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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]

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: 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]

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]

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]

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]

Anxiety is characterized by altered brain networks. Directional information flows among dynamic brain networks concerning neuropathogenesis of anxiety have not yet been investigated. The role of directional influences between networks in gene--environment effects on anxiety remains to be further elucidated. In a large community sample, this resting-state functional MRI study estimated dynamic effective connectivity among large-scale brain networks based on a sliding-window approach and Granger causality analysis, providing dynamic and directional information for signal transmission in networks. We first explored altered effective connectivity among networks related to anxiety in distinct connectivity states. Due to the potential gene--environment effects on brain and anxiety, we further performed mediation and moderated mediation analyses to investigate the role of altered effective connectivity networks in relationships between polygenic risk scores, childhood trauma, and anxiety. State and trait anxiety scores showed correlations with altered effective connectivity among extensive networks in distinct connectivity states (p < .05, uncorrected). Only in a more frequent and strongly connected state, there were significant correlations between altered effective connectivity networks and trait anxiety (PFDR <0.05). Furthermore, mediation and moderated mediation analyses showed that the effective connectivity networks played a mediating role in the effects of childhood trauma and polygenic risk on trait anxiety. State-dependent effective connectivity changes among brain networks were significantly related to trait anxiety, and mediated gene--environment effects on trait anxiety. Our work sheds novel light on the neurobiological mechanisms underlying anxiety, and provides new insights into early objective diagnosis and intervention evaluation. [ABSTRACT FROM AUTHOR]

Background: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome‐wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. Methods: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent‐trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV‐carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population‐matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome‐wide association data, expression, protein–protein‐interactions), were used for final prioritization. Conclusion: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re‐sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations. [ABSTRACT FROM AUTHOR]

Introduction: There is inconsistent evidence on whether genetic risk for dementia modifies the association between hypertension and dementia. Methods: In 198,965 dementia‐free participants aged ≥60 years, Cox proportional‐hazards models were used to investigate the association between hypertension and incident dementia. A polygenic risk score (PRS) based on 38 non‐apolipoprotein E (APOE) single nucleotide polymorphisms and APOE ε4 status were used to determine genetic risk for dementia. Results: Over 15 years follow‐up, 6270 participants developed dementia. Hypertension was associated with a 19% increased risk of dementia (hazard ratio = 1.19, 95% confidence interval 1.11–1.27). The associations remained similar when stratifying by genetic risk, with no evidence for multiplicative interaction by dementia PRS (P = 0.20) or APOE ε4 status (P = 0.16). However, the risk difference between those with and without hypertension was larger among those at higher genetic risk. Discussion: Hypertension was associated with an increased risk of dementia regardless of genetic risk for dementia. [ABSTRACT FROM AUTHOR]

To comprehensively investigate the risk factors associated with depression, traditional Chinese medicine constitution (TCMC) has been found to be related to depression. However, the underlying mechanism remains unclear. This study examined the association between the concept of unbalanced TCMCs and major depressive disorder (MDD), investigated the overlapping polygenic risks between unbalanced TCMC and MDD, and performed a mediation test to establish potential pathways. In total, 11,030 individuals were recruited from the Taiwan Biobank, and the polygenic risk score (PRS) for MDD for each participant was calculated using the data from the Psychiatric Genomics Consortium. Unbalanced TCMC were classified as yang-deficiency, yin-deficiency, and stasis. The MDD PRS was associated with yang-deficiency odds ratio [OR] per standard deviation increase in standardized (PRS = 1.07, p = 0.0080), yin-deficiency (OR = 1.07, p = 0.0030), and stasis constitution (OR = 1.06, p = 0.0331). Yang-deficiency (OR = 2.07, p < 0.0001) and stasis constitutions (OR = 1.65, p = 0.0015) were associated with an increased risk of MDD. A higher number of unbalanced constitutions was associated with MDD (p < 0.0001). The effect of MDD PRS on MDD was partly mediated by yang-deficiency (10.21%) and stasis (8.41%) constitutions. This study provides evidence for the shared polygenic risk mechanism underlying depression and TCMC and the potential mediating role of TCMC in the polygenic liability for MDD., (© 2024 Wiley Periodicals LLC.)

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 <0.001). No associations were found for 4 other PGSs for LA measures or for risk of systemic arterial embolism. Two-sample Mendelian randomization was conducted between LA measures and cardioembolic stroke and indicated a protective effect of higher LA functional measurements., Conclusions: The PGS for LA passive emptying fraction was significantly associated with incident ischemic stroke when considering AF as a competing risk. Consistent results were found in Mendelian randomization analyses. These findings suggest that atrial dysfunction may influence stroke risk independently of AF.

Background: Joint developmental trajectories of internalizing and externalizing problems show considerable heterogeneity; however, this can be parsed into a small number of meaningful subgroups. Doing so offered insights into risk factors that lead to different patterns of internalizing/externalizing trajectories. However, despite both domains of problems showing strong heritability, no study has yet considered genetic risks as predictors of joint internalizing/externalizing problem trajectories. Methods: Using parallel process latent class growth analysis, we estimated joint developmental trajectories of internalizing and externalizing difficulties assessed across ages 4 to 16 using the Strengths and Difficulties Questionnaire. Multinomial logistic regression was used to evaluate a range of demographic, perinatal, maternal mental health, and child and maternal polygenic predictors of group membership. Participants included 11,049 children taking part in the Avon Longitudinal Study of Parents and Children. Polygenic data were available for 7,127 children and 6,836 mothers. Results: A 5‐class model was judged optimal: Unaffected, Moderate Externalizing Symptoms, High Externalizing Symptoms, Moderate Internalizing and Externalizing Symptoms and High Internalizing and Externalizing Symptoms. Male sex, lower maternal age, maternal mental health problems, maternal smoking during pregnancy, higher child polygenic risk scores for ADHD and lower polygenic scores for IQ distinguished affected classes from the unaffected class. Conclusions: While affected classes could be relatively well separated from the unaffected class, phenotypic and polygenic predictors were limited in their ability to distinguish between different affected classes. Results thus add to existing evidence that internalizing and externalizing problems have mostly shared risk factors. [ABSTRACT FROM AUTHOR]

Background: The interplay between cardiovascular disease (CVD) genetic risk indexed by a polygenic risk score (PRS) and diet quality still requires further investigation amongst older adults or those with established or treated CVD. The present study aimed to evaluate the relative contribution of diet quality, measured using the Australian Recommended Food Score (ARFS) and PRS, with respect to explaining variation in plasma lipids CVD outcomes in the Hunter Cohort. Methods: The study comprised a secondary analysis of cross‐sectional data from the Hunter Cohort study. Single‐nucleotide polymorphisms from previously derived polygenic scores (PGSs) for three lipid classes were obtained: low‐density lipoprotein, high‐density lipoprotein and triglycerides, as well as PRS for coronary artery disease (CAD) from the PGS catalogue. Regression modelling and odds ratios were used to determine associations between PRS, ARFS and CVD risk. Results: In total, 1703 participants were included: mean ± SD age 66 ± 7.4 years, 51% female, mean ± SD total ARFS 28.1 ± 8 (out of 74). Total diet quality and vegetable subscale were not significantly associated with measured lipids. By contrast, PGS for each lipid demonstrated a markedly strong, statistically significant correlation with its respective measured lipid. There was a significant association between CAD PRS and 5/6 CVD phenotypes (all except atrial fibrillation), with the largest effect size shown with coronary bypass. Adding dietary intake as a covariate did not change this relationship. Conclusions: Lipid PGS explained more variance in measured lipids than diet quality. However, the poor diet quality observed in the current cohort may have limited the ability to observe any beneficial effects. Future research should investigate whether the diet quality of older adults can be improved and also the effect of these improvements on changes in polygenic risk. Key points: The Australian Recommended Food Score (ARFS) had little association with lipid and cardiovascular disease (CVD) endpoints.Lipid polygenic score (PGS) explained more variance in measured lipids than diet quality.The lipid PGS was associated with all three lipid parameters and some CVD endpoints, especially high cholesterol.Coronary artery disease polygenic risk score was associated with CVD endpoints angina, coronary bypass, heart attack, high cholesterol and hypertension and some lipid parameters (high‐density lipoprotein cholesterol). [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to investigate the effect of genetic risk on whole brain white matter (WM) integrity in patients with Parkinson disease (PD). Methods: Data were acquired from the Parkinson's Progression Markers Initiative (PPMI) database. Polygenic load was estimated by calculating weighted polygenic risk scores (PRS) using (i) all available 26 PD‐risk single nucleotide polymorphisms (SNPs) (PRS1) and (ii) 23 SNPs with minor allele frequency (MAF) > 0.05 (PRS2). According to the PRS2, and combined with clinical and diffusion tensor imaging (DTI) data over 3‐year follow‐up, 60 PD patients were screened and assigned to the low‐PRS group (n = 30) and high‐PRS group (n = 30) to investigate intergroup differences in clinical profiles and WM microstructure measured by DTI cross‐sectionally and longitudinally. RESULTS: PRS were associated with younger age at onset in patients with PD (PRS1, Spearman ρ = −0.190, p = 0.003; PRS2, Spearman ρ = −0.189, p = 0.003). The high‐PRS group showed more extensive WM microstructural degeneration compared with the low‐PRS group, mainly involving the anterior thalamic radiation (AThR) and inferior fronto‐occipital fasciculus (IFOF) (p < 0.05). Furthermore, WM microstructural changes in AThR correlated with declining cognitive function (r = −0.401, p = 0.028) and increasing dopaminergic deficits in caudate (r = −0.405, p = 0.030). Conclusions: These findings suggest that PD‐associated polygenic load aggravates the WM microstructural degeneration and these changes may lead to poor cognition with continuous dopamine depletion. This study provides advanced evidence that combined with a cumulative PRS and DTI methods may predict disease progression in PD patients. [ABSTRACT FROM AUTHOR]

Introduction: SuperAgers are individuals over age 80 with superior episodic memory, at a level consistent with individuals 20 to 30 years their junior and who seem to show resistance to age-related neurofibrillary degeneration. Here we examine whether low genetic risk for Alzheimer's disease (AD) contributes to SuperAgers' unusually high episodicmemory performance in advanced age. Methods: TheADpolygenic hazard score (PHS) was calculated for each SuperAger and cognitively normal participant and compared between groups. Results: A total of 37 SuperAgers (73% female, mean [standard deviation] 82.7 [2.8] years old) and 35 controls (54% female, 83.7 [4.3] years old) were included. There was no significant difference in the AD PHS between SuperAgers and cognitively normal controls. Discussion: Unusually successful cognitive aging cannot be simply explained by low polygenic risk for AD as assessed by common genetic variants. However, rare variants and common protective genetic factors may contribute to resistance or resilience. [ABSTRACT FROM AUTHOR]

Background and Aims: Cannabis use (CU) is an etiologically complex behavior with several social, temperamental, neurocognitive, and behavioral precursors. Biometrical and molecular studies suggest an interplay of environmental and pleiotropic influences. However, it remains unclear whether identified genetic effects related to behavioral and temperamental characteristics have developmentally direct or indirect mechanisms on CU behavior. The Transmissible Liability Index (TLI) is a measure of continuous liability based on developmental precursors of substance use disorders. This study aimed to examine if the TLI plays a role in understanding genetic risk for CU behaviors. Design Genome‐wide association studies (n > 10 000; European Ancestry [EA]) of CU, risk tolerance, neuroticism, anxiety, and depression were used to construct polygenic scores (PGSs). Analyses assessed whether PGSs indirectly impacted risk for repeated use via TLI. Setting: United States of America. Participants: From Add Health study, 4077 individuals of EA age 11 to 21 during baseline interview collection. Measurements Outcomes were initiation and repeated cannabis use (>5× in lifetime). The TLI was parameterized using a latent factor from 21 questions assessing for precursors of disordered use. Findings The marker‐based heritability of TLI, initiation, and repeated use were significant, but modest (14%, P = 0.033; 15%, P = 0.025; and 17%, P = 0.008, respectively). TLI and repeated use were genetically correlated (rg = 0.76, P = 0.033). The PGS for CU was associated with increased risk for repeated use and PGS for risk tolerance and depression were associated with TLI. Mediation analyses indicated significant, but very weak, indirect effects of PGS for risk tolerance and depression on repeated CU via the TLI. Conclusions: Adolescent behavioral and temperamental characteristics (i.e. the Transmissible Liability Index) appear to be early indicators of repeated cannabis use in adulthood. Although polygenic scores for cannabis use directly increased risk for repeated cannabis use, weak evidence was found for the role of polygenic scores of other internalizing/externalizing traits acting through adolescent derived Transmissible Liability Index on cannabis use behavior. [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]

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross‐validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10‐fold cross‐validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross‐validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47‐4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65‐0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans. What's new? Polygenic models can provide personalized estimates of cancer risk. However, Africans are a population generally under‐served in genome‐wide studies. In this report, the authors used machine learning to identify three SNPs that significantly improved the performance of an established polygenic‐hazard model of prostate‐cancer risk vs age at diagnosis, specifically tailored to men of African genetic ancestry. Inclusion of these SNPs improved the performance of this novel 'PHS46+African' score by as much as 79% compared to the original model, to levels comparable with Europeans. [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]

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]

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]

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]

Introduction: Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. Methods: We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three‐ to eight‐year follow‐up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. Results: We found associations of cognitive task performance with all‐cause and cause‐specific dementia (P <.01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. Discussion: This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models. [ABSTRACT FROM AUTHOR]

Background: Genomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples. Methods: In 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol‐related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self‐Rating of the Effects of Ethanol Questionnaire (SRE‐T), DSM‐IV alcohol dependence (DSM4AD), DSM‐5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol‐related outcomes. We performed mixed‐effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD. Results: PRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R2 = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2 = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2 = 0.49%), MAXD (Δmarginal R2 = 0.31%), and SRE‐T (Δmarginal R2 = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e−5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Δmarginal R2 after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant. Conclusions: Genetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking. [ABSTRACT FROM AUTHOR]

Genome wide association studies have identified a number of common genetic variants - single nucleotide polymorphisms (SNPs) - that combine to increase breast cancer risk. SNP profiling may enhance the accuracy of risk assessment and provides a personalized risk estimate. SNP testing for breast cancer risks may supplement other genetic tests in the future, however, before it can be implemented in the clinic we need to know how it will be perceived and received. Semi-structured qualitative interviews were conducted with 39 women who had previously had a breast cancer diagnosis and undergone BRCA1/2 testing, participated in the Variants in Practice (ViP) study and received personalized risk (SNP) profiles. Interviews explored their understanding and experiences of receiving this SNP information. Women reported feeling positive about receiving their personalized risk profile, because it: provided an explanation for their previous diagnosis of cancer, vindicated previous risk management decisions and clarified their own and other family members’ risks. A small group was initially shocked to learn of the increased risk of a second primary breast cancer. This study suggests that the provision of personalized risk information about breast cancer generated by SNP profiling is understood and well received. However, a model of genetic counseling that incorporates monogenic and polygenic genetic information will need to be developed prior to clinical implementation. [ABSTRACT FROM AUTHOR]

Objective Schizophrenia ( SZ) and bipolar disorder ( BD) are heritable, polygenic disorders with shared clinical characteristics and genetic risk indicating a psychosis continuum. This is the first study using polygenic risk score ( PGRS) to investigate the localization of diagnostic subcategories along the entire psychosis spectrum. Method Based on results from the Psychiatric Genomics Consortium ( PGC), we assigned a SZ and BD PGRS to each individual in our independent sample [ N = 570 BD spectrum cases, 452 SZ spectrum cases and 415 healthy controls ( CTR)]. Potential differences in mean SZ and BD PGRS across diagnostic spectrums and subcategories were explored. Results SZ and BD PGRSs were significantly associated with both SZ and BD spectrums compared with CTR. For the subcategories, SZ PGRS was significantly associated with SZ, schizoaffective disorder, psychosis not otherwise specified, and BD1, while BD PGRS was significantly associated with BD1 and BD2. There were no significant differences between any of the diagnostic spectrums or subgroups for neither the SZ nor BD PGRS. Lifetime psychosis was significantly associated with SZ PGRS but not with BD PGRS. Conclusion These findings further support the psychosis continuum model and provide molecular polygenetic validation of the localization of diagnostic subcategories within this continuum. [ABSTRACT FROM AUTHOR]

Background Recent genetic discoveries in stroke have unleashed the potential of using genetic information for risk prediction and health interventions aimed at disease prevention. We sought to estimate the lifetime risk of stroke (LTRS) by levels of genetic risk and to investigate whether optimal cardiovascular health can offset the negative impact of high genetic risk on lifetime risk of stroke. Methods and Results Study participants were 11 568 middle-aged adults (56% women, 23% Black adults), who were free of stroke at baseline and were followed up for a median of 28 years. The remaining LTRS was estimated according to levels of genetic risk based on a validated stroke polygenic risk score, and to levels of cardiovascular health based on the American Heart Association Life's Simple 7 recommendations. At age 45, individuals with high, intermediate, and low polygenic risk score had a remaining LTRS of 23.2% (95% CI, 20.8%-25.5%), 13.8% (95% CI, 11.7%-15.8%), and 9.6% (95% CI, 7.3%-11.8%), respectively. Those with both a high genetic risk and an inadequate Life's Simple 7 experienced the highest LTRS: 24.8% (95% CI, 22.0%-27.6%). Across all polygenic risk score categories, those with an optimal Life's Simple 7 had a ≈30% to 43% lower LTRS than those with an inadequate Life's Simple 7. This corresponded to almost 6 additional years lived free of stroke. Conclusions The LTRS varies by levels of polygenic risk and cardiovascular health. Maintaining an optimal cardiovascular health can partially offset a high genetic risk, emphasizing the importance of modifiable risk factors and illustrating the potential of personalizing genetic risk information to motivate lifestyle changes for stroke prevention.

Suicide accounts for >800,000 deaths annually worldwide; prevention is an urgent public health issue. Identification of risk factors remains challenging due to complexity and heterogeneity. The study of suicide deaths with increased extended familial risk provides an avenue to reduce etiological heterogeneity and explore traits associated with increased genetic liability. Using extensive genealogical records, we identified high-risk families where distant relatedness of suicides implicates genetic risk. We compared phenotypic and polygenic risk score (PRS) data between suicides in high-risk extended families (high familial risk (HFR), n = 1,634), suicides linked to genealogical data not in any high-risk families (low familial risk (LFR), n = 147), and suicides not linked to genealogical data with unknown familial risk (UFR, n = 1,865). HFR suicides were associated with lower age at death (mean = 39.34 years), more suicide attempts, and more PTSD and trauma diagnoses. For PRS tests, we included only suicides with >90% European ancestry and adjusted for residual ancestry effects. HFR suicides showed markedly higher PRS of suicide death (calculated using cross-validation), supporting specific elevation of genetic risk of suicide in this subgroup, and also showed increased PRS of PTSD, suicide attempt, and risk taking. LFR suicides were substantially older at death (mean = 49.10 years), had fewer psychiatric diagnoses of depression and pain, and significantly lower PRS of depression. Results suggest extended familiality and trauma/PTSD may provide specificity in identifying individuals at genetic risk for suicide death, especially among younger ages, and that LFR of suicide warrants further study regarding the contribution of demographic and medical risks., (© 2022 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Suicide is a major public health problem. The contribution of common genetic variants for major depressive disorder (MDD) independent of personal and parental history of MDD has not been established. Polygenic risk score (using PRS-CS) for MDD was calculated for US Army soldiers of European ancestry. Associations between polygenic risk for MDD and lifetime suicide attempt (SA) were tested in models that also included parental or personal history of MDD. Models were adjusted for age, sex, tranche (where applicable), and 10 principal components reflecting ancestry. In the first cohort, 417 (6.3%) of 6,573 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.83, 95% CI:3.09-4.75] and parental history of MDD [OR = 1.43, 95% CI:1.13-1.82 for one parent and OR = 1.64, 95% CI:1.20-2.26 for both parents), MDD PRS was significantly associated with SA (OR = 1.22 [95% CI:1.10-1.36]). In the second cohort, 204 (4.2%) of 4,900 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.82, 95% CI:2.77-5.26] and parental history of MDD [OR = 1.42, 95% CI:0.996-2.03 for one parent and OR = 2.21, 95% CI:1.33-3.69 for both parents) MDD PRS continued to be associated (at p = .0601) with SA (OR = 1.15 [95% CI:0.994-1.33]). A soldier's PRS for MDD conveys information about likelihood of a lifetime SA beyond that conveyed by two predictors readily obtainable by interview: personal or parental history of MDD. Results remain to be extended to prospective prediction of incident SA. These findings portend a role for PRS in risk stratification for suicide attempts., (© 2021 Wiley Periodicals LLC.)

A letter to the editor is presented in response to the article "Polygenic risk scores for smoking: predictors for alcohol and cannabis use?" by J. M. Vink et al. in the 2014 issue.

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European-ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12-30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty-two disease-associated SNPs from the PGC-BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10(-5) , AUC = 0.60). In families with a high-polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at-risk youth, regardless of affected status, compared to unrelated controls (GEE-χ(2) = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease-associated variants than unrelated controls and first-degree relatives, and illustrate the potential utility of PRS assessment in a family context., (© 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.)