A systems-medicine approach towards distinct and shared resilience and pathological mechanisms of substance use disorders

According to the WHO, 2 billion people drink alcohol, 1.3 billion smoke, 182 million consume cannabis, and almost 250 million use illicit drugs. Many of those alcohol, tobacco and drug users become addicted. Substance use disorders (SUDs) generate the largest disease burden and are categorized by DSM-5 and ICD11. SUDs are defined by compulsive drug use, craving, and re-lapses that can occur even after years of abstinence. SUDs encompass several drug classes including alcohol, nicotine, cannabis, opioids, and stimulants. One fundamental question in psy-chiatric research is: “How distinct are the different SUDs and what are the shared pathological phenomena?” Here we aim to determine the extent to which alcohol, nicotine, heroin, cannabis, and cocaine use disorders share genetic, epigenetic, transcriptomic and neurochemical mecha-nisms. In a convergent approach, multiple system levels in SUDs will be studied concurrently in humans and rats. Large samples from SUDs patients from several consortia (e.g. PGC and UK biobank) together with post-mortem brain tissue of deceased patients will give us comparative insights into distinct and overlapping genetic, epigenetic, and transcriptomic signatures of SUDs.

Illustration of the subprojects how they synergistically interact with each other

Illustration of the subprojects how they synergistically interact with each other

Comparative analysis of brain organoids derived from SUD patients will reveal drug-induced transcriptional changes on a single cell level. A novel in silico approach and spectroscopy in pa-tients will reveal alterations in neurochemical connectomes in SUDs. Rat models for addiction provide great face, construct and predictive validity and will be used to examine the functional relevance of our multi-level analyses of human biomaterial and in silico driven predictions. In sum, our interdisciplinary consortium will lead to an understanding of distinct and shared resilience and pathomechanisms of SUDs. This will have implications for diagnosis, precision medicine, comor-bidities, addiction theories, and socio-political decisions such as legalization and taxation.

Heritability of SUDs.

Heritability of SUDs. Left part shows the heritability (weighted mean and range) of the 5 SUDs to be studied by the SysMedSUD consortium. Heritability was calculated using data from studies on twins (number of twin pairs provided in brackets). On the right panel heritability is plotted against the approxi-mate ranking for relative risk of addiction. Relative risk of addiction is expressed on a five-point scale, one indicates the lowest risk and five denotes the highest risk. Modified from Goldman et al. (2015).

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