Consortium on Vulnerability to Externalizing Disorders and Addictions [c-VEDA]

Alcohol use disorders (AUD) account for a disproportionately high share of the health burden in India and other low- and middle-income countries. This increasing burden is linked to societal changes in emerging nations, which include growing availability of alcohol, greater normalization of use and rapid changes in socio-economic conditions. Individuals with externalising behaviour, which are characterised by altered brain activity during reward processing and behavioural control have a higher risk for AUD. AUD and externalizing disorders share moderate to high heritability with environmental factors being important contributors. While both environmental and genetic factors conveying risk and resilience have been identified it is not established to what extent these factors are dependent on the wider socio-cultural and psychosocial context they are embedded in, or whether they are influenced by epigenetic and genetic factors that are specific for certain ethnicities. It is therefore unknown to what extent environmental and genetic risk factors are similar or distinct in industrialised nations and emerging societies such as in India. Furthermore, some environmental risk factors are largely specific to emerging societies, including exposure to nutritional stress, environmental neurotoxins and culturally dependent forms of psychosocial stress.
We propose to investigate in collaboration with Prof. Vivek Benegal of the National Institute for Mental Health and Neurosciences (NIMHANS), Bangalore and our Indian partners from Bangalore, Mysore, Calcutta, Chandigarh and Pune if environmental and genetic risk factors in industrialised countries and emerging societies shape brain function and behaviour in distinct ways, thus leading to different risk constellations and neurobehavioural trajectories for substance misuse and externalising disorders.
To address this aim we will establish a comprehensive database allowing comparative analyses of behavioural trajectories in childhood and adolescence, which provide a platform for sustained India-UK collaborations in mental health research. This platform will ascertain a great variety of environmental factors (exposome), biological samples as well as detailed neuroimaging analyses. We propose to compare insights into etiology and trajectories into substance abuse and externalising disorders gained from major European and UK studies including the longitudinal imaging genetics study "Reinforcement-related behaviour in normal development and psychopathology" (IMAGEN) and the "Avon Longitudinal Study of Parents and Children" (ALSPAC) with existing Indian cohorts. The Indian cohorts, which comprise >14.000 participants with aged 0-25 years include both high risk for substance misuse and population-based individuals from different social and environmental (rural and urban) backgrounds. They have been selected to cover the developmental period assessed in the UK cohorts, thus rendering the studies comparable. We aim to enrich the Indian cohorts, which have mainly been designed to investigate somatic disorders by adding a comprehensive assessment of mental health, externalising behaviour and substance use disorders involving psychometric and neuropsychological characterisation, as well as biological sampling in >10.000 participants with an age range of 6-23 years. Assessment instruments and protocols have been selected to allow comparison to IMAGEN and ALSPAC. We will randomly select among the cohort participants 1000 individuals aged between 10 and 23 years for neuroimaging, genetic and epigenetic analyses. We will control for socio-cultural and environmental influences by investigating determinants of substance abuse in SCAMP, a UK cohort recruiting 6.500 11-13 year old adolescents, >1000 of which are of South Asian descent. Together these data will allow for the most comprehensive comparative analysis of brain development and behaviour across different social and cultural environments to date.

Alcohol use disorders (AUD) account for a high share of the health burden in India. While environmental and genetic factors conveying risk for AUD and related externalizing disorders have been identified it is not established if these factors are dependent on the socio-cultural and psychosocial context, or whether they are influenced by epigenetic and genetic factors specific for certain ethnicities. Furthermore, some environmental risk factors are specific to emerging societies, including exposure to nutritional stress, environmental neurotoxins and culturally dependent forms of psychosocial stress. We will investigate in collaboration with the National Institute for Mental Health and Neurosciences, Bangalore and partners from Bangalore, Mysore, Calcutta, Chandigarh and Pune if environmental and genetic risk factors in industrialised countries and emerging societies shape brain function and behaviour in distinct ways, thus leading to different risk constellations and neurobehavioural trajectories for substance misuse and externalising disorders. Our objectives are: (1)Establishment of an accelerated longitudinal cohort of >10.000 individuals in India aged 6-23 years. (2)Assessment of addictive behaviour and detailed behavioural and clinical characterisation, with emphasis on externalising behaviour. (3)Assessment of environmental exposures to risk and resilience factors impacting gene expression, brain development, temperaments and behaviours. (4)Collection of biological samples in all participants. (5)Assessing neural processes using functional and structural neuroimaging in a subgroup of 1000 individuals. (6)Investigation of gene x environment modulation of brain development, and externalising and addictive behaviour through genetic and epigenetic studies. (7)Establishment of a bioresource with integrated database and biobank. (8)Capacity building through joint UK-Indian research activities. (9)Providing pilot data for a nationwide mental health cohort in India.

This study will for the first time compare trajectories into substance abuse and externalising disorder in emerging nations and industrialised societies, and investigate their neurobehavioural underpinnings. As the majority of the world's population is living in emerging societies, and development of mental disorders in these societies has been understudied, our subject is of global public health relevance. Various stakeholders will benefit from our project and include:
1.) Academic researchers will benefit from the new knowledge generated within two years from the start of the project, as well as from the databank and bioresource established for future projects.
2.) Joint UK-India academic research benefits through the extensive collaborative network and the establishment of a sustained infrastructure and datasets which facilitate follow-up research projects as early as two years after the start of the project.
3.) A national mental health cohort, which can be planned on the basis of the expertise generated by this project, which will provide unparalleled information about mental health and disorders, and their determinants in the second most populous country in the world.
4.) Indian researchers will benefit immediately through the transfer of know how, methodologies and technology.
5.) Young investigators having an opportunity to become highly skilled in a cutting edge area of mental health research will also benefit immediately.
6.) Policy makers will benefit through detailed data on risk for substance use disorders and mental disorders which we will provide at the end of the project.
7.) Public policies at the regional and national level will be influenced by our report to the Government of India and other dissemination activities in the course of the project. International influence might be exerted by engaging and disseminating our findings to WHO and other international organisations.
8.) Clinical practice by public sector and charities might be influenced by specifically targeting at risk populations in early interventions. This benefit might be exerted five years after the end of the project.
9.) Enhancing quality of life, health and well-being through targeted interventions five years after the end of the project.
10.) Contributing to increasing public awareness and understanding of science through the dissemination of evidenced-based mental health information throughout the project.