The Presence of the mtDNA4977 Deletion Does Not Necessarily Mean That It is Responsible for Major Depression [Letter]

Dear editor

We were interested to read the article by He et al on a case-control study on the association between mitochondrial DNA (mtDNA) deletion of 4977 base pairs (mtDNA⁴⁹⁷⁷ deletion) and major depressive disorder (MDD).¹ Of the 253 MDD patients included, 49% carried the mtDNA4977 deletion, compared to only 28% in the control group.¹ It was concluded that the mtDNA⁴⁹⁷⁷ deletion could be a marker for MDD.¹ The study is noteworthy, but several points should be discussed.

First of all, it should be clarified whether the authors are talking about the deletion of a single base pair at mtDNA position 4977 or whether they really mean a mtDNA deletion of a total of 4977 base pairs, as stated in the methods section.¹ A deletion of 4977 base pairs of mtDNA can manifest not only phenotypically with MDD, but also with a number of other manifestations depending on the genes that are missing in this deletion. Therefore, we should know which manifestations of the deletion other than MDD were found in the included patients. Single large deletions have been associated with mitochondrial myopathy, Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO). The deletion of a single base pair at position 4977 has been associated with cancer, dementia, growth retardation, infertility and photoaging of the skin.^2–4

The second point is that no explanation has been given as to why patients carrying the mtDNA⁴⁹⁷⁷ deletion have MDD but not other diseases previously reported to be associated with MDD.¹ Since the phenotypic expression of mtDNA variants is highly dependent on heteroplasmy rate, mtDNA copy number and haplotype, we should know whether these parameters of phenotypic expression have been determined and included in the analysis. Knowledge of these parameters is essential for the determination of genotype-phenotype correlation, for the evaluation of disease progression and for genetic counseling. Carrying the mtDNA⁴⁹⁷⁷ deletion does not necessarily mean that it will manifest clinically. What factors have led to the variant manifesting clinically?

The third point is that the family history was not provided. Since mtDNA deletions are inherited through the maternal line in 4% of cases,⁵ it would have been essential to test the patients’ mothers for the presence of the deletion as well. Knowing whether the deletion occurred sporadically or was inherited is crucial for assessing whether the variant segregated within the family.

The fourth point is that single large-scale mtDNA deletions can be associated other large-scale mtDNA deletions. Were the included patients screened not only for the presence of the mtDNA⁴⁹⁷⁷ deletion but also for multiple mtDNA deletions?

To summarize, this interesting study has limitations that affect the results and their interpretation. Addressing these limitations could strengthen the conclusions and support the message of the study. The presence of the mtDNA⁴⁹⁷⁷ deletion does not necessarily mean that it is responsible for MDD, as its phenotypic expression depends on several factors that need to be included in the analysis before a causal link mtDNA deletion in MDD can be established.

Funding Statement

There is no funding to report.

Data Sharing Statement

All data are available from the corresponding author.

Disclosure

The author reports no conflicts of interest in this communication.