Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health concern given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10; N=11,875), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17; N=4,326) and IMAGEN (EUROPE, age of 14; N=1888). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta-analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school support index had the most significant and consistent impact across all three cohorts. In both meta, and mega-analysis, SNP rs79878474 in chr11p15 emerged as a particularly promising candidate associated with anxiety and depression, despite not reaching genomic significance. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine, and a trend of enrichment in the cerebellum. Our findings provide evidences of consistent environmental impact from early life stress and school support index on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels, which support the stress-depression connection via hypothalamic-pituitary-adrenal axis, along with the potential modulating role of potassium channels.

Association between impulsivity and depressive symptoms in recently detoxified patients with alcohol dependence.

Background: Depression and impulsivity are etiologically linked to alcohol dependence (AD) and are known to affect course and outcomes. The relationship between impulsivity and depressive symptoms has been investigated only in a few studies of individuals with AD. Aim: This study aimed to explore the association between impulsivity and depressive symptoms in patients with AD. Materials and Methods: Our study was conducted in the inpatient setup of a tertiary care psychiatry institute. The study design is cross-sectional. The Barratt Impulsiveness Scale (BIS-11) and stop signal task (SST) were used to assess levels of global impulsivity and behavioral impulsivity, respectively, among 60 recently detoxified inpatients with AD. The Hamilton Depression Rating Scale (HAM-D) was used to measure depressive symptoms. The results were analyzed to examine the association of depressive symptoms with impulsivity. Pearson's coefficient of correlation or Spearman's rank correlation and linear regression analysis were performed to explore the association between quantitative variables. Results: Patients with higher HAM-D scores were found to have significantly higher score on all three subscales of the BIS-11. The attention impulsivity subscale had the strongest correlations (r = 0.53, P < 0.001). Depressive symptoms were more strongly correlated with cognitive impulsivity (r = 0.54, P< 0.0001) compared with motor impulsivity and were not significantly associated with behavioral impulsivity. Adjusting for other variables, cognitive impulsivity was found to be the strongest predictor of the severity of depressive symptoms. Conclusions: The study showed a strong association between impulsivity and depressive symptoms in individuals with AD. This relationship may apply more to cognitive impulsivity, reflecting the role of impulsive decisions compared with impulsive actions.

A cross ancestry genetic study of psychiatric disorders from India.

Genome-wide association studies across diverse populations may help validate and confirm genetic contributions to risk of disease. We estimated the extent of population stratification as well as the predictive accuracy of polygenic scores (PGS) derived from European samples to a data set from India. We analysed 2685 samples from two data sets, a population neurodevelopmental study (cVEDA) and a hospital-based sample of bipolar affective disorder (BD) and obsessive-compulsive disorder (OCD). Genotyping was conducted using Illumina's Global Screening Array. Population structure was examined with principal component analysis (PCA), uniform manifold approximation and projection (UMAP), support vector machine (SVM) ancestry predictions, and admixture analysis. PGS were calculated from the largest available European discovery GWAS summary statistics for BD, OCD, and externalizing traits using two Bayesian methods that incorporate local linkage disequilibrium structures (PGS-CS-auto) and functional genomic annotations (SBayesRC). Our analyses reveal global and continental PCA overlap with other South Asian populations. Admixture analysis revealed a north-south genetic axis within India (FST 1.6%). The UMAP partially reconstructed the contours of the Indian subcontinent. The Bayesian PGS analyses indicates moderate-to-high predictive power for BD. This was despite the cross-ancestry bias of the discovery GWAS dataset, with the currently available data. However, accuracy for OCD and externalizing traits was much lower. The predictive accuracy was perhaps influenced by the sample size of the discovery GWAS and phenotypic heterogeneity across the syndromes and traits studied. Our study results highlight the accuracy and generalizability of newer PGS models across ancestries. Further research, across diverse populations, would help understand causal mechanisms that contribute to psychiatric syndromes and traits.

Knowledge, Attitude, and Expectancies Related to Cannabis Use: A Cross-sectional Community Study Among College Students from Bangalore, Karnataka.

Background: Cannabis use among youth is increasing; this study aimed to assess college students' knowledge, attitude, and expectancies toward cannabis use. Methods: Cross-sectional survey using standardized tools among undergraduate and postgraduate college students in urban Bangalore, India (N = 405). Results: Ten percent reported past three-month cannabis use, with 1% reporting daily use. Users were significantly older (median age 21, IQR 22,20 [vs. 20, IQR 21,19], p < .001) and belonged to families with higher monthly incomes (p = .02). Use was significantly higher among males than females (65.9% vs. 34.1%, p = .006) and postgraduate students than undergraduates (51.2% vs. 48%, p = .001). Users were also significantly more favorable toward cannabis use (median score 4, IQR 6,2 [vs. median 3, IQR 4,2], p = .005) and had more positive expectancies from use (median score 2, IQR 3,2 [vs. median 2, IQR 2,0], p = .001). Nearly 30% were unaware that cannabis can affect a person's ability to drive safely or that it can affect executive functions, including academic performance. Over one-third were unaware of the current legal status of cannabis in India. Overall, 36%, 25%, and 17%, respectively, said that cannabis use is safe when used for recreational purposes, cannabis should be legalized as it helps to relieve stress, and cannabis use among youngsters should be acceptable in society as it is "part of college life." Conclusion: Findings build on existing literature on cannabis use among college youth in India, which can guide preventive interventions and policies for this vulnerable group.

A descriptive study of hepatitis C in people who inject drugs.

BACKGROUND OBJECTIVES: The seroprevalence of the hepatitis C virus (HCV) in general population is higher than that of human immunodeficiency virus (HIV) in India. People who inject drugs (PWIDs) constitute a high-risk group for all blood-borne infections. Multiple behavioural surveillance surveys have provided a rich typology of HIV-infected PWIDs, but this information is missing for HCV infection. We describe awareness, transmission risk factors and the treatment continuum for HCV infection among PWID. We also report spatial clustering of HCV infection in PWIDs residing in Bengaluru. METHODS: Information from clinical records was collected and telephonic interviews of retrospectively identified PWIDs who received treatment at a tertiary-level addiction treatment facility between 2016 and 2021 were conducted. RESULTS: We identified 391 PWIDs; 220 (56.26%) received an anti-HCV antibody test (4 th Generation HCV-Tridot). Individuals reporting unsafe injection practices were more often tested than those who did not ( χ2 =44.9, df=1, P <0.01). Almost half of the tested and more than a quarter of the whole sample (109/220, 49.9%; 109/391, 27.9%) were seropositive for HCV infection. The projected seropositivity in this group was between 27.9 per cent (best case scenario, all untested assumed negative) and 71.6 per cent (worst case scenario, all untested assumed positive). Only a minority of participants interviewed were aware of HCV (27/183, 14.7%). HCV infection and its associated risk behaviour (PWID) were clustered in certain localities (Diggle and Chetwynd Test; P =0.001) in Bengaluru in the southern district of Karnataka. INTERPRETATION CONCLUSIONS: Undetected HCV infection is common in PWIDs; awareness and treatment uptake is poor in this group. Spatial clustering of infections in a district shows transmission in close networks and provides opportunities for targeted interventions.

A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis.

BACKGROUND: Genetic and epigenetic factors are associated with the development of alcohol-associated liver disease (AALD). The single nucleotide polymorphisms (SNPs), rs738409 in Patatin-like phospholipase domain-containing protein (PNPLA3) and rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) are strongly associated with AALD in different global populations, Hence, we analyzed the genetic risk score for these variants and deoxyribonucleic acid (DNA) methylation levels of the PNPLA3 and TM6SF2 genes among cases (alcohol liver cirrhosis) and controls (heavy drinkers without cirrhosis). METHOD: We studied patients with alcohol use disorder (AUD) with cirrhosis (AUD-C + ve, n = 136) and without cirrhosis (AUD-C-ve, n = 107) drawn from the clinical services of St. John's Medical College Hospital (SJMCH) (Gastroenterology and Psychiatry) and Centre for Addiction Medicine (CAM), National Institute of Mental Health and Neurosciences, (NIMHANS). Genotype data was generated for rs738409 (PNPLA3) and rs58542926 (TM6SF2) and used to calculate unweighted genetic risk score (uGRS) and weighted genetic risk scores (wGRS). DNA methylation levels were estimated by pyrosequencing at PNPLA3 and TM6SF2 loci. RESULTS: Overall we observed a significantly higher genetic risk score (weighted genetic risk score, wGRS) in individuals with alcohol use disorder compared to control population (p = < 0.01). Further, uGRS and wGRS were associated with the diagnosis of cirrhosis, even after correcting for age of onset, quantity and frequency of drinking. We also found hypomethylation at CpG2 of TM6SF2 gene in AUD-C + ve compared to AUD-C-ve (P = 0.02). CONCLUSION: We found that a genetic risk score based on SNPs in the PNPLA3 and TM6SF2 genes was significantly associated with cirrhosis in patients with AUD, suggesting a potential utility in identifying patients at risk and providing pre-emptive interventions. These may include interventions that aim to alter DNA methylation, which may be one of the mechanisms through which elevated genetic risk may influence the development of cirrhosis.

Hypomethylation of Long Interspersed Nucleotide Elements and Aldehyde Dehydrogenase in Patients of Alcohol Use Disorder with Cirrhosis.

Alcohol use disorder (AUD) and cirrhosis are key outcomes of excessive alcohol use, and a genetic influence in these outcomes is increasingly recognized. While 80-90% of heavy alcohol users show evidence of fatty liver, only 10-20% progress to cirrhosis. There is currently no clear understanding of the causes of this difference in progression. The aim of this study is to evaluate genetics and epigenetics at the aldehyde dehydrogenase (ALDH2) locus in patients with AUD and liver complications. Study participants were inpatients from the clinical services of Gastroenterology and Psychiatry at St. John's Medical College Hospital (SJMCH) and the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Men diagnosed as having AUD with cirrhosis (AUDC+ve, N = 136) and AUD without cirrhosis (AUDC-ve, N = 107) were assessed. FibroScan/sonographic evidence was used to rule out fibrosis in the AUDC-ve group. Genomic DNA was used for genotyping at the ALDH2 (rs2238151) locus. A subset of 89 samples was used for DNA methylation (AUDC+ve, N = 44; and AUDC-ve, N = 45) analysis at long interspersed nucleotide element 1 (LINE-1) and ALDH2 cytosine-phosphate-guanine (CpG) loci by pyrosequencing. ALDH2 DNA methylation was significantly lower in the AUDC+ve group compared with the AUDC-ve group (p < 0.001). Lower methylation was associated with a risk allele (T) of the ALDH2 locus (rs2238151) (p = 0.01). Global (LINE-1) DNA methylation levels were also significantly lower in the AUDC+ve group compared with the AUDC-ve group (p = 0.01). Compromised global methylation (LINE-1) and hypomethylation at the ALDH2 gene was observed in patients with cirrhosis compared with those without cirrhosis. DNA methylation could be explored as a biomarker for cirrhosis and liver complications.

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health issue given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study investigated the impact of environmental factors and genomics on anxiety and depression in children and adolescents across three cohorts: the Adolescent Brain and Cognitive Development Study (US), the Consortium on Vulnerability to Externalizing Disorders and Addictions (India), and IMAGEN (Europe). Linear mixed-effect models, recursive feature elimination regression, and LASSO regression models were used to identify the environmental impact on anxiety/depression. Genome-wide association analyses were then performed for all three cohorts with consideration of significant environmental effects. The most significant and consistent environmental factors were early life stress and school risk. A novel SNP, rs79878474 in chr11p15, was identified as the most promising SNP associated with anxiety and depression. Gene set analysis found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, particularly Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes, respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine and a trend of enrichment in the cerebellum. The study highlights the consistent impact of early life stress and school risk on anxiety and depression during development and suggests the potential role of mutations in potassium channels and the cerebellum region. Further investigation is needed to better understand these findings.

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health issue given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17) and IMAGEN (EUROPE, age of 14). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta-analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school risk had the most significant and consistent impact across all three cohorts. Both meta and mega-analysis identified a novel SNP rs79878474 in chr11p15 to be the most promising SNP associated with anxiety and depression. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine and a trend of enrichment in the cerebellum. Our findings provide evidence of consistent environmental impact from early life stress and school risks on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels along with the potential role of the cerebellum region, which are worthy of further investigation.

Management of Alcohol Use Disorder in Patients With Alcoholic Liver Disease.

Alcohol use disorder (AUD) is a common condition that develops on the background of heavy alcohol use and is characterised by the loss of control over alcohol use and a compulsion to use alcohol, often despite negative consequences. AUD is a leading cause for the resumption of alcohol use in patients with alcoholic liver disease (ALD) after treatment. Hence it is essential to screen all patients with ALD for the presence of AUD. Screening tools such as alcohol use disorders identification test (AUDIT) and AUDIT-C are used, following which the diagnosis and severity of AUD are determined using DSM-5 criteria. The management of AUD in patients with ALD is best carried out using an integrated approach involving psychiatrists and gastroenterologists/hepatologists. The treatment most often involves a combination of pharmacotherapy and psychosocial interventions which try to achieve and maintain abstinence. Although, there is limited evidence, Baclofen is the first line pharmacological agent for long-term management of AUD in patients with ALD. Intensive psychological interventions such as motivation enhancement therapy and cognitive behavioural therapy are also seen to be beneficial. Treatment retention and follow-up are vital and can positively influence outcomes.

Management of Alcohol Withdrawal Syndrome in Patients with Alcoholic Liver Disease.

Alcohol withdrawal syndrome (AWS) is a common condition that is seen in treatment-seeking patients with Alcohol use disorder (AUD) and alcoholic liver disease (ALD). AWS, which typically starts within 4-6 h of the last alcohol use, can range from mild symptoms such as insomnia, tremors, and autonomic hyperactivity to more severe symptoms such as seizures and delirium tremens. Clinical Institute Withdrawal Assessment Scale-Alcohol Revised (CIWA-Ar) is the most commonly used scale to assess AWS in clinical practice. The presence of moderate withdrawal as indicated by a score of more than 8 is an indication for pharmacotherapy. Lorazepam and oxazepam are preferred agents for the management of AWS in the setting of ALD. In severe ALD, benzodiazepines should be used cautiously with monitoring due to the risk of excessive sedation or precipitating hepatic encephalopathy.

Neurocognition and its association with adverse childhood experiences and familial risk of mental illness.

Environmental factors such as adverse childhood experiences (ACEs) may affect neurocognition, an endophenotype for several mental illnesses. This study examines the effect of ACEs on neurocognitive performance in first-degree relatives (FDRs) of patients with severe mental illness to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition. Unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder, or alcohol use disorder) (n = 324) and healthy controls (with no familial risk) (n = 188) underwent neurocognitive tests for processing speed, new learning, working memory and Theory of Mind. ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Score and their interaction (familial risk*ACE-IQ score). The main effect of familial risk predicted poor performance in all domains of neurocognition (p < 0.01), and the interaction had a negative association with global neurocognition (ß = -0.093, p = 0.009), processing speed (ß = -0.109, p = 0.003) and working memory (ß = -0.092, p = 0.01). Among the ACEs sub-domains, only maltreatment (specifically the main effect of physical neglect and the interaction effect of sexual abuse with familial risk) predicted poorer neurocognition. In FDRs of schizophrenia and bipolar disorder, only the main effects of familial risk were significantly associated with poorer neurocognition. We conclude that there is a relationship between ACEs (especially maltreatment) and neurocognitive functioning, which is moderated by the familial risk of mental illnesses. Genetic/familial vulnerability may have a stronger association with neurocognition in schizophrenia and bipolar disorder.

Concurrent catatonia and COVID-19 infection - An experiential account of challenges and management of cases from a tertiary care psychiatric hospital in India.

Catatonia has been reported as one among many neuropsychiatric manifestations associated with COVID-19 infection. Catatonia and COVID-19 co-occurrence remain clinical concerns, often posing challenges pertaining to diagnosis, and especially management. Limited information is available regarding the appropriate approaches to the management of catatonia in COVID-19 infection, particularly with reference to the safety and efficacy of benzodiazepines and Electro-convulsive therapy (ECT). We present our experience of five patients with catatonia consequent to heterogeneous underlying causes and concurrent COVID-19 infection, who received care at the psychiatric COVID unit of our tertiary care psychiatric hospital. An interesting observation included varying underlying causes for catatonia and the potential role that COVID-19 infection may have played in the manifestation of catatonia. In our experience, new-onset catatonia with or without pre-existing psychiatric illness and concurrent COVID-19 can be safely and effectively managed with lorazepam and/or ECTs. However, critical to the same is the need to implement modified protocols that integrate pre-emptive evaluation for COVID-19 disease and proactive monitoring of its relevant clinical parameters, thereby permitting judicious and timely implementation of catatonia-specific treatment options.

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes.

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 74 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimer's disease and cognitive abilities in genome wide association studies. We then checked whether any of these 74 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 74 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.