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A polygenic risk score (PRS) derived from genome-wide association studies of posttraumatic stress disorder (PTSD) may inform risk for this disorder. To date, however, no known study has examined whether social environmental factors such as attachment style may moderate the relation between PRS and PTSD. We evaluated main and interactive effects of PRS and attachment style on PTSD symptoms in a nationally representative sample of trauma-exposed European-American U.S. military veterans (N = 2030). PRS was derived from a genome-wide association study of PTSD re-experiencing symptoms (N = 146,660) in the Million Veteran Program cohort. Using one-sample Mendelian randomization with data from the UK Biobank (N = 115,099), we evaluated the effects of re-experiencing PRS and attachment style on PTSD symptoms. Higher re-experiencing PRS and secure attachment style were independently associated with PTSD symptoms. A significant PRS-by-attachment style interaction was also observed (β = −.11, p =. 006), with a positive association between re-experiencing PRS and PTSD symptoms observed only among veterans with an insecure attachment style. One-sample Mendelian randomization analyses suggested that the association between PTSD symptoms and attachment style is bidirectional. PRS enrichment analyses revealed a significant interaction between attachment style and a variant mapping to the IGSF11 gene (rs151177743, p = 2.1 × 10−7), which is implicated in regulating excitatory synaptic transmission and plasticity. Attachment style may moderate polygenic risk for PTSD symptoms, and a novel locus implicated in synaptic transmission and plasticity may serve as a possible biological mediator of this association. These findings may help inform interpersonally oriented treatments for PTSD for individuals with high polygenic risk for this disorder. [ABSTRACT FROM AUTHOR]

Individuals most often use several rather than one substance among alcohol, cigarettes or cannabis. This widespread co-occurring use of multiple substances is thought to stem from a common liability that is partly genetic in origin. Genetic risk may indirectly contribute to a common liability to substance use through genetically influenced mental health vulnerabilities and individual traits. To test this possibility, we used polygenic scores indexing mental health and individual traits and examined their association with the common versus specific liabilities to substance use. We used data from the Avon Longitudinal Study of Parents and Children (N = 4218) and applied trait-state-occasion models to delineate the common and substance-specific factors based on four classes of substances (alcohol, cigarettes, cannabis and other illicit substances) assessed over time (ages 17, 20 and 22). We generated 18 polygenic scores indexing genetically influenced mental health vulnerabilities and individual traits. In multivariable regression, we then tested the independent contribution of selected polygenic scores to the common and substance-specific factors. Our results implicated several genetically influenced traits and vulnerabilities in the common liability to substance use, most notably risk taking (bstandardised = 0.14; 95% confidence interval [CI] [0.10, 0.17]), followed by extraversion (bstandardised = -0.10; 95% CI [-0.13, -0.06]), and schizophrenia risk (bstandardised = 0.06; 95% CI [0.02, 0.09]). Educational attainment (EA) and body mass index (BMI) had opposite effects on substance-specific liabilities such as cigarette use (bstandardised-EA = -0.15; 95% CI [-0.19, -0.12]; bstandardised-BMI = 0.05; 95% CI [0.02, 0.09]) and alcohol use (bstandardised-EA = 0.07; 95% CI [0.03, 0.11]; bstandardised-BMI = -0.06; 95% CI [-0.10, -0.02]). These findings point towards largely distinct sets of genetic influences on the common versus specific liabilities. [ABSTRACT FROM AUTHOR]

Background: Cannabis use and cannabis use disorder (CUD) is increased in patients with schizophrenia. It is important to establish if this is explained by non-causal factors, such as shared genetic vulnerability. We aimed to investigate whether the polygenic risk scores (PRS) for schizophrenia and other psychiatric disorders would predict CUD in controls, patients with schizophrenia, and patients with other psychiatric disorders. Methods: We linked nationwide Danish registers and genetic information obtained from dried neonatal bloodspots in an observational analysis. We included people with schizophrenia, other psychiatric disorders, and controls. The exposures of interest were the PRS for schizophrenia, attention-deficit hyperactivity disorder (ADHD) autism spectrum disorder, and anorexia nervosa. The main outcome of interest was the diagnosis of CUD. Results: The study included 88 637 individuals. PRS for schizophrenia did not predict CUD in controls [hazard ratio (HR) = 1.16, 95% CI 0.95–1.43 per standard-deviation increase in PRS, or HR = 1.47, 95% CI 0.72–3.00 comparing highest v. remaining decile], but PRS for ADHD did (HR = 1.27, 95% CI 1.08–1.50 per standard-deviation increase, or HR = 2.02, 95% CI 1.27–3.22 for the highest decile of PRS). Among cases with schizophrenia, the PRS for schizophrenia was associated with CUD. While CUD was a strong predictor of schizophrenia (HR = 4.91, 95% CI 4.36–5.53), the inclusion of various PRS did not appreciably alter this association. Conclusion: The PRS for schizophrenia was not associated with CUD in controls or patients with other psychiatric disorders than schizophrenia. This speaks against the hypothesis that shared genetic vulnerability would explain the association between cannabis and schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia is a heritable neurodevelopmental disorder characterized by neuroanatomical changes in the brain, but exactly how increased genetic burden for schizophrenia influences brain structure is unknown. Similarly, how environmental risk factors for schizophrenia impact brain structure is not fully understood. Here we investigated how genetic burden for schizophrenia (indexed by a poly-genic risk score, PRS-SCZ) was associated with cortical thickness (CT), surface area (SA), cortical volume (CV), and subcortical structures within 18 088 White British ancestry participants with derived brain phenotypes from UK Biobank. We also explored whether environmental risk factors for schizophrenia (childhood trauma, cannabis use, birth weight, season of birth, and Townsend social deprivation index) exacerbated the impact of PRS-SCZ on brain structure. We found that PRS-SCZ was associated with lower CT in the frontal lobe, insula lobe, lateral orbito-frontal cortex, medial orbitofrontal cortex, posterior cin-gulate cortex, and inferior frontal cortex, and reduced SA and CV in the supramarginal and superior temporal cortex, but not with subcortical volumes. When models included environmental risk factors as covariates, PRS-SCZ was only associated with lower SA/CV within the supramarginal cortex, superior temporal cortex, and inferior frontal cortex. Moreover, no interactions were observed between PRS-SCZ and each of the environmental risk factors on brain structure. Overall, we identified brain structural correlates of PRS-SCZ predominantly within frontal and temporal regions and some of these associations were independent of environmental risk factors, suggesting that they may represent vulnerable biomarkers of genetic risk for schizophrenia. Future research is warranted to establish these associations beyond older White British individuals. [ABSTRACT FROM AUTHOR]

Background: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM., Methods: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 ( n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders., Results: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa., Conclusions: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

Background & Aims: It is unclear to what extent lifestyle and genetic factors affect the incidence of chronic liver disease (CLD) in the general population and if lifestyle affects CLD independently of underlying cardiometabolic perturbations and genetic predisposition., Methods: We examined 27,991 men and women aged 44-73 years from the Malmö Diet and Cancer Study recruited between 1991-1996 and followed until the end of 2020 using registry linkage (median follow-up time 25.1 years; 382 incident first-time CLD events). Associations between cardiometabolic factors, polygenic risk scores (PRSs), and lifestyle factors in relation to CLD were examined using multivariable Cox proportional hazards regression models., Results: The incidence of CLD increased with number of cardiometabolic risk factors (the hazard ratio per each additional cardiometabolic risk factor was 1.33; 95% CI 1.21-1.45; p = 5.1 x 10 -10 ). Two novel PRSs for metabolic dysfunction-associated steatotic liver disease and a PRS for cirrhosis were associated with higher risk of CLD but provided marginal predictive utility on top of other risk factors and compared to the PNPLA3 rs738409 genetic variant. An unhealthy lifestyle (high alcohol intake, current smoking, physical inactivity and unhealthy diet) markedly increased the risk of CLD (hazard ratio 3.97, 95% CI 2.59-6.10). Observed associations between examined lifestyle factors and CLD were largely independent of cardiometabolic perturbations and polygenic risk., Conclusions: We confirmed the importance of cardiometabolic dysfunction in relation to risk of CLD in the general population. Lifestyle risk factors were shown to be independently associated with CLD and added predictive information on top of cardiometabolic risk factors. Information on the polygenic risk of liver disease does not currently improve the prediction of CLD in the general population., Impact and Implications: This large population-based prospective study suggests largely independent roles of cardiometabolic, lifestyle, and genetic risk factors in the development of chronic liver disease. Findings strengthen the evidence base for a beneficial effect of modification of high-risk lifestyle behaviors in the primary prevention of chronic liver disease in the general population., (© 2024 The Author(s).)

Background: During the course of adulthood and aging, white matter (WM) structure and organization are characterized by slow degradation processes such as demyelination and shrinkage. An acceleration of such aging processes has been linked to the development of a range of diseases. Thus, an accurate description of healthy brain maturation, particularly in terms of WM features, is fundamental to the understanding of aging., Methods: We used longitudinal diffusion magnetic resonance imaging to provide an overview of WM changes at different spatial and temporal scales in the UK Biobank (UKB) ( n  = 2678; age scan 1  = 62.38 ± 7.23 years; age scan 2  = 64.81 ± 7.1 years). To examine the genetic overlap between WM structure and common clinical conditions, we tested the associations between WM structure and polygenic risk scores for the most common neurodegenerative disorder, Alzheimer's disease, and common psychiatric disorders (unipolar and bipolar depression, anxiety, obsessive-compulsive disorder, autism, schizophrenia, attention-deficit/hyperactivity disorder) in longitudinal ( n  = 2329) and cross-sectional ( n  = 31,056) UKB validation data., Results: Our findings indicate spatially distributed WM changes across the brain, as well as distributed associations of polygenic risk scores with WM. Importantly, brain longitudinal changes reflected genetic risk for disorder development better than the utilized cross-sectional measures, with regional differences giving more specific insights into gene-brain change associations than global averages., Conclusions: We extend recent findings by providing a detailed overview of WM microstructure degeneration on different spatial levels, helping to understand fundamental brain aging processes. Further longitudinal research is warranted to examine aging-related gene-brain associations., (© 2024 The Authors.)

Background: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment., Methods: Induced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation., Results: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits., Discussion: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau., Highlights: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Gray matter (GM) abnormalities in depression are potentially attributable to some combination of trait, state, and illness history factors. Here, we sought to determine the contributions of polygenic risk for depression, depressive disease status, and the interaction of these factors to these GM abnormalities., Methods: We conducted a cross-sectional comparison using a 2 × 3 factorial design examining effects of polygenic risk for depression (lower vs. upper quartile) and depression status (never depressed, currently depressed, or remitted depression) on regional GM concentration and GM volume. Participants were a subset of magnetic resonance imaging-scanned UK Biobank participants comprising 2682 people (876 men, 1806 women) algorithmically matched on 16 potential confounders., Results: In women but not men, we observed that elevated polygenic risk for depression was associated with reduced cerebellar GM volume. This deficit occurred in salience and dorsal attention network regions of the cerebellum and was associated with poorer performance on tests of attention and executive function but not fluid intelligence. Moreover, in women with current depression compared to both women with remitted depression and women who never had depression, we observed GM reductions in ventral and medial prefrontal, insular, and medial temporal regions. These state-related abnormalities remained when accounting for antidepressant medication status., Conclusions: Neuroanatomical deficits attributed broadly to major depression are more likely due to an aggregation of independent factors. Polygenic risk for depression accounted for cerebellar structural abnormalities that themselves accounted for cognitive deficits observed in this disorder. Medial and ventral prefrontal, insular, and temporal cortex deficits constituted a much larger proportion of the aggregate deficit and were attributable to the depressed state., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

BackgroundThe genetic architecture of psychotic disorders is complex, with hundreds of genetic risk loci contributing to a polygenic model of disease. Overlap in the genetics of psychotic disorders and brain measures has been found in European populations, but has not been explored in populations of African ancestry. The aim of this study was to determine whether a relationship exists between a schizophrenia-derived PRS and (i) methamphetamine associated psychosis (MAP), and (ii) brain structural measures, in a South African population.MethodsThe study sample consisted of three participant groups: 31 individuals with MAP, 48 with apsychotic methamphetamine dependence, and 49 healthy controls. Using PRSice, PRS was generated for each of the participants with GWAS summary statistics from the Psychiatric Genomics Consortium Schizophrenia working group (PGC-SCZ2) as the discovery dataset. Regression analyses were performed to determine associations of PRS, with diagnosis, whole brain, and regional gray and white matter measures.ResultsSchizophrenia-derived PRS did not significantly predict MAP diagnosis. After correction for multiple testing, no significant associations were found between PRS and brain measures across all groups.DiscussionThe lack of significant associations here may indicate that the study is underpowered, that brain volumes in MAP are due to factors other than polygenic risk for schizophrenia, or that PRS derived from a largely European discovery set has limited utility in individuals of African ancestry. Larger studies, that include diverse populations, and more nuanced brain measures, may help elucidate the relationship between schizophrenia-PRS, brain structural changes, and psychosis.ConclusionThis research presents the first PRS study to investigate shared genetic effects across psychotic disorders and brain structural measures in an African population. Ancestrally comparable discovery datasets may be useful for future African genetic research.

Background: The Psychosis Polyrisk Score (PPS) is a potential biomarker integrating non-purely genetic risk/protective factors for psychosis that may improve identification of individuals at risk and prediction of their outcomes at the individual subject level. Biomarkers that are easy to administer are direly needed in early psychosis to facilitate clinical implementation. This study digitally implements the PPS and pilots its feasibility of use in the real world.Methods: The PPS was implemented digitally and prospectively piloted across individuals referred for a CHR-P assessment (n = 16) and healthy controls (n = 66). Distribution of PPS scores was further simulated in the general population.Results: 98.8% of individuals referred for a CHR-P assessment and healthy controls completed the PPS assessment with only one drop-out. 96.3% of participants completed the assessment in under 15 min. Individuals referred for a CHR-P assessment had high PPS scores (mean = 6.2, SD = 7.23) than healthy controls (mean = -1.79, SD = 6.78, p < 0.001). In simulated general population data, scores were normally distributed ranging from -15 (lowest risk, RR = 0.03) to 39.5 (highest risk, RR = 8912.51).Discussion: The PPS is a promising biomarker which has been implemented digitally. The PPS can be easily administered to both healthy controls and individuals at potential risk for psychosis on a range of devices. It is feasible to use the PPS in real world settings to assess individuals with emerging mental disorders. The next phase of research should be to include the PPS in large-scale international cohort studies to evaluate its ability to refine the prognostication of outcomes. [ABSTRACT FROM AUTHOR]

Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score "FE‐PRS" that combines small effect sizes of thousands of common variants from the largest FE‐GWAS (genome‐wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE‐PRS compared to 20 435 matched population controls and observed heterogeneous FE‐PRS burden among the subgroups. The highest phenotypic variance explained by FE‐PRS was identified in a cluster analysis–defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better‐powered FE‐PRS might have clinical utility. [ABSTRACT FROM AUTHOR]

Seasonal changes in mood and diurnal preference are two well‐characterized chronobiological phenotypes in major depressive disorder (MDD) and bipolar disorder (BD). The biological mechanisms regulating physiological changes related to seasonality and chronotype involve several genes known as "clock" or circadian genes. Our goal was to study the relationship between the polygenic risk score (PRS) obtained from a set of clock genes and chronobiological traits in patients with mood disorders. The sample included 445 patients with mood disorders (256 MDD; 189 BD). Seasonality was assessed using the Seasonal Pattern Assessment Questionnaire (SPAQ), and chronotype was assessed using the Horne and Östberg Morningness–Eveningness Questionnaire. We selected 248 single nucleotide polymorphisms located within 19 genes. PRS for both MDD and BD was calculated using the Psychiatric Genetics Consortium latest datasets as discovery samples. Another PRS was calculated using results from a genome‐wide association study focusing on chronotype. SPAQ results were significantly associated with MDD‐PRS (p = 0.037) and chronotype‐PRS (p = 0.019), which also showed a significant interaction with age (p = 0.039). No significant association was observed between the measured PRS and chronotype. Our results reflect that small effect variants associated with MDD and chronotype within clock genes are associated with seasonality traits in patients with mood disorders, further explaining the mechanism through which the circadian system might influence mood disorder clinical presentation. Future studies measuring PRS from specific gene sets and focusing on biological endophenotypes will help to elucidate the pathways from genetic variations to clinical outcome. [ABSTRACT FROM AUTHOR]

The polygenic risk score (PRS) allows for quantification of the relative contributions of genes and environment in population-based studies of mental health. We analyzed the impact of transdiagnostic schizophrenia PRS and measures of familial and environmental risk on the level of and change in general mental health (Short-Form-36 mental health) in the Netherlands Mental Health Survey and Incidence Study-2 general population sample, interviewed 4 times over a period of 9 years, yielding 8901 observations in 2380 individuals. Schizophrenia PRS, family history, somatic pain, and a range of environmental risks and social circumstances were included in the regression model of level of and change in mental health. We calculated the relative contribution of each (group of) risk factor(s) to the variance in (change in) mental health. In the combined model, familial and environmental factors explained around 17% of the variance in mental health, of which around 5% was explained by age and sex, 30% by social circumstances, 16% by pain, 22% by environmental risk factors, 24% by family history, and 3% by PRS for schizophrenia (PRS-SZ). Results were similar, but attenuated, for the model of mental health change over time. Childhood trauma and gap between actual and desired social status explained most of the variance. PRS for bipolar disorder, cross-disorder, and depression explained less variance in mental health than PRS-SZ. Polygenic risk for mental suffering, derived from significance-testing in massive samples, lacks impact in analyses focusing on prediction in a general population epidemiological setting. Social-environmental circumstances, particularly childhood trauma and perceived status gap, drive most of the attributable variation in population mental health. [ABSTRACT FROM AUTHOR]

Background: The genetic architecture of psychotic disorders is complex, with hundreds of genetic risk loci contributing to a polygenic model of disease. Overlap in the genetics of psychotic disorders and brain measures has been found in European populations, but has not been explored in populations of African ancestry. The aim of this study was to determine whether a relationship exists between a schizophrenia-derived PRS and (i) methamphetamine associated psychosis (MAP), and (ii) brain structural measures, in a South African population. Methods: The study sample consisted of three participant groups: 31 individuals with MAP, 48 with apsychotic methamphetamine dependence, and 49 healthy controls. Using PRSice, PRS was generated for each of the participants with GWAS summary statistics from the Psychiatric Genomics Consortium Schizophrenia working group (PGC-SCZ2) as the discovery dataset. Regression analyses were performed to determine associations of PRS, with diagnosis, whole brain, and regional gray and white matter measures. Results: Schizophrenia-derived PRS did not significantly predict MAP diagnosis. After correction for multiple testing, no significant associations were found between PRS and brain measures across all groups. Discussion: The lack of significant associations here may indicate that the study is underpowered, that brain volumes in MAP are due to factors other than polygenic risk for schizophrenia, or that PRS derived from a largely European discovery set has limited utility in individuals of African ancestry. Larger studies, that include diverse populations, and more nuanced brain measures, may help elucidate the relationship between schizophrenia-PRS, brain structural changes, and psychosis. Conclusion: This research presents the first PRS study to investigate shared genetic effects across psychotic disorders and brain structural measures in an African population. Ancestrally comparable discovery datasets may be useful for future African genetic research. [ABSTRACT FROM AUTHOR]

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done. [ABSTRACT FROM AUTHOR]

Background: Psychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation.Methods: Psychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses.Results: Genetic predisposition for T2DM was associated with PEs (adjusted OR = 1.21; 95% CI, 1.01-1.45) and psychotic disorder (adjusted OR = 1.51; 95% CI, 1.04-2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR = 1.10; 95% C·I, 0.99-1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP (p = .040).Conclusions: Comorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood. [ABSTRACT FROM AUTHOR]

Objective: Genomic discoveries should be investigated in generalizable child psychiatric samples in order to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRSs with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRSs manifest a distinctive clinical profile.Method: Participants were 433 youth, ages 7-18 years, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD genome-wide association study to date. We replicated key findings in 5,140 adult patients from a local health system biobank.Results: Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R2 values ∼2%-3%), as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRSs were associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than youth with a low burden (β coefficients ∼.2).Conclusion: Among child and adolescent outpatients, ADHD polygenic risk was associated with ADHD and related phenotypes as well as clinical severity. These results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research. [ABSTRACT FROM AUTHOR]

Background: A complex set of interactions between biological, genetic, and environmental factors likely underlies the development of Alzheimer's disease (AD). Identifying which of these factors is most associated with AD is important for early diagnosis and treatment.Objective: We sought to examine genetic risk and structural brain volume on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD.Methods: 686 adults (55-91 years old) completed a 3T MRI scan, baseline cognitive assessments, and biospecimen collection through the Alzheimer's Disease Neuroimaging Initiative. Hierarchical linear regression analyses examined main and interaction effects of medial temporal lobe (MTL) volume and polygenic hazard score (PHS), indicating genetic risk for AD, on a validated episodic memory composite score.Results: Genetic risk moderated the relationship between MTL volume and memory, such that individuals with high PHS and lower hippocampal and entorhinal volume had lower memory composite scores [ΔF (1,677) = 4.057, p = 0.044, ΔR2 = 0.002]. Further analyses showed this effect was driven by the left hippocampus [ΔF(1,677) = 5.256, p = 0.022, ΔR2 = 0.003] and right entorhinal cortex [ΔF (1,677) = 6.078, p = 0.014, ΔR2 = 0.003].Conclusions: Among those with high genetic risk for AD, lower volume was associated with poorer memory. Results suggest that the interaction between AD genetic risk and MTL volume increases the likelihood for memory impairment among older adults. Results from this study suggest that genetic risk and brain volume should be considered key factors in tracking cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ. Methods: The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants. Results: There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons. Conclusions: Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general. [ABSTRACT FROM AUTHOR]

Aims: 1) To investigate whether genetic liability to attention‐deficit/hyperactivity disorder (ADHD), indexed by polygenic risk scores for ADHD (PRS‐ADHD), is associated with substance use disorders (SUD) in individuals with ADHD. 2) To investigate whether other individual‐ or family‐related risk factors for SUD could mediate or confound this association. Design Population‐based cohort study Setting and participants: ADHD cases in the iPSYCH sample (a Danish case‐cohort sample of genotyped cases with specific mental disorders), born in Denmark between 1981 and 2003 (N = 13 116). Register‐based information on hospital diagnoses of SUD was available until December 31, 2016. Measurements We estimated odds ratios (ORs) with 95% confidence intervals (CIs) for any SUD as well as for different SUD types (alcohol, cannabis, and other illicit drugs) and severities (use, abuse, and addiction), with effect sizes corresponding to a comparison of the highest PRS‐ADHD decile to the lowest. Findings PRS‐ADHD were associated with any SUD (OR = 1.30, 95% CI: 1.11–1.51). Estimates were similar across different types and severity levels of SUD. Other risk factors for SUD (male sex, age at ADHD diagnosis, comorbid conduct problems, and parental factors including SUD, mental disorders, and socio‐economic status) were independently associated with increased risk of SUD. PRS‐ADHD explained a minor proportion of the variance in SUD (0.2% on the liability scale) compared to the other risk factors. The association between PRS‐ADHD and any SUD was slightly attenuated (OR = 1.21, 95% CI: 1.03–1.41) after adjusting for the other risk factors for SUD. Furthermore, associations were nominally higher in females than in males (ORfemales = 1.59, 95% CI: 1.19–2.12, ORmales = 1.18, 95% CI: 0.98–1.42). Conclusions: A higher genetic liability to attention‐deficit/hyperactivity disorder appears to be associated with higher risks of substance use disorders in individuals with attention‐deficit/hyperactivity disorder. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by 1) constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders and of intelligence and 2) testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n = 5160) of patients with HD. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD. [ABSTRACT FROM AUTHOR]

Background: Low maternal vitamin D levels [serum 25-hydroxyvitamin D (25(OH)D)] during pregnancy have been linked to offspring neuropsychiatric outcomes such as schizophrenia and autism, but studies on depression are lacking. We examined the association between maternal vitamin D status during pregnancy and offspring depression during childhood and adolescence and investigated whether any associations were modified by offspring genetic risk for depression.Methods: Mother-singleton birth offspring pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC) that had maternal 25(OH)D measurements, offspring genetic data, and offspring depression measures collected in childhood (mean age=10.6 years; n = 2938) and/or adolescence (mean age=13.8 years; n = 2485) were included in the analyses. Using multivariable logistic regression, we assessed associations between maternal vitamin D status and offspring polygenic risk score (PRS) for depression on childhood/adolescent depression risk.Results: There was no evidence for an association between maternal vitamin D status during pregnancy and offspring depression in childhood (p = 0.72) or adolescence (p = 0.07). Offspring depression PRS were independently associated with childhood depression (p = 0.003), but did not interact with maternal vitamin D status. These results were robust to adjustments for potential confounders and different cut-offs for vitamin D insufficiency/deficiency.Limitations: 25(OH)D measurements were only available at a single time point during pregnancy.Conclusion: These findings suggest that maternal vitamin D status during pregnancy does not affect an offspring's risk for early life depression. [ABSTRACT FROM AUTHOR]

Background and Aims: The use of cannabis has previously been linked to both depression and self‐harm; however, the role of genetics in this relationship is unclear. This study aimed to estimate the phenotypic and genetic associations between cannabis use and depression and self‐harm. Design Cross‐sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self‐harm. UK Biobank genetic data were then combined with consortia genome‐wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods. Setting: United Kingdom, with additional international consortia data. Participants: A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank. Measurements Phenotypic outcomes were life‐time history of cannabis use (including initial and continued cannabis use), depression (including single‐episode and recurrent depression) and self‐harm. Genome‐wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data. Findings In UK Biobank, cannabis use is associated with an increased likelihood of depression [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59–1.70] and self‐harm (OR = 2.85, 95% CI = 2.69–3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome‐wide summary statistics, significant genetic correlations are seen between cannabis use and depression [rg = 0.289, standard error (SE) = 0.036]. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self‐harm within a UK Biobank target sample. However, two‐sample Mendelian randomization analyses were not significant. Conclusions: Cannabis use appeared to be both phenotypically and genetically associated with depression and self‐harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRSs) are increasingly being implemented to assess breast cancer risk. This study aimed to assess and determine factors associated with uptake of PRS among women at increased risk of breast cancer for whom genetic testing to date had been uninformative. Participants were recruited from the Variants in Practice study from which breast cancer PRS had been calculated. Four hundred women were notified by letter of the availability of their PRS and invited to complete a self‐administered survey comprising several validated scales. Considering non‐participants, uptake of PRS was between 61.8% and 42.1%. Multivariate logistic regression identified that women were more likely to receive their PRS if they reported greater benefits (odds ratio [OR] = 1.17, P =.011) and fewer barriers to receiving their PRS (OR = 0.80, P =.007), had completed higher level education (OR = 3.32, P =.004), and did not have daughters (0.29, P =.006). Uptake of breast cancer PRS varied according to several testing‐ and patient‐related factors. Knowledge of these factors will facilitate the implementation of polygenic testing in clinical practice and support informed decision making by patients. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have proved to be a powerful approach for gene discovery in schizophrenia; their findings have important implications not just for our understanding of the genetic architecture of the disorder, but for the potential applications of personalised medicine through improved classification and targeted interventions. In this article we review the current status of the GWAS literature in schizophrenia including functional annotation methods and polygenic risk scoring, as well as the directions and challenges of future research. We consider recent findings in East Asian populations and the advancements from trans-ancestry analysis, as well as the insights gained from research looking across psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Childhood maltreatment is a well‐known risk factor for developing a more severe and complex form of bipolar disorders (BD). However, knowledge is scarce about the interactions between childhood maltreatment and underlying genetic vulnerability on the clinical expression of BD. Method: We assigned a BD‐polygenic risk score (BD‐PRS), calculated from the Psychiatric Genomics Consortium, to each individual in a sample of 402 cases with BD. The lifetime clinical expression of BD was characterized using structured interviews and patients completed the Childhood Trauma Questionnaire (CTQ) to assess the severity of childhood maltreatment. Results: Cases who reported more severe childhood maltreatment had a lower BD‐PRS (rho = −0.12, P =.01), especially when considering emotional abuse (rho = −0.16, P =.001). An interaction between BD‐PRS and childhood maltreatment was observed for the risk of rapid cycling (P =.01). No further interactions between BD‐PRS and childhood maltreatment were observed for other clinical characteristics (age at onset, suicide attempts, number of mood episodes, mixed features, substance use disorders and psychotic symptoms). Conclusion: Our study is the first to show that less genetic risk may be needed to develop a more unstable form of BD when exposed to childhood maltreatment. Our study supports childhood trauma as an independent risk factor for BD. [ABSTRACT FROM AUTHOR]

Background: Physical activity is increasingly recognized as an important modifiable factor for depression. However, the extent to which individuals with stable risk factors for depression, such as high genetic vulnerability, can benefit from the protective effects of physical activity, remains unknown. Using a longitudinal biobank cohort integrating genomic data from 7,968 individuals of European ancestry with high-dimensional electronic health records and lifestyle survey responses, we examined whether physical activity was prospectively associated with reduced risk for incident depression in the context of genetic vulnerability.Methods: We identified individuals with incident episodes of depression, based on two or more diagnostic billing codes for a depressive disorder within 2 years following their lifestyle survey, and no such codes in the year prior. Polygenic risk scores were derived based on large-scale genome-wide association results for major depression. We tested main effects of physical activity and polygenic risk scores on incident depression, and effects of physical activity within stratified groups of polygenic risk.Results: Polygenic risk was associated with increased odds of incident depression, and physical activity showed a protective effect of similar but opposite magnitude, even after adjusting for BMI, employment status, educational attainment, and prior depression. Higher levels of physical activity were associated with reduced odds of incident depression across all levels of genetic vulnerability, even among individuals at highest polygenic risk.Conclusions: Real-world data from a large healthcare system suggest that individuals with high genetic vulnerability are more likely to avoid incident episodes of depression if they are physically active. [ABSTRACT FROM AUTHOR]

We sought to explore whether genetic risk for, and self-reported, short sleep are associated with biological aging and whether age and sex moderate these associations. Participants were a subset of individuals from the Baltimore Longitudinal Study of Aging who had complete data on self-reported sleep (n = 567) or genotype (n = 367). Outcomes included: Intrinsic Horvath age, Hannum age, PhenoAge, GrimAge, and DNAm-based estimates of plasminogen activator inhibitor-1 (PAI-1) and granulocyte count. Results demonstrated that polygenic risk for short sleep was positively associated with granulocyte count; compared to those reporting <6 hr sleep, those reporting >7 hr demonstrated faster PhenoAge and GrimAge acceleration and higher estimated PAI-1. Polygenic risk for short sleep and self-reported sleep duration interacted with age and sex in their associations with some of the outcomes. Findings highlight that polygenic risk for short sleep and self-reported long sleep is associated with variation in the epigenetic landscape and subsequently aging. [ABSTRACT FROM AUTHOR]

Abstract Background The ‘common variant, common disease’ model predicts that a significant component of hereditary breast cancer unexplained by pathogenic variants in moderate or high-penetrance genes is due to the cumulative effect of common risk variants in DNA (polygenic risk). Assessing a woman’s breast cancer risk by testing for common risk variants can provide useful information for women who would otherwise receive uninformative results by traditional monogenic testing. Despite increasing support for the utility of common risk variants in hereditary breast cancer, research findings have not yet been integrated into clinical practice. Translational research is therefore critical to ensure results are effectively communicated, and that women do not experience undue adverse psychological outcomes. Methods In this prospective study, 400 women with a personal and/or high risk family history of breast cancer will be recruited from six familial cancer centers (FCCs) in Australia. Eligible women will be invited to attend a FCC and receive their personal polygenic risk result for breast cancer. Genetic health professionals participating in the study will receive training on the return of polygenic risk information and a training manual and visual aids will be developed to facilitate patient communication. Participants will complete up to three self-administered questionnaires over a 12-months period to assess the short-and long-term psychological and behavioral outcomes of receiving or not receiving their personal polygenic risk result. Discussion This is the world’s first study to assess the psychological and behavioral impact of offering polygenic risk information to women from families at high risk of breast cancer. Findings from this research will provide the basis for the development of a new service model to provide polygenic risk information in familial cancer clinics. Trial registration The study was retrospectively registered on 27th April 2017 with the Australian and New Zealand Clinical Trials Group (Registration no: ACTRN12617000594325; clinical trial URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372743 ).

Genome-wide association studies (GWASs) and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem. Computer simulations of polygenic late-onset diseases (LODs) in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores (PRSs) becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes. The incidence rate for LODs grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for GWASs overrepresent older individuals with lower PRSs, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and GWASs. It also explains the relatively constant-with-age heritability found for LODs of lower prevalence, exemplified by cancers.

Subjective cognitive decline (SCD) has been described as a probable early stage of dementia, as it has consistently appeared to precede the onset of objective cognitive impairment. SCD is related to many risk factors, including genetic predisposition for dementia. The Apolipoprotein (APOE) ε4 allele, which has been thoroughly studied, seems to explain genetic risk for SCD only partially. Therefore, we aimed to summarize existing data regarding genetic factors related to SCD, beyond APOE ε4, in order to improve our current understanding of SCD. We conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keywords "subjective cognitive decline" and "genetic predisposition" with specific inclusion and exclusion criteria. From the 270 articles identified, 16 were finally included for the qualitative analysis. Family history of Alzheimer's disease (AD) in regard to SCD was explored in eight studies, with conflicting results. Other genes implicated in SCD, beyond APOE ε4, were investigated in six studies, which were not strong enough to provide clear conclusions. Very few data have been published regarding the association of polygenic risk for AD and SCD. Thus, many more genes related to AD must be studied, with polygenic risk scores appearing to be really promising for future investigation.

Background: The transition from childhood to adolescence is characterized by enhanced neural plasticity and a consequent susceptibility to both beneficial and adverse aspects of one's milieu., Methods: To understand the implications of the interplay between protective and risk-enhancing factors, we analyzed longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (n = 834; 394 female). We probed the maturational correlates of positive lifestyle variables (friendships, parental warmth, school engagement, physical exercise, healthy nutrition) and genetic vulnerability to neuropsychiatric disorders (major depressive disorder, Alzheimer's disease, anxiety disorders, bipolar disorder, schizophrenia) and sought to further elucidate their implications for psychological well-being., Results: Genetic risk factors and lifestyle buffers showed divergent relationships with later attentional and interpersonal problems. These effects were mediated by distinguishable functional neurodevelopmental deviations spanning the limbic, default mode, visual, and control systems. More specifically, greater genetic vulnerability was associated with alterations in the normative maturation of areas rich in dopamine (D 2 ), glutamate, and serotonin receptors and of areas with stronger expression of astrocytic and microglial genes, a molecular signature implicated in the brain disorders discussed here. Greater availability of lifestyle buffers predicted deviations in the normative functional development of higher density GABAergic (gamma-aminobutyric acidergic) receptor regions. The two profiles of neurodevelopmental alterations showed complementary roles in protection against psychopathology, which varied with environmental stress levels., Conclusions: Our results underscore the importance of educational involvement and healthy nutrition in attenuating the neurodevelopmental sequelae of genetic risk factors. They also underscore the importance of characterizing early-life biomarkers associated with adult-onset pathologies., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: We leveraged common genetic variation underlying ADHD, educational attainment (EA) and cognition (COG) to understand the nature of the Behavior Rating Inventory for Executive Functions (BRIEF) and its relationship to academic functioning., Method: Participants were 991 youth, ages 7 to 17, consecutively referred for neuropsychiatric evaluation. Polygenic scores (PGS) for ADHD, EA, and COG were related to the BRIEF using regression analyses. Structural equation models were used to examine the associations between the PGS, BRIEF and academic outcomes (math, reading, and special education services [EDPLAN])., Results: After modeling the PGS together, only the EA and ADHD PGS significantly associated with the BRIEF. The BRIEF partially mediated the relationships between EA PGS with math and EDPLAN and fully mediated the relationship between ADHD PGS and EDPLAN., Conclusion: Genetic data extend evidence that the BRIEF measures a construct relevant to educational success that differs from what is indexed by cognitive testing., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Braaten receives royalties from Guilford Press. The other authors have no relevant conflicts of interest or financial interests to disclose.

Background: As the global population ages, cognitive impairment (CI) becomes more prevalent. Tea has been one of the most popular drinks in the world. Several studies have demonstrated that tea consumption has an impact on cognitive function., Objective: This study aims to examine the association between tea consumption and cognitive function and explore the potential effect of genetics on the relationship between tea consumption and CI risk in older adults., Design: This is a prospective longitudinal study using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS)., Setting: Six waves of data from CLHLS containing 76,270 subjects were analyzed. Generalized estimation equations (GEE) with a logit link function were adopted to estimate the effect of tea consumption on CI risk from a cross-sectional and longitudinal perspective., Participants: A population-based cohort of adults aged 65-105 years., Measurements: The frequency and type of tea consumption were obtained by questionnaires. CI was measured based on MMSE. Polygenic risk was measured using the polygenic score approach described by the International Schizophrenia., Results: The results showed that drinking green tea had a better protective effect on cognitive function than other types of tea, the incidence of CI gradually decreased with the increase of tea consumption frequency, and men were more likely to benefit from tea consumption. Additionally, we also found a significant interaction between tea consumption and genetic risk, measured by polygenic risk score (PRS)., Conclusions: Based on current research evidence, tea consumption, may be a simple and important measure for CI prevention., Competing Interests: The authors have no relevant financial or non-financial competing interests to declare with this manuscript.

Background: Catatonia is an under-recognized disorder characterized by psychomotor (increased, decreased, or abnormal) changes, affective symptoms, and disturbance of volition, which may arise in the setting of decompensated psychiatric or non-psychiatric medical disorders. Genetic studies of catatonia are limited, and to the best of our knowledge no prior genome wide association studies of catatonia have been performed to date., Methods: First we performed a genome wide association study of catatonia regardless of etiology (psychiatric or non-psychiatric). Secondarily we evaluated whether there was an elevated genetic risk profile for predisposing psychiatric disorders (schizophrenia spectrum disorder, bipolar affective disorder, etc.) in patients with catatonia. We used a matched case control design and applied polygenic risk scores to evaluate for a shared polygenetic contribution to catatonia from common psychiatric phenotypes that show a high prevalence of catatonia in their decompensated states., Results: Anxiety, bipolar affective disorder, schizophrenia spectrum disorder and cross disorder polygenic risk scores were significantly associated with catatonia case status in both unadjusted and adjusted logistic regression models for the European Ancestry set even after correcting for multiple comparisons. Depression, Alzheimer's, Autism Spectrum Disorder and Obsessive Disorder polygenic risk scores were not significantly associated with catatonia status in participants of European Ancestry. In the African Ancestry set, no psychiatric polygenic risk scores were significantly associated with catatonia status in either the unadjusted or adjusted regression models., Conclusions: Even after controlling for relevant covariates, anxiety, bipolar affective disorder, schizophrenia spectrum disorder and cross disorders were significantly associated with catatonia status suggesting that there might be a shared genetic risk for those disorders amongst patients with catatonia., Competing Interests: Declaration of competing interest The authors disclose that the research was conducted in the absence of any commercial or financial relationships that could be seen as a potential conflict of interest., (Published by Elsevier B.V.)