Most genetic studies of psychiatric disorders have been conducted predominantly in populations of European ancestry, limiting evidence for the transferability of polygenic scores (PGS) to other populations. This cross-sectional study evaluated the predictive performance of European-derived PGS for bipolar disorder (BD) and obsessive-compulsive disorder (OCD) in an Indian sample. Participants (N = 2531) included individuals with BD (N = 463), OCD (N = 554), and controls (N = 1514) recruited from hospital- and community-based samples. Genotyping was performed using the Illumina Global Screening Array. PGS were derived from the summary statistics of European-ancestry genome-wide association studies using two Bayesian methods, PRS-CS-auto and SBayesRC. Principal component analyses demonstrated genetic overlap of the study population with other South Asian populations. BD PGS showed significant predictive performance, explaining approximately 6%-7% of liability-scale variance with PGS-only AUCs of ~0.71. OCD PGS showed lower but significant predictive performance, explaining ~2%-3% of variance with AUCs of approximately 0.59. Bayesian approaches showed better predictive performance than conventional clumping-and-thresholding. These findings demonstrate that European-derived psychiatric PGS can retain predictive information in an Indian population, although performance differed between disorders. The application of Bayesian PGS methods in this Indian cohort supports their utility for cross-ancestry prediction, while reinforcing the need for larger genomic studies in South Asian and other underrepresented populations.
2026J Affect Disord
A transdiagnostic evaluation of adult temperamental profiles and their interactions with childhood adversities across major psychiatric disorder
Dayalamurthy, P.; Balachander, S.; Lakkireddy, S. P.; ...; ADBS-CBM Consortium
BACKGROUND: Temperamental profiles and adverse childhood experiences (ACEs) have been reported in most major psychiatric disorders. However, the nature of this relationship is complex and under-studied. METHODS: A total of 1162 individuals (N = 532 affected; N = 457 unaffected first-degree relatives (FDRs) and N = 173 healthy controls) were included. Affected individuals and their FDRs were from 393 multiplex families of schizophrenia, bipolar disorder, obsessive-compulsive disorder, or alcohol use disorder. They were assessed using the self-reported Adult Temperament Questionnaire (ATQ), and the ACEs International Questionnaire. We performed frequentist and Bayesian mixed-effects regression models, to look for associations between the ATQ domains, ACEs score and their interaction with each diagnosis/familial risk. External validity of our final model was tested to predict diagnosis in an independent cohort. Receiver operator characteristic plots and the area under the curve (AUC) were used to evaluate its prediction accuracy. RESULTS: All temperamental domains: negative affectivity (NA), extraversion (EV), effortful control (EC) and orienting sensitivity (OS) had significant associations in a unique configuration within each of the four diagnoses and their familial risk. ACEs, and its interactions were significantly associated with alcohol use disorder only. In the external validation dataset, the final model was found to successfully predict AUD (AUC = 0.822), BD (AUC = 0.742) and OCD (AUC = 0.752), but not SCZ (AUC = 0.526). CONCLUSIONS: These findings provide unique insights into the complexities of temperament in major psychiatric disorders and emphasize the importance of evaluating temperament in conjunction with childhood adversity to characterize risk.
2026Asian Journal of Psychiatry
For better and for worse: Evidence of differential susceptibility to environmental adversity in youth substance use from the cVEDA cohort
Bajpai, A.; Holla, B.; Sharma, E.; ...; Benegal, V.
BACKGROUND: Familial vulnerability and environmental adversity are both associated with adolescent substance-use, yet their joint effects remain insufficiently characterized. This study examined their interaction using a latent gene-environment (GxE) framework in the cVEDA cohort. METHODS: The sample included 3786 adolescents and young adults aged 12-24 years. Familial vulnerability was indexed as the family-history density (FHD) scores derived from the pedigree for medical and psychiatric conditions, adjusted for degree of relatedness. Environmental adversity was captured using measures of childhood adversity, school climate, and parenting experiences. Substance use summarized as a global continuum of risk score from the WHO ASSIST. Weighted latent G×E models were estimated using an alternating optimization approach, adjusting for age and sex. Competing susceptibility patterns were compared, and predictive performance was evaluated using five-fold cross validation. RESULTS: Familial vulnerability and environmental adversity were each associated with greater substance use involvement, with evidence that familial vulnerability amplified environmental effects. The latent familial composite was driven primarily by family history of alcohol dependence (ηp2=0.03) and other psychiatric disorders (ηp2=0.044). The latent environmental composite was dominated by adverse childhood experiences (ηp2=0.042) and unsafe school climate (ηp2=0.029), with smaller contributions from childhood neglect and negative parenting practices (ηp2textless0.01). Model comparisons suggested a weak differential susceptibility pattern. Cross validation showed good discrimination (AUC=0.84). CONCLUSIONS: Youth with greater familial vulnerability appear more environmentally sensitive, consistent with a "for-better-and-for-worse" pattern typical of differential susceptibility model. Integrating family risk screening with interventions targeting school climate, childhood adversity, and parenting may help identify targets for substance use prevention.
2026Asian J Psychiatr
The competency-control paradox in parenting adolescents: Evidence from an Indian mixed-methods study
Sharma, E.; Jacob, P.; Binu, V. S.; ...; cVEDA consortium
BACKGROUND: Adolescence is a critical developmental period during which parenting practices interact with temperament and sociocultural context to shape mental health and adaptation. Most parenting models are derived from Western settings, with limited evidence from India. METHODS: This simultaneous mixed methods study drew on cross sectional data from the Indian Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA) cohort, including adolescents aged 12-17 years (parent report n = 931; child report n = 836). Exploratory factor analysis was conducted on parent and child versions of the Alabama Parenting Questionnaire. Qualitative data were obtained through in-depth interviews with 31 adolescents and their parents and analysed using thematic analysis. Findings were integrated at the interpretation stage. FINDINGS: The original APQ structure did not replicate. Parent reports yielded three dimensions-Involvement/Positive Parenting, Poor Monitoring, and Corporal Punishment-while child reports yielded five, distinguishing father's and mother's involvement. Inconsistent disciplining did not emerge as a distinct construct. Qualitative findings indicated high involvement and behavioural and psychological control, largely driven by academic goals. Adolescents experienced these practices as both supportive and restrictive, with parental openness shaping communication. Contextual pressures, including resource constraints and urban stressors, contributed to a competency-control paradox. INTERPRETATIONS: Parenting of adolescents in India must be understood within its relational and sociocultural ecology. While involvement and control function as primary supports, excessive control may constrain broader competency development. Integrating parent and adolescent perspectives is essential for culturally grounded research and intervention.
2026Translational Psychiatry
Plasma Glial Fibrillary Acidic Protein (GFAP) shows age-dependent associations with externalizing psychopathology and atypical brain connectivity
Niveditha, B. S.; Holla, B.; Subramanian, S.; ...; Srinivas Bharath, M. M.
Externalizing disorders are common neurodevelopmental conditions, yet their underlying biology is not fully understood. Integrating peripheral biomarkers with brain imaging offers a powerful approach to elucidate the pathophysiology of these disorders. This study aimed to investigate the association between indicators of glial activation (glial fibrillary acidic protein; GFAP) and axonal injury (neurofilament light chain; NfL) in plasma with functional brain connectivity, and externalizing psychopathology (EXT) in a neurodevelopmental cohort. Towards this, a cross-sectional study was conducted with 144 participants selected from the Indian cVEDA cohort and balanced into EXT and healthy control (HC) groups using Mahalanobis distance matching. Plasma GFAP and NfL were quantified using Simoa technology. Resting-state fMRI data were used to generate between-network connectivity deviation scores via normative modelling. We used Gamma General Linear Models (Gamma GLMs) to test for an age-by-EXT interaction on GFAP/ NfL levels and sparse partial least squares (sPLS) regression to identify connectivity features that correlated with them. We found a significant age-by-EXT interaction for GFAP (p = 0.002), where EXT was associated with higher GFAP levels only in younger participants (<14 years). No significant effects were found for NfL. The sPLS analysis identified a significant five-feature brain connectivity signature that correlated with GFAP levels. This pattern was characterized by atypically strong connectivity between sensorimotor-limbic and attention-default mode networks, and weaker-than-expected connectivity within the default mode network. In conclusion, our findings identify a strong association between plasma GFAP and EXT in youth in an age dependent manner, suggesting a key role for glial activation in the early pathophysiology of these disorders. This process is linked to a specific, multivariate pattern of brain dysconnectivity, providing a potential neurobiological signature that warrants further investigation.
2026J Am Acad Child Adolesc Psychiatry
Dimensional Associations Between Conduct Problems and Brain Structure Across 18 International Cohorts in ENIGMA
Staginnus, M.; Gao, Y.; Townend, S.; ...; Fairchild, G.
OBJECTIVE: Although conduct problems (CPs) are continuously distributed, little is known about how dimensional measures of CPs map onto brain structure. Therefore a large sample was used to comprehensively assess associations between dimensionally measured CPs and brain structure. METHOD: T1-weighted structural brain magnetic resonance imaging scans from 14,160 youths (5-21 years old, 46.2% female) across 18 international case-control, community-based, and population-based cohorts were preprocessed using ENIGMA-standardized protocols. Regression models examined associations between CPs and cortical thickness, surface area, and subcortical volumes, adjusting for age, sex, and intracranial volume. Moderation by sex, age, and callous-unemotional traits was also investigated. RESULTS: Widespread but small (β = -0.02 to -0.07) negative associations were observed between CPs and surface area (total surface area, 23/34 regions), cortical thickness (average thickness, 15/34 regions), and amygdalar and hippocampal volumes. Sex was a key moderator, with many surface area associations limited to boys and some thickness associations limited to girls. Some associations were stronger in younger children and at lower levels of callous-unemotional traits. The impact of adjusting for IQ and other psychopathology varied by outcome (eg, most surface area findings survived IQ adjustment, whereas cortical thickness associations did not). CONCLUSION: CPs were associated with subtle, yet widespread, alterations in brain structure. Findings overlapped with differences observed in categorically measured conduct disorder, but novel associations with cortical thickness were identified. This provides further evidence that neuroanatomical differences are not limited to youth with clinically elevated CPs. Our findings have potential implications for neurocognitive models of CPs as they extend beyond the regions highlighted in these models. STUDY REGISTRATION INFORMATION: Investigating dimensional relationships between conduct problems and brain structure: an ENIGMA mega-analysis; https://osf.io/nzj3r/.
2025BMC Psychiatry
The PAthways to Resilience And Mental health (PARAM) project: protocol for a multi-site developmental cohort in India
Holla, B.; Sharma, E.; Venkataramanan, S.; ...; Benegal, V.
BACKGROUND: Psychiatric disorders are increasingly conceptualised within a neurodevelopmental framework, in which genetic liability interacts with environmental exposures across the lifespan to shape brain and behavioural trajectories. Deviations in these trajectories may confer vulnerability or resilience to later psychopathology. Longitudinal cohorts spanning critical developmental windows are required to map these pathways and their associated risk and protective factors. METHODS: The PAthways to Resilience And Mental health (PARAM) project is a multi-site longitudinal cohort in India, enrolling approximately 9,000 participants from the antenatal period to 30 years of age. PARAM extends the Consortium on the Vulnerability to Externalizing Disorders and Addictions (cVEDA) cohort, which recruited more than 9,000 individuals aged 6-23 years, by adding intensive follow-up from the fetal period to early childhood. Eight sites across India participate, with five recontacting their original cVEDA participants for repeated assessments. Repeated measures include questionnaires on development, temperament, and mental health; family medical and psychiatric history; assessments of environmental exposures such as adverse experiences, diet, maternal stress, toxic exposures, and screen use; and satellite-derived indicators of urbanisation and air pollution over time. Detailed examinations comprise anthropometry and body composition, neurocognitive testing, neurophysiological measures including heart rate variability and body sway, neuroimaging with 3T MRI and fNIRS, and biospecimen collection (blood, buccal swabs, hair, nails, urine, stool) for genomic, toxicological, and metabolic assays. Data are stored in a harmonised digital archive linked to a barcoded biorepository. Follow-up employs a closed cohort design for children younger than two years and an accelerated longitudinal design for older participants. Planned analyses include mixed-effects and generalized additive models for trajectories, multi-site imaging harmonisation and normative modelling, multivariate integration of multi-omic and imaging features, and predictive modelling with nested cross-validation and external validation where feasible. Missing data and attrition will be addressed using multiple imputation and inverse probability weighting. DISCUSSION: PARAM will offer insights into population-based developmental trajectories, identify modifiable risk and protective factors, and support predictive models for psychopathology. The findings are expected to inform precision interventions and public health strategies, while contributing a socio-culturally diverse resource to global mental health research.
2025Biol Psychiatry
Shared and distinct alterations in brain structure of youth with internalizing or externalizing disorders: Findings from the ENIGMA Antisocial Behavior, ADHD, MDD, and Anxiety Working Groups
Sophie Townend; Staginnus, M.; Gao, Y.; ...; Fairchild, G.
BACKGROUND: Externalizing and internalizing disorders are common in youth but are often studied separately, preventing researchers from identifying shared (i.e., transdiagnostic) alterations in brain structure. Using data from the ENIGMA Consortium, we conducted a mega-analysis to identify shared and distinct cortical and subcortical brain alterations across internalizing (anxiety disorders and depression) and externalizing disorders (attention-deficit/hyperactivity disorder [ADHD] and conduct disorder [CD]) in youth. METHODS: 3D T1-weighted MRI data from youth (aged 4-21 years) with anxiety disorders (n=1,044), depression (n=504), ADHD (n=1,317), and CD (n=1,172), along with healthy controls (n=4,743) were analyzed. We assessed group differences in regional cortical thickness, surface area, and subcortical volume using linear models, adjusted for site, age, and sex, and total intracranial volume in the surface area and subcortical volume models. RESULTS: We observed transdiagnostic associations, with both internalizing and externalizing disorders characterized by lower surface area in the insula, entorhinal cortex, and middle temporal gyrus, and lower amygdala volume (Cohen's ds=-0.07 to -0.24), as well as total surface area and intracranial volume (ds=-0.11 to -0.25). Externalizing-specific reductions in surface area were observed in fronto-parietal regions (ds=-0.08 to -0.13), but no internalizing-specific associations were identified. Disorder-specific alterations were identified for ADHD, CD, and anxiety disorders, but not depression. CONCLUSIONS: Both common and disorder-specific alterations were identified, with regions involved in salience attribution and emotion processing implicated across internalizing and externalizing disorders. These findings can guide future research targeting common biological processes across youth psychiatric disorders as well as features unique to individual disorders.
2025Eur Psychiatry
Human development, inequality, and their associations with brain structure across 29 countries
Medel, V.; Alliende, L. M.; Bethlehem, R.; ...; Crossley, N. A.
BACKGROUND: The macro-social and environmental conditions in which people live, such as the level of a country's development or inequality, are associated with brain-related disorders. However, the relationship between these systemic environmental factors and the brain remains unclear. We aimed to determine the association between the level of development and inequality of a country and the brain structure of healthy adults. METHODS: We conducted a cross-sectional study pooling brain imaging (T1-based) data from 145 magnetic resonance imaging (MRI) studies in 7,962 healthy adults (4,110 women) in 29 different countries. We used a meta-regression approach to relate the brain structure to the country's level of development and inequality. RESULTS: Higher human development was consistently associated with larger hippocampi and more expanded global cortical surface area, particularly in frontal areas. Increased inequality was most consistently associated with smaller hippocampal volume and thinner cortical thickness across the brain. CONCLUSIONS: Our results suggest that the macro-economic conditions of a country are reflected in its inhabitants' brains and may explain the different incidence of brain disorders across the world. The observed variability of brain structure in health across countries should be considered when developing tools in the field of personalized or precision medicine that are intended to be used across the world.
2025PLoS One
Examining the impact of maternal experiences of domestic violence on the mental health of their adolescent children in India
Gourisankar, A.; Ravi, P.; Kalokhe, A.; ...; Kalyanram, K.
BACKGROUND: Domestic violence (DV) is experienced by one in three women in India and is linked to poor mental health outcomes. We hypothesize that maternal experiences of DV can have negative impacts on the mental health of their children. Previous studies have demonstrated this link in Western countries, however culturally specific manifestations of DV and mental health disorders and socio-cultural differences in parent-child relationships and home environments necessitate deeper understanding of the impacts of maternal experiences of DV on children in the Indian context. METHODS: This study presents a secondary analysis of data collected from a seven-center study in urban and rural India examining mental health disorders among adolescents aged 12-17 years and psychological, physical, and sexual abuse affecting their mothers. The Indian Family Violence and Control Scale (IFVCS) was used to examine experiences of DV among mothers and the Mini International Neuropsychiatric Interview-Kid (MINI-Kid) was used to examine mental health outcomes among adolescents. Multivariate analyses examined the associations between maternal DV and adolescent mental disorders. RESULTS: Data from 2,784 adolescent-mother pairs were analyzed. In bivariate analyses, maternal experiences of physical, psychological, and sexual abuse were significantly associated with adolescent common mental disorders including anxiety and depression (p < 0.05). After adjusting for adolescent gender, site, and education status in the multivariate analysis, physical, sexual, and any DV were significantly associated with adolescent anxiety disorders and common mental disorders. Physical abuse was significantly associated with adolescent depressive disorders. CONCLUSIONS: These results suggest that exposure to maternal DV significantly impacts adolescent mental health in India and underscore the need to develop trauma-informed school programs and enhance DV prevention for women in India.
2025Scientific Data
DICOM datasets for reproducible neuroimaging research across manufacturers and software versions
Rorden, C.; Béranger, B.; Cheng, H.; ...; Morgan, P. S.
DICOM is an industry-standard for medical imaging data targeted at interoperability across systems. This enables transfer, storage and processing of imaging data regardless of the manufacturer. Pragmatically, manufacturers often store detailed acquisition parameters in private rather than public DICOM tags. In parallel, the DICOM standard itself has gradually evolved by introducing new public tags and properties to better capture emerging imaging technologies. Accurately extracting these details is essential for reproducible neuroimaging research. To address this need, we created a series of DICOM datasets illustrating how various manufacturers encode acquisition details that are critical for modern processing and analysis. These minimal test cases, covering CT and MR modalities, highlight manufacturer-specific conventions, including the use of public tags, private tags, and proprietary data structures. For each DICOM dataset, we provide corresponding NIfTI-formatted images with metadata JSON files following the BIDS standard, using consistent terminology to mitigate variations in how manufacturers encode acquisition details. Our repository provides validation datasets for any tool that is intended to extract acquisition details from medical imaging data.
2025INDIAN JOURNAL OF PSYCHIATRY
Conducting Large Scale Psychiatric Genetic Studies in India-Opportunities and Challenges
Mahadevan, J.; Ganesh, S.; Purushottam, M.; ...; Holla, B.
INDIAN JOURNAL OF PSYCHIATRY, 67(SUPPL 1), S127-S127
2025medRxiv
A transdiagnostic evaluation of adult temperamental profiles and their interactions with childhood adversities across major psychiatric disorders
Dayalamurthy, P.; Balachander, S.; Lakkireddy, S. P.; ...; Jain, S.
Background Temperamental profiles and adverse childhood experiences (ACEs) have been reported in most major psychiatric disorders. However, the nature of this relationship is complex and under-studied.Methods A total of 1162 individuals (N=532 affected; N=457 unaffected first-degree relatives (FDRs) and N=173 healthy controls) were included. Affected individuals and their FDRs were from 393 multiplex families of schizophrenia, bipolar disorder, obsessive-compulsive disorder, or alcohol use disorder. They were assessed using the self-reported Adult Temperament Questionnaire (ATQ), and the ACEs International Questionnaire. We performed frequentist and Bayesian mixed-effects regression models, to look for associations between the ATQ domains, ACEs score and their interaction with each diagnosis/familial risk. External validity of our final model was tested to predict diagnosis in an independent cohort. Receiver operator characteristic plots and the area under the curve (AUC) were used to evaluate its prediction accuracy.Results All temperamental domains: negative affectivity (NA), extraversion (EV), effortful control (EC) and orienting sensitivity (OS) had significant associations in a unique configuration within each of the four diagnoses and their familial risk. ACEs, and its interactions were significantly associated with alcohol use disorder only. In the external validation dataset, the final model was found to successfully predict AUD (AUC=0.82), BD (AUC=0.75) and OCD (AUC=0.74), but not SCZ (AUC=0.53).Conclusions These findings provide unique insights into the complexities of temperament in major psychiatric disorders, and emphasize the importance of evaluating temperament in conjunction with childhood adversity to characterize risk.Graphical Abstract (Study Methodology):Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis research is funded by the Accelerator program for Discovery in Brain disorders using Stem cells (ADBS) (jointly funded by the Department of Biotechnology, Government of India, and the Pratiksha trust; Grant BT/PR17316/MED/31/326/2015) and), and the Centre for Brain and Mind (CBM) grant of the Rohini Nilekani Philanthropies. BV is funded by the Intermediate (Clinical and Public Health) Fellowship (IA/CPHI/20/1/505266) of the DBT/Wellcome Trust India Alliance. The validation dataset was derived from the Consortium for Vulnerability to Externalizing Disorders and Addictions (c-VEDA), which is jointly funded by the Indian Council for Medical Research (ICMR/MRC/3/M/2015-NCD-I) and the Newton Grant from the Medical Research Council (MR/N000390/1), United KingdomAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The project was reviewed and approved by the Institutional Ethics Review Board of the National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, IndiaI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe study datasets will be made available upon request to the Principal Investigators of the ongoing ADBS (adbsnimhans.org) and c-VEDA (cveda-project.org) studies. The R codes used for statistical analysis can be provided upon request to the corresponding author (SB).
2024Nature
Study design features increase replicability in brain-wide association studies
Kang, K.; Seidlitz, J.; Bethlehem, R. A. I.; ...; Vandekar, S.
Brain-wide association studies (BWAS) are a fundamental tool in discovering brain-behaviour associations(1,2). Several recent studies have shown that thousands of study participants are required for good replicability of BWAS(1-3). Here we performed analyses and meta-analyses of a robust effect size index using 63 longitudinal and cross-sectional MRI studies from the Lifespan Brain Chart Consortium(4) (77,695 total scans) to demonstrate that optimizing study design is critical for increasing standardized effect sizes and replicability in BWAS. A meta-analysis of brain volume associations with age indicates that BWAS with larger variability of the covariate and longitudinal studies have larger reported standardized effect size. Analysing age effects on global and regional brain measures from the UK Biobank and the Alzheimer's Disease Neuroimaging Initiative, we showed that modifying study design through sampling schemes improves standardized effect sizes and replicability. To ensure that our results are generalizable, we further evaluated the longitudinal sampling schemes on cognitive, psychopathology and demographic associations with structural and functional brain outcome measures in the Adolescent Brain and Cognitive Development dataset. We demonstrated that commonly used longitudinal models, which assume equal between-subject and within-subject changes can, counterintuitively, reduce standardized effect sizes and replicability. Explicitly modelling the between-subject and within-subject effects avoids conflating them and enables optimizing the standardized effect sizes for each separately. Together, these results provide guidance for study designs that improve the replicability of BWAS.
2024European Neuropsychopharmacology
F98. EFFECT OF CHILDHOOD ADVERSITY ON DNA METHYLATION AT THE GLUCOCORTICOID RECEPTOR (NR3C1) LOCUS
Shankarappa, B.; Janardhanan, M.; Parthaje, S.; ...; Benegal, V.
Background Childhood maltreatment may lead to various mental and physical health issues later in the life across the lifespan. Increasing evidence supports the hypothesis that childhood maltreatment is associated with epigenetic modifications that may serve as a mechanism of disease. Hypothalamus-Pituitary-Adrenal axis (HPA axis), which is stimulated by stress, followed by release of glucocorticoids. Earlier studies have reported association of DNA methylation with childhood maltreatment focused on glucocorticoid receptor gene (NR3C1), which alters the responsiveness of the HPA axis due to stress. We aim to study the association of NR3C1 DNA methylation with childhood adversity. Results Out of the 86 participants, males comprised 47.67 % while females were 51.16%. The average age of the participants was 14.87 years. On the adversity scale, participants had an average binary score of 5.28, ranging from 1 to 10, with a standard deviation of ±1.94, suggesting differing levels of adversity experiences. Additionally, the mean frequency of adversity reported was 1.56, with a range of 0 to 7 and a standard deviation of ±1.83, highlighting variations in the frequency of adverse events encountered by the participants. Among the 9 CpG sites studied at NR3C1 locus, we found DNA methylation levels at CpG2 was associated with adversity binary and frequency score which is nominally significant. We did not observe association with the other adversity parameters. Discussion In our study, we are reporting the association of DNA methylation at NR3C1 locus and childhood adversity. Several studies have reported childhood maltreatment and alteration of DNA methylation at NR3C1. Our findings indicate that childhood maltreatment may be associated with altered methylation of NR3C1 gene that regulates the stress response, potentially providing insight into how maltreatment and other adversities could impact health outcomes negatively.
2024Front Psychiatry
Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression
Thapaliya, B.; Ray, B.; Farahdel, B.; ...; Liu, J.
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.
2024Lancet Psychiatry
Cortical structure and subcortical volumes in conduct disorder: a coordinated analysis of 15 international cohorts from the ENIGMA-Antisocial Behavior Working Group
Gao, Y.; Staginnus, M.; ENIGMA-Antisocial Behavior Working Group
BACKGROUND: Conduct disorder is associated with the highest burden of any mental disorder in childhood, yet its neurobiology remains unclear. Inconsistent findings limit our understanding of the role of brain structure alterations in conduct disorder. This study aims to identify the most robust and replicable brain structural correlates of conduct disorder. METHODS: The ENIGMA-Antisocial Behavior Working Group performed a coordinated analysis of structural MRI data from 15 international cohorts. Eligibility criteria were a mean sample age of 18 years or less, with data available on sex, age, and diagnosis of conduct disorder, and at least ten participants with conduct disorder and ten typically developing participants. 3D T1-weighted MRI brain scans of all participants were pre-processed using ENIGMA-standardised protocols. We assessed group differences in cortical thickness, surface area, and subcortical volumes using general linear models, adjusting for age, sex, and total intracranial volume. Group-by-sex and group-by-age interactions, and DSM-subtype comparisons (childhood-onset vs adolescent-onset, and low vs high levels of callous-unemotional traits) were investigated. People with lived experience of conduct disorder were not involved in this study. FINDINGS: We collated individual participant data from 1185 young people with conduct disorder (339 [28.6%] female and 846 [71.4%] male) and 1253 typically developing young people (446 [35.6%] female and 807 [64.4%] male), with a mean age of 13.5 years (SD 3.0; range 7-21). Information on race and ethnicity was not available. Relative to typically developing young people, the conduct disorder group had lower surface area in 26 cortical regions and lower total surface area (Cohen's d 0.09-0.26). Cortical thickness differed in the caudal anterior cingulate cortex (d 0.16) and the banks of the superior temporal sulcus (d -0.13). The conduct disorder group also had smaller amygdala (d 0.13), nucleus accumbens (d 0.11), thalamus (d 0.14), and hippocampus (d 0.12) volumes. Most differences remained significant after adjusting for ADHD comorbidity or intelligence quotient. No group-by-sex or group-by-age interactions were detected. Few differences were found between DSM-defined conduct disorder subtypes. However, individuals with high callous-unemotional traits showed more widespread differences compared with controls than those with low callous-unemotional traits. INTERPRETATION: Our findings provide robust evidence of subtle yet widespread brain structural alterations in conduct disorder across subtypes and sexes, mostly in surface area. These findings provide further evidence that brain alterations might contribute to conduct disorder. Greater consideration of this under-recognised disorder is needed in research and clinical practice. FUNDING: Academy of Medical Sciences and Economic and Social Research Council.
2024Psychol Med
Childhood adversities characterize the heterogeneity in the brain pattern of individuals during neurodevelopment
Kashyap, R.; Holla, B.; Bhattacharjee, S.; ...; Benegal, V.
BACKGROUND: Several factors shape the neurodevelopmental trajectory. A key area of focus in neurodevelopmental research is to estimate the factors that have maximal influence on the brain and can tip the balance from typical to atypical development. METHODS: Utilizing a dissimilarity maximization algorithm on the dynamic mode decomposition (DMD) of the resting state functional MRI data, we classified subjects from the cVEDA neurodevelopmental cohort (n = 987, aged 6-23 years) into homogeneously patterned DMD (representing typical development in 809 subjects) and heterogeneously patterned DMD (indicative of atypical development in 178 subjects). RESULTS: Significant DMD differences were primarily identified in the default mode network (DMN) regions across these groups (p < 0.05, Bonferroni corrected). While the groups were comparable in cognitive performance, the atypical group had more frequent exposure to adversities and faced higher abuses (p < 0.05, Bonferroni corrected). Upon evaluating brain-behavior correlations, we found that correlation patterns between adversity and DMN dynamic modes exhibited age-dependent variations for atypical subjects, hinting at differential utilization of the DMN due to chronic adversities. CONCLUSION: Adversities (particularly abuse) maximally influence the DMN during neurodevelopment and lead to the failure in the development of a coherent DMN system. While DMN's integrity is preserved in typical development, the age-dependent variability in atypically developing individuals is contrasting. The flexibility of DMN might be a compensatory mechanism to protect an individual in an abusive environment. However, such adaptability might deprive the neural system of the faculties of normal functioning and may incur long-term effects on the psyche.
2024medRxiv
A cross ancestry genetic study of psychiatric disorders from India
Holla, B.; Mahadevan, J.; Ganesh, S.; ...; Viswanath, B.
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 (F(ST) 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.
2023Dev Psychopathol
Risk clustering and psychopathology from a multi-center cohort of Indian children, adolescents, and young adults
Developmental adversities early in life are associated with later psychopathology. Clustering may be a useful approach to group multiple diverse risks together and study their relation with psychopathology. To generate risk clusters of children, adolescents, and young adults, based on adverse environmental exposure and developmental characteristics, and to examine the association of risk clusters with manifest psychopathology. Participants (n = 8300) between 6 and 23 years were recruited from seven sites in India. We administered questionnaires to elicit history of previous exposure to adverse childhood environments, family history of psychiatric disorders in first-degree relatives, and a range of antenatal and postnatal adversities. We used these variables to generate risk clusters. Mini-International Neuropsychiatric Interview-5 was administered to evaluate manifest psychopathology. Two-step cluster analysis revealed two clusters designated as high-risk cluster (HRC) and low-risk cluster (LRC), comprising 4197 (50.5%) and 4103 (49.5%) participants, respectively. HRC had higher frequencies of family history of mental illness, antenatal and neonatal risk factors, developmental delays, history of migration, and exposure to adverse childhood experiences than LRC. There were significantly higher risks of any psychiatric disorder [Relative Risk (RR) = 2.0, 95% CI 1.8-2.3], externalizing (RR = 4.8, 95% CI 3.6-6.4) and internalizing disorders (RR = 2.6, 95% CI 2.2-2.9), and suicidality (2.3, 95% CI 1.8-2.8) in HRC. Social-environmental and developmental factors could classify Indian children, adolescents and young adults into homogeneous clusters at high or low risk of psychopathology. These biopsychosocial determinants of mental health may have practice, policy and research implications for people in low- and middle-income countries.
2023JAMA Netw Open
Neurocognitive Analysis of Low-level Arsenic Exposure and Executive Function Mediated by Brain Anomalies Among Children, Adolescents, and Young Adults in India
Vaidya, N.; Holla, B.; Heron, J.; ...; Schumann, G.
IMPORTANCE: Arsenic, a contaminant of groundwater and irrigated crops, is a global public health hazard. Exposure to low levels of arsenic through food extends well beyond the areas with high arsenic content in water. OBJECTIVE: To identify cognitive impairments following commonly prevalent low-level arsenic exposure and characterize their underlying brain mechanisms. DESIGN, SETTING, AND PARTICIPANTS: This multicenter population-based cohort study analyzed cross-sectional data of the Indian Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA) cohort, recruited between November 4, 2016, and May 4, 2019. Participants aged 6 to 23 years were characterized using deep phenotyping measures of behavior, neuropsychology, psychopathology, brain neuroimaging, and exposure to developmental adversities and environmental neurotoxins. All analyses were performed between June 1, 2020, and December 31, 2021. EXPOSURE: Arsenic levels were measured in urine as an index of exposure. MAIN OUTCOMES AND MEASURES: Executive function measured using the cVEDA neuropsychological battery, gray matter volume (GMV) from T1-weighted magnetic resonance imaging, and functional network connectivity measures from resting state functional magnetic resonance imaging. RESULTS: A total of 1014 participants aged 6 to 23 years (589 male [58.1%]; mean [SD] age, 14.86 [4.79] years) were included from 5 geographic locations. Sparse-partial least squares analysis was used to describe a negative association of arsenic exposure with executive function (r = -0.12 [P = 5.4 × 10-4]), brain structure (r = -0.20 [P = 1.8 × 10-8]), and functional connectivity (within network, r = -0.12 [P = 7.5 × 10-4]; between network, r = -0.23 [P = 1.8 × 10-10]). Alterations in executive function were partially mediated by GMV (b = -0.004 [95% CI, -0.007 to -0.002]) and within-network functional connectivity (b = -0.004 [95% CI, -0.008 to -0.002]). Socioeconomic status and body mass index moderated the association between arsenic and GMV, such that the association was strongest in participants with lower socioeconomic status and body mass index. CONCLUSIONS AND RELEVANCE: The findings of this cross-sectional study suggest that low-level arsenic exposure was associated with alterations in executive functioning and underlying brain correlates. These results indicate potential detrimental consequences of arsenic exposure that are below the currently recommended guidelines and may extend beyond endemic risk areas. Precision medicine approaches to study global mental health vulnerabilities highlight widespread but potentially modifiable risk factors and a mechanistic understanding of the impact of low-level arsenic exposure on brain development.
2023Asian J Psychiatr
Growth trajectories for executive and social cognitive abilities in an Indian population sample: Impact of demographic and psychosocial determinants
Sharma, E.; Ravi, G. S.; Kumar, K.; ...; Benegal, V.
Cognitive abilities are markers of brain development and psychopathology. Abilities, across executive, and social domains need better characterization over development, including factors that influence developmental change. This study is based on the cVEDA [Consortium on Vulnerability to Externalizing Disorders and Addictions] study, an Indian population based developmental cohort. Verbal working memory, visuo-spatial working memory, response inhibition, set-shifting, and social cognition (faux pas recognition and emotion recognition) were cross-sectionally assessed in > 8000 individuals over the ages 6-23 years. There was adequate representation across sex, urban-rural background, psychosocial risk (psychopathology, childhood adversity and wealth index, i.e. socio-economic status). Quantile regression was used to model developmental change. Age-based trajectories were generated, along with examination of the impact of determinants (sex, childhood adversity, and wealth index). Development in both executive and social cognitive abilities continued into adulthood. Maturation and stabilization occurred in increasing order of complexity, from working memory to inhibitory control to cognitive flexibility. Age related change was more pronounced for low quantiles in response inhibition (β∼4 versus </=2 for higher quantiles), but for higher quantiles in set-shifting (β > -1 versus -0.25 for lower quantiles). Wealth index had the largest influence on developmental change across cognitive abilities. Sex differences were prominent in response inhibition, set-shifting and emotion recognition. Childhood adversity had a negative influence on cognitive development. These findings add to the limited literature on patterns and determinants of cognitive development. They have implications for understanding developmental vulnerabilities in young persons, and the need for providing conducive socio-economic environments.
2023Neuroinformatics
Federated Analysis in COINSTAC Reveals Functional Network Connectivity and Spectral Links to Smoking and Alcohol Consumption in Nearly 2,000 Adolescent Brains
Gazula, H.; Rootes-Murdy, K.; Holla, B.; ...; Calhoun, V. D.
With the growth of decentralized/federated analysis approaches in neuroimaging, the opportunities to study brain disorders using data from multiple sites has grown multi-fold. One such initiative is the Neuromark, a fully automated spatially constrained independent component analysis (ICA) that is used to link brain network abnormalities among different datasets, studies, and disorders while leveraging subject-specific networks. In this study, we implement the neuromark pipeline in COINSTAC, an open-source neuroimaging framework for collaborative/decentralized analysis. Decentralized exploratory analysis of nearly 2000 resting-state functional magnetic resonance imaging datasets collected at different sites across two cohorts and co-located in different countries was performed to study the resting brain functional network connectivity changes in adolescents who smoke and consume alcohol. Results showed hypoconnectivity across the majority of networks including sensory, default mode, and subcortical domains, more for alcohol than smoking, and decreased low frequency power. These findings suggest that global reduced synchronization is associated with both tobacco and alcohol use. This proof-of-concept work demonstrates the utility and incentives associated with large-scale decentralized collaborations spanning multiple sites.
2023European Neuropsychopharmacology
F31. CROSS-ANCESTRY POLYGENIC RISK SCORES FOR PSYCHIATRIC DISORDERS IN INDIAN POPULATIONS
Holla, B.; Ganesh, S.; Janardhanan, M.; ...; Viswanath, B.
Background Psychiatric disorders, while globally prevalent, exhibit heterogeneity in manifestation and risk across diverse populations. This variability can be attributed to a complex interplay of genetic and environmental factors. India's genetic diversity, due to unique demographic events and population substructure, presents a rich but under-explored backdrop for psychiatric genetics research. To bridge this gap, we analyzed approx. 3000 samples from two cohorts from India: cVEDA, a multi-centric pan-India neurodevelopmental cohort; and a clinic-based sample of Bipolar Affective Disorder (BPAD) and Obsessive-Compulsive Disorder (OCD) patients from NIMHANS, India. Methods We utilized Illumina's Global Screening Array (GSA) for genotyping and performed quality control (QC) procedures to maintain dataset integrity. Post-QC, imputation accuracy of our data was assessed against three reference panels: 1000 Genomes (1000G), Genome Asia, and Haplotype Reference Consortium (HRC), with HRC showing superior INFO scores. Principal Component Analysis (PCA) addressed genetic structure and population stratification at global, continental, and regional levels. Ancestry of our samples was further delineated using a Support Vector Machines (SVM) model trained on labeled data from the reference panels (1000 Genome Phase 3, Human Genome Diversity Project and Genome Asia Pilot data.). We conducted unsupervised admixture analysis to explore potential substructure within our Indian samples and estimated the fixation index (Fst) to gauge genetic diversity. The main goal of our analysis was testing the cross-ancestry predictive accuracy of Polygenic Risk Scores (PRS) for Bipolar Disorder (BPAD) and Obsessive-Compulsive Disorder (OCD) derived from European GWAS summary statistics on Indian samples. We employed the Bayesian PRS-CS-auto method with a European LD reference panel and applied continuous shrinkage to refine the estimation of SNP effect sizes, thus enhancing the predictive power of the PRS. The PRS were computed using summary statistics from the PGC's 2017 meta-analysis for OCD and a 2021 meta-analysis for BPAD. Results The global PCA depicted our Indian samples overlapping with South Asian (SAS) samples from the 1000 Genomes Project. A more detailed sub-continental PCA, leveraging the GenomeAsia dataset, highlighted the extension of the Indian peninsula from SAS towards Oceania, South-East Asia, and North-East Asia. The SVM models predicted the continental labels better than the sub-continental labels. Admixture analysis suggested a 2-ancestry solution, reflecting genetic diversity within Indian populations, comparable to the genomic diversity observed across Europe. The BPAD PRS demonstrated significant predictive power for the disorder [Nagelkerke R2=0.0314, 10th decile OR (95%CI)= 3.08 (1.8, 5.0), N=1993 (Cases: 472, Controls: 1,521)], whereas the OCD PRS did not [N=2078 (Cases: 557, Controls: 1,521)]. Discussion The differential PRS prediction accuracy could be due to the smaller sample size of the OCD discovery GWAS and variations in allele frequencies and effect estimates across ancestries. Our results underscore the need for a comprehensive understanding of ancestry's role in psychiatric risk prediction, especially in genetically diverse populations like India. Future genetic research should aim to involve larger and more diverse samples to improve the accuracy and inclusivity of genetic risk predictions for psychiatric disorders across various ancestries.
2023medRxiv
Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression
Thapaliya, B.; Ray, B.; Farahdel, B.; ...; Liu, J.
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.
2023Proc Natl Acad Sci U S A
Country-level gender inequality is associated with structural differences in the brains of women and men
Zugman, A.; Alliende, L. M.; Medel, V.; ...; Crossley, N. A.
Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.
2022Nature
Brain charts for the human lifespan
Bethlehem, R. A. I.; Seidlitz, J.; White, S. R.; ...; Alexander-Bloch, A. F.
Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight(1). Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories(2) of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones(3), showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
2021European Neuropsychopharmacology
W91. GENE-ENVIRONMENT INTERACTION AND BRAIN NETWORKS IN THE PATHOPHYSIOLOGY OF EXTERNALIZING BEHAVIORS AND SUBSTANCE USE RISK
Holla, B.; Viswanath, B.; Venkatasubramanian, G.; ...; Benegal, V.
BACKGROUND: Adverse childhood experiences (ACEs) increases vulnerability to externalising disorders such as substance misuse. The study aims to determine the prevalence of ACEs and its association with substance misuse. METHODS: Data from the Consortium on Vulnerability to Externalising Disorders and Addictions (cVEDA) in India was used (n = 9010). ACEs were evaluated using the World Health Organisation (WHO) Adverse Childhood Experiences International Questionnaire whilst substance misuse was assessed using the WHO Alcohol, Smoking and Substance Involvement Screening Test. A random-effects, two-stage individual patient data meta-analysis explained the associations between ACEs and substance misuse with adjustments for confounders such as sex and family structure. RESULTS: 1 in 2 participants reported child maltreatment ACEs and family level ACEs. Except for sexual abuse, males report more of every individual childhood adversity and are more likely to report misusing substances compared with females (87.3% vs. 12.7%). In adolescents, family level ACEs (adj OR 4.2, 95% CI 1.5-11.7) and collective level ACEs (adj OR 6.6, 95% CI 1.4-31.1) show associations with substance misuse whilst in young adults, child level ACEs such as maltreatment show similar strong associations (adj OR 2.0, 95% CI 1.1-3.5). CONCLUSION: ACEs such as abuse and domestic violence are strongly associated with substance misuse, most commonly tobacco, in adolescent and young adult males in India. The results suggest enhancing current ACE resilience programmes and 'trauma-informed' approaches to tackling longer-term impact of ACEs in India. FUNDING: Newton Bhabha Grant jointly funded by the Medical Research Council, UK (MR/N000390/1) and the Indian Council of Medical Research (ICMR/MRC-UK/3/M/2015-NCD-I).
2020Mol Psychiatry
The Consortium on Vulnerability to Externalizing Disorders and Addictions (c-VEDA): an accelerated longitudinal cohort of children and adolescents in India
Zhang, Y.; Vaidya, N.; Iyengar, U.; ...; Schumann, G.
The global burden of disease attributable to externalizing disorders such as alcohol misuse calls urgently for effective prevention and intervention. As our current knowledge is mainly derived from high-income countries such in Europe and North-America, it is difficult to address the wider socio-cultural, psychosocial context, and genetic factors in which risk and resilience are embedded in low- and medium-income countries. c-VEDA was established as the first and largest India-based multi-site cohort investigating the vulnerabilities for the development of externalizing disorders, addictions, and other mental health problems. Using a harmonised data collection plan coordinated with multiple cohorts in China, USA, and Europe, baseline data were collected from seven study sites between November 2016 and May 2019. Nine thousand and ten participants between the ages of 6 and 23 were assessed during this time, amongst which 1278 participants underwent more intensive assessments including MRI scans. Both waves of follow-ups have started according to the accelerated cohort structure with planned missingness design. Here, we present descriptive statistics on several key domains of assessments, and the full baseline dataset will be made accessible for researchers outside the consortium in September 2019. More details can be found on our website [cveda.org].
2020Sci Bull (Beijing)
Population normative models of human brain growth across development
Holla, B.; Seidlitz, J.; Bethlehem, R. A. I.; Schumann, G.
BACKGROUND: Low and middle-income countries like India with a large youth population experience a different environment from that of high-income countries. The Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA), based in India, aims to examine environmental influences on genomic variations, neurodevelopmental trajectories and vulnerability to psychopathology, with a focus on externalizing disorders. METHODS: cVEDA is a longitudinal cohort study, with planned missingness design for yearly follow-up. Participants have been recruited from multi-site tertiary care mental health settings, local communities, schools and colleges. 10,000 individuals between 6 and 23 years of age, of all genders, representing five geographically, ethnically, and socio-culturally distinct regions in India, and exposures to variations in early life adversity (psychosocial, nutritional, toxic exposures, slum-habitats, socio-political conflicts, urban/rural living, mental illness in the family) have been assessed using age-appropriate instruments to capture socio-demographic information, temperament, environmental exposures, parenting, psychiatric morbidity, and neuropsychological functioning. Blood/saliva and urine samples have been collected for genetic, epigenetic and toxicological (heavy metals, volatile organic compounds) studies. Structural (T1, T2, DTI) and functional (resting state fMRI) MRI brain scans have been performed on approximately 15% of the individuals. All data and biological samples are maintained in a databank and biobank, respectively. DISCUSSION: The cVEDA has established the largest neurodevelopmental database in India, comparable to global datasets, with detailed environmental characterization. This should permit identification of environmental and genetic vulnerabilities to psychopathology within a developmental framework. Neuroimaging and neuropsychological data from this study are already yielding insights on brain growth and maturation patterns.
2020Hum Brain Mapp
A series of five population-specific Indian brain templates and atlases spanning ages 6-60 years
Holla, B.; Taylor, P. A.; Glen, D. R.; ...; Benegal, V.
Anatomical brain templates are commonly used as references in neurological MRI studies, for bringing data into a common space for group-level statistics and coordinate reporting. Given the inherent variability in brain morphology across age and geography, it is important to have templates that are as representative as possible for both age and population. A representative-template increases the accuracy of alignment, decreases distortions as well as potential biases in final coordinate reports. In this study, we developed and validated a new set of T1w Indian brain templates (IBT) from a large number of brain scans (total n = 466) acquired across different locations and multiple 3T MRI scanners in India. A new tool in AFNI, make_template_dask.py, was created to efficiently make five age-specific IBTs (ages 6-60 years) as well as maximum probability map (MPM) atlases for each template; for each age-group's template-atlas pair, there is both a "population-average" and a "typical" version. Validation experiments on an independent Indian structural and functional-MRI dataset show the appropriateness of IBTs for spatial normalization of Indian brains. The results indicate significant structural differences when comparing the IBTs and MNI template, with these differences being maximal along the Anterior-Posterior and Inferior-Superior axes, but minimal Left-Right. For each age-group, the MPM brain atlases provide reasonably good representation of the native-space volumes in the IBT space, except in a few regions with high intersubject variability. These findings provide evidence to support the use of age and population-specific templates in human brain mapping studies.
2019INDIAN JOURNAL OF PSYCHIATRY
Tracking Deviations in Neurodevelopmental Trajectories to Predict Adult Psychopathology
Benegal, V.; Vaidya, N.; Sharma, E.; Holla, B.
INDIAN JOURNAL OF PSYCHIATRY, 61(9), S395-S395
2019Lancet Glob Health
Precision medicine and global mental health
Schumann, G.; Benegal, V.; Yu, C.; ...; Global Imaging Genetics in Adolescents Consortium
