Mitochondrial Haplogroup Influences Motor Function in Long-Term HIV-1-Infected Individuals

Abstract

Evolutionary divergence of the mitochondrial genome has given rise to distinct haplogroups. These haplogroups have arisen in specific geographical locations and are responsible for subtle functional changes in the mitochondria that may provide an evolutionary advantage in a given environment. Based on these functional differences, haplogroups could define disease susceptibility in chronic settings. In this study, we undertook a detailed neuropsychological analysis of a cohort of long-term HIV-1-infected individuals in conjunction with sequencing of their mitochondrial genomes. Stepwise regression analysis showed that the best model for predicting both working memory and declarative memory were age and years since diagnosis. In contrast, years since diagnosis and sub-haplogroup were significantly predictive of psychomotor speed. Consistent with this, patients with haplogroup L3e obtained better scores on psychomotor speed and dexterity tasks when compared to the remainder of the cohort, suggesting that this haplogroup provides a protective advantage when faced with the combined stress of HIV-1 infection and long-term antiretroviral therapies. Differential performance on declarative memory tasks was noted for individuals with other sub-L haplogroups, but these differences were not as robust as the association between L3e and psychomotor speed and dexterity tasks. This work provides evidence that mitochondrial haplogroup is related to neuropsychological test performance among patients in chronic disease settings such as HIV-1 infection.

Fig 1. Principle component analysis identifies functional groups among neurocognitive tests.

A) Rotated component matrix of norm-derived neuropsychological test scores used to determine neuropsychological composite scores. Component 1 = declarative memory; component 2 = motor; component 3 = working memory. Red boxes show groupings for each component determined by the PCA. B) The nine neurocognitive evaluation scores were compiled in SPSS. Total variance explained by each component is contained under the 3 columns listed under Initial Eigenvalues. Components identified as explaining the maximum amount of variance in the data are listed under Extraction Sums of Squared Loadings. Total amount of variance in the model explained by each of these 3 components after varimax rotation is listed under Rotation Sum of Squared Loadings. Total variance explained by the PCA and variance explained by each component of the PCA is outlined in red boxes. C) Histograms showing that the three composite scores were normally distributed.

Fig 2. Principle component analysis on patient genotype information.

A) Principle component analysis revealed 3 genotype groupings. Color-coding showed patients clustering in 3 major groups L0, L1 and all other haplogroups. Performed using SNPRelate R package B-D) Box whisker plot grouping haplogroups as follows L0 vs L1 vs L2+L3+NL vs. the 3 complied neuropsychological composite scores. E) Statistical analysis between the 3 groups was performed using SPSS and Kruskal-Wallis testing (p<0.05). Red dotted lines indicate mean T-scores.

Fig 3. Major haplogroups show no association with neurocognitive performance.

A-C) Box whisker plots of the haplogroups against the three compiled neuropsychological composite scores: A- Psychomotor speed B- Working memory C-Declarative memory. Red dotted lines indicate average T-scores. D) SPSS table reporting p-values for Kruskal-Wallis testing.

Fig 4. Sub-haplogroups show no association with neurocognitive performance when compared to one another.

A-C) Box whisker plots of the sub-haplogroups against the three compiled neuroscores: A- Psychomotor speed B- Working memory C-Declarative memory. Red dotted lines indicate the mean T-scores. D) SPSS table reporting p-values for Kruskal-Wallis testing.

Fig 5. Sub-haplogroups L2a and L3e show statistically significant association with neurocognitive performance when segregated from the cohort as a whole.

A-B) Box whisker plots of 2 sub-haplogroups (L2a and L3e) significantly associated with performance on at least one neuropsychological composite score with respect to the rest of the cohort. Working memory (A) and psychomotor speed and dexterity (B.) Mann-Whitney U statistical testing (p-value <0.05). Red dotted lines indicate mean values expressed as T-scores.

Fig 6. Variants overrepresented in the L3e sub-haplogroup showing association with psychomotor speed and dexterity.

A) Fisher’s exact test was used to determine the top 10 variants that were overrepresented in the L3e sub-haplogroup (Fishers exact: p-value < 0.001). Table shows variant, the gene containing the variant, S- synonymous amino acid change vs NS- non-synonymous amino acid change and percent of individuals in L3e or non-L3e who possess each variant. B) Dot plot showing individuals motor score with or without the variant at position 150 (./. reference base in RCRS). Red dotted line indicates mean values of the SENAS control population for the T-scores. C) Individual test scores, which, comprise the PCA derived motor score, were individually evaluated between L3e and non-L3e individuals. Red box indicates simple motor scores, Green box represents complex motor score.