Contribution of copy number variations to education, socioeconomic status and cognition from a genome-wide study of 305,401 subjects.

Educational attainment (EA), socioeconomic status (SES) and cognition are phenotypically and genetically linked to health outcomes. However, the role of copy number variations (CNVs) in influencing EA/SES/cognition remains unclear. Using a large-scale (n = 305,401) genome-wide CNV-level association analysis, we discovered 33 CNV loci significantly associated with EA/SES/cognition, 20 of which were novel (deletions at 2p22.2, 2p16.2, 2p12, 3p25.3, 4p15.2, 5p15.33, 5q21.1, 8p21.3, 9p21.1, 11p14.3, 13q12.13, 17q21.31, and 20q13.33, as well as duplications at 3q12.2, 3q23, 7p22.3, 8p23.1, 8p23.2, 17q12 (105 kb), and 19q13.32). The genes identified in gene-level tests were enriched in biological pathways such as neurodegeneration, telomere maintenance and axon guidance. Phenome-wide association studies further identified novel associations of EA/SES/cognition-associated CNVs with mental and physical diseases, such as 6q27 duplication with upper respiratory disease and 17q12 (105 kb) duplication with mood disorders. Our findings provide a genome-wide CNV profile for EA/SES/cognition and bridge their connections to health. The expanded candidate CNVs database and the residing genes would be a valuable resource for future studies aimed at uncovering the biological mechanisms underlying cognitive function and related clinical phenotypes.

Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia.

INTRODUCTION: The heritability of Alzheimer's disease (AD) is estimated to be 58%-79%. However, known genes can only partially explain the heritability. METHODS: Here, we conducted gene-based exome-wide association study (ExWAS) of rare variants and single-variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank. RESULTS: Gene-based ExWAS identified 11 genes predicting a higher ADRD risk, including five novel ones, namely FRMD8, DDX1, DNMT3L, MORC1, and TGM2, along with six previously reported ones, SORL1, GRN, PSEN1, ABCA7, GBA, and ADAM10. Single-variant ExWAS identified two ADRD-associated novel genes, SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. The druggability evidence suggests that DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets. DISCUSSION: Our study contributes to the current body of evidence on the genetic etiology of ADRD. HIGHLIGHTS: Gene-based analyses of rare variants identified five novel genes for Alzheimer's disease and related dementia (ADRD), including FRMD8, DDX1, DNMT3L, MORC1, and TGM2. Single-variant analyses of common variants identified two novel genes for ADRD, including SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Genome-wide association study of cerebellar white matter microstructure and genetic overlap with common brain disorders.

BACKGROUND: The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown. METHODS: We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders. RESULTS: We identified 11 genetic loci (P < 8.3 × 10-9) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories. CONCLUSIONS: Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders.

Circulating metabolites and risk of incident dementia: A prospective cohort study.

Identifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions. This cohort study included a total of 87 885 participants (median follow-up of 9.1 years, 54% female) without dementia at baseline from the UK Biobank. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer's disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow-up. Dementia-associated metabolites were further analyzed for association with cognitive deficits (N = 87 885) and brain volume (N = 7756) using logistic regression and linear regression. We identified 26 metabolites associated with incident dementia, of which 6 were associated with incident AD and 5 were associated with incident VD. These 26 dementia-related metabolites were subfractions of intermediate-density lipoprotein, large low-density lipoprotein (L-LDL), small high-density lipoprotein (S-HDL), very-low-density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L-LDL (L-LDL-C%) was associated with lower risk of AD (HR [95% CI] = 0.92 [0.87-0.97], p = 0.002), higher brain cortical (ß = 0.047, p = 3.91 × 10-6 ), and hippocampal (ß = 0.043, p = 1.93 × 10-4 ) volume. Cholesteryl ester-to-total lipid ratio in L-LDL (L-LDL-CE%) was associated with lower risk of AD (HR [95% CI] = 0.93 [0.90-0.96], p = 1.48 × 10-4 ), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (ß = 0.027, p = 0.009). Cholesteryl esters in S-HDL (S-HDL-CE) were associated with lower risk of VD (HR [95% CI] = 0.81 [0.71-0.93], p = 0.002), but not AD. Taken together, circulating levels of L-LDL-CE% and L-LDL-C% were robustly associated with risk of AD and AD phenotypes, but not with VD. S-HDL-CE was associated with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations.

Plasma Glial Fibrillary Acidic Protein in the Alzheimer Disease Continuum: Relationship to Other Biomarkers, Differential Diagnosis, and Prediction of Clinical Progression.

BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD). METHODS: Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators. RESULTS: A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aß-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-ß=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers. CONCLUSIONS: Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD.

Lung function and risk of incident dementia: A prospective cohort study of 431,834 individuals.

BACKGROUND: Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. METHODS: This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. FINDINGS: During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14-1.34], P = 1.10 × 10-07; forced vital capacity [liter]: 1.16 [1.08-1.24], P = 2.04 × 10-05; peak expiratory flow [liter/min]: 1.0013 [1.0010-1.0017], P = 2.73 × 10-13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function. INTERPRETATION: Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention.

Peripheral immunity is associated with the risk of incident dementia.

Central immunity components especially microglia in dementia have been well studied and corresponding immunotherapy gradually caught the attention. However, few studies focused on peripheral immunity and dementia. To address the issue, we examined the longitudinal association between incident dementia and peripheral immunity markers encompassing immune cell counts, and their derived ratios including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR), utilizing data of 361,653 participants from the UK Biobank (UKB). During a median follow-up of 8.99 years, 4239 participants developed dementia. The results revealed that increased innate immunity markers were associated with higher dementia risk (per SD increment hazard ratio [HR]; 95% confidence interval [CI] 1.14; 1.09-1.19 for neutrophils, 1.16; 1.11-1.20 for NLR and 1.11; 1.07-1.16 for SII), while increased adaptive immunity markers were associated with lower dementia risk (0.93; 0.90-0.97 for lymphocytes and 0.94; 0.90-0.98 for LMR). Our study pinpoints the differential role of innate and adaptive immunity in dementia incidence, which may provide some new perspectives in etiology and therapy of dementia.

Sleep, physical activity, sedentary behavior, and risk of incident dementia: a prospective cohort study of 431,924 UK Biobank participants.

Although sleep, physical activity and sedentary behavior have been found to be associated with dementia risk, findings are inconsistent and their joint relationship remains unclear. This study aimed to investigate independent and joint associations of these three modifiable behaviors with dementia risks. A total of 431,924 participants (median follow-up 9.0 years) without dementia from UK Biobank were included. Multiple Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Models fitted with restricted cubic spline were conducted to test for linear and nonlinear shapes of each association. Sleep duration, leisure-time physical activity (LTPA), and screen-based sedentary behavior individually associated with dementia risks in different non-linear patterns. Sleep duration associated with dementia in a U-shape with a nadir at 7 h/day. LTPA revealed a curvilinear relationship with dementia in diminishing tendency, while sedentary behavior revealed a J-shaped relationship. The dementia risk was 17% lower in the high LTPA group (HR[95%CI]: 0.83[0.76-0.91]) and 22% higher in the high sedentary behavior group (1.22[1.10-1.35]) compared to the corresponding low-level group, respectively. A combination of seven-hour/day sleep, moderate-to-high LTPA, and low-to-moderate sedentary behavior showed the lowest dementia risk (0.59[0.50-0.69]) compared to the referent group (longer or shorter sleep/low LTPA/high sedentary behavior). Notably, each behavior was non-linearly associated with brain structures in a pattern similar to its association with dementia, suggesting they may affect dementia risk by affecting brain structures. Our findings highlight the potential to change these three daily behaviors individually and simultaneously to reduce the risk of dementia.

Association of life course adiposity with risk of incident dementia: a prospective cohort study of 322,336 participants.

Cohort studies report inconsistent associations between body mass index (BMI) and all-cause incident dementia. Furthermore, evidence on fat distribution and body composition measures are scarce and few studies estimated the association between early life adiposity and dementia risk. Here, we included 322,336 participants from UK biobank to investigate the longitudinal association between life course adiposity and risk of all-cause incident dementia and to explore the underlying mechanisms driven by metabolites, inflammatory cells and brain structures. Among the 322,336 individuals (mean (SD) age, 62.24 (5.41) years; 53.9% women) in the study, during a median 8.74 years of follow-up, 5083 all-cause incident dementia events occurred. The risk of dementia was 22% higher with plumper childhood body size (p < 0.001). A strong U-shaped association was observed between adult BMI and dementia. More fat and less fat-free mass distribution on arms were associated with a higher risk of dementia. Interestingly, similar U-shaped associations were found between BMI and four metabolites (i.e., 3-hydroxybutrate, acetone, citrate and polyunsaturated fatty acids), four inflammatory cells (i.e., neutrophil, lymphocyte, monocyte and leukocyte) and abnormalities in brain structure that were also related to dementia. The findings that adiposity is associated with metabolites, inflammatory cells and abnormalities in brain structure that were related to dementia risk might provide clues to underlying biological mechanisms. Interventions to prevent dementia should begin early in life and include not only BMI control but fat distribution and body composition.

Pharmacological treatment of neuropsychiatric symptoms of dementia: a network meta-analysis.

BACKGROUND: Pharmacological treatments are very common to be used for alleviating neuropsychiatric symptoms (NPS) in dementia. However, decision on drug selection is still a matter of controversy. AIMS: To summarise the comparative efficacy and acceptability of currently available monotherapy drug regimens for reducing NPS in dementia. METHOD: We searched PubMed, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials between inception and 26 December 2022 without language restrictions; and reference lists scanned from selected studies and systematic reviews. Double-blind randomised controlled trials were identified from electronic databases for reporting NPS outcomes in people with dementia. Primary outcomes were efficacy and acceptability. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 59 trials (15,781 participants; mean age, 76.6 years) and 15 different drugs in quantitative syntheses. Risperidone (standardised mean difference [SMD] -0.20, 95% credible interval [CrI] -0.40 to -0.10) and galantamine (-0.20, -0.39 to -0.02) were more effective than placebo in short-term treatment (median duration: 12 weeks). Galantamine (odds ratio [OR] 1.95, 95% CrI 1.38-2.94) and rivastigmine (1.87, 1.24-2.99) were associated with more dropouts than placebo, and some active drugs. Most of the results were rated as low or very low according to CINeMA. CONCLUSIONS: Despite the scarcity of high-quality evidence, risperidone is probably the best pharmacological option to consider for alleviating NPS in people with dementia in short-term treatment when considering the risk-benefit profile of drugs.

Differences between ante mortem Alzheimer's disease biomarkers in predicting neuropathology at autopsy.

INTRODUCTION: This study aimed to assess whether biomarkers related to amyloid, tau, and neurodegeneration can accurately predict Alzheimer's disease (AD) neuropathology at autopsy in early and late clinical stages. METHODS: We included 100 participants who had ante mortem biomarker measurements and underwent post mortem neuropathological examination. Based on ante mortem clinical diagnosis, participants were divided into non-dementia and dementia, as early or late clinical stages. RESULTS: Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) amyloid beta (Aß)42/phosphorylated tau (p-tau)181 showed excellent performance in differentiating autopsy-confirmed AD and predicting the risk of neuropathological changes in early and late clinical stages. However, CSF Aß42 performed better in the early clinical stage, while CSF p-tau181, CSF t-tau, and plasma p-tau181 performed better in the late clinical stage. DISCUSSION: Our findings provide important clinical information that, if using PET, CSF, and plasma biomarkers to detect AD pathology, researchers must consider their differential performances at different clinical stages of AD. HIGHLIGHTS: Amyloid PET and CSF Aß42/p-tau181 were the most promising candidate biomarkers for predicting AD pathology. CSF Aß42 can serve as a candidate predictive biomarker in the early clinical stage of AD. CSF p-tau181, CSF t-tau, and plasma p-tau181 can serve as candidate predictive biomarkers in the late clinical stage of AD. Combining APOE ε4 genotypes can significantly improve the predictive accuracy of AD-related biomarkers for AD pathology.

Associations of grip strength, walking pace, and the risk of incident dementia: A prospective cohort study of 340212 participants.

INTRODUCTION: Grip strength and walking pace have been linked to cognitive dysfunction. Their relationships, however, demand further clarification as the evidence is derived primarily from less-comprehensive investigations. METHODS: A total of 340212 UK Biobank participants without dementia and cardiovascular diseases at baseline were analyzed. Cox proportional hazard models assessed the longitudinal associations. RESULTS: Over a mean follow-up of 8.51 ± 2.68 years, 2424 incident dementia cases were documented. A 5 kg increment of absolute grip strength was associated with lower risks of all-cause dementia (hazard ratio [HR] 0.857), Alzheimer's disease (HR 0.874), and vascular dementia (HR 0.788). The patterns of associations remained similar when grip strength was expressed in relative terms and quintiles. A slow walking pace demonstrated consistent associations with increased risks of all dementia types. DISCUSSION: Our findings provide amplified evidence and suggest that muscle fitness, reflected by objective grip strength measures and self-reported walking pace, may be imperative for estimating the risks of dementia.

Circulating metabolites associated with incident myocardial infarction and stroke: A prospective cohort study of 90 438 participants.

The relevance between circulating metabolites and vascular events remains controversial and comprehensive studies are lacking. We sought to investigate the prospective associations of plasma metabolomics with risks of incident stroke, ischemic stroke (IS), hemorrhagic stroke (HS), and myocardial infarction (MI). Within the UK Biobank cohort, 249 circulating metabolites were measured in 90 438 participants without baseline vascular diseases. Cox proportional hazards regressions were applied to estimate adjusted hazard ratios (HRs) for per 1 standard deviation increment in metabolites. The least absolute shrinkage and selection operator algorithm was used for selecting metabolite subsets. During a median of 9.0 years of follow-up, we documented 833 incident stroke and 1256 MI cases. Lipid constituents, comprising cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids, in very low- (VLDL), intermediate- (IDL), and low-density lipoprotein (LDL) particles were positively associated with MI risk (HR = 1.12 to 1.36; 95% CI = 1.06 to 1.44), while in high-density lipoprotein (HDL) particles showed inverse associations (HR = 0.68 to 0.81; 95% CI = 0.63 to 0.87). Similar association pattern with MI was also observed for VLDL, IDL, LDL, and HDL particles themselves. In contrast, triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI risk (HR = 1.14 to 1.28; 95% CI = 1.08 to 1.35) and, to a slightly lesser extent, with stroke and IS. Unsaturation of fatty acids and albumin were inversely associated with risks of stroke, IS, and MI. In contrast, the linear association for HS is absent. When combining multiple metabolites, the metabolite risk score captured a drastically elevated risk of all vascular events, about twice that of any single metabolite. Taken together, circulating metabolites showed remarkably widespread associations with incident MI, but substantially weakened associations with risks of stroke and its subtypes. Exhaustive metabolomics profiling may shed light on vascular risk prediction and, in turn, guide pertinent strategies of intervention and treatment.

Time spent in outdoor light is associated with the risk of dementia: a prospective cohort study of 362094 participants.

BACKGROUND: Data on the association between free-living daytime sunlight exposure and incident dementia are scarce. The objective is to evaluate whether the time spent in outdoor light is related to the dementia risk and to investigate whether the optimal duration varies with clinical parameters. METHODS: Data were from a prospective cohort of 362,094 UK Biobank participants. A questionnaire survey was conducted to investigate how many hours the participants spent outdoors on typical summer and winter days. A restricted cubic spline (RCS) was performed to explore the potential nonlinear relationship between sunlight exposure and the risk of dementia. We used multivariate Cox proportional hazard regression models to estimate the hazard ratios (HRs) for the associations between sunlight exposure and dementia outcomes, with the change points as a reference. RESULTS: After a median follow-up of 9.0 years, 4149 (1.15%) individuals were diagnosed with dementia. RCS showed a J-shaped relationship between time spent in outdoor light and the dementia risk, with the lowest risk at three change points (1.5 h/day on average, 2 h/day in summer, and 1 h/day in winter). Cox hazard regression models showed a marked increase in risk at low exposure (HR=1.287, 95%CI 1.094-1.515) but a relatively slow increase at higher exposure (HR=1.070, 95%CI 1.031-1.10). Results are more pronounced among participants over 60 years old, females, and those with exactly 7 h of sleep every night. CONCLUSIONS: Sunlight exposure had a J-shaped association with dementia risk. Giving detailed guidance on sunlight exposure can effectively prevent dementia.

Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood.

BACKGROUND: Genome-wide association studies (GWAS) have revealed numerous loci associated with stroke. However, the underlying mechanisms at these loci in the pathogenesis of stroke and effective stroke drug targets are elusive. Therefore, we aimed to identify causal genes in the pathogenesis of stroke and its subtypes. METHODS: Utilizing multidimensional high-throughput data generated, we integrated proteome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and Bayesian colocalization analysis to prioritize genes that contribute to stroke and its subtypes risk via affecting their expression and protein abundance in brain and blood. RESULTS: Our integrative analysis revealed that ICA1L was associated with small-vessel stroke (SVS), according to robust evidence at both protein and transcriptional levels based on brain-derived data. We also identified NBEAL1 that was causally related to SVS via its cis-regulated brain expression level. In blood, we identified 5 genes (MMP12, SCARF1, ABO, F11, and CKAP2) that had causal relationships with stroke and stroke subtypes. CONCLUSIONS: Together, via using an integrative analysis to deal with multidimensional data, we prioritized causal genes in the pathogenesis of SVS, which offered hints for future biological and therapeutic studies.

Genetic determinants of circulating metabolites and the risk of stroke and its subtypes.

BACKGROUND AND PURPOSE: Circulating metabolites have been implicated in stroke pathogenesis, but their genetic determinants are understudied. Using a Mendelian randomization approach, our aim was to provide evidence for the relationship of circulating metabolites and the risk of stroke and its subtypes. METHODS: Genetic instruments of 102 circulating metabolites were obtained from a genome-wide association study, including 24,925 European individuals. Stroke was extracted from the MEGASTROKE dataset (67,162 cases; 454,450 controls) and a lacunar stroke dataset (7338 cases; 254,798 controls). The magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury were evaluated by a genome-wide association study of white matter hyperintensities (N = 18,381), fractional anisotropy (N = 17,663), mean diffusivity (N = 17,467) and brain microbleeds (N = 25,862). The inverse-variance weighted method Mendelian randomization was used as the primary analytical method, and directional pleiotropy and heterogeneity were examined in sensitivity analyses. RESULTS: A genetic predisposition to a higher level of cholesterol in small and low-density lipoprotein (LDL) was associated with risk of stroke (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.08-1.21, p = 5.98 × 10-7 ), especially for large-artery atherosclerotic stroke (OR 1.34, 95% CI 1.19-1.52, p = 1.90 × 10-6 ). Total lipids in LDL particles were also associated with risk of stroke. A genetically determined higher cholesterol level in high-density lipoprotein (HDL-C) was associated with risk of intracerebral haemorrhage (OR 1.74, 95% CI 1.23-2.45, p = 1.66 × 10-3 ). No statistically significant association was found between genetic predisposition to circulating metabolites and magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury. CONCLUSIONS: Genetically determined levels of lipids in small LDL were associated with the risk of stroke, suggesting that a therapeutic strategy targeting small LDL levels may be crucial for stroke prevention. HDL-C was positively associated with the risk of intracerebral haemorrhage.

Investigating causal relationships between exposome and human longevity: a Mendelian randomization analysis.

BACKGROUND: Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach. METHODS: A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset. RESULTS: Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10-8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10-7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10-5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10-14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10-9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite. CONCLUSIONS: The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations.

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In order to understand the response and adaptation mechanisms of photosynthetic characteristics and growth for Cunninghamia lanceolata saplings in the subtropical region to global warming, we conducted the root-box warming experiment (ambient, ambient+4 ℃) at the Sanming Forest Ecosystem National Observation and Research Station in Fujian Province to investigate the effects of soil warming on the photosynthetic characteristics and growth of C. lanceolata saplings in different seasons. The results showed that the net photosynthetic rate (Pn) and stomatal conductance (gs) of C. lanceolata significantly decreased in summer compared with in spring and autumn. Soil warming had no effect on the Pn and gs of C. lanceolata. However, the interaction between warming and season significantly impacted the leaf water use efficiency (WUE). The tree height and ground diameter growth of C. lanceolata significantly increased in spring compared with in summer and autumn. Warming significantly reduced ground diameter growth, and it diminished the net diameter growth by 48.1% in autumn. However, warming had no impact on the tree height growth of C. lanceolata in each season. The specific leaf area, soluble sugar, and non-structural carbohydrates contents of C. lanceolata significantly improved in summer and autumn compared with in spring. Warming had rarely influence on leaf functional traits in each season. In conclusion, the response of photosynthesis for C. lanceolata to soil warming was insignificant. The photosynthesis of C. lanceolata exhibited significant seasonal dynamics, primarily controlled by gs. C. lanceolata adapted to soil warming by adjusting WUE, and it adjusted to high temperatures and drought stress in summer by increasing soluble sugar content and specific leaf area. The effect of warming on ground diameter growth of C. lanceolata was primarily driven by soil moisture. The seasonal difference in the growth of C. lanceolata was influenced by the photosynthesis of C. lanceolata and the trade-off between the utilization and storage of photosynthetic products.