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The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves' disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies., (© 2024. The Author(s).)

Alcohol consumption is a heritable behavior seriously endangers human health. However, genetic studies on alcohol consumption primarily focuses on common variants, while insights from rare coding variants are lacking. Here we leverage whole exome sequencing data across 304,119 white British individuals from UK Biobank to identify protein-coding variants associated with alcohol consumption. Twenty-five variants are associated with alcohol consumption through single variant analysis and thirteen genes through gene-based analysis, ten of which have not been reported previously. Notably, the two unreported alcohol consumption-related genes GIGYF1 and ANKRD12 show enrichment in brain function-related pathways including glial cell differentiation and are strongly expressed in the cerebellum. Phenome-wide association analyses reveal that alcohol consumption-related genes are associated with brain white matter integrity and risk of digestive and neuropsychiatric diseases. In summary, this study enhances the comprehension of the genetic architecture of alcohol consumption and implies biological mechanisms underlying alcohol-related adverse outcomes., (© 2024. The Author(s).)

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson's (STAB1, KCNA10), Alzheimer's (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson's. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders., (© 2024. The Author(s).)

Physical frailty and genetic factors are both risk factors for increased dementia; nevertheless, the joint effect remains unclear. This study aimed to investigated the long-term relationship between physical frailty, genetic risk, and dementia incidence. A total of 274,194 participants from the UK Biobank were included. We applied Cox proportional hazards regression models to estimate the association between physical frailty and genetic and dementia risks. Among the participants (146,574 females [53.45%]; mean age, 57.24 years), 3,353 (1.22%) new-onset dementia events were recorded. Compared to non-frailty, the hazard ratio (HR) for dementia incidence in prefrailty and frailty was 1.396 (95% confidence interval [CI], 1.294-1.506, P < 0.001) and 2.304 (95% CI, 2.030-2.616, P < 0.001), respectively. Compared to non-frailty and low polygenic risk score (PRS), the HR for dementia risk was 3.908 (95% CI, 3.051-5.006, P < 0.001) for frailty and high PRS. Furthermore, among the participants, slow walking speed (HR, 1.817; 95% CI, 1.640-2.014, P < 0.001), low physical activity (HR, 1.719; 95% CI, 1.545-1.912, P < 0.001), exhaustion (HR, 1.670; 95% CI, 1.502-1.856, P < 0.001), low grip strength (HR, 1.606; 95% CI, 1.479-1.744, P < 0.001), and weight loss (HR, 1.464; 95% CI, 1.328-1.615, P < 0.001) were independently associated with dementia risk compared to non-frailty. Particularly, precise modulation for different dementia genetic risk populations can also be identified due to differences in dementia risk resulting from the constitutive pattern of frailty in different genetic risk populations. In conclusion, both physical frailty and high genetic risk are significantly associated with higher dementia risk. Early intervention to modify frailty is beneficial for achieving primary and precise prevention of dementia, especially in those at high genetic risk., (© 2024. The Author(s).)

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification., (© 2024. The Author(s).)

The fornix is a white matter bundle located in the center of the hippocampaldiencephalic limbic circuit that controls memory and executive functions, yet its genetic architectures and involvement in brain disorders remain largely unknown. We carried out a genome-wide association analysis of 30,832 UK Biobank individuals of the six fornix diffusion magnetic resonance imaging (dMRI) traits. The post-GWAS analysis allowed us to identify causal genetic variants in phenotypes at the single nucleotide polymorphisms (SNP), locus, and gene levels, as well as genetic overlap with brain health-related traits. We further generalized our GWAS in adolescent brain cognitive development (ABCD) cohort. The GWAS identified 63 independent significant variants within 20 genomic loci associated (P < 8.33 × 10 -9 ) with the six fornix dMRI traits. Geminin coiled-coil domain containing (GMNC) and NUAK family SNF1-like kinase 1 (NUAK1) gene were highlighted, which were found in UKB and replicated in ABCD. The heritability of the six traits ranged from 10% to 27%. Gene mapping strategies identified 213 genes, where 11 were supported by all of four methods. Gene-based analyses revealed pathways relating to cell development and differentiation, with astrocytes found to be significantly enriched. Pleiotropy analyses with eight neurological and psychiatric disorders revealed shared variants, especially with schizophrenia under the conjFDR threshold of 0.05. These findings advance our understanding of the complex genetic architectures of fornix and their relevance in neurological and psychiatric disorders., (© 2023. The Author(s).)

The amygdala is a crucial interconnecting structure in the brain that performs several regulatory functions, yet its genetic architectures and involvement in brain disorders remain largely unknown. We carried out the first multivariate genome-wide association study (GWAS) of amygdala subfield volumes in 27,866 UK Biobank individuals. The whole amygdala was segmented into nine nuclei groups using Bayesian amygdala segmentation. The post-GWAS analysis allowed us to identify causal genetic variants in phenotypes at the SNP, locus, and gene levels, as well as genetic overlap with brain health-related traits. We further generalized our GWAS in Adolescent Brain Cognitive Development (ABCD) cohort. The multivariate GWAS identified 98 independent significant variants within 32 genomic loci associated (P < 5 × 10 -8 ) with amygdala volume and its nine nuclei. The univariate GWAS identified significant hits for eight of the ten volumes, tagging 14 independent genomic loci. Overall, 13 of the 14 loci identified in the univariate GWAS were replicated in the multivariate GWAS. The generalization in ABCD cohort supported the GWAS results with the 12q23.2 (RNA gene RP11-210L7.1) being discovered. All of these imaging phenotypes are heritable, with heritability ranging from 15% to 27%. Gene-based analyses revealed pathways relating to cell differentiation/development and ion transporter/homeostasis, with the astrocytes found to be significantly enriched. Pleiotropy analyses revealed shared variants with neurological and psychiatric disorders under the conjFDR threshold of 0.05. These findings advance our understanding of the complex genetic architectures of amygdala and their relevance in neurological and psychiatric disorders., (© 2023. The Author(s).)

Circadian rhythm disruption (CRD) is a shared characteristic of various brain disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and major depression disorder (MDD). Disruption of circadian rhythm might be a risk factor for brain disorder incidents. From 7-day accelerometry data of 72,242 participants in UK Biobank, we derived a circadian relative amplitude variable, which to some extent reflected the degree of circadian rhythm disruption. Records of brain disorder incidents were obtained from a wide range of health outcomes across self-report, primary care, hospital inpatient data, and death data. Using multivariate Cox proportional hazard ratio regression, we created two models adjusting for different covariates. Then, linear correlations between relative amplitude and several brain morphometric measures were examined in participants with brain MRI data. After a median follow-up of around 6.1 years, 72,242 participants were included in the current study (female 54.9%; mean age 62.1 years). Individuals with reduced relative amplitude had increasing risk of all-cause dementia (Hazard ratio 1.23 [95% CI 1.15 to 1.31]), PD (1.33 [1.25 to 1.41]), stroke (1.13 [1.06 to 1.22]), MDD (1.18 [1.13 to 1.23]), and anxiety disorder (1.14 [1.09 to 1.20]) in fully adjusted models. Additionally, significant correlations were found between several cortical regions and white matter tracts and relative amplitude that have been linked to dementia and psychiatric disorders. We confirm CRD to be a risk factor for various brain disorders. Interventions for regulating circadian rhythm may have clinical relevance to reducing the risk of various brain disorders., (© 2022. The Author(s).)

Prevention of dementia is a public health priority, and the identification of potential biomarkers may provide benefits for early detection and prevention. This study investigates the association of common serum laboratory tests with the risk of incident dementia. Among 407,190 participants from the UK Biobank (median follow-up of 9.19 years), we investigated the linear and nonlinear effects of 30 laboratory measures on the risk of all-cause dementia using Cox models and restricted cubic spline models. We found that dementia incidence was associated with low vitamin D concentration (hazard ratio 0.994, 95% confidence interval 0.993-0.996), indicators of endocrine disorders: IGF-1 level (P for non-linearity = 1.1E-05), testosterone level (P for non-linearity = 0.006); high sex-hormone-binding globulin level (HR 1.004, 95% CI: 1.003-1.006); reduced liver function: lower alanine aminotransferase (HR 0.990, 95% CI: 0.986-0.995); renal dysfunction: cystatin C level (P for non-linearity = 0.028); oxidative stress: lower urate level (HR 0.998, 95% CI: 0.998-0.999); lipids dysregulation: lower LDL (HR 0.918, 95% CI: 0.872-0.965) and triglycerides (HR 0.924, 95% CI: 0.882-0.967) concentrations; insulin resistance: high glucose (HR 1.093, 95% CI: 1.045-1.143) and HbA1c (HR 1.017, 95% CI: 1.009-1.025) levels; immune dysbiosis: C-reactive protein (P for non-linearity = 5.5E-09). In conclusion, markers of vitamin D deficiency, GH-IGF-1 axis disorders, bioactive sex hormone deficiency, reduced liver function, renal abnormalities, oxidation, insulin resistance, immune dysbiosis, and lipids dysregulation were associated with incident dementia. Our results support a contributory role of systemic disorders and diverse biological processes to onset of dementia., (© 2022. The Author(s).)

As a widely consumed beverage, tea boasts diverse health benefits. Herein, we aimed to investigate the association between tea consumption and dementia risk. We conducted a prospective cohort study with 377 592 UK Biobank participants during a 9-year follow-up. Cox regression models adjusted for age, sex, ethnicity, Townsend deprivation index, education, body mass index, lifestyle factors, dietary factors and apolipoprotein E4 status were used to examine the association of tea consumption with dementia risk. Subgroup analyses stratified by age, sex and forms of dementia (Alzheimer's disease [AD] and vascular dementia [VD]) were performed. Moreover, the restricted cubic splines were used to calculate the nonlinear relationship between daily dosage of tea and dementia risk. After adjustment for all covariates, tea drinkers were 16% (95% confidence interval: 8-23) less likely to develop dementia compared with non-drinkers. Moderate consumption (1-6 cups/day) of tea exerted significant protective effects. Subgroup analyses showed that mid-aged participants or males benefited more from tea consumption. Moreover, moderate drinkers had a 16-19% lower hazard of AD and a 25-29% lower hazard of VD. Furthermore, a U-shaped association between tea consumption and dementia risk was shown (P non-linearity  = 7E -04 ), and the consumption of around three cups per day showed the strongest protective effect. Within 3 cups/day, drinking one extra cup of tea per day brought a 6% reduction of incidence. In conclusion, moderate consumption of tea was significantly associated with a reduced risk of dementia, suggesting that tea consumption could be a modifiable lifestyle factor for dementia., (© 2022. The Author(s).)

Progressive loss of neurons in a specific brain area is one of the manifestations of Alzheimer's disease (AD). Much effort has been devoted to investigating brain atrophy and AD. However, the causal relationship between cortical structure and AD is not clear. We conducted a bidirectional two-sample Mendelian randomization analysis to investigate the causal relationship between cortical structure (surface area and thickness of the whole cortex and 34 cortical regions) and AD risk. Genetic variants used as instruments came from a large genome-wide association meta-analysis of cortical structure (33,992 participants of European ancestry) and AD (AD and AD-by-proxy, 71,880 cases, 383,378 controls). We found suggestive associations of the decreased surface area of the temporal pole (OR (95% CI): 0.95 (0.9, 0.997), p = 0.04), and decreased thickness of cuneus (OR (95% CI): 0.93 (0.89, 0.98), p = 0.006) with higher AD risk. We also found a suggestive association of vulnerability to AD with the decreased surface area of precentral (β (SE): -43.4 (21.3), p = 0.042) and isthmus cingulate (β (SE): -18.5 (7.3), p = 0.011). However, none of the Bonferroni-corrected p values of the causal relationship between cortical structure and AD met the threshold. We show suggestive evidence of an association of the atrophy of the temporal pole and cuneus with higher AD risk. In the other direction, there was a suggestive causal relationship between vulnerability to AD and the decreased surface area of the precentral and isthmus cingulate. Our findings shed light on the associations of cortical structure with the occurrence of AD., (© 2021. The Author(s).)