Disadvantaged social status contributed to sleep disorders: An observational and genome-wide gene-environment interaction analysis.

BACKGROUND: Sleep is a natural and essential physiological need for individuals. Our study aimed to research the associations between accumulated social risks and sleep disorders. METHODS: In this study, we came up with a polysocial risk score (PsRS), which is a cumulative social risk index composed of 13 social determinants of health. This research includes 239,165 individuals with sleep disorders and social determinants of health data from the UK Biobank cohort. First, logistic regression models were performed to examine the associations of social determinants of health and sleep disorders, including chronotype, narcolepsy, insomnia, snoring, short and long sleep duration. Then, PsRS was calculated based on statistically significant social determinants of health for each sleep disorder. Third, a genome-wide gene-environment interaction study was conducted to explore the interactions between single-nucleotide polymorphisms and PsRS in relation to sleep disorders. RESULTS: Higher PsRS scores were associated with worse sleep status, with the adjusted odds ratio (OR) ranging from 1.10 (95% Confidence interval [CI]: 1.09-1.11) to 1.29 (95% CI: 1.27-1.30) for sleep disorders. Emotional stress (OR = 1.36, 95% CI: 1.28-1.43) and not in paid employment (OR = 2.62, 95% CI: 2.51-2.74) were found to have significant contributions for sleep disorders. Moreover, multiple single-nucleotide polymorphisms were discovered to have interactions with PsRS, such as FRAS1 (P = 2.57 × 10-14) and CACNA1A (P = 8.62 × 10-14) for narcolepsy, and ACKR3 (P = 1.24 × 10-8) for long sleep. CONCLUSIONS: Our findings suggested that cumulative social risks was associated with sleep disorders, while the interactions between genetic susceptibility and disadvantaged social status are risk factors for the development of sleep disorders.

Whole-Transcriptome Sequencing of Knee Joint Cartilage from Kashin-Beck Disease and Osteoarthritis Patients.

The aim of this study was to provide a comprehensive understanding of similarities and differences in mRNAs, lncRNAs, and circRNAs within cartilage for Kashin-Beck disease (KBD) compared to osteoarthritis (OA). We conducted a comparison of the expression profiles of mRNAs, lncRNAs, and circRNAs via whole-transcriptome sequencing in eight KBD and ten OA individuals. To facilitate functional annotation-enriched analysis for differentially expressed (DE) genes, DE lncRNAs, and DE circRNAs, we employed bioinformatic analysis utilizing Gene Ontology (GO) and KEGG. Additionally, using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we validated the expression levels of four cartilage-related genes in chondrocytes. We identified a total of 43 DE mRNAs, 1451 DE lncRNAs, and 305 DE circRNAs in KBD cartilage tissue compared to OA (q value < 0.05; |log2FC| > 1). We also performed competing endogenous RNA network analysis, which identified a total of 65 lncRNA-mRNA interactions and 4714 miRNA-circRNA interactions. In particular, we observed that circRNA12218 had binding sites for three miRNAs targeting ACAN, while circRNA12487 had binding sites for seven miRNAs targeting COL2A1. Our results add a novel set of genes and non-coding RNAs that could potentially serve as candidate diagnostic biomarkers or therapeutic targets for KBD patients.

Mendelian randomization study of the relationship between blood and urine biomarkers and schizophrenia in the UK Biobank cohort.

BACKGROUND: The identification of suitable biomarkers is of crucial clinical importance for the early diagnosis of treatment-resistant schizophrenia (TRS). This study aims to comprehensively analyze the association between TRS and blood and urine biomarkers. METHODS: Candidate TRS-related single nucleotide polymorphisms (SNPs) were obtained from a recent genome-wide association study. The UK Biobank cohort, comprising 376,807 subjects with blood and urine biomarker testing data, was used to calculate the polygenic risk score (PRS) for TRS. Pearson correlation analyses were performed to evaluate the correlation between TRS PRS and each of the biomarkers, using calculated TRS PRS as the instrumental variables. Bidirectional two-sample Mendelian randomization (MR) was used to assess potential causal associations between candidate biomarkers with TRS. RESULTS: Here we identify a significant association between TRS PRS and phosphate (r = 0.007, P = 1.96 × 10-4). Sex subgroup analyses identify seven and three candidate biomarkers associated with TRS PRS in male and female participants, respectively. For example, total protein and phosphate for males, creatinine and phosphate for females. Bidirectional two-sample MR analyses indicate that TRS is negatively associated with cholesterol (estimate = -0.363, P = 0.008). Conversely, TRS is positively associated with total protein (estimate = 0.137, P = 0.027), mean corpuscular volume (estimate = 0.032, P = 2.25 × 10-5), and mean corpuscular hemoglobin (estimate = 0.018, P = 0.007). CONCLUSIONS: Our findings provide insights into the roles of blood and urine biomarkers in the early detection and treatment of TRS.

People with schizophrenia experience periods of time during which they misperceive reality. Some people with schizophrenia do not respond well to the usual drugs that are used to relieve their symptoms. This type of schizophrenia is known as treatment-resistant schizophrenia (TRS). We looked at differences in the genes (inherited characteristics), blood and urine of a group of people in the UK with schizophrenia to see if people with TRS have particular characteristics that would enable them to be distinguished from patients with schizophrenia who tend to respond to usual treatment. We found several differences in the blood that could be used to predict which people might get TRS, including some that were specific to men or women. These discoveries are important because they can help doctors identify people who are more likely to develop TRS earlier, enabling them to avoid using treatments that might not work well for them.

Enhanced polygenic risk score incorporating gene-environment interaction suggests the association of major depressive disorder with cardiac and lung function.

BACKGROUND: Depression has been linked to an increased risk of cardiovascular and respiratory diseases; however, its impact on cardiac and lung function remains unclear, especially when accounting for potential gene-environment interactions. METHODS: We developed a novel polygenic and gene-environment interaction risk score (PGIRS) integrating the major genetic effect and gene-environment interaction effect of depression-associated loci. The single nucleotide polymorphisms (SNPs) demonstrating major genetic effect or environmental interaction effect were obtained from genome-wide SNP association and SNP-environment interaction analyses of depression. We then calculated the depression PGIRS for non-depressed individuals, using smoking and alcohol consumption as environmental factors. Using linear regression analysis, we assessed the associations of PGIRS and conventional polygenic risk score (PRS) with lung function (N = 42 886) and cardiac function (N = 1791) in the subjects with or without exposing to smoking and alcohol drinking. RESULTS: We detected significant associations of depression PGIRS with cardiac and lung function, contrary to conventional depression PRS. Among smokers, forced vital capacity exhibited a negative association with PGIRS (ß = -0.037, FDR = 1.00 × 10-8), contrasting with no significant association with PRS (ß = -0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (ß = 0.088, FDR = 0.010), whereas no such association was found with PRS (ß = 0.040, FDR = 0.265). Notably, in individuals who both smoked and drank, forced expiratory volume in 1-second demonstrated a negative association with PGIRS (ß = -0.042, FDR = 6.30 × 10-9), but not with PRS (ß = -0.003, FDR = 0.857). CONCLUSIONS: Our findings underscore the profound impact of depression on cardiac and lung function, highlighting the enhanced efficacy of considering gene-environment interactions in PRS-based studies.

Long-term ambient air pollution and the risk of musculoskeletal diseases: A prospective cohort study.

Evidence of the associations of air pollution and musculoskeletal diseases is inconsistent. This study aimed to examine the associations between air pollutants and the risk of incident musculoskeletal diseases, such as degenerative joint diseases (n = 38,850) and inflammatory arthropathies (n = 20,108). An air pollution score was constructed to assess the combined effect of PM2.5, PM2.5-10, NO2, and NOX. Cox proportional hazard model was applied to assess the relationships between air pollutants and the incidence of each musculoskeletal disease. The air pollution scores exhibited the modest association with an increased risk of osteoporosis (HR = 1.006, 95% CI: 1.002-1.011). Among the individual air pollutants, PM2.5 and PM2.5-10 exhibited the most significant effect on elevated risk of musculoskeletal diseases, such as PM2.5 on osteoporosis (HR = 1.064, 95% CI: 1.020-1.110), PM2.5-10 on inflammatory arthropathies (HR = 1.059, 95% CI: 1.037-1.081). Females were found to have a higher risk of incident musculoskeletal diseases when exposed to air pollutants. Individuals with extreme BMI or lower socioeconomic status had a higher risk of developing musculoskeletal diseases. Our findings reveal that long-term exposure to ambient air pollutants may contribute to an increased risk of musculoskeletal diseases.

Associations of classical HLA alleles with depression and anxiety.

Immune dysregulation has been widely observed in patients with psychiatric disorders. This study aims to examine the association between HLA alleles and depression and anxiety. Using data from the UK Biobank, we performed regression analyses to assess the association of 359 HLA alleles with depression and anxiety, as determined by Patient Health Questionnaire (PHQ) score (n = 120,033), self-reported depression (n = 121,685), general anxiety disorder (GAD-7) score (n = 120,590), and self-reported anxiety (n = 108,310). Subsequently, we conducted gene environmental interaction study (GEIS) to evaluate the potential effects of interactions between HLA alleles and environmental factors on the risk of depression and anxiety. Sex stratification was implemented in all analysis. Our study identified two significant HLA alleles associated with self-reported depression, including HLA-C*07:01 (ß = -0.015, p = 5.54 × 10-5 ) and HLA-B*08:01 (ß = -0.015, p = 7.78 × 10-5 ). Additionally, we identified four significant HLA alleles associated with anxiety score, such as HLA-DRB1*07:01 (ß = 0.084, p = 9.28 × 10-5 ) and HLA-B*57:01 (ß = 0.139, p = 1.22 × 10-4 ). GEIS revealed that certain HLA alleles interacted with environmental factors to influence mental health outcomes. For instance, HLA-A*02:07 × cigarette smoking was associated with depression score (ß = 0.976, p = 1.88 × 10-6 ). Moreover, sex stratification analysis revealed significant sex-based differences in the interaction effects of certain HLA alleles with environmental factors. Our findings indicate the considerable impact of HLA alleles on the risks of depression and anxiety, providing valuable insights into the functional relevance of immune dysfunction in these conditions.

Identification of novel rare variants for anxiety: an exome-wide association study in the UK Biobank.

BACKGROUND: Rare variants are believed to play a substantial role in the genetic architecture of mental disorders, particularly in coding regions. However, limited evidence supports the impact of rare variants on anxiety. METHODS: Using whole-exome sequencing data from 200,643 participants in the UK Biobank, we investigated the contribution of rare variants to anxiety. Firstly, we computed genetic risk score (GRS) of anxiety utilizing genotype data and summary data from a genome-wide association study (GWAS) on anxiety disorder. Subsequently, we identified individuals within the lowest 50% GRS, a subgroup more likely to carry pathogenic rare variants. Within this subgroup, we classified individuals with the highest 10% 7-item Generalized Anxiety Disorder scale (GAD-7) score as cases (N = 1869), and those with the lowest 10% GAD-7 score were designated as controls (N = 1869). Finally, we conducted gene-based burden tests and single-variant association analyses to assess the relationship between rare variants and anxiety. RESULTS: Totally, 47,800 variants with MAF ≤0.01 were annotated as non-benign coding variants, consisting of 42,698 nonsynonymous SNVs, 489 nonframeshift substitution, 236 frameshift substitution, 617 stop-gain and 40 stop-loss variants. After variation aggregation, 5066 genes were included in gene-based association analysis. Totally, 11 candidate genes were detected in burden test, such as RNF123 (PBonferroni adjusted = 3.40 × 10-6), MOAP1(PBonferroni adjusted = 4.35 × 10-4), CCDC110 (PBonferroni adjusted = 5.83 × 10-4). Single-variant test detected 9 rare variants, such as rs35726701(RNF123)(PBonferroni adjusted = 3.16 × 10-10) and rs16942615(CAMTA2) (PBonferroni adjusted = 4.04 × 10-4). Notably, RNF123, CCDC110, DNAH2, and CSKMT gene were identified in both tests. CONCLUSIONS: Our study identified novel candidate genes for anxiety in protein-coding regions, revealing the contribution of rare variants to anxiety.

Unraveling the Molecular Mechanisms of Alcohol-Mediated Skin Permeation Enhancement: Insights from Molecular Dynamics Simulations.

The application of alcohols as permeation enhancers in pharmaceutical and cosmetic formulations has attracted considerable attention, owing to their skin permeation-enhancing effect. Nonetheless, the elucidation of the fundamental mechanisms underlying the skin permeation-enhancing effect remains elusive. In this study, molecular dynamics (MD) simulations were employed to investigate the effect of 1,2-propanediol (1,2-PDO), 1,2-butanediol (1,2-BDO), and ethanol (EtOH) on the stratum corneum (SC) model membrane. The results showed that the effect of alcohols on the SC model membrane displayed a concentration-dependent nature. The alcohols can interact with SC lipids and exhibit a remarkable ability to selectively extract free fatty acid (FFA) molecules from the SC model membrane and make the SC looser. Meanwhile, 1,2-BDO and EtOH can penetrate into SC lipid bilayers at higher concentrations, leading to the formation of continuous hydrophilic defects in SC. The FFA extraction and the formation of continuous hydrophilic defects induced ceramide (CER) tail chains to become more disordered and fluid and also weakened the hydrogen bonding (H-bonding) network among SC lipids. Both the FFA extraction and the continuous hydrophilic defect formation endowed alcohols with the permeation-enhancing effect. The constrained simulations revealed that the free energy barriers decreased for the permeation of the hydrophilic model molecule (COL) across the SC model membranes containing alcohols, particularly for 1,2-BDO and EtOH. The possible permeation-enhancing mechanisms of alcohols were proposed correspondingly. This work not only provided a deep understanding of the transdermal permeation-enhancing behavior of alcohols at the molecular level but also provided necessary reference information for designing effective transdermal drug delivery systems in applications.

A multidimensional social risk atlas of depression and anxiety: An observational and genome-wide environmental interaction study.

Background: Mental disorders are largely socially determined, yet the combined impact of multidimensional social factors on the two most common mental disorders, depression and anxiety, remains unclear. Methods: We constructed a polysocial risk score (PsRS), a multidimensional social risk indicator including components from three domains: socioeconomic status, neighborhood and living environment and psychosocial factors. Supported by the UK Biobank cohort, we randomly divided 110 332 participants into the discovery cohort (60%; n = 66 200) and the replication cohort (40%; n = 44 134). We tested the associations between 13 single social factors with Patient Health Questionnaire (PHQ) score, Generalized Anxiety Disorder Scale (GAD) score and self-reported depression and anxiety. The significant social factors were used to calculate PsRS for each mental disorder by considering weights from the multivariable linear model. Generalized linear models were applied to explore the association between PsRS and depression and anxiety. Genome-wide environmental interaction study (GWEIS) was further performed to test the effect of interactions between PsRS and SNPs on the risk of mental phenotypes. Results: In the discovery cohort, PsRS was positively associated with PHQ score (ß = 0.37; 95% CI = 0.35-0.38), GAD score (ß = 0.27; 95% CI = 0.25-0.28), risk of self-reported depression (OR = 1.29; 95% CI = 1.28-1.31) and anxiety (OR = 1.19; 95% CI = 1.19-1.23). Similar results were observed in the replication cohort. Emotional stress, lack of social support and low household income were significantly associated with the development of depression and anxiety. GWEIS identified multiple candidate loci for PHQ score, such as rs149137169 (ST18) (Pdiscovery = 1.08 × 10-8, Preplication = 3.25 × 10-6) and rs3759812 (MYO9A) (Pdiscovery = 3.87 × 10-9, Preplication = 6.21 × 10-5). Additionally, seven loci were detected for GAD score, such as rs114006170 (TMPRSS11D) (Pdiscovery = 1.14 × 10-9, Preplication = 7.36 × 10-5) and rs77927903 (PIP4K2A) (Pdiscovery = 2.40 × 10-9, Preplication = 0.002). Conclusions: Our findings reveal the positive effects of multidimensional social factors on the risk of depression and anxiety. It is important to address key social disadvantage in mental health promotion and treatment.

Insight into the Causal Relationship between Gut Microbiota and Back Pain: A Two Sample Bidirectional Mendelian Randomization Study.

Observational studies have shown that alterations in gut microbiota composition are associated with low back pain. However, it remains unclear whether the association is causal. To reveal the causal association between gut microbiota and low back pain, a two-sample bidirectional Mendelian randomization (MR) analysis is performed. The inverse variance weighted regression (IVW) is performed as the principal MR analysis. MR-Egger and Weighted Median is further conducted as complementary analysis to validate the robustness of the results. Finally, a reverse MR analysis is performed to evaluate the possibility of reverse causation. The inverse variance weighted (IVW) method suggests that Peptostreptococcaceae (odds ratio [OR] 1.056, 95% confidence interval [CI] [1.015-1.098], P IVW = 0.010), and Lactobacillaceae (OR 1.070, 95% CI [1.026-1.115], P IVW = 0.003) are positively associated with back pain. The Ruminococcaceae (OR 0.923, 95% CI [0.849-0.997], P IVW = 0.033), Butyricicoccus (OR 0.920, 95% CI [0.868 - 0.972], P IVW = 0.002), and Lachnospiraceae (OR 0.948, 95% CI [0.903-0.994], P IVW = 0.022) are negatively associated with back pain. In this study, underlying causal relationships are identified among gut microbiota and low back pain. Notably, further research is needed on the biological mechanisms by which gut microbiota influences low back pain.

WISP1 Is Involved in the Pathogenesis of Kashin-Beck Disease via the Autophagy Pathway.

OBJECTIVE: Kashin-Beck disease (KBD) is a kind of endemic and chronic osteochondropathy in China. This study aims to explore the functional relevance and potential mechanism of Wnt-inducible signaling pathway protein 1 (WISP1) in the pathogenesis of KBD. DESIGN: KBD and control cartilage specimens were collected for tissue section observation and primary chondrocyte culture. Firstly, the morphological and histopathological observations were made under a light and electron microscope. Then, the expression levels of WISP1 as well as molecular markers related to the autophagy pathway and extracellular matrix (ECM) synthesis were detected in KBD and control chondrocytes by qRT-PCR, Western blot, and immunohistochemistry. Furthermore, the lentiviral transfection technique was applied to make a WISP1 knockdown cell model based on KBD chondrocytes. In vitro intervention experiments were conducted on the C28/I2 human chondrocyte cell line using human recombinant WISP1 (rWISP1). RESULTS: The results showed that the autolysosome appeared in the KBD chondrocytes. The expression of WISP1 was significantly higher in KBD chondrocytes. Additionally, T-2 toxin, a risk factor for KBD onset, could up-regulate the expression of WISP1 in C28/I2. The autophagy markers ATG4C and LC3II were upregulated after the low-concentration treatment of T-2 toxin and downregulated after the high-concentration treatment. After knocking down WISP1 expression in KBD chondrocytes, MAP1LC3B decreased while ATG4C and COL2A1 increased. Moreover, the rWISP1 protein treatment in C28/I2 chondrocytes could upregulate the expression of ATG4C and LC3II at the beginning and downregulate them then. CONCLUSIONS: Our study suggested that WISP1 might play a role in the pathogenesis of KBD through autophagy.

Dissecting the Association between Gut Microbiota and Brain Structure Change Rate: A Two-Sample Bidirectional Mendelian Randomization Study.

The connection between the gut microbiota and brain structure changes is still unclear. We conducted a Mendelian randomization (MR) study to examine the bidirectional causality between the gut microbiota (211 taxa, including 131 genera, 35 families, 20 orders, 16 classes and 9 phyla; N = 18,340 individuals) and age-independent/dependent longitudinal changes in brain structure across the lifespan (N = 15,640 individuals aged 4~99 years). We identified causal associations between the gut microbiota and age-independent/dependent longitudinal changes in brain structure, such as family Peptostreptococcaceae with age-independent longitudinal changes of cortical gray matter (GM) volume and genus Faecalibacterium with age-independent average cortical thickness and cortical GM volume. Taking age-independent longitudinal changes in brain structure across the lifespan as exposures, there were causal relationships between the surface area and genus Lachnospiraceae. Our findings may serve as fundamentals for further research on the genetic mechanisms and biological treatment of complex traits and diseases associated with the gut microbiota and the brain structure change rate.

Epigenetic analysis suggests aberrant cerebellum brain aging in old-aged adults with autism spectrum disorder and schizophrenia.

The aberrant aging hypothesis of schizophrenia (SCZ) and autism spectrum disorder (ASD) has been proposed, and the DNA methylation (DNAm) clock, which is a cumulative evaluation of DNAm levels at age-related CpGs, could serve as a biological aging indicator. This study evaluated epigenetic brain aging of ASD and SCZ using Horvath's epigenetic clock, based on two public genome-wide DNA methylation datasets of post-mortem brain samples (NASD = 222; NSCZ = 142). Total subjects were further divided into subgroups by gender and age. The epigenetic age acceleration (AgeAccel) for each sample was calculated as the residual value resulting from the regression model and compared between groups. Results showed DNAm age has a strong correlation with chronological age in both datasets across multiple brain regions (P < 0.05). When divided into equally sized age groups, the AgeAccel of the cerebellum (CB) region from people over 45 years of age was greater compared to the control sample (AgeAccel of ASD vs control: 5.069 vs -6.249; P < 0.001). And a decelerated epigenetic aging process was observed in the CB region of individuals with SCZ aged 50-70 years (AgeAccel of SCZ vs control: -3.171 vs 2.418; P < 0.05). However, our results showed no significant difference in AgeAccel between ASD and control groups, and between SCZ and control groups in the total and gender-specific groups (P > 0.05). This study's results revealed some evidence for aberrant epigenetic CB brain aging in old-aged patients with ASD and SCZ, indicating a different pattern of CB aging in older adults with these two diseases. However, further studies of larger ASD and SCZ cohorts are necessary to make definitive conclusions on this observation.

Integrative Analysis of Proteome-wide Association Studies and Functional Enrichment Analysis to Identify Genes and Chemicals Associated with Alcohol Dependence.

OBJECTIVES: Alcohol dependence accounts for a large proportion of the global burden of disease and disability. This study aims to investigate the candidate genes and chemicals associated with alcohol dependence. METHODS: Using data from published alcohol dependence genome-wide association studies, we first conducted a proteome-wide association study of alcohol dependence by integrating alcohol dependence genome-wide association studies with 2 human brain reference proteomes of dorsolateral prefrontal cortex from the Religious Order Study and Rush Memory and Aging Project and the Banner Sun Health Research Institute. Then, based on the identified genes in proteome-wide association study, we conducted functional enrichment analysis and chemical-related functional enrichment analysis to detect the related Gene Ontology terms and chemicals. RESULTS: Proteome-wide association study identified several potential candidate genes for alcohol dependence, such as GOT2 ( P = 7.59 × 10 -6 ) and C3orf33 ( P = 5.00 × 10 -3 ). Furthermore, functional enrichment analysis identified multiple candidate Gene Ontology terms associated with alcohol dependence, such as glyoxylate metabolic process (adjusted P = 2.99 × 10 -6 ) and oxoglutarate metabolic process (adjusted P = 9.95 × 10 -6 ). Chemical-related functional enrichment analysis detected several alcohol dependence-related candidate chemicals, such as pitavastatin ( P = 2.00 × 10 -4 ), cannabinoids ( P = 4.00 × 10 -4 ), 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid ( P = 4.00 × 10 -4 ), and gabapentin ( P = 2.00 × 10 -3 ). CONCLUSIONS: Our study reports multiple candidate genes and chemicals associated with alcohol dependence, providing novel clues for understanding the biological mechanism of alcohol dependence.

Evaluating the interaction between 3'aQTL and alcohol consumption/smoking on anxiety and depression: 3'aQTL-by-environment interaction study in UK Biobank cohort.

BACKGROUND: Smoking and alcohol consumption were associated with the development of depression and anxiety. 3'UTR APA quantitative trait loci (3'aQTLs) have been associated with multiple health states and conditions. Our aim is to evaluate the interactive effects of 3'aQTLs-alcohol consumption/tobacco smoking on the risk of anxiety and depression. METHODS: The 3'aQTL data of 13 brain regions were extracted from the large-scale 3'aQTL atlas. The phenotype data (frequency of cigarette smoking and alcohol drinking, anxiety score, self-reported anxiety, depression score and self-reported depression) of 90,399-103,011 adults aged 40-69 years living in the UK and contributing to the UK Biobank during 2006-2010, were obtained from the UK Biobank cohort. The frequency of cigarette smoking and alcohol drinking of each subject were defined by the amount of smoking and alcohol drinking of self-reported, respectively. The continuous alcohol consumption/smoking terms were further categorized in tertiles. 3'aQTL-by-environmental interaction analysis was then performed to evaluate the associations of gene-smoking/alcohol consumption interactions with anxiety and depression using generalized linear model (GLM) of PLINK 2.0 with an additive mode of inheritance. Furthermore, GLM was also used to explore the relationship between alcohol consumption/smoking with hazard of anxiety/depression stratified by allele for the significant genotyped SNPs that modified the alcohol consumption/smoking-anxiety/depression association. RESULTS: The interaction analysis identified several candidate 3'aQTLs-alcohol consumption interactions, such as rs7602638 located in PPP3R1 (ß = 0.08, P = 6.50 × 10-6) for anxiety score; rs10925518 located in RYR2 (OR = 0.95, P = 3.06 × 10-5) for self-reported depression. Interestingly, we also observed that the interactions between TMOD1 (ß = 0.18, P = 3.30 × 10-8 for anxiety score; ß = 0.17, P = 1.42 × 10-6 for depression score), ZNF407 (ß = 0.17, P = 2.11 × 10-6 for anxiety score; ß = 0.15, P = 4.26 × 10-5 for depression score) and alcohol consumption was not only associated with anxiety, but related to depression. Besides, we found that relationship between alcohol consumption and hazard of anxiety/depression was significantly different for different SNPs genotypes, such as rs34505550 in TMOD1 (AA: OR = 1.03, P = 1.79 × 10-6; AG: OR = 1.00, P = 0.94; GG: OR = 1.00, P = 0.21) for self-reported anxiety. LIMITATIONS: The identified 3'aQTLs-alcohol consumption/smoking interactions were associated with depression and anxiety, and its potential biological mechanisms need to be further revealed. CONCLUSIONS: Our study identified important interactions between candidate 3'aQTL and alcohol consumption/smoking on depression and anxiety, and found that the 3'aQTL may modify the associations between consumption/smoking with depression and anxiety. These findings may help to further explore the pathogenesis of depression and anxiety.

Mitochondria-wide association study observed significant interactions of mitochondrial respiratory and the inflammatory in the development of anxiety and depression.

The aim of this study was to investigate the possible interaction of mitochondrial dysfunction and inflammatory cytokines in the risk of anxiety and depression. We utilized the UK Biobank for the sample of this study. A mitochondria-wide association(MiWAS) and interaction analysis was performed to investigate the interaction effects of mitochondrial DNA (mtDNA)×C-reactive protein (CRP) on the risks of self-reported anxiety (N = 72,476), general anxiety disorder (GAD-7) scores (N = 80,853), self-reported depression (N = 80,778), Patient Health Questionnaire (PHQ-9) scores (N = 80,520) in total samples, females and males, respectively, adjusting for sex, age, Townsend deprivation index (TDI), education score, alcohol intake, smoking and 10 principal components. In all, 25 mtSNPs and 10 mtSNPs showed significant level of association with self-reported anxiety and GAD-7 score respectively. A total of seven significant mtDNA × CRP interactions were found for anxiety, such as m.3915G>A(MT-ND1) for self-reported anxiety in total subjects (P = 6.59 × 10-3), m.4561T>C(MT-ND2) (P = 3.04 × 10-3) for GAD-7 score in total subjects. For depression, MiWAS identified 17 significant mtSNPs for self-reported depression and 14 significant mtSNPs for PHQ-9 scores. 17 significant mtDNA associations (2 for self-reported depression and 15 for PHQ-9 score) was identified, such as m.14869G>A(MT-CYB; P = 2.22 × 10-3) associated with self-reported depression and m.4561T>C (MT-ND2; P value = 3.02 × 10-8) associated with PHQ-9 score in all subjects. In addition, 5 common mtDNA shared with anxiety and depression were found in MiWAS, and 4 common mtDNA variants were detected to interact with CRP for anxiety and depression, such as m.9899T>C(MT-CO3). Our study suggests the important interaction effects of mitochondrial function and CRP on the risks of anxiety and depression.

Exploratory factor analysis of shared and specific genetic associations in depression and anxiety.

BACKGROUND: Previous genetic studies of anxiety and depression were mostly based on independent phenotypes. This study aims to investigate the shared and specific genetic structure between anxiety and depression. METHOD: To identify the underlying factors of Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and their combined scale (joint scale), we employed exploratory factor analysis (EFA) using the eigenvalue of parallel analysis. Subsequently, we conducted a genome-wide association study (GWAS) for these factors. In addition, we utilized LD Score Regression (LDSC) to determine the genetic correlations between the identified factors and four common mental disorders, three sleep phenotypes, and other traits that have been previously linked to anxiety and depression. RESULTS: The EFA uncovered two factors for the GAD-7 scale, namely nervousness and disturbance, two factors for the PHQ-9 scale, namely negative affect and sleep/appetite disturbance, and four factors for the joint scale, specifically nervousness, anhedonia, sleep/appetite disturbance, and fidget. We identified two genome-wide significant genomic loci, with overlap across GAD-7 factor 1 and joint scale factor 1: rs148579586 (PGAD-7 = 1.365 × 10-09, PJoint scale = 1.434 × 10-09) and rs201074060 (PGAD-7 = 3.672 × 10-09, PJoint scale = 3.824 × 10-09). Genetic correlations in factors ranged from 0.722 to 1.000 (all p < 1.786 × 10-03) with 27 of 28 correlations being significantly smaller than one. The genetic correlations with external phenotypes showed small variation across the eight factors. CONCLUSION: Unidimensional structures can provide more precise scores, which can aid in identifying the shared and specific genetic associations between anxiety and depression. This is a crucial step in characterizing the genetic structure of these conditions and their co-occurrence.

Evaluating the role of anxiety on the association between irritable bowel syndrome and brain volumes: a mediation analysis in the UK Biobank cohort.

There is a strong link between irritable bowel syndrome and brain volumes, yet, to date, research examining the mediators of this association has been little. Based on the phenotypic data of 15 248 participants from the UK Biobank, a two-stage mediation analysis was performed to assess the association among brain volumes, anxiety, and irritable bowel syndrome. In the first stage, we identified the candidate mediating role of anxiety for irritable bowel syndrome associated with brain volumes using regression models. Then, we quantified the magnitude of the mediation effects by evaluating the average causal-mediated effect and proportion of mediation through performing mediation analyses in the R package in the second stage. In the first stage, we identified the partly mediating role of anxiety in the association between irritable bowel syndrome and the volume of thalamus (P left = 1.16 × 10-4, P right = 2.41 × 10-4), and grey matter (P left = 3.22 × 10-2, P right = 1.18 × 10-2) in the VIIIa cerebellum. In the second stage, we observed that the proportion of the total effect of irritable bowel syndrome on volume of thalamus mediated by anxiety was 14.3% for the left region (ß Average causal-mediated effect = -0.008, P Average causal-mediated effect = 0.004) and 14.6% for the right region (ß Average causal-mediated effect = -0.007, P Average causal-mediated effect = 0.006). Anxiety mediated 30.8% for the left region (ß Average causal-mediated effect = -0.013, P Average causal-mediated effect = 0.002) and 21.6% for the right region (ß Average causal-mediated effect = -0.010, P Average causal-mediated effect x= 0.018) of the total effect of irritable bowel syndrome on the volume of grey matter in the VIIIa cerebellum. Our study revealed the indirect mediating role of anxiety in the association between irritable bowel syndrome and brain volumes, promoting our understanding of the functional mechanisms of irritable bowel syndrome and its related psychosocial factors.

Integrating genome-wide association study with regulatory SNP annotations identified novel candidate genes for osteoporosis.

Osteoporosis (OP) is a metabolic bone disease, characterized by a decrease in bone mineral density (BMD). However, the research of regulatory variants has been limited for BMD. In this study, we aimed to explore novel regulatory genetic variants associated with BMD. We conducted an integrative analysis of BMD genome-wide association study (GWAS) and regulatory single nucleotide polymorphism (rSNP) annotation information. Firstly, the discovery GWAS dataset and replication GWAS dataset were integrated with rSNP annotation database to obtain BMD associated SNP regulatory elements and SNP regulatory element-target gene (E-G) pairs, respectively. Then, the common genes were further subjected to HumanNet v2 to explore the biological effects. Through discovery and replication integrative analysis for BMD GWAS and rSNP annotation database, we identified 36 common BMD-associated genes for BMD irrespective of regulatory elements, such as FAM3C (pdiscovery GWAS = 1.21 × 10-25, preplication GWAS = 1.80 × 10-12), CCDC170 (pdiscovery GWAS = 1.23 × 10-11, preplication GWAS = 3.22 × 10-9), and SOX6 (pdiscovery GWAS = 4.41 × 10-15, preplication GWAS = 6.57 × 10-14). Then, for the 36 common target genes, multiple gene ontology (GO) terms were detected for BMD such as positive regulation of cartilage development (p = 9.27 × 10-3) and positive regulation of chondrocyte differentiation (p = 9.27 × 10-3). We explored the potential roles of rSNP in the genetic mechanisms of BMD and identified multiple candidate genes. Our study results support the implication of regulatory genetic variants in the development of OP.

Association between birth by caesarian section and anxiety, self-harm: a gene-environment interaction study using UK Biobank data.

BACKGROUND: Limited efforts have been paid to explore the underlying genetic mechanisms of birth by caesarian section (CS) affecting the risks of adult anxiety and self-harm. METHODS: Using UK Biobank cohort, the logistic regression model was first applied to evaluate the associations of adult anxiety and self-harm with birth by CS. Using birth by CS as exposure variables, genome-wide by environment interaction study (GWEIS) was then applied by PLINK2.0 to identify associated genes interacting with birth by CS for anxiety and self-harm. RESULTS: In the observational study, significant associations were observed between birth by CS and anxiety (odds ratio (OR) = 1.24; 95% confidence interval (CI), 1.12-1.38; P = 4.86 × 10- 5), and self-harm (OR = 1.12; 95% CI, 1.01-1.24; P = 2.90 × 10- 2). GWEIS revealed multiple suggestive genes interacted with birth by CS for anxiety, such as DKK2 (rs13137764, P = 1.24 × 10- 9, adjusted P = 2.68 × 10- 7) and ATXN1 (rs62389045, P = 4.38 × 10- 8, adjusted P = 3.55 × 10- 6). For self-harm, significant gene-environment interactions of birth by CS on self-harm were detected, such as ALDH1A2 (rs77828167, P = 1.62 × 10- 8; rs116899929, P = 1.92 × 10- 8) and DAB1 (rs116124269, P = 3.20 × 10- 8; rs191070006, P = 3.63 × 10- 8). CONCLUSIONS: Our results suggested that birth by CS was associated with the risk of adult anxiety and self-harm. We also discovered some genes interacted with birth by CS might influence the risk of anxiety and self-harm, which may provide novel clues for the pathogenesis of those mental disorders.