Objective: Toexamine genetic and environmental risk factors for developing sub-clinical, psychosis-like symptoms (PLIKS) during adolescence. Specifically:

1. To investigate whether genetic variation within NRG1, DTNBP1, DAAO, G72, RGS4 and CHRNA7 are associated with PLIKS.

2. To investigate whether cannabis or tobacco alter risk of PLIKS.

3. To examine the interplay between genetic variation and cannabis or tobacco exposure on risk of PLIKS, as well as the interplay with other risk factors for schizophrenia, including markers of neurodevelopmental abnormalities.

Background:Approximately 15% of the population report psychotic-like experiences not meeting criteria for clinical disorders. These occur more commonly than schizophrenia, and are likely to be closer to underlying aetiological pathways. Studies of PLIKS may increase understanding of schizophrenia aetiology, and help focus prevention and intervention strategies. All the genes above, as well as cannabis and tobacco, are thought to effect glutamatergic transmission. Examination of gene-environment interplay may provide further insights into aetiological mechanisms.

Design: Cohort study (nested case-control for genetic associations).

Method: The ALSPAC birth cohort of 14,000 children, currently age 11-12 will be used. Large quantities of data, including DNA, are already available. PLIKS and substance use data were collected at age 11-12 and will be re-collected at 13-14 & 15-16. Outcome to be investigated is risk of PLIKS (quantitative and dichotomous measures). Genetic analyses will include examinationunder different genetic models, haplotype analysis, and family-based association. Regressionmodels will also be used to examine association with cannabis/tobacco usewhilst adjusting for confounders, and for exploratory analysis of gene-environment interplay.