J Affect Disord. 2025 Sep 5:120206. doi: 10.1016/j.jad.2025.120206. Online ahead of print.
ABSTRACT
OBJECTIVE: This study aimed to identify potential mutations associated with major depressive disorder (MDD) and evaluate disease-associated risk factors.
METHODS: Total genomic DNAwas extracted from the participants’ blood samples, and the complete mitochondrial genome wasamplified by PCR, purified, and sequenced. Mutation burden analysis and functional mutation analysis was performed, including total mutation counts, highly conserved mutations (Conservation Index >75 %), and structurally disruptive mutations. Additionally, mitochondrial haplotypes were analyzed using binary logistic regression to evaluate disease risk.
RESULTS: Although no significant difference in overall mutation counts was observed between groups (p > 0.05), 16 mutation sites were potentially associated with the onset of MDD: MR-RNR1 (m.735 A > G, m.895C > A), MT-RNR2 (m.2363 A > Gm.2363 A > G), MT-ATP8 (m.8459 A > G (p.N32D)), MT-ATP6 (m.9128 T > C (p.I201T)), MT-CO3 (m.9856 T > C (p.I217T), m.9957 T > C (p.F251L)), MT-ND6 (m.14502 T > C (p.I58V)), MT-CYB (m.14978 A > G (p.I78V), m.14979 T > C (p.I78T), m.15651C > T (p.A302V), m.15860 A > G (p.I372V)), MT-TN (m.5720C > T), MT-TC (m.5783G > A), MT-TD (m.7561 T > C) and MT-TT (m.15924 A > G). Notably, a previously unreported mutation, MT-ND1 (m.3536 T > G (p.L77W)), was identified, which exhibited a 100 % conservation index (CI) and was highly associated with mitochondrial dysfunction. Haplotype analysis revealed that haplotype B4 was significantly associated with a protective effect (P = 0.026, AOR = 0.228).
CONCLUSIONS: This study suggests that mitochondrial DNA (mtDNA) mutation in MDD may not be solely attributed to mutational load but may involve some specific functional mutations. The protective role of haplotype B4 indicates potential therapeutic targets, requiring further investigation.
PMID:40915505 | DOI:10.1016/j.jad.2025.120206
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