# Multimorbidity in Severe Mental Illness as Part of the Neurodevelopmental Continuum: Physical Health-Related Endophenotypes of Schizophrenia—A Narrative Review

## TL;DR

This paper reviews how physical health issues like heart disease are linked to severe mental illnesses like schizophrenia through shared genetic factors.

## Contribution

The paper proposes that somatic diseases in severe mental illness can be considered distinct endophenotypes with shared genetic architecture.

## Key findings

- There is considerable overlap in genetic susceptibility loci between severe mental illnesses and cardiovascular diseases.
- Somatic diseases in severe mental illness may be reframed as physical health-related endophenotypes.
- Reframing schizophrenia as a multisystem disease could stimulate new research into somatic comorbidities.

## Abstract

Background. The majority of deaths in patients with schizophrenia and other severe mental illnesses (SMIs) are caused by natural causes, such as cardiovascular diseases (CVDs). The increased risk of CVD and other somatic diseases in SMIs cannot be fully explained by the contribution of traditional risk factors, behavioral risk factors, patients’ lifestyle peculiarities, and the influence of antipsychotics. The present review has the following main objectives: (1) to aggregate evidence that neurodevelopmental disorders are the basis of SMIs; (2) to provide a review of studies that have addressed the shared genetic architecture of SMI and cardiovascular disease; and (3) to propose and substantiate the consideration of somatic diseases as independent endophenotypes of SMIs, which will make it possible to place the research of somatic diseases in SMIs within the framework of the concepts of the “neurodevelopmental continuum and gradient” and “endophenotype”. Methods. A comprehensive literature search was performed on 1 July 2024. The search was performed using PubMed and Google Scholar databases up to June 2024. Results. The current literature reveals considerable overlap between the genetic susceptibility loci for SMIs and CVDs. We propose that somatic diseases observed in SMIs that have a shared genetic architecture with SMIs can be considered distinct physical health-related endophenotypes. Conclusions. In this narrative review, the results of recent studies of CVDs in SMIs are summarized. Reframing schizophrenia as a multisystem disease should contribute to the activation of new research on somatic diseases in SMIs.