Siddharth Roy

Profile

Project Title: Molecular mechanisms of impulse control

Summary: Impulsivity is a heritable behavioural trait impacting decision making and is associated with poorer educational achievement and mal-adaptive internet use. Although impulsivity is known to be highly heritable, we lack a thorough understanding of how the associated genetic variants contribute to behavioural outcomes.

Using human data and leveraging novel multivariate genomic methods (i.e., Genomic Structural Equation Modelling) we create a refined and empowered multivariate genome wide association study (GWAS) for impulse control. We then subject summary statistics from the GWAS to gene-set analysis to identify biological pathways involved. Transcriptome wide association study based on our multivariate GWAS summary statistics will be used to infer gene expression changes associated with impulsivity using brain eQTL summary statistics. Differentially expressed gene sets from human analysis will be combined with RNAseq data from mutant lines of zebrafish that show deficits in impulse control. All gene sets will be assessed for pathway enrichment and examined for similarities using multivariate statistics and machine learning.

We use CRISPR/cas9 gene editing to generate targeted loss of function mutants in candidate genes selected from our pathway analysis. Behavioural and cell biological analysis of mutant lines at developmental and adult stages will be used to test causality and hypotheses regarding mechanism of action of identified candidate genes. The results of our work has the potential to inform pharmacological and non-pharmacological treatment of impulsivity disorders or lead to the development of interventions to improve life outcomes and prevent progression to maladaptive behaviours in the healthy population.

Supervisor:

• Prof Caroline Brennan

Research