TP2 - SysMedSUDs

Comparative and integrative computational analysis of distinct and shared genetic, epigenetic, and transcriptomic signatures in SUDs

This project aims to identify shared and distinct genetic variants and molecular mechanisms underlying different substance use disorders (SUDs) using an integrating multi-omics approach. We will use postmortem brain tissue from deceased individuals diagnosed with SUD and age-matched healthy controls to obtain omics data for genome-wide association study (GWAS), epigenome-wide association study (EWAS) and gene expression (RNA sequencing).

Our previous work has shown genetic overlap between alcohol and nicotine use disorders, and associated endophenotypes and personality traits. We further seek to extend our genetic approach by including cannabis, opioid and cocaine use disorders. Shared and unique genetic background of the different SUDs will be assessed using computational methods such as polygenic risk scores which allow integration of genome wide data to assess genetic correlation of different phenotypes.

Most human omics data derive through analysis of peripheral tissues, which are at best a proxy for neurobiological mechanisms. Although the most relevant tissue to study the neurobiology of SUDs is the brain, samples are rare and difficult to obtain and thus extremely valuable. We have collected a large postmortem brain sample set from AUDs, nicotine dependence, and controls and have generated genome-wide genetic, epigenetic and gene expression data. We will now enlarge and extend our tissue samples and -omics data by collecting new samples with cannabis, opioid and cocaine use disorders from established brain banks and collaboration partners. Using a comparative and integrative computational approach, where we combine all omics data from postmortem brains, we will identify shared and distinct genetic variants, resilience and pathomechanisms underlying SUDs that will be further functionally validated.