Anhedonia is an important symptom in major mental disorders and is difficult to address due to a limited understanding of its neurobiological and genetic underpinnings. Here, we investigated the effect of a polygenic risk score (PRS) for anhedonia on brain activation during a well-established monetary incentive delay (MID) task, while performing functional magnetic resonance imaging. We derived an anhedonia PRS from a large genome wide analysis (n=375,275) in our sample of 517 subjects. This sample consisted of four subgroups (healthy controls (n=373), major depressive disorder (n=57), schizophrenia (n=39) and bipolar disorder (n=48)). We tested for correlation between the individual PRS and brain activation during reward and during loss anticipation and feedback. Additionally, we analysed the correlation between PRS and structural volume size of three reward-related brain areas as well as between PRS and anhedonia scores. We showed that increased PRS was associated with decreased activation in bilateral putamen and left middle frontal gyrus during anticipation and decreased activation in the right caudate during feedback across all subgroups. Moreover, a higher PRS was also correlated with lower activation in left middle frontal gyrus during loss anticipation and salience processing. During loss feedback, higher PRS was correlated with hyperactivity of bilateral putamen and right caudate. No significant correlation was found between PRS and brain volume or anhedonia scores. Our results highlight the importance of the striatum and prefrontal cortex in the context of a genetic risk for anhedonia.

Type 1 diabetes (T1D) exhibits sex differences in genetic risk, yet most genetic studies treat sex as a covariate rather than a modifier of risk. We hypothesized that sex-stratified genome-wide association studies (GWAS) would uncover sex-specific genetic architecture and improve risk prediction. We performed GWAS in 6,599 T1D cases (3,483 males, 3,109 females, 7 undetermined) and 12,350 controls (6,665 males, 5,658 females, 27 undetermined) of European ancestry, testing additive models and sex-stratified analyses. For mechanistic insights, we performed scRNA-seq of PBMCs from nine matched male-female pediatric pairs. Finally, we tested male-, female-, and standard polygenic risk scores (PRS) in an independent cohort (471 T1D cases, 2,300 controls). Sex-stratified analyses identified 215 genome wide significant SNPs (P<5x10-8) with heterogeneity: 119 male-specific and 94 female-specific. Integration of scRNA-seq data revealed 41 sex-specific T1D genes with cell type-specific differential expression. In the independent cohort, sex-specific PRS outperformed the combined PRS: in males, AUC=0.668 versus 0.623 (p<2.2x10-16); in females, AUC=0.719 versus 0.635 (p<2.2x10-16). Sex-stratified GWAS reveal novel T1D risk loci influenced by sex. Incorporating sex-specific effect sizes into PRS enhances risk discrimination, underscoring the value of sex-aware genetic analyses for precise prediction of T1D.

Pharmacological treatments for attention-deficit/hyperactivity disorder (ADHD) are efficacious and safe; however, substantial interindividual variability in treatment response persists, with many patients experiencing suboptimal outcomes or early discontinuation. Although genetic factors have been proposed as contributors to this variability, clinically actionable predictors remain elusive. Here, we present the first meta-analysis evaluating whether polygenic liability for ADHD and related psychiatric and behavioral-cognitive phenotypes is associated with clinically meaningful response to methylphenidate in 1000 ADHD cases from Norway, Brazil, and Spain assessed in real-world settings. Polygenic scores (PGS) for ADHD, autism, bipolar disorder, educational attainment, major depressive disorder, neuroticism, and schizophrenia were calculated separately for each cohort. Treatment response was assessed using evaluations of global clinical improvement and harmonized by categorizing individuals as responders or non-responders. Cohort-specific associations were combined using fixed-effects meta-analysis. No PGS showed a significant association with treatment response. Effect sizes were small, consistent across cohorts, and characterized by minimal between-study heterogeneity. Sensitivity analyses incorporating clinical and treatment-related covariates yielded convergent results. As the first meta-analytic evaluation of polygenic predictors evaluating clinically meaningful ADHD stimulant response, these findings delineate the current limits of PGS in pharmacogenomic applications. Rather than supporting immediate clinical utility, our results highlight key methodological and conceptual constraints, including limited sample sizes, heterogeneous outcome definitions, and the indirect nature of susceptibility-based PGS for predicting treatment response. By mapping these boundaries, this study provides a framework to recalibrate research priorities and guide the next generation of ADHD pharmacogenomic studies toward larger, harmonized, and more informative definitions of treatment response.

Polygenic risk scores for pediatric obsessive-compulsive symptoms: Mediating effects in samples clinically diagnosed with mental disorders.

Polygenic modulations of decoy and compromise effects by dopaminergic and serotonergic systems.

Marked comorbidity between mental disorders and immune-mediated inflammatory diseases (IMIDs) suggests a bidirectional interplay, yet most prior work has tackled a single analytic direction, leaving the overall structure of time-ordered associations unclear. Using the large, longitudinal UK Biobank cohort, we fitted Cox proportional-hazards models to quantify bidirectional, time-ordered associations between eight prototypical mental disorders and eight common IMIDs. Genetic susceptibility was quantified with polygenic risk scores (PRSs), and mediation models incorporated systemic inflammatory markers and sleep-quality scores. Baseline mental disorders significantly increased IMID incidence (comorbid mental disorders [CMB]→IMIDs: HR=1.84, 95% CI 1.70-1.99). Major depressive disorder showed the widest range of associations, while post-traumatic stress disorder exhibited the strongest single link, notably with sicca syndrome (HR=5.88, 95% CI 1.47-23.6). Conversely, baseline IMIDs heightened subsequent mental-disorder risk (IMID → CMB: HR=1.54, 95% CI 1.45-1.63). In PRS-stratified analyses, psychiatric disorders (exposure) were more strongly associated with later IMID risk (outcome) in participants with lower versus higher genetic IMID risk. In PRS-based effect-modification analyses, we observed super-additive interaction on the additive scale for several pairs. Mediation analyses suggested that systemic inflammation and sleep disturbance accounted for roughly 2-10% and 7-16% of the associations, respectively. This systematic, bidirectional framework maps a complex interaction network linking IMIDs and mental disorders, jointly mediated by genetic vulnerability, systemic inflammation, and sleep dysregulation. The findings furnish a psychoneuroimmunological basis for integrated preventive and therapeutic strategies.

Residential green space, natural environment, domestic garden, and the risk of Parkinson's disease: A prospective cohort study.

Association between systemic redox balance and osteoporosis: prospective evidence, polygenic modification, and proteomic and inflammatory mediation in the UK Biobank.

Daily coffee drinking and mental health outcomes: Sex differences and the role of caffeine metabolism genotypes.

Genetic liability for schizophrenia has been associated with cognitive deficits and clinical phenotypes during neurodevelopment. However, the possible role of executive function (EF) as a mediator between the polygenic risk score for schizophrenia (PRS-SZ) and subsequent outcomes, including transdiagnostic general psychopathology (the p-factor), has yet to be examined. In this study, we investigated whether EF mediates the effect of PRS-SZ on psychopathology and functional phenotypes in a community-based youth sample. We analyzed cross-sectional data from 698 participants (aged 6-14) of the Brazilian High-Risk Cohort. PRS-SZ was calculated using summary statistics from the Psychiatric Genetics Consortium (PGC-3). EF was assessed through working memory, inhibitory control, and time processing tasks, condensed into a single latent EF trait. Independent linear models were tested to examine direct associations between PRS-SZ and EF, general psychopathology, anxiety symptoms, psychotic experiences (PE), and school performance. Mediation models were applied to evaluate EF as a mediator of the associations between PRS-SZ and each outcome. PRS-SZ predicted lower EF scores (β=-0.091, t=-2.435, p=0.015). No direct associations were found between PRS-SZ and the other measures. EF mediated the association between PRS-SZ and general psychopathology (p-factor) (Effect=0.0079, BootSE=0.0049, LLCI=0.0004, ULCI=0.0191), anxiety symptoms (Effect=0.0075, BootSE=0.0047, LLCI=0.0001, ULCI=0.0182), and school performance (Effect=-0.0167, BootSE=0.0077, LLCI=-0.0327, ULCI=-0.0028), but not PE. PRS-SZ was associated with poorer EF, which in turn mediated its associations with increased general psychopathology (p-factor) and anxiety symptoms, and reduced school performance in this community youth sample. EF may represent a hub through which PRS-SZ contributes to negative behavioral and functional outcomes.

Epidemiologic studies suggest that patients with Parkinson disease (PD) may have lower levels of vitamin B12 compared with healthy controls, and it was proposed that patients with PD could benefit from vitamin B12 supplementation. Functional studies have shown that B12 could modify LRRK2 activity and may directly interact with alpha-synuclein. The aim of this study was to investigate the role of common and rare variants in genes related to B12 metabolism and assess the potential causal relationships between B12 levels and PD risk, age at onset, and motor/cognitive progression. We investigated the association between common and rare variants in genes involved in vitamin B12 metabolism. Rare variants (minor allele frequency <0.01) were analyzed using the optimal sequence kernel association test in 4,815 patients with PD and 65,607 controls from 2 independent cohorts. We constructed pathway-specific polygenic risk scores (PRSs) for genes essential to B12 metabolism and for genes identified in previous genome-wide association studies (GWASs) on B12 metabolism. Mendelian randomization and genetic correlation analyses were applied to explore the relationship between vitamin B12 levels and PD risk, age at onset, and disease progression. Our analysis showed no associations between common variants of genes crucial in B12 metabolism and PD. Pathway PRSs identified nominal association between B12-related genes and PD (odds ratio [OR] = 1.061, 95% CI 1.004-1.121, p = 0.038), which did not survive Bonferroni correction. In the rare-variant analysis, we identified a significant association between variants with high Combined Annotation Dependent Depletion scores in the CUBN gene (p = 6.07E-05; Pfdr = 0.005) in the Accelerating Medicines Partnership-PD cohort, driven by the benign variant p.G3114S (OR = 3.3; p = 3.56E-05); however, this was not validated in the meta-analysis. We did not identify a potentially causal relationship between vitamin B12 levels and the risk, age at onset, or progression of PD. In addition, no genetic correlation was observed between vitamin B12 and PD risk or age-at-onset GWASs. Overall, our analyses indicate lack of genetic link between B12 levels or metabolism and PD.

Hyperuricemia (HUA), a complex metabolic disorder, has shown a continuous increase in global prevalence and a trend toward younger age at onset. Its management strategies now face the key challenge of transitioning from a “one-size-fits-all” approach to precision care tailored to individual needs. This review systematically summarizes the epidemiology, pathogenesis, and limitations of current dietary guidelines for HUA, highlighting that genetic background, gut microbiota, and dietary patterns collectively generate marked inter-individual variability. Medicinal food homologous substances, which regulate uric acid metabolism through multiple targets—by inhibiting xanthine oxidase, modulating uric acid transporters, alleviating inflammation, and reshaping the gut microbiota—have become promising resources for precision intervention. However, their complex composition and heterogeneous responses hinder clinical translation. Artificial intelligence (AI), with its powerful multi-modal data integration and pattern recognition capabilities, offers a novel avenue for constructing a precision intervention system for HUA. We elaborate on AI-enabled risk prediction (polygenic risk scores and machine-learning models), dynamic monitoring (wearable devices coupled with LSTM networks), intelligent TCM (Traditional Chinese Medicine)-syndrome identification, and the development of personalized food recommendation systems (PFRS). By integrating genomics, clinical data, behavioral information, and TCM phenotyping, AI can build an individual “metabolic profile”, realizing a closed loop of full-cycle management from early warning and syndrome discrimination to dynamic generation of personalized diets and medicinal-food recommendations. This paradigm shift from “one-size-fits-all” to “one person, one policy” lays the theoretical foundation for an intelligent, whole-cycle HUA health-management system. Future efforts should focus on multi-center data integration, model validation, and clinical translation.

Both genetic and environmental factors affect human stature, including overall height and familial short stature (FSS), and it is associated with various health outcomes. However, the study of genetic connections between stature and health conditions remains lacking in East Asian populations. Hence, we conducted parallel genome-wide association studies (GWAS) of body height and FSS in the Han Taiwanese population, aiming to elucidate the genetic influences of stature on health and facilitate the formulation of precision-health strategies. We analyzed large-scale GWAS data on adult height (120,301 Han Taiwanese) and FSS (FSS; 2,050 cases, 27,966 controls) to examine cross-trait genetic correlations across five East Asian biobanks, and applied phenome-wide association studies (PheWAS) and polygenic risk score (PRS) analyses to assess clinical outcomes using Cox proportional hazard models and Kaplan-Meier analyses. We identified 293 loci for height and five for FSS, with cross-biobank genetic correlations linking stature to body size, lung function, and cardiovascular/reproductive traits (atrial flutter/fibrillation [AF], menarche, and endometriosis). PheWAS showed that height PRS increased risks of AF and endometriosis, while FSS PRS had a protective effect against endometriosis. MR analyses showed that taller stature increased AF risk independently and endometriosis risk through menarche/weight, while shorter stature had a weak protective effect against endometriosis. Survival analyses showed the association of higher height PRS with greater AF risk and an earlier divergence of cumulative incidence curves. These time-to-event patterns were consistently replicated using meta-analysis-derived PRSs. The findings highlight stature-related genetic determinants, associated health outcomes, and polygenic risk scores as effective tools for early risk prediction and precision health strategies in East Asian populations.

Mild traumatic brain injury (mTBI) disproportionately affects children and adolescents and has been associated with poorer neurocognitive performance, but the biological mechanisms driving symptom variability and severity remain understudied. In accordance with the omnigenic disease model, we integrated gene-by-mTBI interaction genome-wide association studies on neurocognition from the Adolescent Brain Cognitive Development (ABCD) cohort with single-cell RNA sequencing gene regulatory networks to elucidate the cell type-specific key regulators and molecular mechanisms governing neurocognitive outcome of mTBI, specifically learning and memory performance. Our analysis revealed distinct network regulators in neuronal and glial cell types across hippocampal and cortical brain regions to orchestrate key neurodevelopmental pathways. Examples include APP for synaptic signaling in excitatory neurons, COX5A for mitochondrial function in inhibitory neurons, MOG for myelination in oligodendrocytes in the hippocampus; GRM7 for synaptic signaling in excitatory neurons, SV2A for synaptic signaling in inhibitory neurons, and MOG for myelination in oligodendrocytes in the cortex. These mechanisms also associate with learning and memory through pathway-based polygenic risk score modeling in ABCD. Our findings provide brain region- and cell type-specific insights into the complex regulatory network landscape of mTBI pathology and potential therapeutic candidates at the pathway and network levels.

BackgroundHabitual daytime napping is a significant aspect of many older adults' sleep-wake cycle. Growing evidence links napping and cognition in the context of Alzheimer's disease (AD), yet little is known about how genetic risk influences this relationship.ObjectiveThis study investigates interactions between genetic risk for AD and napping on cognition in 1655 cognitively healthy middle-aged to older adults.MethodsCognition was assessed using a self-administered online battery and reduced to three variables: memory, visuospatial abilities and executive functions. Genetic risk was assessed with the presence of APOE ɛ4 allele and polygenic risk scores for AD (PRS; excluding APOE). ANCOVA assessed interactions.ResultsThere was a significant interaction between APOE ɛ4 and napping duration on the memory component (F(2,1645) = 3.84, p = 0.022, ηp2 = 0.005). APOE ɛ4 carriers reporting long naps demonstrated better memory than non-carriers also reporting long naps. Among APOE ɛ4 carriers, those who napped for ≥ 1 h performed better than those reporting shorter naps. In a separate analysis, there was a significant interaction between PRS and napping (F(2653) = 3.44, p = 0.033, ηp2 = 0.010). Low PRS was related to better memory than high PRS among those who did not nap. Within the low PRS group, participants who did not nap outperformed those reporting short naps. Results remained significant after accounting for overnight sleep efficiency.ConclusionsFindings suggest that the relationship between napping and memory may vary as a function of genetic risk for AD. Results could inform studies looking into personalized preventative treatment based on genetic profiles.

Adolescent pain reports share genetic overlap with adult chronic pain conditions: A polygenic score analysis using the ABCD study.

Kidney stone disease (KSD) is heritable and genetic testing is becoming increasingly relevant to its management. However, it is unclear who should be offered genetic testing and what these investigations should entail. This review gives an overview of the existing evidence and future directions. In highly selected cohorts, genetic testing for monogenic disease can yield high diagnostic rates. These diagnoses can facilitate genetic counselling, familial testing, and targeted medical therapies.Our understanding of the role of rare intermediate effect size and common low effect size genetic variants is evolving. The clinical utility of polygenic risk scores and genetic sequencing in unselected cohorts remains uncertain. Genetic testing for monogenic KSD is advised in individuals with a strong family history and with recurrent stones. There is a need for large-scale studies, including in urology settings, to determine optimal criteria for patient selection in real world settings. Further research is required to define the role of genetic testing, including polygenic risk scores, in risk prediction, personalised management, and disease recurrence.

In the present study, the novel family genetic risk score (FGRS) method, a reliable quantification of latent genetic risk, was applied to posttraumatic stress disorder (PTSD) to examine associations between genetic liability and clinical features of PTSD among 3,097,180 individuals in the Swedish national registries. FGRS was calculated based on lifetime PTSD status for first- through fifth-degree relatives and examined both in PTSD cases with any lifetime registration (PTSD total) and in cases with more than one registration (recurrent PTSD) in relation to sex, age at onset (AAO), recurrence, mode of ascertainment (inpatient [IP], outpatient specialty care [SC], primary care [PC]), and comorbidities. Sex differences were not found for recurrent PTSD, but for PTSD total, female registrants had a lower FGRS value compared to male registrants, M = -.017, 95% CI of difference [-.029-.005]. Higher FGRS was found at earlier AAO for PTSD total and recurrent PTSD, ps <.001, and scores were higher among individuals with comorbidities, ps <.001. Higher FGRS was related to the number of PTSD recurrences among both total PTSD and recurrent PTSD, ps <.001 (linear effect). For both PTSD types, FGRS scores were as follows: PC < SC < IP, ps <.001. The findings indicate that genetic risk for PTSD is associated with several clinical features of the disorder, which should be included in future studies of genetic risk for PTSD. Continued investigation of these clinical features in epidemiological and molecular genetic studies of PTSD is warranted to further validate the findings.

Chronotype has been linked to a wide variety of psychiatric conditions. In particular, evening chronotype could be a transdiagnostic risk factor for different mental health difficulties. In this study, we examine how chronotype relates to psychopathology and whether it can be conceptualized as a part of the global construct of psychopathology (p-factor) by studying the genetic and environmental overlap between these variables. We utilize data from a genetically informative design to study: (1) the association between chronotype and psychopathology; (2) the genetic and environmental overlap between chronotype and psychopathology; and (3) the predictive value of polygenic score (PGS) for chronotype for psychopathology. Chronotype was measured using an abbreviated version of the Munich Chronotype Questionnaire. Measures of psychopathology included: depression, anxiety, alcohol use, and psychotic experiences among others. We used different psychopathology and chronotype-related polygenic scores. Association between chronotype and psychopathology were examined with three approaches: (1) phenotypic associations; (2) genetic and environmental associations using the twin design; and (3) genetic associations using PGS. There were small, though largely significant, associations between chronotype and psychopathology with significant genetic and environmental overlap. Chronotype PGS significantly predicted a very small proportion of the variance for some measures of psychopathology (e.g. symptoms of attention deficit hyperactivity disorder). However, overall, our results also suggest that the majority of genetic/environmental influences (96 per cent) on chronotype do not overlap with those on the psychopathology factor. Results from this study highlight existence of significant associations between chronotype and certain psychopathology traits. However, the very small associations do not support the idea that chronotype is a core element of the general "p-factor."

Too little is known about the mood and functioning of older adults at elevated risk for attention deficit/hyperactivity disorder (ADHD). We aimed to examine the clinical characteristics of individuals aged 65 + years with higher polygenic risk scores (PRS) for ADHD. A population-based cohort of 1471 dementia-free adults with median age 72 years. We calculated the ADHD-PRS and examined its cross-sectional associations with Clinical Dementia Rating (CDR), and individual CDR domains, depression and anxiety scores, individual depression symptoms, independence in everyday activities of daily living (ADL) and instrumental ADL (IADL), self-rated health. After adjusting for covariates, a one-unit increase in the ADHD-PRS was significantly associated with mild cognitive impairment (CDR=0.5) in the overall CDR rating and specifically in the memory and judgment/problem-solving domains. Higher ADHD-PRS was also associated with worse self-rated health and greater difficulty independently carrying out ADLs and IADLs. In exploratory item-level analyses, associations with poor appetite and difficulty focusing lost significance after False Discovery Rate (FDR) adjustment. In this population-based sample of older adults, greater genetic risk for ADHD was associated with higher odds of mild cognitive impairment, difficulty with memory and judgment/problem-solving, worse self-rated health, difficulty in performing ADLs and IADLS, poor appetite and difficulty focusing. The presence of these difficulties in an older population highlights a need for greater recognition of the long-term impact of ADHD on cognitive and functional wellbeing across the lifespan.