Complex correlations between mitochondrial DNA variants and gut microbiome in major depressive disorder: a...

Gut microbiota disturbances and impaired mitochondrial function are both linked with the development of major depressive disorder (MDD). However, little is known about how they interact in MDD.

We used shotgun metagenomic sequencing to explore fecal microbiome based on 63 MDD patients and 30 healthy controls (HCs). Then we performed GWAS for the discriminative taxonomic features of gut microbiota to identify genetic associations between gut microbiome and mitochondrial DNA (mtDNA) in MDD.

Characteristic gut microbiome-based features, including significant differences in gut microbiota composition and 101 differentially enriched gut microbial species, were found in MDD group vs. HC group. 68 mitochondrial single-nucleotide polymorphisms (mtSNPs) shared between the two groups were identified through GWAS at a Bonferroni-corrected significance level of p < 0.05. The genetic variants and their associated gut microbes were mapped to mitochondrial genome, most of which were located in coding regions, including MT-ND, MT-ND4L, MT-ND5, MT-ND6; MT-CO, MT-CO3; MT-RNR, MT-RNR, and MT-TE. Manhattan plots showed 9 mtSNPs in MDD group and 10 mtSNPs in HC group were associated with 20 gut microbial species at a significance of -log10(p) >20. Furthermore, Sankey diagram was used to visualize the relationships of gut microbiota and mtDNA. 36 mtSNPs (-log10(p) >5) were shown to be associated with 54 gut microbes in crosslinked patterns.

The current findings provide substantial evidence that complex interactions between gut microbiota and mtDNA contribute to MDD, which enables a better understanding of MDD pathogenesis and suggests new leads for future investigations.

ChiCTR2000029703. Registration Date: Feb. 9^th, 2020. Registration Details are available at the website of Chinese Clinical Trial Registry (https://www.chictr.org.cn).