Mitochondrial Contributions to Schizophrenia Symptom Severity: A GWAS Approach in a South African Population

Schizophrenia (SCZ) is increasingly recognized as a disorder of compromised brain bioenergetics. Therefore, this study investigated the contribution of mitochondrial genomic variation and mitonuclear crosstalk to clinical symptom severity in a South African First Episode Schizophrenia (FES) cohort (N=103). Utilizing genome-wide association data, the study employed General Linear Models to assess mitochondrial single nucleotide variants (SNVs), cumulative mitochondrial gene burdens, and epistatic interactions between mitochondrial SNVs and nuclear-encoded mitochondrial genes (NEMtGs) against Positive and Negative Syndrome Scale (PANSS) scores. Although no associations survived multiple testing corrections, exploratory analyses revealed biologically coherent patterns distinguishing symptom domains. Negative symptom severity was nominally associated with variants in electron transport chain (ETC) and mitoribosomal genes, alongside epistatic interactions involving the SLC25A solute carrier family. These findings support a pathogenic model wherein substrate starvation and respiratory chain collapse drive the bioenergetic failure and oxidative toxicity underlying hypofrontality. Positive symptom severity was predominantly linked to variants in mitoribosomal and mitochondrial maintenance genes, implicating compromised mitochondrial protein synthesis fidelity. Collectively, these results suggest that clinical heterogeneity in SCZ is modulated by mitonuclear incompatibility rather than isolated genetic variance. The data indicates that symptom severity arises from specific failures in ATP production and calcium homeostasis, where the nuclear background determines the pathogenicity of mitochondrial variants.

Grantor dc:publisher

Stellenbosch : Stellenbosch University

Year dc:date.issued

2026

Author dc:creator

• Gray, Cassidy

Advisors dc:contributor.advisor

• Pearce, Brendon
• McGregor, Nathaniel

Language dc:language.iso

en

Repository record dc:identifier.uri

https://scholar.sun.ac.za/handle/10019.1/136037

OAI identifier oai:identifier

oai:scholar.sun.ac.za:10019.1/136037