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Greater Mitochondrial Polygenic Risk is Associated with Reduced Sustained Attention among Youth with Bipolar Disorder

This study demonstrates that higher mitochondrial polygenic risk is significantly associated with reduced sustained attention in youth with bipolar disorder, particularly among females, suggesting a link between mitochondrial genetic factors and neurocognitive deficits in this population.

Original authors: Nidhi P. Kulkarni, Clement C. Zai, Mikaela K. Dimick, Alysha A. Sultan, Ana C. Andreazza, Vanessa F. Goncalves, L. Trevor Young, Benjamin I. Goldstein

Published 2026-10-22

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CC BY 4.0

Original authors: Nidhi P. Kulkarni, Clement C. Zai, Mikaela K. Dimick, Alysha A. Sultan, Ana C. Andreazza, Vanessa F. Goncalves, L. Trevor Young, Benjamin I. Goldstein

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

The human brain is an energy-hungry organ, consuming a vast amount of fuel to keep thoughts flowing and attention focused. At the cellular level, tiny structures called mitochondria act as the power plants, generating the energy required for these complex tasks. When these power plants malfunction, the consequences can ripple through the body and mind. This is particularly relevant for bipolar disorder, a condition marked by intense shifts in mood and energy levels. Scientists have long suspected that problems with how cells produce and use energy are central to this illness, but the precise link between genetic risk for these energy failures and the specific thinking skills of young people has remained unclear.

A new study from the Centre for Addiction and Mental Health in Toronto seeks to illuminate this connection. The researchers focused on a group of young people, mostly teenagers and young adults, some of whom had been diagnosed with bipolar disorder and others who did not. They wanted to know if a person's genetic risk for mitochondrial problems could predict how well they could sustain their attention over time. Attention is a critical skill, allowing a person to stay focused on a task without getting distracted, and it is often one of the first abilities to suffer in those with bipolar disorder. By examining the genetic code of these 129 participants, the team looked for a specific pattern: a score that reflects the combined influence of many small genetic variations related to mitochondrial function.

The researchers calculated this genetic score for each participant and then asked them to perform a series of computerized mental tasks. These tasks measured various cognitive abilities, such as memory, decision-making, and the ability to shift focus. The specific test for sustained attention required participants to watch a screen and respond quickly to a specific visual signal while ignoring others, a task that demands steady, unbroken concentration. The team analyzed the results while carefully accounting for factors like age, intelligence, and sex to ensure that any patterns they found were truly linked to the genetic score and not other variables.

The results revealed a clear and specific relationship. In the group of young people with bipolar disorder, those with a higher genetic risk for mitochondrial issues performed significantly worse on the sustained attention task. This association was strong enough to be considered a reliable finding within the study. However, this link did not appear in the control group of young people without the disorder, suggesting that the genetic risk interacts specifically with the biology of bipolar disorder to affect attention. The study also found that this effect was driven almost entirely by female participants. Among the young women with bipolar disorder, a higher mitochondrial genetic risk corresponded to a noticeable drop in attentional performance, whereas no such pattern emerged for the young men in the study.

These findings held true even when the researchers adjusted for other factors that could influence the results, such as the medications the participants were taking, their body weight, or the severity of their mood symptoms at the time of testing. The association remained significant even when looking only at those who were currently experiencing symptoms of the disorder. This suggests that the genetic influence on attention is not merely a side effect of being sick or taking medication, but rather a fundamental trait that may be present early in the course of the illness. The study did not find similar links between this genetic risk and other cognitive skills like memory or planning, indicating that the impact of mitochondrial genetics on the brain might be highly specific to the ability to maintain focus.

While the study provides compelling evidence for this connection, the authors are careful to note that it is a preliminary step. The sample size was modest, and the research was conducted at a single location, which means the findings need to be confirmed in larger and more diverse groups of people. The study also cannot prove that the genetic risk causes the attention problems, only that they are associated. Nevertheless, the work offers a new perspective on why young people with bipolar disorder struggle with attention. It points toward the energy systems within brain cells as a potential biological pathway for these difficulties, suggesting that the roots of cognitive challenges may lie in how the brain's power plants are built by our genes. This insight could eventually help researchers develop better ways to support the brain's energy needs, potentially leading to interventions that protect or restore attention in those who need it most.

Technical Summary: Greater Mitochondrial Polygenic Risk is Associated with Reduced Sustained Attention among Youth with Bipolar Disorder

Problem Statement
Bipolar disorder (BD) is a polygenic condition characterized by neurocognitive impairments and energy dysfunction, with mitochondrial dysfunction proposed as a core underlying mechanism. While mitochondrial DNA (mtDNA) variants and nuclear gene expression related to energy production have been linked to BD, the specific contribution of mitochondrial genetic risk to neurocognitive performance in youth remains underexplored. Previous research established that a general BD polygenic risk score (PRS) correlates with poorer sustained attention in youth, but the specific biological pathways driving this association were not examined. This study addresses the gap by investigating whether a mitochondrial-specific polygenic risk score (Mito-PRS), derived from nuclear-encoded genes involved in mitochondrial pathways, is associated with neurocognitive deficits in youth with and without BD.

Methodology
The study utilized a cross-sectional design with a sample of 129 genetically European youth (ages 13–21), comprising 72 individuals with BD (types I, II, or OSBRD) and 57 healthy controls.

Genetic Analysis: Mito-PRS was calculated using summary statistics from a large adult BD genome-wide association study (GWAS). Variants were filtered to include only those located within or near genes annotated in curated mitochondrial databases (MitoCarta v3.0 and MSigDB), representing pathways such as oxidative phosphorylation, mitophagy, and mitochondrial dynamics. The score was standardized and adjusted using PRS-CS-auto.
Neurocognitive Assessment: Participants completed six tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), covering domains including affective processing, decision-making, sustained attention, cognitive flexibility, visuospatial working memory, and spatial planning. Scores were converted to Z-scores to generate composite scores for each domain.
Statistical Modeling: General linear models (GLM) were employed to examine associations between Mito-PRS and neurocognitive performance. Analyses were conducted on the overall sample, and stratified by diagnosis (BD vs. controls), sex, and mood state (symptomatic vs. euthymic). Models controlled for age, sex, IQ, and the first two genetic principal components. Sensitivity analyses further adjusted for psychotropic medications, BMI, and mood severity.

Key Results

Primary Association: Higher Mito-PRS was significantly associated with poorer sustained attention (measured by the Rapid Visual Information Processing task, RVP) in the overall sample ( $\beta = -0.19, p = 0.02$ ).
Diagnostic Specificity: This association was driven primarily by the BD group ( $\beta = -0.30, p = 0.01$ ), where higher mitochondrial risk predicted worse sustained attention. No significant association was found within the control group ( $\beta = -0.10, p = 0.44$ ).
Sex Differences: Stratified analyses revealed that the association between Mito-PRS and sustained attention was significant only in females (Overall: $\beta = -0.23, p = 0.04$ ; BD group: $\beta = -0.35, p = 0.02$ ). No significant associations were observed in males.
Domain Specificity: The association was specific to sustained attention; no significant relationships were found for other neurocognitive domains (e.g., decision-making, working memory, cognitive flexibility) or the global neurocognition composite.
Robustness: Findings remained significant in sensitivity analyses controlling for medications (including second-generation antipsychotics and lithium), BMI, and mood severity. In exploratory analyses, the association persisted in symptomatic BD participants but was not significant in the smaller euthymic subgroup, though effect sizes in the euthymic group were moderate-to-large.

Significance and Claims
The paper claims to provide preliminary evidence that mitochondrial genetic variation acts as a static risk factor for specific neurocognitive deficits—specifically sustained attention—in youth with BD. Key contributions and claims include:

Early Manifestation: The association is observed in youth with relatively short illness duration and less exposure to cumulative treatment effects, suggesting that mitochondrial genetic influences on cognition manifest early in the disease course rather than solely as a consequence of prolonged illness burden.
Mechanistic Insight: The findings support the hypothesis that mitochondrial dysfunction contributes to BD pathology via bioenergetic mechanisms. The authors posit that sustained attention, which relies on energy-intensive prefrontal-parietal networks, is particularly sensitive to alterations in oxidative phosphorylation and ATP availability driven by mitochondrial genetic risk.
Sex-Specificity: The study highlights a potential sex-specific mechanism, noting that the genetic risk impact is more pronounced in females, aligning with known sex differences in mitochondrial structure and function.
Distinct from General BD Risk: The authors note that the correlation between Mito-PRS and the general BD-PRS was negligible, suggesting that the observed cognitive deficits are linked specifically to mitochondrial pathways rather than general BD genetic liability.

The authors maintain a modest tone, acknowledging limitations such as the cross-sectional design, the use of an adult-derived GWAS for a youth sample, and the lack of power for subgroup analyses (particularly in males and euthymic participants). They conclude that while the findings are promising, larger, prospective studies in diverse populations are required to validate these associations and elucidate the underlying brain mechanisms.

Technical Summary: Greater Mitochondrial Polygenic Risk is Associated with Reduced Sustained Attention among Youth with Bipolar Disorder

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