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We assessed the association of prescription data with clinical manifestations and polygenic risk scores (PRS) in patients with bipolar I disorder. We enrolled 1471 individuals with BID and divided them into several groups according to treatment options and clinical manifestations. BD-PRS of each patient was calculated using the Psychiatric Genomics Consortium data. Data on single nucleotide polymorphisms, clinical manifestations, and prescriptions were extracted from BiGS. Chronicity, suicidality, substance misuse, mixed symptoms, and deterioration of life functioning were significantly more severe in the group that was not prescribed any mood stabilizers (MS). Chronicity, psychotic symptoms, suicidality, and deterioration of life functioning were significantly severe in the group that received two or more antipsychotics (APs). BD-PRS between the group with AP(s) only and that with other treatment options significantly differed. BD-PRS of the group with AP(s) only was significantly lower than that with other treatment options. Our linear regression results showed that high severity of particular clinical aspects, lower BD-PRS, and prescriptions with fewer MSs or more APs were independently associated with poor life functioning. This study had a cross-sectional design, without differentiating the bipolar phase, which could influence our results. Poor life functioning in patients with BID was associated with a high severity of particular clinical aspects, BD-PRS, and prescriptions including fewer MSs or more APs. BD-PRS was significantly higher in the group receiving only AP(s) than that in the groups receiving other drugs. • Particular clinical aspects were significantly more severe in the group that was not prescribed any mood stabilizers (MS). • Particular clinical aspects were significantly severe in the group that received two or more antipsychotics (APs). • Poor life functioning was associated with a high severity of particular clinical aspects, BD-PRS, and some prescriptions. • BD-PRS was higher in the group receiving only AP(s) than that in the groups receiving other drugs. [ABSTRACT FROM AUTHOR]

The effects of tea consumption on delaying aging and the onset of age‐related disabilities have been reported; however, it is unclear whether these benefits are impacted by genes. This study aimed to examine the associations between tea consumption and activities of daily living (ADL) and explore the role of genetic factors. Data from 46,487 older adults aged 64–105 who participated in at least one data wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) conducted in 2002, 2005, 2008, 2011, 2014, and 2018 were analyzed. Genetic data were produced using the Affymetrix Axiom™myDesign™ (384‐format) Human Genotyping Array. The generalized estimation equation and multiple logistic regression models were constructed to examine the effects of tea consumption, polygenic risk score, and their interactions on ADL. Tea consumption was related to reduced ADL decline—the effect was statistically significant among men but not women. A significant interaction between tea consumption and polygenic risk score (PRS) was observed. Tea consumption was associated with a decreased risk of ADL disability only among individuals with a low PRS. These findings indicate that tea consumption plays a role in preventing disability in older adults with low polygenic risk. [ABSTRACT FROM AUTHOR]

Background It is well established that there is a substantial genetic component to eating disorders (EDs). Polygenic risk scores (PRSs) can be used to quantify cumulative genetic risk for a trait at an individual level. Recent studies suggest PRSs for anorexia nervosa (AN) may also predict risk for other disordered eating behaviors, but no study has examined if PRS for AN can predict disordered eating as a global continuous measure. This study aimed to investigate whether PRS for AN predicted overall levels of disordered eating, or specific lifetime disordered eating behaviors, in an Australian adolescent female population. Methods PRSs were calculated based on summary statistics from the largest Psychiatric Genomics Consortium AN genome-wide association study to date. Analyses were performed using genome-wide complex trait analysis to test the associations between AN PRS and disordered eating global scores, avoidance of eating, objective bulimic episodes, self-induced vomiting, and driven exercise in a sample of Australian adolescent female twins recruited from the Australian Twin Registry (N = 383). Results After applying the false-discovery rate correction, the AN PRS was significantly associated with all disordered eating outcomes. Conclusions Findings suggest shared genetic etiology across disordered eating presentations and provide insight into the utility of AN PRS for predicting disordered eating behaviors in the general population. In the future, PRSs for EDs may have clinical utility in early disordered eating risk identification, prevention, and intervention. [ABSTRACT FROM AUTHOR]

Cognitive decline is a public health concern affecting about 50 million individuals worldwide. Neuroticism, defined as the trait disposition to experience intense and frequent negative emotions, has been associated with an increased risk of late-life cognitive decline. However, the underlying biological mechanisms of this association remain unknown. This study investigated the relationship between genetic predisposition to neuroticism, computed by polygenic risk score (PRS), and performance in cognitive domains of reasoning, processing speed, visual attention, and memory in individuals over age 60. The sample consisted of UK Biobank participants with genetic and cognitive data available (N = 10,737, 4686 females; mean age = 63.4 ± 2.71). The cognitive domains were assessed at baseline for all participants and seven years later for a subset (N = 645, 262 females; mean age = 62.9 ± 2.44). Neuroticism PRS was not associated cross-sectionally with cognitive measures (p > 0.05). However, the trajectory of change for processing speed (β = 0.020; 95% CI = [0.006, 0.035], adjusted p = 0.0148), visual attention (β = −0.077; 95% CI = [−0.0985, −0.0553], adjusted p = 1.412 × 10−11), and memory (β = −0.033; 95% CI = [−0.0535, −0.0131], adjusted p = 0.005) was significantly associated with neuroticism PRS. Specifically, a higher genetic predisposition to neuroticism was associated with less decline in these cognitive domains. This trend persisted after sensitivity analysis using complete cases, although it only remained nominally significant for visual attention. [ABSTRACT FROM AUTHOR]

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

Recent decades have seen the increase of genome-wide analyses performed in the general population to compute the risk for multifactorial conditions. Polygenic risk tests, already available to clients via the direct-To-consumer (DTC) market, recently expanded to preimplantation genetic assessment of embryos in the context of fertility treatments (Preimplantation Polygenic Genetic Testing or PGT-P). While both kinds of tests rely on the same methodologies and are fueled by the promise of health optimization, they propose different interventions. Here, we compare the advertising strategies for companies offering DTC or PGT-P. We show that each company presents genotype–phenotype relationships to accommodate the intervention they propose and the clients' expectations. While DTC companies grant a greater role to the environment and to genotype–environment interaction on health, discourse on PGT-P neglects any such interaction and undermines environmental factors. In all cases analyzed, while it is recognized that risk is a group property, the estimate is presented as an individual trait, and sometimes confounded with health status. Moreover, all companies recognize the uncertainty of risk estimations but frame it as a result of the lack of detailed information, justifying the gathering of clients' data, and fueling promises of the betterment of future population health through individual action. [ABSTRACT FROM AUTHOR]

Early in the SARS-CoV2 pandemic, in this journal, Hou et al. (BMC Med 18:216, 2020) interpreted public genotype data, run through functional prediction tools, as suggesting that members of particular human populations carry potentially COVID-risk-increasing variants in genes ACE2 and TMPRSS2 far more often than do members of other populations. Beyond resting on predictions rather than clinical outcomes, and focusing on variants too rare to typify population members even jointly, their claim mistook a well known artifact (that large samples reveal more of a population's variants than do small samples) as if showing real and congruent population differences for the two genes, rather than lopsided population sampling in their shared source data. We explain that artifact, and contrast it with empirical findings, now ample, that other loci shape personal COVID risks far more significantly than do ACE2 and TMPRSS2—and that variation in ACE2 and TMPRSS2 per se unlikely exacerbates any net population disparity in the effects of such more risk-informative loci. [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. [ABSTRACT FROM AUTHOR]

Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration. [ABSTRACT FROM AUTHOR]

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (−). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A−T− status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T− status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T− status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A−T− to A+T−, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70–4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84–1.42; P = 0.53). Conversely, for the transition from A+T− to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05–2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27–2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05–6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87–3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Higher neuroticism might be associated with dementia risk. Here we investigated modification by genetic predisposition to dementia, mediation by mental health and vascular conditions, neuroimaging outcomes, and cognitive function. METHODS: Cox proportional‐hazards models were used to assess the association between neuroticism score and incident dementia over up to 15 years in 1,74,164 participants. Cross‐sectional analyses on dementia‐related neuroimaging outcomes and cognitive function were conducted in 39,459 dementia‐free participants. RESULTS: Higher neuroticism was associated with an 11% higher risk of incident dementia, especially vascular dementia (15% higher risk), regardless of genetic predisposition to dementia. Mental and vascular conditions mediated the association of neuroticism with all‐cause dementia and vascular dementia. Neuroticism was associated with higher cerebrovascular pathology, lower gray matter volume, and worse function across multiple cognitive domains. DISCUSSION: Neuroticism could represent a risk factor for dementia, and vascular and mental health might drive these associations. Highlights: Neuroticism was associated with an increased risk of incident all‐cause dementia, particularly vascular dementia.Associations were not modified by genetic predisposition to dementia.Associations were largely mediated by mental and vascular conditions.Neuroticism was associated with increased cerebrovascular pathology and lower gray matter volume.Neuroticism was associated with worse function across multiple cognitive domains. [ABSTRACT FROM AUTHOR]

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow‐up Study (1993–2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk‐reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer‐specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow‐up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk‐reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58–0.94]) and lethal prostate cancer (0.43 [0.21–0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60–0.95]; lethal, 0.46 [0.23–0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13–0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%–5.0%) among those with healthy lifestyles and 9.5% (5.3%–16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer. [ABSTRACT FROM AUTHOR]

Background While atrial fibrillation (AF) is a key risk factor for stroke, recent studies have suggested that atrial cardiomyopathy may also increase stroke risk in the absence of AF. This study aimed to evaluate genetic determinants for left atrial (LA) function and volumes and risk of stroke. Methods and Results Polygenic scores (PGSs) for LA measures were constructed and used in 380 017 individuals in the UK Biobank, without history of ischemic stroke, systemic arterial embolism, or AF at enrollment. Risk of ischemic stroke was estimated using time‐to‐event models, considering all‐cause death and incident AF as competing events. Systemic arterial embolism was investigated as a secondary end point. The PGS for LA passive emptying fraction was associated with risk of ischemic stroke. Individuals with a PGS for LA passive emptying fraction in the lowest quartile had a hazard ratio (HR) of 1.12 for ischemic stroke compared with those in the top quartile (P=0.004). These associations were robust in a subgroup free of prevalent cardiovascular disease at baseline (HR for lowest quartile versus top quartile, 1.22; P

Summary: Background: We describe BMI by socioeconomic disadvantage and by polygenic risk in parallel cohorts of children and adults (their parents). We examine whether hypothetically intervening to reduce childhood disadvantage could reduce adolescent obesity. Methods: From a population-based cohort (N = 5107) with a mixed design (survey and direct assessment), 24–31% had genotype data: 1607 children (50% male) followed biennially from age 2–3 to 14–15; 2406 adults (36% male) followed from mean age 35–47 years. Exposures were polygenic risk score for BMI, and neighbourhood- and family-level socioeconomic disadvantage categorised as ‘most’ (top two cohort-specific quintiles), ‘average’, or ‘least’ disadvantage (bottom two quintiles). We explored trends in estimated BMI and risk of overweight/obesity by disadvantage, stratified by polygenic risk. We used generalised linear regression to estimate the reduction in overweight/obesity at 14–15 years in children living in ‘least/average disadvantage’ in early childhood relative to those in ‘most disadvantage’, adjusted for confounders. Causal effect estimates were obtained separately for children with higher and lower polygenic risk. Findings: A positive trend between disadvantage and overweight/obesity was most apparent among participants with high polygenic risk. Among children with higher polygenic risk (n = 805), hypothetical target trial results imply that intervening to lessen population-wide neighbourhood disadvantage from most to least disadvantage could reduce adolescent overweight/obesity by 32% (risk ratio (RR) 0.68, 95% CI 0.50–0.92), or by 42% if intervening to lessen family disadvantage (RR 0.58, 95% CI 0.42–0.79). Positive effects were smaller when isolating the population to those with lower polygenic risk (7–17%), and for the whole population, regardless of polygenic risk (25–39%). Interpretation: Children at higher polygenic risk of obesity suffer disproportionate BMI impacts of disadvantage. At the population-level, and especially for those with higher polygenic risk, tackling disadvantage could potentially reduce obesity and associated morbidity, mortality, and costs. Funding: Australian National Health and Medical Research Council. Funding information is detailed in the funding statement.

Summary: Background: Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies. Methods: We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models. Findings: 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, padj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (padj = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype–phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp. Interpretation: We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with ‘monogenic’ epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients. Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Theories of risk for suicidal thoughts and behaviors (STB) implicate both interpersonal and biological factors. Divorce/separation and aggregate genetic liability are robustly associated with STB, but have seldom been evaluated in conjunction with one another. Furthermore, whether these factors are effective predictors in high-risk populations is not clear. Analyses were conducted in a sample of Han Chinese women with severe recurrent major depressive disorder (maximum N = 4380). Logistic regressions were used to evaluate the associations between divorce/separation and polygenic scores (PGS) for suicidal ideation or behavior with STB. Where appropriate, additive interactions between divorce and PGS were tested. Divorce/separation was significantly associated with increased risk of suicidal ideation, plans, and attempts (odds ratios = 1.28–1.61). PGS for suicidal ideation were not associated with STB, while PGS for suicidal behavior were associated with ideation and plans (odds ratios = 1.08–1.09). There were no significant interactions between divorce/separation and PGS. Consistent with theories of suicidality, the disruption or end of an important interpersonal relationship is an indicator of risk for STB. Aggregate genetic liability for suicidal behavior more modestly contributes to risk, but does not exacerbate the negative impact of divorce. Thus, even within a high-risk sample, interpersonal and biological exposures distinguish between those who do and do not experience STB, and could motivate targeted screening. Further research is necessary to evaluate whether and how the context of divorce contributes to variation in its effect on STB risk. • Divorce and genetic liability increase risk of suicidal thoughts and behaviors. • Genetic liability does not exacerbate the effect of divorce on risk. • Even in a high risk sample, variation in genetic liability matters. [ABSTRACT FROM AUTHOR]

To establish the impact of a 3-minute computerized cognitive training program (START) on cognition in older adults with and without genetic risk of Alzheimer's disease. Two-arm randomized controlled trial of the START program. Remote online trial in adults older than 50 taking part from home. The trial compared the START program with placebo in 6544 people older than 50. Primary outcome was executive function measured through Trailmaking B, with other secondary cognitive measures. Genetic risk profile and ApoE4 status were determined by Illumina Array. START conferred benefit to executive function, attention, memory, and a composite measure, including in people with the ApoE4 genotype. The 3-minute START task offers a means of supporting cognitive health in older adults and could be used at scale and within a precision medicine approach to reduce risk of cognitive decline in a targeted way. [ABSTRACT FROM AUTHOR]

Suicide is a leading cause of death worldwide. Whereas some studies have suggested that a direct measure of common genetic liability for suicide attempts (SA), captured by a polygenic risk score for SA (SA-PRS), explains risk independent of parental history, further confirmation would be useful. Even more unsettled is the extent to which SA-PRS is associated with lifetime non-suicidal self-injury (NSSI). We used summary statistics from the largest available GWAS study of SA to generate SA-PRS for two non-overlapping cohorts of soldiers of European ancestry. These were tested in multivariable models that included parental major depressive disorder (MDD) and parental SA. In the first cohort, 417 (6.3 %) of 6573 soldiers reported lifetime SA and 1195 (18.2 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.26, 95%CI:1.13–1.39, p < 0.001] per standardized unit SA-PRS]. In the second cohort, 204 (4.2 %) of 4900 soldiers reported lifetime SA, and 299 (6.1 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.20, 95%CI:1.04–1.38, p = 0.014]. A combined analysis of both cohorts yielded similar results. In neither cohort or in the combined analysis was SA-PRS significantly associated with NSSI. PRS for SA conveys information about likelihood of lifetime SA (but not NSSI, demonstrating specificity), independent of self-reported parental history of MDD and parental history of SA. At present, the magnitude of effects is small and would not be immediately useful for clinical decision-making or risk-stratified prevention initiatives, but this may be expected to improve with further iterations. Also critical will be the extension of these findings to more diverse populations. • Polygenic risk for suicide attempt (SA) is associated with history of suicide attempts in US Army soldiers. • This association is seen for suicide attempts but not with non-suicidal self-injury • Polygenic risk indices for SA may contribute in the future to the identification of at-risk individuals. [ABSTRACT FROM AUTHOR]

AbstractObjective: Our study aimed to explore whether physical condition might affect the association between genetic predisposition for Alzheimer’s Disease (AD) and AD incidence. Methods: The sample of participants consisted of 561 community-dwelling adults over 64 years old, without baseline dementia (508 cognitively normal and 53 with mild cognitive impairment), deriving from the HELIAD, an ongoing longitudinal study with follow-up evaluations every 3 years. Physical condition was assessed at baseline through walking time (WT), while a Polygenic Risk Score for late onset AD (PRS-AD) was used to estimate genetic predisposition. The association between WT and PRS-AD with AD incidence was evaluated with Cox proportional hazard models adjusted for age, sex, education years, global cognition score and APOE ε-4 genotype. Then, the association between WT and AD incidence was investigated after stratifying participants by low and high PRS-AD. Finally, we examined the association between PRS-AD and AD incidence after stratifying participants by WT. Results: Both WT and PRS-AD were connected with increased AD incidence (p < 0.05), after adjustments. In stratified analyses, in the slow WT group participants with a greater genetic risk had a 2.5-fold higher risk of developing AD compared to participants with lower genetic risk (p = 0.047). No association was observed in the fast WT group or when participants were stratified based on PRS-AD. Conclusions: Genetic predisposition for AD is more closely related to AD incidence in the group of older adults with slow WT. Hence, physical condition might be a modifier in the relationship of genetic predisposition with AD incidence. [ABSTRACT FROM AUTHOR]

Background: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. Results: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02–5.61, P = 1.1E−03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. Conclusions: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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; agescan 1 = 62.38 ± 7.23 years; agescan 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.

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.

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Cognitive decline is a public health concern affecting about 50 million individuals worldwide. Neuroticism, defined as the trait disposition to experience intense and frequent negative emotions, has been associated with an increased risk of late-life cognitive decline. However, the underlying biological mechanisms of this association remain unknown. This study investigated the relationship between genetic predisposition to neuroticism, computed by polygenic risk score (PRS), and performance in cognitive domains of reasoning, processing speed, visual attention, and memory in individuals over age 60. The sample consisted of UK Biobank participants with genetic and cognitive data available (N = 10,737, 4686 females; mean age = 63.4 ± 2.71). The cognitive domains were assessed at baseline for all participants and seven years later for a subset (N = 645, 262 females; mean age = 62.9 ± 2.44). Neuroticism PRS was not associated cross-sectionally with cognitive measures (p > 0.05). However, the trajectory of change for processing speed (β = 0.020; 95% CI = [0.006, 0.035], adjusted p = 0.0148), visual attention (β = −0.077; 95% CI = [−0.0985, −0.0553], adjusted p = 1.412 × 10−11), and memory (β = −0.033; 95% CI = [−0.0535, −0.0131], adjusted p = 0.005) was significantly associated with neuroticism PRS. Specifically, a higher genetic predisposition to neuroticism was associated with less decline in these cognitive domains. This trend persisted after sensitivity analysis using complete cases, although it only remained nominally significant for visual attention.

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

Abstract Background Associations between kidney function and dementia risk are inconclusive. Chronic kidney disease (CKD) severity is determined by levels of both estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR). However, whether there is a graded increase in dementia risk for worse eGFR in each ACR category is unclear. Also, whether genetic risk for dementia impacts the associations is unknown. The current study aims to investigate the associations between eGFR and albuminuria with dementia risk both individually and jointly, whether the associations vary by different follow-up periods, and whether genetic factors modified the associations. Methods In 202,702 participants aged ≥ 60 years from the UK Biobank, Cox proportional-hazards models were used to examine the associations between eGFR and urine albumin creatinine ratio (ACR) with risk of incident dementia. GFR was estimated based on serum creatinine, cystatin C, or both. The models were restricted to different follow-up periods (

Abstract Background & aims We aimed to assess the performance of European-derived polygenic risk scores (PRSs) for common metabolic diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D) in the South Asian (SAS) individuals in the UK Biobank. Additionally, we studied the interaction between PRS and family history (FH) in the same population. Methods To calculate the PRS, we used a previously published model derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. Each PRS was adjusted according to an individual’s genotype location in the principal components (PC) space to derive an ancestry adjusted PRS (aPRS). We calculated the percentiles based on aPRS and stratified individuals into three aPRS categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates. Further, we measured the combined role of aPRS and first-degree family history (FH) in the SAS population. Results The risk of developing severe obesity for SAS individuals was almost twofold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 1.95 (95% CI = 1.71–2.23, P

Background: Understanding the interplay between psychosocial factors and polygenic risk scores (PRS) may help elucidate the biopsychosocial etiology of high alcohol consumption (HAC). This study examined the psychosocial moderators of HAC, determined by polygenic risk in a 10-year longitudinal study of US military veterans. We hypothesized that positive psychosocial traits (e.g. social support, personality traits, optimism, gratitude) may buffer risk of HAC in veterans with greater polygenic liability for alcohol consumption (AC). Methods: Data were analyzed from 1323 European-American US veterans who participated in the National Health and Resilience in Veterans Study, a 10-year, nationally representative longitudinal study of US military veterans. PRS reflecting genome-wide risk for AC (AUDIT-C) was derived from a Million Veteran Program genome-wide association study (N = 200 680). Results: Among the total sample, 328 (weighted 24.8%) had persistent HAC, 131 (weighted 9.9%) had new-onset HAC, 44 (weighted 3.3%) had remitted HAC, and 820 (weighted 62.0%) had no/low AC over the 10-year study period. AUDIT-C PRS was positively associated with persistent HAC relative to no/low AC [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI) = 1.23–1.67] and remitted HAC (RRR = 1.63, 95% CI = 1.07–2.50). Among veterans with higher AUDIT-C PRS, greater baseline levels of agreeableness and greater dispositional gratitude were inversely associated with persistent HAC. Conclusions: AUDIT-C PRS was prospectively associated with persistent HAC over a 10-year period, and agreeableness and dispositional gratitude moderated this association. Clinical interventions designed to target these modifiable psychological traits may help mitigate risk of persistent HAC in veterans with greater polygenic liability for persistent HAC. [ABSTRACT FROM AUTHOR]

Background: Depression and anxiety are common and highly comorbid, and their comorbidity is associated with poorer outcomes posing clinical and public health concerns. We evaluated the polygenic contribution to comorbid depression and anxiety, and to each in isolation. Methods: Diagnostic codes were extracted from electronic health records for four biobanks [ N = 177 865 including 138 632 European (77.9%), 25 612 African (14.4%), and 13 621 Hispanic (7.7%) ancestry participants]. The outcome was a four-level variable representing the depression/anxiety diagnosis group: neither, depression-only, anxiety-only, and comorbid. Multinomial regression was used to test for association of depression and anxiety polygenic risk scores (PRSs) with the outcome while adjusting for principal components of ancestry. Results: In total, 132 960 patients had neither diagnosis (74.8%), 16 092 depression-only (9.0%), 13 098 anxiety-only (7.4%), and 16 584 comorbid (9.3%). In the European meta-analysis across biobanks, both PRSs were higher in each diagnosis group compared to controls. Notably, depression-PRS (OR 1.20 per s.d. increase in PRS; 95% CI 1.18–1.23) and anxiety-PRS (OR 1.07; 95% CI 1.05–1.09) had the largest effect when the comorbid group was compared with controls. Furthermore, the depression-PRS was significantly higher in the comorbid group than the depression-only group (OR 1.09; 95% CI 1.06–1.12) and the anxiety-only group (OR 1.15; 95% CI 1.11–1.19) and was significantly higher in the depression-only group than the anxiety-only group (OR 1.06; 95% CI 1.02–1.09), showing a genetic risk gradient across the conditions and the comorbidity. Conclusions: This study suggests that depression and anxiety have partially independent genetic liabilities and the genetic vulnerabilities to depression and anxiety make distinct contributions to comorbid depression and anxiety. [ABSTRACT FROM AUTHOR]

To deepen the understanding of genetic mechanisms influencing mortality risk, we investigated the impact of genetic predisposition to longevity and APOE -ε4, on all-cause mortality and specific causes of mortality. We further investigated the mediating effects of dementia on these relationships. Using data on 7 131 adults aged ≥50 years (mean = 64.7 years, standard deviation [ SD ] = 9.5) from the English Longitudinal Study of Aging, genetic predisposition to longevity was calculated using the polygenic score approach (PGSlongevity). APOE -ε4 status was defined according to the absence or presence of ε4 alleles. The causes of death were ascertained from the National Health Service central register, which was classified into cardiovascular diseases, cancers, respiratory illness, and all other causes of mortality. Of the entire sample, 1 234 (17.3%) died during an average 10-year follow-up. One- SD increase in PGSlongevity was associated with a reduced risk for all-cause mortality (hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.88–0.98, p =.010) and mortalities due to other causes (HR = 0.81, 95% CI: 0.71–0.93, p =.002) in the following 10 years. In gender-stratified analyses, APOE -ε4 status was associated with a reduced risk for all-cause mortality and mortalities related to cancers in women. Mediation analyses estimated that the percent excess risk of APOE -ε4 on other causes of mortality risk explained by the dementia diagnosis was 24%, which increased to 34% when the sample was restricted to adults who were aged ≤75 years old. To reduce the mortality rate in adults who are aged ≥50 years old, it is essential to prevent dementia onset in the general population. [ABSTRACT FROM AUTHOR]

Early‐onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early‐life factors and EOCRC risk, with a particular focus on long‐term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC‐related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early‐onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early‐life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early‐onset CRC (OR = 1.48, 95% CI = 1.01‐2.17, P =.046) and adenomas (OR = 1.40, 95% CI = 1.17‐1.68, P <.001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early‐onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79‐1.52, P =.587, for CC genotype; OR = 1.75, 95% CI = 1.16‐2.64, P =.008, for TT genotype; Pinteraction =.089). Our study suggested that LRAU during early life is associated with increased risk of early‐onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome‐related pathway underlying colorectal carcinogenesis, are warranted. [ABSTRACT FROM AUTHOR]

Background: Little is known about environmental factors that may influence associations between genetic liability to suicidality and suicidal behavior. Methods: This study examined whether a suicidality polygenic risk score (PRS) derived from a large genome-wide association study (N = 122,935) was associated with suicide attempts in a population-based sample of European-American US military veterans (N = 1664; 92.5% male), and whether cumulative lifetime trauma exposure moderated this association. Results: Eighty-five veterans (weighted 6.3%) reported a history of suicide attempt. After adjusting for sociodemographic and psychiatric characteristics, suicidality PRS was associated with lifetime suicide attempt (odds ratio 2.65; 95% CI 1.37–5.11). A significant suicidality PRS-by-trauma exposure interaction emerged, such that veterans with higher levels of suicidality PRS and greater trauma burden had the highest probability of lifetime suicide attempt (16.6%), whereas the probability of attempts was substantially lower among those with high suicidality PRS and low trauma exposure (1.4%). The PRS-by-trauma interaction effect was enriched for genes implicated in cellular and developmental processes, and nervous system development, with variants annotated to the DAB2 and SPNS2 genes, which are implicated in inflammatory processes. Drug repurposing analyses revealed upregulation of suicide gene-sets in the context of medrysone, a drug targeting chronic inflammation, and clofibrate, a triacylglyceride level lowering agent. Conclusion: Results suggest that genetic liability to suicidality is associated with increased risk of suicide attempt among veterans, particularly in the presence of high levels of cumulative trauma exposure. Additional research is warranted to investigate whether incorporation of genomic information may improve suicide prediction models. [ABSTRACT FROM AUTHOR]

The polygenic risk score (PRS), together with the ɛ4 allele of the APOE gene (APOE-ɛ4), has shown high potential for Alzheimer's disease (AD) risk prediction. The aim of this study was to validate the model of polygenic risk in Russian patients with dementia. A microarray-based assay was developed to identify 21 markers of polygenic risk and ɛ alleles of the APOE gene. This case–control study included 348 dementia patients and 519 cognitively normal volunteers. Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau protein levels were assessed in 57 dementia patients. PRS and APOE-ɛ4 were significant genetic risk factors for dementia. Adjusted for APOE-ɛ4, individuals with PRS corresponding to the fourth quartile had an increased risk of dementia compared to the first quartile (OR 1.85; p-value 0.002). The area under the curve (AUC) was 0.559 for the PRS model only, and the inclusion of APOE-ɛ4 improved the AUC to 0.604. PRS was positively correlated with tTau and pTau181 and inversely correlated with Aβ42/Aβ40 ratio. Carriers of APOE-ɛ4 had higher levels of tTau and pTau181 and lower levels of Aβ42 and Aβ42/Aβ40. The developed assay can be part of a strategy for assessing individuals for AD risk, with the purpose of assisting primary preventive interventions. [ABSTRACT FROM AUTHOR]

Early‐onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early‐onset AD patients without an identified autosomal dominant cause, we hypothesized that their early‐onset disease reflects further enrichment of the common risk‐conferring single nucleotide polymorphisms associated with late‐onset AD. We applied a previously validated polygenic hazard score for late‐onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early‐onset AD. For comparison, we included 179 participants with late‐onset AD and 70 healthy controls. Polygenic hazard scores were similar in early‐ versus late‐onset AD. The polygenic hazard score was not associated with age‐of‐onset or disease biomarkers within early‐onset AD. Early‐onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late‐onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted. Highlights: There is a unique genetic architecture of early‐ versus late‐onset Alzheimer's disease (AD).Late‐onset AD polygenic risk is not an explanation for early‐onset AD.Polygenic risk of late‐onset AD does not predict early‐onset AD biology.Unique genetic architecture of early‐ versus late‐onset AD parallels AD heterogeneity. [ABSTRACT FROM AUTHOR]

Abstract Early‐onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early‐onset AD patients without an identified autosomal dominant cause, we hypothesized that their early‐onset disease reflects further enrichment of the common risk‐conferring single nucleotide polymorphisms associated with late‐onset AD. We applied a previously validated polygenic hazard score for late‐onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early‐onset AD. For comparison, we included 179 participants with late‐onset AD and 70 healthy controls. Polygenic hazard scores were similar in early‐ versus late‐onset AD. The polygenic hazard score was not associated with age‐of‐onset or disease biomarkers within early‐onset AD. Early‐onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late‐onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted. Highlights There is a unique genetic architecture of early‐ versus late‐onset Alzheimer's disease (AD). Late‐onset AD polygenic risk is not an explanation for early‐onset AD. Polygenic risk of late‐onset AD does not predict early‐onset AD biology. Unique genetic architecture of early‐ versus late‐onset AD parallels AD heterogeneity.

Objective: To examine sex differences in risk factors for anorexia nervosa (AN). Method: This population‐based study involved 44,743 individuals (6,239 AN cases including 5,818 females and 421 males, and 38,504 controls including 18,818 females and 19,686 males) born in Denmark between May 1981 and December 2009. Follow‐up began on the individual's sixth birthday and ended at AN diagnosis, emigration, death, or December 31, 2016, whichever occurred first. Exposures included socioeconomic status (SES), pregnancy, birth, and early childhood factors based on data from Danish registers, and psychiatric and metabolic polygenic risk scores (PRS) based on genetic data. Hazard ratios were estimated using weighted Cox proportional hazards models stratified by sex (assigned at birth), with AN diagnosis as the outcome. Results: The effects of early life exposures and PRS on AN risk were comparable between females and males. Although we observed some differences in the magnitude and direction of effects, there were no significant interactions between sex and SES, pregnancy, birth, or early childhood exposures. The effects of most PRS on AN risk were highly similar between the sexes. We observed significant sex‐specific effects of parental psychiatric history and body mass index PRS, though these effects did not survive corrections for multiple comparisons. Conclusions: Risk factors for AN are comparable between females and males. Collaboration across countries with large registers is needed to further investigate sex‐specific effects of genetic, biological, and environmental exposures on AN risk, including exposures in later childhood and adolescence as well as the additive effects of exposures. Public significance: Sex differences in the prevalence and clinical presentation of AN warrant examination of sex‐specific risk factors. This population‐based study indicates that the effects of polygenic risk and early life exposures on AN risk are comparable between females and males. Collaboration between countries with large registers is needed to further investigate sex‐specific AN risk factors and improve early identification of AN. [ABSTRACT FROM AUTHOR]

Dietary advanced glycation end products (AGEs) might exert adverse effects on cognition. The associations between dietary AGEs and long-term risk of dementia are yet to be assessed in large population studies. We aimed to explore whether elevated dietary AGEs intake is associated with increased risk of dementia, and whether this association might be affected by genetic risk. A prospective cohort study, which included a total of 93,830 participants (aged≥ 50 years) free from dementia at baseline of the UK Biobank study (2006–2010) and had at least two 24-h dietary assessments and were followed up until 2021. Dietary AGEs, including Nε-(1-Carboxyethyl)- l -lysine (CEL), Nε-(carboxymethyl) lysine (CML), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated via averaged data from the multiple 24-h food assessments according to the ultra-performance LC–tandem MS based dAGEs database. Incidence of all-cause dementia was ascertained through hospital inpatient and mortality records. Multivariable Cox regression models were utilized to estimate hazards ratios (HRs) and 95% confidence interval (CI) of dementia risk associated with dietary AGEs. During a median follow-up of 11.9 years, 728 participants developed dementia. In multivariable adjusted model, when comparing the highest with the lowest tertile of intake level, HRs (95% CI) of dementia were 1.43 (1.16, 1.76) for total AGEs Z score, 1.53 (1.25, 1.89) for CEL, 1.27 (1.03, 1.56) for CML and 1.24 (1.02, 1.52) for MG-H1 (all P trend<0.01). There was no significant interaction between dietary AGEs intake, genetic risk and APOE ε4 carrier status for dementia. Higher intakes of dietary AGEs including CEL, CML and MG-H1 were associated with a higher risk of dementia, independent from genetic risk, highlighting the significance of dietary AGEs restriction for dementia prevention. [ABSTRACT FROM AUTHOR]

Schizotypy is a multidimensional construct that captures a continuum of risk for developing schizophrenia-spectrum psychopathology. Existing 3-factor models of schizotypy, consisting of positive, negative, and disorganized dimensions have yielded mixed evidence of genetic continuity with schizophrenia using polygenic risk scores. Here, we propose an approach that involves splitting positive and negative schizotypy into more specific subdimensions that are phenotypically continuous with distinct positive symptoms and negative symptoms recognized in clinical schizophrenia. We used item response theory to derive high-precision estimates of psychometric schizotypy using 251 self-report items obtained from a non-clinical sample of 727 (424 females) adults. These subdimensions were organized hierarchically using structural equation modeling into 3 empirically independent higher-order dimensions enabling associations with polygenic risk for schizophrenia to be examined at different levels of phenotypic generality and specificity. Results revealed that polygenic risk for schizophrenia was associated with variance specific to delusional experiences (γ = 0.093, P =.001) and reduced social interest and engagement (γ = 0.076, P =.020), and these effects were not mediated via the higher-order general, positive, or negative schizotypy factors. We further fractionated general intellectual functioning into fluid and crystallized intelligence in 446 (246 females) participants that underwent onsite cognitive assessment. Polygenic risk scores explained 3.6% of the variance in crystallized intelligence. Our precision phenotyping approach could be used to enhance the etiologic signal in future genetic association studies and improve the detection and prevention of schizophrenia-spectrum psychopathology. [ABSTRACT FROM AUTHOR]

Background: Associations between kidney function and dementia risk are inconclusive. Chronic kidney disease (CKD) severity is determined by levels of both estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR). However, whether there is a graded increase in dementia risk for worse eGFR in each ACR category is unclear. Also, whether genetic risk for dementia impacts the associations is unknown. The current study aims to investigate the associations between eGFR and albuminuria with dementia risk both individually and jointly, whether the associations vary by different follow-up periods, and whether genetic factors modified the associations. Methods: In 202,702 participants aged ≥ 60 years from the UK Biobank, Cox proportional-hazards models were used to examine the associations between eGFR and urine albumin creatinine ratio (ACR) with risk of incident dementia. GFR was estimated based on serum creatinine, cystatin C, or both. The models were restricted to different follow-up periods (< 5 years, 5–10 years, and ≥ 10 years) to investigate potential reverse causation. Results: Over 15 years of follow-up, 6,042 participants developed dementia. Decreased kidney function (eGFR < 60 ml/min/1.73m2) was associated with an increased risk of dementia (Hazard Ratio [HR] = 1.42, 95% Confidence Interval [CI] 1.28–1.58), compared to normal kidney function (≥ 90 ml/min/1.73m2). The strength of the association remained consistent when the models were restricted to different periods of follow-up. The HRs for incident dementia were 1.16 (95% CI 1.07–1.26) and 2.24 (95% CI 1.79–2.80) for moderate (3-30 mg/mmol) and severely increased ACR (≥ 30 mg/mmol) compared to normal ACR (< 3 mg/mmol). Dose–response associations were observed when combining eGFR and ACR, with those in the severest eGFR and ACR group having the greatest risk of dementia (HR = 4.70, 95% CI 2.34–9.43). APOE status significantly modified the association (p = 0.04), with stronger associations observed among participants with a lower genetic risk of dementia. There was no evidence of an interaction between kidney function and non-APOE polygenic risk of dementia with dementia risk (p = 0.42). Conclusions: Kidney dysfunction and albuminuria were individually and jointly associated with higher dementia risk. The associations were greater amongst participants with a lower genetic risk of dementia based on APOE, but not non-APOE polygenic risk. [ABSTRACT FROM AUTHOR]

Alterations in fMRI-based brain functional network connectivity (FNC) are associated with schizophrenia (SCZ) and the genetic risk or subthreshold clinical symptoms preceding the onset of SCZ, which often occurs in early adulthood. Thus, age-sensitive FNC changes may be relevant to SCZ risk-related FNC. We used independent component analysis to estimate FNC from childhood to adulthood in 9,236 individuals. To capture individual brain features more accurately than single-session fMRI, we studied an average of three fMRI scans per individual. To identify potential familial risk-related FNC changes, we compared age-related FNC in first-degree relatives of SCZ patients mostly including unaffected siblings (SIB) with neurotypical controls (NC) at the same age stage. Then, we examined how polygenic risk scores for SCZ influenced risk-related FNC patterns. Finally, we investigated the same risk-related FNC patterns in adult SCZ patients (oSCZ) and young individuals with subclinical psychotic symptoms (PSY). Age-sensitive risk-related FNC patterns emerge during adolescence and early adulthood, but not before. Young SIB always followed older NC patterns, with decreased FNC in a cerebellar-occipitoparietal circuit and increased FNC in two prefrontal-sensorimotor circuits when compared to young NC. Two of these FNC alterations were also found in oSCZ, with one exhibiting reversed pattern. All were linked to polygenic risk for SCZ in unrelated individuals (R2 varied from 0.02 to 0.05). Young PSY showed FNC alterations in the same direction as SIB when compared to NC. These results suggest that age-related neurotypical FNC correlates with genetic risk for SCZ and is detectable with MRI in young participants. [ABSTRACT FROM AUTHOR]

Background & aims: We aimed to assess the performance of European-derived polygenic risk scores (PRSs) for common metabolic diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D) in the South Asian (SAS) individuals in the UK Biobank. Additionally, we studied the interaction between PRS and family history (FH) in the same population. Methods: To calculate the PRS, we used a previously published model derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. Each PRS was adjusted according to an individual's genotype location in the principal components (PC) space to derive an ancestry adjusted PRS (aPRS). We calculated the percentiles based on aPRS and stratified individuals into three aPRS categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates. Further, we measured the combined role of aPRS and first-degree family history (FH) in the SAS population. Results: The risk of developing severe obesity for SAS individuals was almost twofold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 1.95 (95% CI = 1.71–2.23, P < 0.01). At the same time, the risk of severe obesity was lower in the low-aPRS group (OR = 0.60, CI = 0.53–0.67, P < 0.01). Results in the same direction were found in the EUR data, where the low-PRS group had an OR of 0.53 (95% CI = 0.51–0.56, P < 0.01) and the high-PRS group had an OR of 2.06 (95% CI = 2.00-2.12, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS are associated with a higher risk of these diseases, implying a greater genetic predisposition. Conclusion: Our findings suggest that CAD, obesity, and T2D GWAS summary statistics generated predominantly from the EUR population can be potentially used to derive aPRS in SAS individuals for risk stratification. With future GWAS recruiting more SAS participants and tailoring the PRSs towards SAS ancestry, the predictive power of PRS is likely to improve further. [ABSTRACT FROM AUTHOR]

BACKGROUND: The aging of the worlds population leads to an increase in the prevalence of age-related diseases, including cognitive impairment. At the stage of dementia, therapeutic interventions become usually ineffective. Therefore, researchers and clinical practitioners today are looking for methods that allow for early diagnosis of cognitive impairment, including techniques that are based on the use of biological markers. AIM: The aim of this literature review is to delve into scientific papers that are centered on modern laboratory tests for Alzheimers disease, including tests for biological markers at the early stages of cognitive impairment. METHODS: The authors have carried out a descriptive review of scientific papers published from 2015 to 2023. Studies that are included in the PubMed and Web of Science electronic databases were analyzed. A descriptive analysis was used to summarized the gleaned information. RESULTS: Blood and cerebrospinal fluid (CSF) biomarkers, as well as the advantages and disadvantages of their use, are reviewed. The most promising neurotrophic, neuroinflammatory, and genetic markers, including polygenic risk models, are also discussed. CONCLUSION: The use of biomarkers in clinical practice will contribute to the early diagnosis of cognitive impairment associated with Alzheimers disease. Genetic screening tests can improve the detection threshold of preclinical abnormalities in the absence of obvious symptoms of cognitive decline. The active use of biomarkers in clinical practice, in combination with genetic screening for the early diagnosis of cognitive impairment in Alzheimers disease, can improve the timeliness and effectiveness of medical interventions.

Abstract Background The identification of effective dementia prevention strategies is a major public health priority, due to the enormous and growing societal cost of this condition. Consumption of a Mediterranean diet (MedDiet) has been proposed to reduce dementia risk. However, current evidence is inconclusive and is typically derived from small cohorts with limited dementia cases. Additionally, few studies have explored the interaction between diet and genetic risk of dementia. Methods We used Cox proportional hazard regression models to explore the associations between MedDiet adherence, defined using two different scores (Mediterranean Diet Adherence Screener [MEDAS] continuous and Mediterranean diet Pyramid [PYRAMID] scores), and incident all-cause dementia risk in 60,298 participants from UK Biobank, followed for an average 9.1 years. The interaction between diet and polygenic risk for dementia was also tested. Results Higher MedDiet adherence was associated with lower dementia risk (MEDAS continuous: HR = 0.77, 95% CI = 0.65–0.91; PYRAMID: HR = 0.86, 95% CI = 0.73–1.02 for highest versus lowest tertiles). There was no significant interaction between MedDiet adherence defined by the MEDAS continuous and PYRAMID scores and polygenic risk for dementia. Conclusions Higher adherence to a MedDiet was associated with lower dementia risk, independent of genetic risk, underlining the importance of diet in dementia prevention interventions.

Abstract Background Schizophrenia (SZ) arises from a complex interplay involving genetic and molecular factors. Early intervention of SZ hinges upon understanding its vulnerability and resiliency factors in study of SZ and genetic high risk for SZ (GHR). Methods Herein, using integrative and multimodal strategies, we first performed a longitudinal study of neural function as measured by amplitude of low frequency function (ALFF) in 21 SZ, 26 GHR, and 39 healthy controls to characterize neurodevelopmental trajectories of SZ and GHR. Then, we examined the relationship between polygenic risk score for SZ (SZ-PRS), lipid metabolism, and ALFF in 78 SZ, and 75 GHR in cross-sectional design to understand its genetic and molecular substrates. Results Across time, SZ and GHR diverge in ALFF alterations of the left medial orbital frontal cortex (MOF). At baseline, both SZ and GHR had increased left MOF ALFF compared to HC (P