The proposal is being developed. The main purpose is to develop cohorts in India and compare risks and exposures for developing substance use and mental health problems between India and UK - using ALSPAC and IMAGEN.

Background:-

In both, developed and emerging nations externalising behaviours are known to be risk factors for substance abuse and substance abuse is highly correlated with externalising disorders. Environmental risk factors for substance abuse, its relation to externalizing behaviour and its moderation by genetic and epigenetic factors have not been extensively investigated in emerging societies. Given that emerging societies show the biggest increase in alcohol and tobacco use, there is an urgent need to validate and adapt our understanding of etiology and determinants of substance abuse in these countries. Here we compare insights into etiology and trajectories into substance abuse gained from two major European and UK studies, IMAGEN and ALSPAC with Indian cohorts of different social and environmental backgrounds. We will also control for socio-cultural and environmental influences by investigating determinants of substance abuse in SCAMP, a UK cohort containing adolescents of both, European and South Asian descent.

Our project capitalizes on existing cohorts in India with over 18.000 participants, which it aims to enrich using the expertise and infrastructure created by the individual teams. The cohorts have been selected to allow an accelerated longitudinal design covering an age range of 0 to 25 years. These assets will be complemented by European and UK cohorts of approximately 20.000 participants, including IMAGEN (www.imagen-europe.com), ALSPAC and SCAMP, which have established the relevant neuroimaging, neuropsychological, behavioural and clinical assessments which will be applied in our project. As the ongoing SCAMP projects will recruit greater than 1000 13 year old adolescents of South Asian origin we will harmonize the assessment of our study and SCAMP. Together with data available in IMAGEN and ALSPAC this will allow the most comprehensive comparative analysis of brain development and behaviour in different social and cultural environments. In addition, we will use candidate gene sets identified in large GWAS meta-analysis consortia of over 300.000 participants, including ENIGMA, Alcogen and the Psychiatric Genetics Consortium, which are relevant for addictive behaviour and externalising symptoms. Using these assets we will test the following hypotheses:

a.)Exposure to environmental risk or resilience factors, which are pertinent to emerging societies both ante-natal as well as throughout childhood and adolescence are correlated with structural and functional impairments of reinforcement-related brain function, and externalizing behaviour including addictions. These risk factors include (but are not limited to) socio-cultural environment, psychosocial stress, malnutrition and exposure to neurotoxins,

b.)Environmental risk factors influence epigenetic methylation profiles and interact with candidate genotypes across the developmental span, altering development trajectories of growth and brain development, which give rise to variations in temperament and addictive behaviours. Relevant measures include birth weight, anthropometric -somatic and endocrinological measures, brain endophenotypes, cognitive abilities, temperament.

c.)Susceptibility to substance abuse and externalising disorders is dependent on ethnicity and/or socio-cultural influences in comparisons between UK and Indian cohorts