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IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

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/m2), overweight (25.0–29.9 kg/m2), and obesity (≥ 30.0 kg/m2). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The two major determining factors for Alzheimer's disease (AD) are genetics and lifestyle. Alleles of the apolipoprotein E (APOE) gene play important roles in the development of late-onset AD, with APOEɛ4 increasing risk, APOEɛ3 being neutral, and APOEɛ2 reducing risk. Several modifiable lifestyle factors have been studied in terms of how they can modify the risk of AD. Among these factors are dietary pattern, nutritional supplements such as omega-3 fatty acids, and B vitamins, physical exercise, and obesity, and vitamin D. The Western diet increases risk of AD, while dietary patterns such as the Mediterranean and vegetarian/vegan diets reduce risk. Foods associated with reduced risk include coffee, fruits and vegetables, whole grains and legumes, and fish, while meat and ultraprocessed foods are associated with increased risk, especially when they lead to obesity. In multi-country ecological studies, the amount of meat in the national diet has the highest correlation with risk of AD. The history of research regarding dietary patterns on risk of AD is emphasized in this review. The risk of AD can be modified starting at least by mid-life. People with greater genetic risk for AD would benefit more by choosing lifestyle factors to reduce and/or delay incidence of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. Objective: We investigated genetic heterogeneity in AD risk through a multi-step analysis. Methods: We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. Results: PCA revealed three distinct clusters ("constellations") driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. Conclusions: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Non-celiac wheat sensitivity (NCWS) is an emerging clinical condition characterized by gastrointestinal and extraintestinal symptoms following the ingestion of gluten-containing foods in patients without celiac disease (CD) or wheat allergy. Despite the great interest for NCWS, the genetic risk factors still need to be fully clarified. In this study, we first assessed the possible contribution of KIR genes and KIR haplotypes on the genetic predisposition to NCWS. Fifty patients with NCWS, 50 patients with CD, and 50 healthy controls (HC) were included in this study. KIR genes and KIR genotyping were investigated in all subjects by polymerase chain reaction with the sequence oligonucleotide probe (PCR-SSOP) method using Luminex technology. We found a statistically different distribution of some KIR genes among NCWS, CD, and HC. Specifically, NCWS showed a decreased frequency of KIR2DL1, −2DL3, −2DL5, −2DS2, −2DS3, −2DS4, −2DS5, and −3DS1 genes, and an increased frequency of -3DL1 gene respect to both CD and HC. No difference was detected in the KIR haplotype expression. At the multivariate analysis, KIR2DL5, −2DS4, and −2DS5 were independent predictors of NCWS. Our findings suggest a role of KIR genes in NCWS susceptibility, with KIR2DL5, −2DS4, and −2DS5 having a protective effect. Further large-scale multicentric studies are required to validate these preliminary findings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] Systematic evaluation of polygenic scoring methods in 1.2 million individuals across five biobanks finds that no single method performs best. Performance varied more between biobanks than between methods, suggesting that future research should address between-biobank variability. Ensembles provided high, robust, and transferable performance. Workflow and results browser are open source. [ABSTRACT FROM AUTHOR]

Acute disseminated encephalomyelitis (ADEM) is a common phenotype in children with myelin oligodendrocyte glycoprotein IgG (MOG-IgG)-associated disease. We aimed to identify novel genetic variants that distinguish children with MOG-IgG-positive ADEM (MOG-IgG+ ADEM) from children with MOG-IgG-negative ADEM (MOG-IgG− ADEM) using whole exome sequencing (WES) analysis. We conducted a two-stage study design. First, we performed WES on five patients with MOG-IgG+ ADEM and five patients with MOG-IgG− ADEM. Following bioinformatics analysis, the candidate variant list was constructed. Second, 29 children with MOG-IgG+ ADEM and 27 children with MOG-IgG− ADEM, together with discovery cohort, were genotyped to identify the novel variants. WES resulted in 33,999 variants, and 5388 nonsynonymous variants were selected for downstream analysis. In total, 118 protein-affecting variants that were significantly different between the two groups were identified. Together with the five variants extracted from the literature, 49 variants were selected as the candidate variant list for genotyping in the replication cohort. Finally, we identified three variants: rs11171951 in NACα , rs231775 in CTLA4, and rs11171951 in GOLGA5 , which were significantly different between MOG-IgG+ ADEM and MOG-IgG− ADEM. Only rs12440118 in NACα remained significant after Bonferroni correction for multiple testing (P adj < 0.001). We identified strong associations between NACα, CTLA4, and GOLGA5 variants and MOG-IgG+ ADEM in a Han Chinese population of Northern China, which may present novel genetic risk factor distinguishing patients with MOG-IgG+ ADEM from those with MOG-IgG− ADEM. [ABSTRACT FROM AUTHOR]

Several characteristics distinguish lung cancer in female patients from that in male patients, with adenocarcinoma being more prevalent in female patients and occurring more frequently in female patients who do not smoke. Uncertainty surrounds the relationship between female-specific reproductive factors and lung cancer risk. Are sex-specific reproductive factors associated with risk of lung cancer in different genetic risk groups and histologic types? A Cox proportional hazard model was used to evaluate the association between multiple reproductive factors and the risk of lung cancer developing in a prospective cohort study involving 273,190 female individuals from the UK Biobank. Subgroup analyses stratified by age, smoking status, BMI, genetic risk, and histologic subtype were conducted to emphasize the modification effects further. A total of 1,182 cases of lung cancer in female patients were recorded over a median follow-up period of 12.0 years in the cohort study. In multivariable-adjusted models, early menarche (age ≤ 11 years: hazard ratio [HR], 1.22; 95% CI, 1.03-1.46), early menopause (age ≤ 46 years: HR, 1.49; 95% CI, 1.19-1.86), a shorter reproductive span (≤ 32 years: HR, 1.42; 95% CI, 1.18-1.71; and 33-35 years: HR, 1.24; 95% CI, 1.00-1.53), and early age at first birth (age ≤ 20 years: HR, 1.63; 95% CI, 1.33-2.01) were associated with a higher risk of lung cancer. Stratified analysis revealed that several reproductive factors, including early age at menopause, shortened reproductive span, and early age at first birth, showed a substantially stronger relationship with an elevated risk of lung cancer, particularly of lung adenocarcinoma, in populations with high genetic risk and more detrimental behaviors. Early age at menopause, a shortened reproductive life span, and early age at first birth were associated with higher risks of lung cancer, particularly of lung adenocarcinoma, in a subpopulation with higher genetic susceptibility and detrimental behaviors. The evidence provided by this study emphasizes the significance of screening for multiple reproductive factors to prevent lung cancer among female individuals. [Display omitted] [ABSTRACT FROM AUTHOR]

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 (rE = −.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. [ABSTRACT FROM AUTHOR]

Abstract 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 (

Abstract 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.

Abstract 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.

Abstract 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

Abstract 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.

Indices of cumulative risk (CR) have long been used in developmental research to encode the number of risk factors a child or adolescent experiences that may impede optimal developmental outcomes. Initial contributions concentrated on indices of cumulative environmental risk; more recently, indices of cumulative genetic risk have been employed. In this article, regression analytic methods are proposed for interrogating strongly the validity of risk indices by testing optimality of compositing weights, enabling more informative modeling of effects of CR indices. Reanalyses of data from two studies are reported. One study involved 10 environmental risk factors predicting Verbal IQ in 215 four-year-old children. The second study included an index of genetic CR in a G×E interaction investigation of 281 target participants assessed at age 15 years and then again at age 31 years for observed hostility during videotaped interactions with close family relations. Principles to guide evaluation of results of statistical modeling are presented, and implications of results for research and theory are discussed. The ultimate goals of this paper are to develop stronger tests of conjectures involving CR indices and to promote methods for improving replicability of results across studies.

Abstract Background Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP and NfL levels are elevated in the pre-clinical phase of Alzheimer’s disease (AD) and dementia. However, the predictive value of GFAP and NfL for dementia requires more evidence from population-based cohorts. Methods This was a prospective cohort study to evaluate UK Biobank participants enrolled from 2006 to 2010 using plasma GFAP and NfL measurements measured by Olink Target Platform and prospectively followed up for dementia diagnosis. Primary outcome was the risk of clinical diagnosed dementia. Secondary outcomes were cognition. Linear regression was used to assess the associations between peripheral GFAP and NfL with cognition. Cox proportional hazard models with cross-validations were used to estimate associations between elevated GFAP and NfL with risk of dementia. All models were adjusted for covariates. Results A subsample of 48,542 participants in the UK Biobank with peripheral GFAP and NfL measurements were evaluated. With an average follow-up of 13.18 ± 2.42 years, 1312 new all-cause dementia cases were identified. Peripheral GFAP and NfL increased up to 15 years before dementia diagnosis was made. After strictly adjusting for confounders, increment in NfL was found to be associated with decreased numeric memory and prolonged reaction time. A greater annualized rate of change in GFAP was significantly associated with faster global cognitive decline. Elevation of GFAP (hazard ratio (HR) ranges from 2.25 to 3.15) and NfL (HR ranges from 1.98 to 4.23) increased the risk for several types of dementia. GFAP and NfL significantly improved the predictive values for dementia using previous models (area under the curve (AUC) ranges from 0.80 to 0.89, C-index ranges from 0.86 to 0.91). The AD genetic risk score and number of APOE*E4 alleles strongly correlated with GFAP and NfL levels. Conclusions These results suggest that peripheral GFAP and NfL are potential biomarkers for the early diagnosis of dementia. In addition, anti-inflammatory therapies in the initial stages of dementia may have potential benefits.

While major depression has been linked to changes in white matter architecture, it remains unclear whether risk factors for depression are directly associated with these alterations. We reexamined white matter fiber tracts in individuals with depressive symptoms and investigated the connection between genetic and environmental risk for depression and structural changes in the brain. We included 19,183 participants from the UK Biobank imaging cohort, with depression status and adverse life experience based on questionnaire data and genetic liability for depression quantified by polygenic scores. The integrity of 27 white matter tracts was assessed using mean fractional anisotropy derived from diffusion magnetic resonance imaging. White matter integrity was reduced, particularly in thalamic and intracortical fiber tracts, in individuals with depressive symptoms, independent of current symptom status. In a group of healthy individuals without depression, increasing genetic risk and increasing environmental risk were associated with reduced integrity in relevant fiber tracts, particularly in thalamic radiations. This association was stronger than expected based on statistical dependencies between samples, as confirmed by subsequent in silico simulations and permutation tests. White matter alterations in thalamic and association tracts are associated with depressive symptoms and genetic risk for depression in unaffected individuals, suggesting an intermediate phenotype at the brain level. [ABSTRACT FROM AUTHOR]

Genetic factors and night shift work both contribute to the risk of depression, but whether the association of night shift work with depression varies by genetic predisposition remains unclear. To assess whether night shift work is associated with a higher risk of depression regardless of genetic predisposition. We used data from the UK biobank of 247,828 adults aged 38–71 free of depression at baseline from March 13, 2006, to October 1, 2010. Genetic predisposition to depression was assessed using polygenic risk scores (PRS) weighted sums of genetic variant indicator variables and classified as low (lowest tertile), intermediate (tertile 2), and high (highest tertile). Night shift work exposures were collected using a touchscreen questionnaire and were divided into four categories. After a median follow-up of 12.7 years, 7315 participants developed depression. Compared with day workers, HRs (95 % CIs) of depression were 1.28 (1.19–1.38) for shift work, but never or rarely night shifts, 1.32 (1.20–1.45) for irregular night shifts, and 1.20 (1.07–1.34) for permanent night shifts. Considering lifetime employment and compared with never shift workers, >8 nights/month (HR: 1.40; 95 % CI: 1.19–1.66) and <10 years (HR: 1.30; 95 % CI: 1.09–1.54) of night shift work were associated with a higher risk of depression. In joint effect analyses, compared to participants with low genetic predisposition and day workers, the HRs (95 % CIs) of depression were 1.49 (1.32–1.69) in those with high genetic predisposition and shift work, but never or rarely night shifts, and 1.36 (1.20–1.55) for those with high genetic predisposition and irregular/permanent night shifts. In addition, there was neither multiplicative nor additive interaction between genetic predisposition and night shift work on the risk of depression. Night shift work was associated with an increased risk of depression regardless of genetic risk. • It remains unclear whether genetic risk modifies the association between night shift work and depression. • We investigated the association between night shift work with the risk of depression, and whether modified by genetic predisposition. • Rotating night shift work was associated with an increased risk of depression than day work regardless of genetic risk. • Modifying shift work schedules could be a promising preventive intervention to reduce the risk of developing depression. [ABSTRACT FROM AUTHOR]

Background: Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP and NfL levels are elevated in the pre-clinical phase of Alzheimer's disease (AD) and dementia. However, the predictive value of GFAP and NfL for dementia requires more evidence from population-based cohorts. Methods: This was a prospective cohort study to evaluate UK Biobank participants enrolled from 2006 to 2010 using plasma GFAP and NfL measurements measured by Olink Target Platform and prospectively followed up for dementia diagnosis. Primary outcome was the risk of clinical diagnosed dementia. Secondary outcomes were cognition. Linear regression was used to assess the associations between peripheral GFAP and NfL with cognition. Cox proportional hazard models with cross-validations were used to estimate associations between elevated GFAP and NfL with risk of dementia. All models were adjusted for covariates. Results: A subsample of 48,542 participants in the UK Biobank with peripheral GFAP and NfL measurements were evaluated. With an average follow-up of 13.18 ± 2.42 years, 1312 new all-cause dementia cases were identified. Peripheral GFAP and NfL increased up to 15 years before dementia diagnosis was made. After strictly adjusting for confounders, increment in NfL was found to be associated with decreased numeric memory and prolonged reaction time. A greater annualized rate of change in GFAP was significantly associated with faster global cognitive decline. Elevation of GFAP (hazard ratio (HR) ranges from 2.25 to 3.15) and NfL (HR ranges from 1.98 to 4.23) increased the risk for several types of dementia. GFAP and NfL significantly improved the predictive values for dementia using previous models (area under the curve (AUC) ranges from 0.80 to 0.89, C-index ranges from 0.86 to 0.91). The AD genetic risk score and number of APOE*E4 alleles strongly correlated with GFAP and NfL levels. Conclusions: These results suggest that peripheral GFAP and NfL are potential biomarkers for the early diagnosis of dementia. In addition, anti-inflammatory therapies in the initial stages of dementia may have potential benefits. [ABSTRACT FROM AUTHOR]

Despite differences in prostate cancer risk across ancestry groups, relative performance of prostate cancer genetic risks scores (GRS) for positive biopsy prediction in different ancestry groups is unknown. This cross-sectional retrospective analysis examines the association between a polygenic hazard score (PHS290) and risk of prostate cancer diagnosis upon first biopsy in male veterans using 2-sided tests. Our analysis included 36 717 veterans (10 297 of African ancestry). Unadjusted rates of positive first prostate biopsy increased with higher genetic risk (low risk: 34%, high risk: 58%; P  < .001). Among men of African ancestry, higher genetic risk was associated with increased prostate cancer detection on first biopsy (odds ratio = 2.18, 95% confidence interval = 1.93 to 2.47), but the effect was stronger among men of European descent (odds ratio = 3.89, 95% confidence interval = 3.62 to 4.18). These findings suggest that incorporating genetic risk into prediction models could better personalize biopsy decisions, although further study is needed to achieve equitable genetic risk stratification among ancestry groups. [ABSTRACT FROM AUTHOR]

Hypertension is a leading risk factor for cardiovascular disease and is modulated by genetic variants. This study aimed to assess the effect of obesity genetic liability and physical activity on hypertension among European and African ancestry individuals within the UK Biobank (UKB). Participants were 230 115 individuals of European ancestry and 3239 individuals of African ancestry from UKB. Genetic liability for obesity were estimated using previously published data including genetic variants and effect sizes for body mass index (BMI), waist‐hip ratio (WHR) and waist circumference (WC) using Plink software. The outcome was defined as stage 2 hypertension (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of anti‐hypertensive medications). The association between obesity genetic liability and the outcome was assessed across categories of self‐reported physical activity using logistic regression. Among European ancestry participants, there was up to a 1.2 greater odds of hypertension in individuals with high genetic liability and low physical activity compared to individuals with low genetic liability and high physical activity (p < 0.001). In individuals engaging in low levels of physical activity compared with moderate/high physical activity, the effect of BMI genetic liability on hypertension was greater (pinteraction = 0.04). There was no evidence of an association between obesity genetic liability and hypertension in individuals of African ancestry in the whole sample or within separate physical activity groups (p > 0.05). This study suggests that higher physical activity levels are associated with lower odds of stage 2 hypertension among European ancestry individuals who carry high genetic liability for obesity. This cannot be inferred for individuals of African ancestry, possibly due to the low African ancestry sample size within the UKB. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) commonly precedes the initial onset of mania in youth with familial risk for bipolar disorder (BD). Although ADHD youth with and without BD familial risk exhibit different clinical features, associated neuropathophysiological mechanisms remain poorly understood. This study aimed to identify brain functional network abnormalities associated with ADHD in youth with and without familial risk for BD. Resting-state functional magnetic resonance imaging scans were acquired from 37 ADHD youth with a family history of BD (high-risk), 45 ADHD youth without a family history of BD (low-risk), and 32 healthy controls (HC). Individual whole-brain functional networks were constructed, and graph theory analysis was applied to estimate network topological metrics. Topological metrics, including network efficiency, small-worldness and nodal centrality, were compared across groups, and associations between topological metrics and clinical ratings were evaluated. Compared to HC, low-risk ADHD youth exhibited weaker global integration (i.e., decreased global efficiency and increased characteristic path length), while high-risk ADHD youth showed a disruption of localized network components with decreased frontoparietal and frontolimbic connectivity. Common topological deficits were observed in the medial superior frontal gyrus between low- and high-risk ADHD. Distinct network deficits were found in the inferior parietal lobule and corticostriatal circuitry. Associations between global topological metrics and externalizing symptoms differed significantly between the two ADHD groups. Different patterns of functional network topological abnormalities were found in high- as compared to low-risk ADHD, suggesting that ADHD in youth with BD familial risk may represent a phenotype that is different from ADHD alone. [ABSTRACT FROM AUTHOR]

Introduction: The Interpersonal‐Psychological Theory of Suicide proposes that capability for suicide is acquired through exposure to painful and provocative events (PPEs). Although there is robust evidence for a positive association between aggregate measures of PPEs and risk for suicidal behavior, little is known about the contributions of physical injuries. The present study investigated the relationship between injuries and risk of subsequent suicide attempt (SA). Methods: Data were from Swedish population‐based registers. All individuals born in Sweden between 1970 and 1990 were included (N = 1,011,725 females and 1,067,709 males). We used Cox regression models to test associations between 10 types of injuries (eye injury; fracture; dislocation/sprain/strain; injury to nerves and spinal cord; injury to blood vessels; intracranial injury; crushing injury; internal injury; traumatic amputation; and other or unspecified injuries) and risk for later SA. Analyses were stratified by sex and adjusted for year of birth and parental education. Additional models tested for differences in the pattern of associations based on age group and genetic liability for SA. In co‐relative models, we tested the association between each injury type and risk for SA in relative pairs of varying genetic relatedness to control for unmeasured familial confounders. Results: All 10 injury types were associated with elevated risk for SA (hazard ratios [HRs] = 1.2–7.0). Associations were stronger in the first year following an injury (HRs = 1.8–7.0), but HRs remained above 1 more than 1 year after injury exposure (HRs = 1.2–2.6). The strength of associations varied across injury type, sex, age, and genetic liability for SA. For example, the magnitude of the association between crushing injury and risk for SA was larger in females than males, whereas other injuries showed a similar pattern of associations across sex. Moreover, there was evidence to support positive additive interaction effects between several injury types and aggregate genetic liability for SA (relative excess risk due to interaction [RERI] = 0.1–0.3), but the majority of these interactions became non‐significant or changed direction after accounting for comorbid psychiatric and substance use disorders. In co‐relative models, the pattern of associations differed by injury type, such that there was evidence to support a potential causal effect of eye injury, fracture, dislocation/sprain/strain, intracranial injury, and other and unspecified injuries on risk for SA. For the remaining injury types, HRs were not significantly different from 1 in monozygotic twins, which is consistent with confounding by familial factors. Conclusions: Injuries are associated with increased risk for subsequent SA, particularly in the first year following an injury. While genetic and familial environmental factors may partly explain these associations, there is also evidence to support a potential causal effect of several injury types on future risk for SA. [ABSTRACT FROM AUTHOR]

Little is known about the role that combined sleep behaviors play in the association with chronic liver disease (CLD) risk. We included 408,560 participants initially free of CLD from the UK Biobank. A healthy sleep pattern was defined by early chronotype, sleep duration of 7–8 h/day, no insomnia, no snoring, and no excessive daytime sleepiness. Cox regression models were used to examine the association of healthy sleep pattern with incident CLD and their interaction with PNPLA3 genetic risk. During a median 12.5 years of follow-up, we documented 10,915 incident all-cause CLD cases, including 388 viral hepatitis, 4782 non-alcoholic fatty liver disease (NAFLD), 1356 cirrhosis, 973 alcoholic liver disease, and 725 liver cancer cases. Compared to participants with a healthy sleep score of 0–1, the hazard ratio (HR) (95 % confidence interval [CI]) for those with a sleep score of 5 was 0.54 (0.49, 0.60) for CLD, 0.52 (0.30, 0.90) for viral hepatitis, 0.47 (0.41, 0.55) for NAFLD, 0.57 (0.43, 0.75) for cirrhosis, 0.32 (0.23, 0.44) for alcoholic liver disease, and 0.53 (0.37, 0.77) for liver cancer. Healthy sleep pattern and PNPLA3 genetic risk exerted significant additive effects on CLD risk (relative excess risk due to the interaction: 0.05; attributable proportion due to the interaction: 13 %). Measurement error was unavoidable for self-reported data on sleep behaviors. Our analyses provide evidence that healthy sleep pattern was inversely associated with the development of CLD, and participants with higher genetic risk were more likely to develop CLD when exposed to the unhealthy sleep pattern. • Adherence to a healthy sleep pattern was associated with a reduced risk of chronic liver diseases. • Healthy sleep pattern and genetic predisposition may synergistically influence the risks of chronic liver diseases. • Our findings underscore the importance of extensive intervention targeting sleep behaviors should be undertaken to reduce the risk of chronic liver diseases. [ABSTRACT FROM AUTHOR]

Background & Aims: Previous studies have suggested an increased risk of major adverse liver outcomes (MALO) in relatives of patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). However, granular and longitudinal evidence is lacking on the future risk of MALO among family members of individuals with MASLD. Methods: We identified 3526 first‐degree relatives (FDRs) and 11 079 general population comparators to 1328 patients with MASLD diagnosed between 1974 and 2021, with detailed clinical data, including liver histology in 71% of patients. MALO was defined through diagnostic coding for cirrhosis or its complications. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MALO among FDRs compared to general population comparators. Cumulative incidence accounting for competing risks was calculated. Results: During a median follow‐up of 13.4 years, there were 65 (2%, 1.12/1000 person‐years) and 225 (2%, 1.26/1000 person‐years) MALO events in FDRs and general population comparators respectively. After adjusting for demographic factors and comorbidities, FDRs were at no increased risk of MALO (aHR = 0.99, 95% CI: 0.74–1.33). Increased relative rates of MALOs were, however, observed in some subgroups, including parents, although absolute risk estimates were low and comparable to the general population. Conclusions: FDRs of patients with MASLD did not have a higher rate of incident MALO than the general population. Since the absolute risk of MALO in relatives of patients with MASLD was low, these results do not support systematic screening of MASLD‐related fibrosis in relatives of patients with MASLD. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer in women and has been associated with genetic and environmental factors. New developments have led to the creation of genetic risk scores which seek to better approximate an individual's risk of developing cancer and to be used clinically to improve cancer screening. Previous studies have shown that these risk scores can be used to determine an individual's cancer risk, but replication in independent groups is limited. In addition, certain genotyping methods utilize a process called imputation, which has the potential to make polygenic risk scores less accurate. This work aims to validate two breast cancer polygenic risk scores and to interrogate the impact imputation has on their values to improve their clinical utility. Breast cancer (BC) is a complex disease affecting one in eight women in the USA. Advances in population genomics have led to the development of polygenic risk scores (PRSs) with the potential to augment current risk models, but replication is often limited. We evaluated 2 robust PRSs with 313 and 3820 SNPs and the effects of multiple genotype imputation replications in BC cases and control populations. Biological samples from BC cases and cancer-free controls were drawn from three European ancestry cohorts. Genotyping on the Illumina Global Screening Array was followed by stringent quality control measures and 20 genotype imputation replications. A total of 468 unrelated cases and 4337 controls were scored, revealing significant differences in mean PRS percentiles between cases and controls (p < 0.001) for both SNP sets (313-SNP PRS: 52.81 and 48.07; 3820-SNP PRS: 55.45 and 49.81), with receiver operating characteristic curve analysis showing area under the curve values of 0.596 and 0.603 for the 313-SNP and 3820-SNP PRS, respectively. PRS fluctuations (from ~2–3% up to 9%) emerged across imputation iterations. Our study robustly reaffirms the predictive capacity of PRSs for BC by replicating their performance in an independent BC population and showcases the need to average imputed scores for reliable outcomes. [ABSTRACT FROM AUTHOR]

Response inhibition is a core cognitive impairment in bipolar disorder (BD), leading to increased impulsivity in BD. However, the relationship between the neural mechanisms underlying impaired response inhibition and impulsivity in BD is not yet clear. Individuals who are genetically predisposed to BD give a way of identifying potential endophenotypes. A total of 97 participants, including 39 patients with BD, 22 unaffected relatives (UR) of patients with BD, and 36 healthy controls performed a Go/No-Go task during magnetoencephalography. We carried out time-frequency and connectivity analysis on MEG data. Decreased beta power, prolonged latency and increased peak frequency in rIFG, decreased beta power in pre-SMA and reduced rIFG-to-pre-SMA connectivity were found in BD relative to healthy controls. In the UR group, we found a decrease in the beta power of pre-SMA and prolonged latency of rIFG. Furthermore, increased motor impulsiveness in BD was related to abnormal alterations in beta oscillatory activity of rIFG and functional connectivity between rIFG and pre-SMA. Hypoactivity activity in rIFG and impaired dominant role of rIFG in the prefrontal control network may underlie the neuropathology of response inhibition dysfunction, resulting increased motor impulsivity in BD. Our findings point to measuring rIFG dysfunction as a potential means of identifying individuals at genetic high risk for transition to BD disease expression. • Reduced pre-SMA activation and prolonged rIFG activation relate to genetic risk of BD. • Blunted activation in rIFG and attenuated connectivity from rIFG to pre-SMA reflect disease expression for BD. • Hypofunction in rIFG and disconnectivity with pre-SMA during response inhibition are associated with motor impulsivity in BD. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) has a known neurodevelopmental etiology, but limited access to human prenatal brain tissue hampers the investigation of basic disease mechanisms in early brain development. Here, we elucidate the molecular mechanisms contributing to SCZ risk in a disease-relevant model of the prenatal human brain. We generated induced pluripotent stem cell–derived organoids, termed human cortical spheroids (hCSs), from a large, genetically stratified sample of 14 SCZ cases and 14 age- and sex-matched controls. The hCSs were differentiated for 150 days, and comprehensive molecular characterization across 4 time points was carried out. The transcriptional and cellular architecture of hCSs closely resembled that of fetal brain tissue at 10 to 24 postconception weeks, showing strongest spatial overlap with frontal regions of the cerebral cortex. A total of 3520 genes were differentially modulated between SCZ and control hCSs across organoid maturation, displaying a significant contribution of genetic loading, an overrepresentation of risk genes for autism spectrum disorder and SCZ, and the strongest enrichment for axonal processes in all hCS stages. The two axon guidance genes SEMA7A and SEMA5A , the first a promoter of synaptic functions and the second a repressor, were downregulated and upregulated, respectively, in SCZ hCSs. This expression pattern was confirmed at the protein level and replicated in a large postmortem sample. Applying a disease-relevant model of the developing fetal brain, we identified consistent dysregulation of axonal genes as an early risk factor for SCZ, providing novel insights into the effects of genetic predisposition on the neurodevelopmental origins of the disorder. [ABSTRACT FROM AUTHOR]

Background: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life‐limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. Methods: We undertook a UK‐based interview study with 35 individuals, including: 7 people living with genetically‐mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. Results: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open‐ended, tailored support and information provision. Conclusions: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken‐for‐granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public‐facing resource on the healthtalk.org website. Patient or Public Contribution: People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel. [ABSTRACT FROM AUTHOR]

The objective was to examine the impacts of duration of preadoption out-of-home care and adoptive family functioning on later psychiatric morbidity of adoptees with high (HR) and low (LR) genetic risk for schizophrenia spectrum disorders. The study uses nationwide data from the Finnish Adoptive Family Study of Schizophrenia. The study population in this substudy consisted of 43 h adoptees and 128 LR adoptees. Of these adoptees, 90 had spent 0–6 months and 81 over 6 months in preadoption out-of-home care. The family functioning of adoptive families was assessed based on Global Family Ratings and psychiatric disorders on DSM-III-R criteria. The results showed that among the adoptees with over 6 months in preadoption out-of-home care, the likelihood for psychiatric disorders was significantly increased in HR adoptees compared to LR adoptees. In adoptees with 6 months or less in preadoption out-of-home care, an increased likelihood for psychiatric disorders was found among those living in adoptive families with dysfunctional processes. These findings indicate that especially for HR children, a well-functioning early caregiving environment is crucial in terms of subsequent mental wellbeing. The results emphasize that when adoption is necessary, early placement and well-functioning adoptive family environment are beneficial to children. [ABSTRACT FROM AUTHOR]

Background: Lipedema is a progressive condition involving excessive deposition of subcutaneous adipose tissue, predominantly in the lower limbs, which severely compromises quality of life. Despite the impact of lipedema, its molecular and genetic bases are poorly understood, making diagnosis and treatment difficult. Historical evaluation of individuals with lipedema indicates a positive family history in 60%–80% of cases; however, genetic investigation of larger family cohorts is required. Here, we report the largest family-based sequencing study to date, aimed at identifying genetic changes that contribute to lipedema. Methods and Results: DNA samples from 31 individuals from 9 lipedema families were analyzed to reveal genetic variants predicted to alter protein function, yielding candidate variants in 469 genes. We did not identify any individual genes that contained likely disease-causing variants across all participating families. However, gene ontology analysis highlighted vasopressin receptor activity, microfibril binding, and patched binding as statistically significantly overrepresented categories for the set of candidate variants. Conclusions: Our study suggests that lipedema is not caused by a single exomic genetic factor, providing support for the hypothesis of genetic heterogeneity in the etiology of lipedema. As the largest study of its kind in the lipedema field, the results advance our understanding of the disease and provide a roadmap for future research aimed at improving the lives of those affected by lipedema. [ABSTRACT FROM AUTHOR]

Background Models with polygenic risk scores and clinical factors to predict risk of different cancers have been developed, but these models have been limited by the polygenic risk score–derivation methods and the incomplete selection of clinical variables. Methods We used UK Biobank to train the best polygenic risk scores for 8 cancers (bladder, breast, colorectal, kidney, lung, ovarian, pancreatic, and prostate cancers) and select relevant clinical variables from 733 baseline traits through extreme gradient boosting (XGBoost). Combining polygenic risk scores and clinical variables, we developed Cox proportional hazards models for risk prediction in these cancers. Results Our models achieved high prediction accuracy for 8 cancers, with areas under the curve ranging from 0.618 (95% confidence interval = 0.581 to 0.655) for ovarian cancer to 0.831 (95% confidence interval = 0.817 to 0.845) for lung cancer. Additionally, our models could identify individuals at a high risk for developing cancer. For example, the risk of breast cancer for individuals in the top 5% score quantile was nearly 13 times greater than for individuals in the lowest 10%. Furthermore, we observed a higher proportion of individuals with high polygenic risk scores in the early-onset group but a higher proportion of individuals at high clinical risk in the late-onset group. Conclusion Our models demonstrated the potential to predict cancer risk and identify high-risk individuals with great generalizability to different cancers. Our findings suggested that the polygenic risk score model is more predictive for the cancer risk of early-onset patients than for late-onset patients, while the clinical risk model is more predictive for late-onset patients. Meanwhile, combining polygenic risk scores and clinical risk factors has overall better predictive performance than using polygenic risk scores or clinical risk factors alone. [ABSTRACT FROM AUTHOR]

BackgroundAdiposity amplifies the genetic risk of non-alcoholic fatty liver disease (NAFLD).AimWe evaluated the association between overweight-years, a cumulative exposure based on the product of the duration and severity of excess body weight (body mass index (BMI) ≥ 25 kg/m2 ), and genetic risk on liver fat and fibrosis.MethodsThis is a longitudinal analysis derived from a prospective cohort of adults in the Framingham Heart Study who underwent genotyping and vibration-controlled-transient-elastography with controlled attenuation parameter. Univariable and multivariable linear and logistic regression analyses were used to assess the association between overweight-years and liver fat and fibrosis. The association between genetic variants of liver fat (PNPLA3, TM6SF2, GCKR) and fibrosis (PNPLA3, TM6SF2, HSD17B13) was also assessed using a polygenic risk score.ResultsOur sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m2 , respectively. The mean follow-up was 14(±0.9) years, and each participant underwent three study visits. The prevalence of NAFLD was 28.3% (n = 700), and 207 (8.4%) had clinically significant fibrosis. In age-, sex- and diabetes-adjusted multivariable analyses, overweight-years (per SD) had a strong association with NAFLD (aOR 3.53 [95% CI: 3.10-4.02], p

BackgroundLRRK2 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.MethodsWe 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.ResultsMS 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.DiscussionThe 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.

Summary: 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 (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.

The article discusses the increased risk of mental health problems in children born to parents with a mental illness. A comprehensive meta-analysis of data from around the world confirms this increased risk. However, not all children with a genetic predisposition for mental illness develop problems. The study also explores the impact of parental diagnoses on various outcomes, including criminality, suicide, and psychosocial functioning. The findings highlight the importance of understanding and addressing the transgenerational transmission of risk in families affected by mental illness. The article emphasizes the need for preventive strategies and early interventions to support these children. It also acknowledges the impact of mental illness on family life and the importance of providing support and resources for parents. The article concludes by discussing the positive developments in research and awareness of the challenges faced by these families and the potential for interventions to reduce risk and promote resilience. [Extracted from the article]