Distinguishing genetic overlap and causal relationship among attention deficit-hyperactivity disorder and substance use disorders

The ATTENTIVE project will deliver a comprehensive training-through-research to a talented postdoctoral fellow in two leading multi-disciplinary research groups.

I will bring clinical, molecular biology and genetic skills and I will receive extensive training in state-of-the-art genomic data science and cell biology, creating a two-way transfer.

The proposed work will expand my experience, research competencies and professional networks, leading to the possibility to become an independent researcher.

The research part of the proposal is focused on understanding the biological basis of the comorbidity observed between Attention Deficit-Hyperactivity Disorder (ADHD) and Substance Use Disorders (SUDs), as it is unclear which the underlying mechanisms are.

Using large-scale genome-wide association study (GWAS) datasets , we will test whether this epidemiological and genetic correlation is due to shared risk alleles acting independently on both disorders or to causal effects between the disorders.

We will combine different analytical methods, leveraging genome-wide data and brain-specific information related to additional omics domains. We will derive information regarding transcriptomic and epigenomic changes in brain tissues and cells.

GWASs can identify a large number of genetic variants with potential disease association, but functional analysis remains a challenge.

Therefore, we will validate the results through induced pluripotent stem cells (iPSCs) to study cellular pathophysiology.

The iPSCs carrying the variants significant from the GWAS will be differentiated to neural cells and neural mRNA will be analyzed by RNA-Seq.

The expected results will provide novel information regarding the molecular mechanisms at the basis of this pathogenic association, also providing insights that could contribute to develop preventive strategies and therapeutic approaches to address substance abuse and alcohol dependence in subjects with ADHD, a high-risk category.