallstones and gallbladder cancer., Methods: Three adult cohorts were prospectively recruited: 65 patients with gallbladder cancer, 170 obese individuals scheduled for bariatric surgery and 72 patients who underwent endoscopic retrograde cholangiopancreatography due to recurrent choledocholithiasis. The control cohort consisted of 172 gallstone-free adults. The ABCG8 p.D19H (rs11887534) polymorphism was genotyped using TaqMan assays., Results: The minor allele frequency (MAF) of the ABCG8 p.D19H polymorphism was significantly (p = .02) higher among cases with either gallstones or gallbladder cancer (MAF = 8.4%) as compared to controls (MAF = 4.0%). The highest frequency of the risk allele was detected in patients with gallbladder cancer (18.5%) and obese patients with GD (17.5%), followed by individuals with choledocholithiasis (13.9%). Notably, the p.19H variant was associated with an increased risk of developing gallbladder cancer (OR 2.76, 95% CI 1.16-6.54, p = .01) and an increased risk of GD in obese individuals scheduled for bariatric surgery (OR = 2.70, 95% CI 1.05-6.49, p = .03), but did not significantly affect the risk of choledocholithiasis., Conclusions: The ABCG8 p.D19H common risk variant increases the risk of developing gallbladder cancer in Central Europeans and enhances the risk of gallstones in the obese. Carriers of the p.D19H variant might benefit from personalized preventive strategies, particularly regarding gallbladder cancer., (© 2024 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Purpose: A healthy diet reduces the risk of non-alcoholic fatty liver disease (NAFLD) in the general population, especially in individuals who are genetically predisposed to NAFLD. Little is known in patients who suffered from a myocardial infarction (MI). We examined the interaction between diet quality and genetic predisposition in relation to NAFLD in post-MI patients., Methods: We included 3437 post-MI patients from the Alpha Omega Cohort. Diet quality was assessed with adherence to the Dutch Healthy Diet index 2015 (DHD15-index). A weighted genetic risk score (GRS) for NAFLD was computed using 39 genetic variants. NAFLD prevalence was predicted using the Fatty Liver Index. Prevalence ratios (PR) with 95% confidence intervals of DHD15-index and GRS in relation to NAFLD were obtained with multivariable Cox proportional hazards models. The interaction between DHD15-index and GRS in relation to NAFLD was assessed on an additive and multiplicative scale., Results: Patients had a mean age of 69 (± 5.5) years, 77% was male and 20% had diabetes. The DHD15-index ranged from 28 to 120 with a mean of 73. Patients with higher diet quality were less likely to suffer from NAFLD, with a PR of 0.76 (0.62, 0.92) for the upper vs lower quintile of DHD15-index. No association between the GRS and NAFLD prevalence was found (PR of 0.92 [0.76, 1.11]). No statistically significant interaction between the DHD15-index and GRS was observed., Conclusion: In Dutch post-MI patients, adherence to the Dutch dietary guidelines was associated with a lower prevalence of NAFLD, as assessed by the FLI. This association was present regardless of genetic predisposition in this older aged cohort., (© 2024. The Author(s).)

Systemic lupus erythematosus (SLE) patients present a high prevalence of cardiometabolic risk, associated with worse clinical manifestations and mortality. Folate, an essential micronutrient that participates in vital immune cellular functions, could positively affect the cardiometabolic and disease risk in SLE, through the methylenetetrahydrofolate reductase (MTHFR) enzyme, which participates in the folate metabolism, where single nucleotide variants (SNVs) have been described as a potential genetic risk factor for SLE. The aim of this study was to determine the association of the c.+677 C>T (rs1801133) and c.+1298 A>C (rs1801131) MTHFR genetic variants with cardiometabolic risk and clinical disease variables in SLE patients. A case-control study was conducted on 394 unrelated Mexican-mestizo women: 199 with SLE according to the 1997 SLE-ACR criteria and 196 control subjects (CS). Folic acid and homocysteine levels were evaluated by immunoassays. Genotyping of MTHFR genetic variants was carried out by allelic discrimination. No significant differences were found for folic acid ( p = .15) and homocysteine serum levels ( p = .59) between groups. According to the CC c.+677 MTHFR genotype, this was associated with low cardiovascular disease (CVD) risk by the Castelli index (OR = 0.42; p = .03) in SLE patients. The TC (OR = 1.3; p = .03) and the TA (OR = 1.6; p < .01) haplotypes from c.+677 C>T plus c.+1298 MTHFR were associated with SLE risk, while the CC MTHFR haplotype (OR = 0.5; p = .01) was found as a non-risk factor for the disease. In conclusion, the TC and the TA MTHFR haplotypes are associated with disease risk; meanwhile, the CC c.+677 MTHFR genotype confers lower cardiometabolic risk in Mexican-mestizo SLE patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Pulmonary function is associated with the development of chronic liver disease. However, evidence of the association between pulmonary function and cirrhosis risk is still lacking. This study aimed to investigate the longitudinal associations of pulmonary function with the development of cirrhosis, and to explore whether genetic predisposition to cirrhosis could modify these associations., Methods: Of 294,835 participants free of cirrhosis and had undergone spirometry at baseline from the UK Biobank were included. Cirrhosis diagnoses were ascertained through linked hospital records and death registries. Cox proportional hazard models were employed to investigate the longitudinal associations between pulmonary function, genetic predisposition, and cirrhosis risk., Results: During a median follow-up of 12.0 years, 2598 incident cirrhosis cases were documented. Compared to individuals with normal spirometry findings, those with preserved ratio impaired spirometry (PRISm) findings (hazard ratio [HR] and 95% confidence interval [CI]: 1.32 [1.18, 1.48]) and airflow obstruction (HR [95%CI]: 1.19 [1.07, 1.31]) had a higher risk of developing cirrhosis after adjustments. These associations were consistent across all categories of genetic predisposition, with no observed modifying effect of genetic predisposition. In joint exposure analyses, the highest risk was observed in individuals with both a high genetic predisposition for cirrhosis and PRISm findings (HR [95% CI]: 1.74 [1.45, 2.08])., Conclusions: Our findings indicate that worse pulmonary function is a significant risk factor of cirrhosis, irrespective of genetic predisposition. Early identification and appropriate intervention for pulmonary function may lead to more effective healthcare resource utilization and reduce the burden associated with cirrhosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To describe clinical characteristics and management in a large cohort of patients with retinal detachment due to a giant retinal tear (GRT)., Methods: We performed a retrospective cohort study with 222 eyes of 206 patients with a primary and non-traumatic GRTs between 2005 and 2022. We analysed the relevant clinical and surgical data from these patients., Results: Eighty-six per cent (n = 177) of patients were male. We observed no relation between refractive error and GRT size (Spearman's rho: r = -0.018, p = 0.83). We achieved a primary and final treatment success in 77%, respectively 92%, of eyes. The final visual outcome was 20/40 or better in 65% and 36% of eyes in fovea-on and fovea-off GRTs respectively. Thirty-five per cent (n = 73) of patients developed a retinal detachment in the fellow eye. The median time until a retinal detachment in the fellow eye occurred after GRT was 20 months, and 10% developed within 1 month. A prediction model for the development of retinal detachment in the fellow eye resulted in a receiver operating characteristics curve with an area under the curve of 0.68 (95% CI: 0.57-0.78, p = 0.001)., Conclusion: We observed a highly significant gender imbalance in patients with a non-traumatic GRT. One third of patients developed a retinal detachment bilaterally. Ten per cent of fellow eye's retinal detachment that develop after GRT, occur within 1 month. Clinical parameters showed limited predictive value for a retinal detachment in the fellow eye. These findings suggest an underlying genetic factor., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: The most near-term clinical application of genome-wide association studies in lung cancer is a polygenic risk score (PRS)., Methods: A case-control dataset was generated consisting of 4002 lung cancer cases from the LORD project and 20,010 ethnically matched controls from CARTaGENE. A genome-wide PRS including >1.1 million genetic variants was derived and validated in UK Biobank (n = 5419 lung cancer cases). The predictive ability and diagnostic discrimination performance of the PRS was tested in LORD/CARTaGENE and benchmarked against previous PRSs from the literature. Stratified analyses were performed by smoking status and genetic risk groups defined as low (<20th percentile), intermediate (20-80th percentile) and high (>80th percentile) PRS., Findings: The phenotypic variance explained and the effect size of the genome-wide PRS numerically outperformed previous PRSs. Individuals with high genetic risk had a 2-fold odds of lung cancer compared to low genetic risk. The PRS was an independent predictor of lung cancer beyond conventional clinical risk factors, but its diagnostic discrimination performance was incremental in an integrated risk model. Smoking increased the odds of lung cancer by 7.7-fold in low genetic risk and by 11.3-fold in high genetic risk. Smoking with high genetic risk was associated with a 17-fold increase in the odds of lung cancer compared to individuals who never smoked and with low genetic risk., Interpretation: Individuals at low genetic risk are not protected against the smoking-related risk of lung cancer. The joint multiplicative effect of PRS and smoking increases the odds of lung cancer by nearly 20-fold., Funding: This work was supported by the CQDM and the IUCPQ Foundation owing to a generous donation from Mr. Normand Lord., Competing Interests: Declaration of interests B. Arsenault received research grants from Silence Therapeutics, Pfizer and Eli Lilly; received consulting fees from Silence Therapeutics, Novartis, Eli Lilly and Editas Medicine. C. Labbé received consulting fees from Amgen, AstraZeneca, Bristol-Myers-Squibb, EMD Serono, Jazz Pharmaceuticals, LEO Pharma, Lilly, Merck, Pfizer, Roche and Sanofi Genzyme. S. Martel received research grants the Ministry of Health province of Quebec and Canadian Partnership Against Cancer. Y. Bossé has received research grants from the IUCPQ Foundation. The remaining authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate differences in social adjustment during adulthood between adoptees with high genetic risk (HR) and low genetic risk (LR) for schizophrenia spectrum disorders., Methods: This study is a subsample of the Finnish Adoptive Family Study of Schizophrenia. The study sample consisted of 120  adoptees whose biological mothers had DSM-III-R verified schizophrenia spectrum disorders, and 142 socio-demographically matched control adoptees. The social adjustment of the adoptees was assessed using the interview-based Adult Adjustment Scale (AAS)., Results: A lower proportion of the HR adoptees (61.7%) fell into the category of good adaptation compared to LR adoptees (74.6%) (p = 0.024). In addition, the median AAS score among HR adoptees was lower compared to LR adoptees (p = 0.023). Poorer results among HR adoptees were also found regarding some individual items and the social health -domain within the AAS. The psychiatric morbidity, excluding schizophrenia spectrum disorders, was higher among HR adoptees. Psychiatric morbidity was shown to mediate the association of genetic status to total AAS, and, also to the domain of social health., Conclusion: According to our results, genetic susceptibility to schizophrenia is associated with weakened social adjustment during adulthood. Although our results demonstrated that psychiatric morbidity has notable effect on the association of genetic status to adult adjustment scores, the impact of other determinants, like psychosocial factors or health-related behaviour, cannot be ruled out. The comparable rearing environment provided by the adoption design in conjunction with reliable diagnostics provide new information on the relation of genetic susceptibility and social adjustment., (© 2024. The Author(s).)

Background: Vitiligo is an auto-immune progressive depigmentation disorder of the skin due to loss of melanocytes. Genetic risk is one of the important factors for development of vitiligo. Preponderance of vitiligo in certain ethnicities is known which can be analysed by understanding the distribution of allele frequencies across normal populations. Earlier GWAS identified 108 risk alleles for vitiligo in Europeans and East Asians. In this study, 64 of these risk alleles were used for analysing their enrichment and depletion across populations (1000 Genomes Project and IndiGen) with reference to 1000 Genomes dataset. Genetic risk scores were calculated and Fisher's exact test was performed to understand statistical significance of their variation in each population with respect to 1000 Genomes dataset as reference. In addition to SNPs reported in GWAS, significant variation in allele frequencies of 1079 vitiligo-related genes were also analysed. Two-tailed Chi-square test and Bonferroni's multiple adjustment values along with fixation index (≥ 0.5) and minimum allele frequency (≥ 0.05) were calculated and used to prioritise the variants based on pairwise comparison across populations., Results: Risk alleles rs1043101 and rs10768122 belong to 3 prime UTR of glutamate receptor gene SLC1A2 are found to be highly enriched in the South Asian population when compared with the 'global normal' population. Intron variant rs4766578 (ATXN2) was found to be deleted in SAS, EAS and AFR and enriched in EUR and AMR1. This risk allele is found to be under positive selection in SAS, AMR1 and EUR. From the ancillary vitiligo gene list, nonsynonymous variant rs16891982 was found to be enriched in the European and the Admixed American populations and depleted in all others. rs2279238 and rs11039155 belonging to the LXR-α gene involved in regulation of metalloproteinase 2 and 9 (melanocyte precursors) were found to be associated with vitiligo in the North Indian population (in earlier study)., Conclusion: The differential enrichment/depletion profile of the risk alleles provides insight into the underlying inter-population variations. This would provide clues towards prioritisation of SNPs associated with vitiligo thereby elucidating its preponderance in different ethnic groups., (© 2024. The Author(s).)

Objective: Cerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital., Methods: A total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD., Results: Through GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10 - 8 . Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%., Conclusions: Our study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation., (© 2024. The Author(s).)

Background: Proinflammatory and neuroendocrine mediators are implicated in disease aetiopathogenesis. Stress increases concentrations of immune-neuroendocrine biomarkers through a complex network of brain-body signalling pathways. Suboptimal sleep further modulates these processes by altering major effector systems that sensitise the brain to stress. Given the ubiquitous, impactful nature of material deprivation, we tested for a synergistic association of financial stress and suboptimal sleep with these molecular processes., Methods: With data drawn from the English Longitudinal Study of Ageing (ELSA), associations were tested on 4,940 participants (~66±9.4 years) across four-years (2008-2012). Through analytical triangulation, we tested whether financial stress (>60% insufficient resources) and suboptimal sleep (≤5/≥9 hours) were independently and interactively associated with immune-neuroendocrine profiles, derived from a latent profile analysis (LPA) of C-reactive protein, fibrinogen, white blood cell counts, hair cortisol, and insulin-like growth factor-1., Results: A three-class LPA model offered the greatest parsimony. After adjustment for genetic predisposition, sociodemographics, lifestyle, and health, financial stress was associated with short-sleep cross-sectionally (RRR=1.45; 95%CI=1.18-1.79; p <0.001) and longitudinally (RRR=1.31; 95%CI=1.02-1.68; p =0.035), and it increased risk of belonging to the high-risk biomarker profile by 42% (95%CI=1.12-1.80; p =0.004). Suboptimal sleep was not related to future risk of high-risk profile membership, nor did it moderate financial stress-biomarker profile associations., Discussion: Results advance psychoneuroimmunological knowledge by revealing how immune-neuroendocrine markers cluster in older cohorts and respond to financial stress over time. Financial stress associations with short-sleep are supported. The null role of suboptimal sleep, as exposure and mediator, in profile membership, provides valuable insight into the dynamic role of sleep in immune-neuroendocrine processes.

Context: Emerging studies have revealed associations between dietary medium-chain fatty acids (MCFAs) and glucose homeostasis. However, the relationship between serum MCFAs and the incidence of diabetes, and potential interactions with genetic predisposition, remains unclear in prospective cohort studies., Objective: To investigate associations and genetic susceptibility between serum MCFAs and diabetes risk., Methods: We investigated baseline serum MCFAs (n=5) in a nested case-control study comprising incident diabetes cases (n=1,707) and matched normoglycemic control subjects (n=1,707) from the China Cardiometabolic Disease and Cancer Cohort Study. Associations between MCFAs and type 2 diabetes mellitus (T2DM) were examined, both overall and stratified by diabetes genetic susceptibility. Genetic risk scores (GRS) were calculated based on 86 T2DM-associated genetic variants., Results: In the fully adjusted conditional logistic regression model, serum octanoic acid and nonanoic acid exhibited inverse dose-response relationships with diabetes risk, showing odds ratios (95% confidence intervals) of 0.90 (0.82-0.98) and 0.84 (0.74-0.95), respectively. Subgroup analysis demonstrated that inverse associations between MCFAs and incident diabetes were more pronounced among individuals with physical inactivity (Pinteraction = 0.042, 0.034, and 0.037, for octanoic, nonanoic and decanoic acid, respectively). Moreover, inverse associations of octanoic acid with diabetes risk were notably enhanced among individuals with high genetic risk compared to those with low genetic risk. Significant interactions were observed between octanoic acid and GRS on T2DM risk (Pinteraction = 0.003)., Conclusions: These findings provide evidence supporting inverse associations between serum MCFAs and T2DM risk, and reveal potential interplay between genetic susceptibility and circulating octanoic acid in modulating diabetes risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Aim: To investigate the role of family history, race/ethnicity, and genetics in prostate cancer (PCa) screening., Methods: We conducted a systematic review of articles from January 2013 through September 2023 that focused on the association of race/ethnicity and genetic factors on PCa detection. Of 10,815 studies, we identified 43 that fulfilled our pre-determined PICO (Patient, Intervention, Comparison and Outcome) criteria., Results: Men with ≥1 first-degree relative(s) with PCa are at increased risk of PCa, even with negative imaging and/or benign prostate biopsy. Black men have higher PCa risk, while Asian men have lower risk. Most of the differences in risks are attributable to environmental and socioeconomic factors; however, genetic differences may play a role. Among numerous pathogenic variants that increase PCa risk, BRCA2, MSH2, and HOXB13 mutations confer the highest risk of PCa. Polygenic risk score (PRS) models identify men at higher PCa risk for a given age and PSA; these models improve when considering other clinical factors and when the model population matches the study population's ancestry., Conclusions: Family history of PCa, race/ethnicity, pathogenic variants (particularly BRCA2, MSH2, and HOXB13), and PRS are associated with increased PCa risk and should be considered in shared decision-making to determine PCa screening regimens., Competing Interests: Declaration of competing interest No Competing Interest to Declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Methods of estimating polygenic scores (PGSs) from genome-wide association studies are increasingly utilized. However, independent method evaluation is lacking, and method comparisons are often limited. Here, we evaluate polygenic scores derived via seven methods in five biobank studies (totaling about 1.2 million participants) across 16 diseases and quantitative traits, building on a reference-standardized framework. We conducted meta-analyses to quantify the effects of method choice, hyperparameter tuning, method ensembling, and the target biobank on PGS performance. We found that no single method consistently outperformed all others. PGS effect sizes were more variable between biobanks than between methods within biobanks when methods were well tuned. Differences between methods were largest for the two investigated autoimmune diseases, seropositive rheumatoid arthritis and type 1 diabetes. For most methods, cross-validation was more reliable for tuning hyperparameters than automatic tuning (without the use of target data). For a given target phenotype, elastic net models combining PGS across methods (ensemble PGS) tuned in the UK Biobank provided consistent, high, and cross-biobank transferable performance, increasing PGS effect sizes (β coefficients) by a median of 5.0% relative to LDpred2 and MegaPRS (the two best-performing single methods when tuned with cross-validation). Our interactively browsable online-results and open-source workflow prspipe provide a rich resource and reference for the analysis of polygenic scoring methods across biobanks., Competing Interests: Declaration of interests M.I. is a trustee of the Public Health Genomics (PHG) Foundation, is a member of the Scientific Advisory Board of Open Targets, and has a AstraZeneca PLC research collaboration that is unrelated to this study. M.I. is supported by core funding from the British Heart Foundation (RG/18/13/33946) and NIHR Cambridge Biomedical Research Center (BRC-1215-20014; NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. K.L. has participated as an analyst in a collaboration research project at the Institute of Genomics, University of Tartu, which was funded by Geneto OÜ. O.P. provides consultancy services for UCB pharma company., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The extent to which modifiable lifestyle factors offset the determined genetic risk of obesity and obesity-related morbidities remains unknown. We explored how the interaction between genetic and lifestyle factors influences the risk of obesity and obesity-related morbidities. The polygenic score for body mass index was calculated to quantify inherited susceptibility to obesity in 338,645 UK Biobank European participants, and a composite lifestyle score was derived from five obesogenic factors (physical activity, diet, sedentary behavior, alcohol consumption, and sleep duration). We observed significant interaction between high genetic risk and poor lifestyles (p interaction  < 0.001). Absolute differences in obesity risk between those who adhere to healthy lifestyles and those who do not had gradually expanded with an increase in polygenic score. Despite a high genetic risk for obesity, individuals can prevent obesity-related morbidities by adhering to a healthy lifestyle and maintaining a normal body weight. Healthy lifestyles should be promoted irrespective of genetic background., Competing Interests: Declaration of interests P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, TenSixteen Bio, and Tourmaline Bio; equity in MyOme, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. A.C.F. reports being co-founder of Goodpath, serving as scientific advisor to MyOme and HeartFlow, and receiving a research grant from Foresite Labs, all unrelated to this work. R.D. reported receiving grants from AstraZeneca; grants and non-financial support from Goldfinch Bio; being a scientific co-founder, consultant, and equity holder for Pensieve Health (pending); and being a consultant for Variant Bio, all not related to this work. A.V.K. reports work as a consultant for Marea Therapeutics and Foresite labs and is an employee and equity holder for Verve Therapeutics, all not related to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The concept of schizotypal personality disorder (SPD) emerged from observations of personality characteristics common in relatives of schizophrenic patients. While often studied in family designs, few studies and none with genetic measures, have examined SPD in epidemiological samples., Methods: We studied individuals born in Sweden 1940-2000 with an ICD-10 diagnosis of SPD with no prior schizophrenia (SZ) diagnosis ( n = 2292). Demographic features, patterns of comorbidity, and Family Genetic Risk Scores (FGRS) were assessed from multiple Swedish registries. Prediction of progression to SZ was assessed by Cox models., Results: SPD was rare, with a prevalence of 0.044%, and had high levels of comorbidity with autism spectrum disorder (ASD), OCD, ADHD, and major depression (MD), and increased rates of being single, unemployed and in receipt of welfare. Affected individuals had elevated levels of FGRS for SZ (+0.42), ASD (+0.30), MD (+0.29), and ADHD (+0.20). Compared to cases of schizophrenia, they had significantly lower rates of FGRS SZ , but significantly elevated rates of genetic risk for ASD, MD, and ADHD. Over a mean follow-up of 8.7 years, 14.6% of SPD cases received a first diagnosis of SZ, the risk for which was significantly increased by levels of FGRS SZ , male sex, young age at SPD diagnosis and an in-patient SPD diagnosis and significantly decreased by comorbidity with MD, ASD, and ADHD., Conclusions: Our results not only support the designation of SPD as a schizophrenia spectrum disorder but also suggest potentially important etiologic links between SPD and ASD and, to a lesser extent, ADHD, OCD, and MD.

Subjective health ratings are associated with dementia risk such that those who rate their health more poorly have increased risk for dementia. The genetic and environmental mechanisms underlying this association are unclear, as prior research cannot rule out whether the association is due to genetic confounds. The current study addresses this gap in two samples of twins, one from Sweden (N = 548) and one from Denmark (N = 4,373). Using genetically-informed, bivariate regression models, we assessed whether additive genetic effects explained the association between subjective health and dementia risk as indexed by a latent variable proxy measure. Age at intake, sex, education, depressive symptomatology, and follow-up time between subjective health and dementia risk assessments were included as covariates. Results indicate that genetic variance and other sources of confounding accounted for the majority of the effect of subjective health ratings on dementia risk. After adjusting for genetic confounding and other covariates, a small correlation was observed between subjective health and latent dementia risk in the Danish sample (r E  = - .09, p < .05). The results provide further support for the genetic association between subjective health and dementia risk, and also suggest that subjective ratings of health measures may be useful for predicting dementia risk., (© 2024. The Author(s).)