Personality traits are consistently associated with blood mitochondrial DNA copy number estimated from genome sequences in two genetic cohort studies
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Evaluation Summary:
This paper makes a comprehensive survey of the relationship between mtDNAcn and the personality dimensions, as well as how and whether they mediate the relationships between personality dimensions and mortability as well as other behavioural measures that may lead to mortality. More work needs to be performed to truly understand the relationship between personality dimensions and mortality, as well as the physiological traits (like mtDNAcn) that may be mediating it.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Mitochondrial DNA copy number (mtDNAcn) in tissues and blood can be altered in conditions like diabetes and major depression and may play a role in aging and longevity. However, little is known about the association between mtDNAcn and personality traits linked to emotional states, metabolic health, and longevity. This study tests the hypothesis that blood mtDNAcn is related to personality traits and mediates the association between personality and mortality.
Methods:
We assessed the big five personality domains and facets using the Revised NEO Personality Inventory (NEO-PI-R), assessed depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D), estimated mtDNAcn levels from whole-genome sequencing, and tracked mortality in participants from the Baltimore Longitudinal Study of Aging. Results were replicated in the SardiNIA Project.
Results:
We found that mtDNAcn was negatively associated with the Neuroticism domain and its facets and positively associated with facets from the other four domains. The direction and size of the effects were replicated in the SardiNIA cohort and were robust to adjustment for potential confounders in both samples. Consistent with the Neuroticism finding, higher depressive symptoms were associated with lower mtDNAcn. Finally, mtDNAcn mediated the association between personality and mortality risk.
Conclusions:
To our knowledge, this is the first study to show a replicable association between mtDNAcn and personality. Furthermore, the results support our hypothesis that mtDNAcn is a biomarker of the biological process that explains part of the association between personality and mortality.
Funding:
Support for this work was provided by the Intramural Research Program of the National Institute on Aging (Z01-AG000693, Z01-AG000970, and Z01-AG000949) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. AT was also supported by the National Institute on Aging of the National Institutes of Health Grant R01AG068093.
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Evaluation Summary:
This paper makes a comprehensive survey of the relationship between mtDNAcn and the personality dimensions, as well as how and whether they mediate the relationships between personality dimensions and mortability as well as other behavioural measures that may lead to mortality. More work needs to be performed to truly understand the relationship between personality dimensions and mortality, as well as the physiological traits (like mtDNAcn) that may be mediating it.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Oppong and colleagues present a study on the association of mitochondrial DNA abundance in blood and personality traits, both of which have been linked to morbidity and mortality in aging populations. They found that mtDNAcn is negatively associated with traits related to neuroticism as well as positively with a higher personality-mortality index (PMI). The association of the PMI with mortality was attenuated by including mtDNAcn in the model, indicating that the association is mediated by mitochondrial abundance in blood.
General comments:
• Previous studies have shown that mtDNAcn are potentially mediated by hormonal levels and thus menopause. Given the mean age of 57 in the SardiNIA cohort, the authors should investigate in more detail the potential confounding effects of menopause in women.
• The only …Reviewer #1 (Public Review):
Oppong and colleagues present a study on the association of mitochondrial DNA abundance in blood and personality traits, both of which have been linked to morbidity and mortality in aging populations. They found that mtDNAcn is negatively associated with traits related to neuroticism as well as positively with a higher personality-mortality index (PMI). The association of the PMI with mortality was attenuated by including mtDNAcn in the model, indicating that the association is mediated by mitochondrial abundance in blood.
General comments:
• Previous studies have shown that mtDNAcn are potentially mediated by hormonal levels and thus menopause. Given the mean age of 57 in the SardiNIA cohort, the authors should investigate in more detail the potential confounding effects of menopause in women.
• The only personality trait (out of the big five) available in the UK Biobank is neuroticism. Since the authors found that most of their associations are significant for this complex, I would strongly suggest they try to replicate their findings in patients from the UK Biobank which have both, genome-wide sequencing data as well the summary score of neuroticism (Data-Field 20127)
• The amount of mtDNA varies across populations and across different haplogroups. The authors should therefore compute the major haplogroups present in Europeans and adjust/account for those variables in the correlation and mortality analyses. -
Reviewer #2 (Public Review):
This is the first paper accessing the relationship between the big-five personality dimensions with mtDNA copy number (mtDNAcn) quantified from whole-genome sequencing data (WGS) from blood samples, as well as whether mtDNAcn mediates the relationship between personality dimensions and mortality. The authors used data from two epidemiological studies for this work: 722 individuals from the Baltimore Longitudinal Study of Aging (BLSA) from the USA, and 587 individuals from the SardiNIA study from Italy. The authors find that mtDNAcn is significantly associated with personality dimensions, and significantly mediates the relationship between personality and mortality. The authors have employed appropriate statistical approaches and reached robust findings that are generally replicable in two independent cohorts.
Reviewer #2 (Public Review):
This is the first paper accessing the relationship between the big-five personality dimensions with mtDNA copy number (mtDNAcn) quantified from whole-genome sequencing data (WGS) from blood samples, as well as whether mtDNAcn mediates the relationship between personality dimensions and mortality. The authors used data from two epidemiological studies for this work: 722 individuals from the Baltimore Longitudinal Study of Aging (BLSA) from the USA, and 587 individuals from the SardiNIA study from Italy. The authors find that mtDNAcn is significantly associated with personality dimensions, and significantly mediates the relationship between personality and mortality. The authors have employed appropriate statistical approaches and reached robust findings that are generally replicable in two independent cohorts.
1. Strengths of paper
This paper makes a comprehensive survey of the relationship between mtDNAcn and the personality dimensions, as well as how and whether they mediate the relationships between personality dimensions and mortability as well as other behavioural measures that may lead to mortality. The authors were careful in their definition of each phenotype, and used a reasonable measure for mtDNAcn, controlling for appropriate covariates. They conducted the appropriate statistical tests, and demonstrated the robustness of their findings using consistent results from two independent cohorts. The presentation of their findings in figures and tables are clear.
2. Weaknesses of paper
The authors attempt to evaluate the relationship between mtDNAcn, personality traits and mortality. To do this the authors have the first define a personality mortality index (PMI) as well as mortality itself in both cohorts, then test for the mediation effect of mtDNAcn on PMI and mortality. While the authors found a significant mediation effect of mtDNA in BLSA, they do not have the same significant findings in SardiNIA, potentially due to lack of power. Further, they do not test for direct effects of mtDNAcn on mortality, and do not arrive at an inference or hypothesis of the plausible biology behind the investigated relationships.
3. Objectives
The authors have generally achieved their objectives, though their claim that mtDNAcn fully accounts for the relationship between personality and mortality is not fully supported by their findings.
4. Future directions
More work needs to be performed to truly understand the relationship between personality dimensions and mortality, as well as the physiological traits (like mtDNAcn) that may be mediating it. The causal relationships between physiological measures like mtDNAcn and personality or behavioural traits need to be further examined too.
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