# Spectral divergence prioritizes key classes, genes, and pathways shared between substance use disorders and cardiovascular disease

## TL;DR

This paper uses graph spectral clustering to identify distinct biological pathways linking different types of substance use disorders with cardiovascular disease.

## Contribution

The novel use of graph spectral clustering and KL divergence to prioritize key genes and pathways in SUD-CVD comorbidity.

## Key findings

- Spectral graph clustering outperforms traditional connectivity-based methods in distinguishing SUD-CVD relationships.
- Distinct pathways like gamma-aminobutyric acidergic and arginine metabolism are highlighted between cocaine use disorder and CVD.
- The relationship between opioid use disorder and CVD emphasizes neurodegenerative and tyrosine metabolism pathways.

## Abstract

Substance use disorders (SUDs) are heterogeneous diseases with overlapping biological mechanisms and often present with co-occurring disease, such as cardiovascular disease (CVD). Gene networks associated with SUDs also implicate additional biological pathways and may be used to stratify disease subtypes. Node and edge arrangements within gene networks impact comparisons between classes of disease, and connectivity metrics, such as those focused on degrees, betweenness, and centrality, do not yield sufficient discernment of disease network classification. Comparatively, the graph spectrum's use of comprehensive information facilitates hypothesis testing and inter-disease clustering by using a larger range of graph characteristics. By adding a connectivity-based method, network rankings of similarity and relationships are explored between classes of SUDs and CVD.

Graph spectral clustering's utility is evaluated relative to commonly used network algorithms for discernment between two distinct co-occurring disorders and capacity to rank pathways based on their distinctiveness. A collection of graphs' structures and connectivity to functionally identify the relationship between CVD and each of four classes of SUDs, namely alcohol use disorder (AUD), cocaine use disorder (CUD), nicotine use disorder (NUD), and opioid use disorder (OUD) is evaluated. Moreover, a Kullback-Leibler (KL) divergence is implemented to identify maximally distinctive genes (Dg). The emphasis of genes with high Dg enables a Jaccard similarity ranking of pathway distinctiveness, creating a functional “network fingerprint”.

Spectral graph outperforms other connectivity-based approaches and reveals interesting observations about the relationship among SUDs. Between CUD and CVD, the gamma-aminobutyric acidergic and arginine metabolism pathways are distinctive. The neurodegenerative prion disease and tyrosine metabolism are emphasized between OUD and CVD. The graph spectrum between AUD and NUD to CVD is not significantly divergent.

Graph spectral clustering with KL divergence illustrates differences among SUDs with respect to their relationship to CVD, suggesting that despite a high-level co-occurring diagnosis or comorbidity, the nature of the relationship between SUD and CVD varies depending on the substance involved. The graph clustering method simultaneously provides insight into the specific biological pathways underlying these distinctions and may reveal future basic and clinical research avenues into addressing the cardiovascular sequelae of SUD.