BACKGROUND: We assessed the association of prescription data with clinical manifestations and polygenic risk scores (PRS) in patients with bipolar I disorder.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: This study had a cross-sectional design, without differentiating the bipolar phase, which could influence our results.
CONCLUSIONS: 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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
In their study, Korbmacher et al. benchmark healthy aging processes in the brain’s white matter. Findings of degrading white matter at higher ages were consistent with recent cross-sectional and longitudinal findings, particularly outlining changes in ventricle-near and cerebellar white matter. Degenerative processes were also found to accelerate at a higher age. Finally, the polygenic risk to develop psychiatric and neurodegenerative disorders was weakly associated with the white matter change in the otherwise healthily aging participants.

BACKGROUND: Unraveling how Alzheimer\'s disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine.
METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity.
RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication.
CONCLUSIONS: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies.
CONCLUSIONS: Polygenic risk for Alzheimer\'s disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

Numerous studies have reported critical roles for the gut microbiota in obesity. However, the specific microbes that causally contribute to obesity and the underlying mechanisms remain undetermined. Here, we conducted shotgun metagenomic sequencing in a Chinese cohort of 631 obese subjects and 374 normal-weight controls and identified a Megamonas-dominated, enterotype-like cluster enriched in obese subjects. Among this cohort, the presence of Megamonas and polygenic risk exhibited an additive impact on obesity. Megamonas rupellensis possessed genes for myo-inositol degradation, as demonstrated in vitro and in vivo, and the addition of myo-inositol effectively inhibited fatty acid absorption in intestinal organoids. Furthermore, mice colonized with M. rupellensis or E. coli heterologously expressing the myo-inositol-degrading iolG gene exhibited enhanced intestinal lipid absorption, thereby leading to obesity. Altogether, our findings uncover roles for M. rupellensis as a myo-inositol degrader that enhances lipid absorption and obesity, suggesting potential strategies for future obesity management.

BACKGROUND: 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.
CONCLUSIONS: Neuroticism could represent a risk factor for dementia, and vascular and mental health might drive these associations.
CONCLUSIONS: 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.

UNASSIGNED: Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder characterized by increased circulating low-density lipoprotein cholesterol and accelerated atherosclerosis. Even among this high-risk group, prior studies note considerable variability in risk of coronary artery disease (CAD).
UNASSIGNED: The purpose of this study was to evaluate the cumulative impact of many common DNA variants-as quantified by a polygenic score-on incident CAD among individuals carrying a HeFH variant.
UNASSIGNED: We analyzed data from a prospective cohort study of 1,315 individuals who carried a HeFH variant and 1,315 matched family noncarriers derived from a nationwide screening program in the Netherlands, with subsequent replication in 151,009 participants of the UK Biobank.
UNASSIGNED: Despite identification and lipid management within the Dutch screening program, 84 (6.4%) of HeFH variant carriers developed CAD as compared to 45 (3.4%) of matched family members (median follow-up 10.2 years, HR 1.88, 95% CI: 1.31-2.70). Among HeFH variant carriers, a polygenic score was associated with CAD with an effect size similar to low-density lipoprotein cholesterol - HR of 1.35 (95% CI: 1.07-1.70) and 1.41 (95% CI: 1.17-1.70) per standard deviation increase, respectively. When compared to noncarriers, CAD risk increased from 1.24-fold (95% CI: 0.64-2.34) to 3.37-fold (95% CI: 2.11-5.36) across quintiles of the polygenic score. A similar risk gradient, 1.36-fold (95% CI: 0.65-2.85) to 2.88-fold (95% CI: 1.59-5.20), was observed in 429 carriers in the UK Biobank.
UNASSIGNED: In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.

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.

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.

Objective: 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.