Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts

Yuankai Zhang; Xue Liu; Kerri L. Wiggins; Nuzulul Kurniansyah; Xiuqing Guo; Amanda L. Rodrigue; Wei Zhao; Lisa R. Yanek; Scott M. Ratliff; Achilleas Pitsillides; Juan Sebastian Aguirre Patiño; Tamar Sofer; Dan E. Arking; Thomas R. Austin; Alexa S. Beiser; John Blangero; Eric Boerwinkle; Jan Bressler; Joanne E. Curran; Lifang Hou; Timothy M. Hughes; Sharon L.R. Kardia; Lenore J. Launer; Daniel Levy; Thomas H. Mosley; Ilya M. Nasrallah; Stephen S. Rich; Jerome I. Rotter; Sudha Seshadri; Wassim Tarraf; Kevin A. González; Vasan Ramachandran; Kristine Yaffe; Paul A. Nyquist; Bruce M. Psaty; Charles S. Decarli; Jennifer A. Smith; David C. Glahn; Hector M. González; Joshua C. Bis; Myriam Fornage; Susan R. Heckbert; Annette L. Fitzpatrick; Chunyu Liu; Claudia L. Satizabal

doi:10.1212/WNL.0000000000207157

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts

Yuankai Zhang, Xue Liu, Kerri L. Wiggins, Nuzulul Kurniansyah, Xiuqing Guo, Amanda L. Rodrigue, Wei Zhao, Lisa R. Yanek, Scott M. Ratliff, Achilleas Pitsillides, Juan Sebastian Aguirre Patiño, Tamar Sofer, Dan E. Arking, Thomas R. Austin, Alexa S. Beiser, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E. Curran, Lifang HouTimothy M. Hughes, Sharon L.R. Kardia, Lenore J. Launer, Daniel Levy, Thomas H. Mosley, Ilya M. Nasrallah, Stephen S. Rich, Jerome I. Rotter, Sudha Seshadri, Wassim Tarraf, Kevin A. González, Vasan Ramachandran, Kristine Yaffe, Paul A. Nyquist, Bruce M. Psaty, Charles S. Decarli, Jennifer A. Smith, David C. Glahn, Hector M. González, Joshua C. Bis, Myriam Fornage, Susan R. Heckbert, Annette L. Fitzpatrick, Chunyu Liu, Claudia L. Satizabal^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Background and ObjectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality.ResultsWe included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.DiscussionHigher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

Original language	English (US)
Pages (from-to)	E1930-E1943
Journal	Neurology
Volume	100
Issue number	18
DOIs	https://doi.org/10.1212/WNL.0000000000207157
State	Published - May 2 2023

Funding

Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393-02S1; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study (R01AG059727). Additional cohort-specific funding is provided in the supplementary material.

ASJC Scopus subject areas

Clinical Neurology

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10.1212/WNL.0000000000207157

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Zhang, Y., Liu, X., Wiggins, K. L., Kurniansyah, N., Guo, X., Rodrigue, A. L., Zhao, W., Yanek, L. R., Ratliff, S. M., Pitsillides, A., Patiño, J. S. A., Sofer, T., Arking, D. E., Austin, T. R., Beiser, A. S., Blangero, J., Boerwinkle, E., Bressler, J., Curran, J. E., ... Satizabal, C. L. (2023). Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. Neurology, 100(18), E1930-E1943. https://doi.org/10.1212/WNL.0000000000207157

@article{c7e178218eae4aee9edba3e98fb542b1,

title = "Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts",

abstract = "Background and ObjectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality.ResultsWe included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.DiscussionHigher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.",

author = "Yuankai Zhang and Xue Liu and Wiggins, {Kerri L.} and Nuzulul Kurniansyah and Xiuqing Guo and Rodrigue, {Amanda L.} and Wei Zhao and Yanek, {Lisa R.} and Ratliff, {Scott M.} and Achilleas Pitsillides and Pati{\~n}o, {Juan Sebastian Aguirre} and Tamar Sofer and Arking, {Dan E.} and Austin, {Thomas R.} and Beiser, {Alexa S.} and John Blangero and Eric Boerwinkle and Jan Bressler and Curran, {Joanne E.} and Lifang Hou and Hughes, {Timothy M.} and Kardia, {Sharon L.R.} and Launer, {Lenore J.} and Daniel Levy and Mosley, {Thomas H.} and Nasrallah, {Ilya M.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Sudha Seshadri and Wassim Tarraf and Gonz{\'a}lez, {Kevin A.} and Vasan Ramachandran and Kristine Yaffe and Nyquist, {Paul A.} and Psaty, {Bruce M.} and Decarli, {Charles S.} and Smith, {Jennifer A.} and Glahn, {David C.} and Gonz{\'a}lez, {Hector M.} and Bis, {Joshua C.} and Myriam Fornage and Heckbert, {Susan R.} and Fitzpatrick, {Annette L.} and Chunyu Liu and Satizabal, {Claudia L.}",

note = "Publisher Copyright: {\textcopyright} American Academy of Neurology.",

year = "2023",

month = may,

day = "2",

doi = "10.1212/WNL.0000000000207157",

language = "English (US)",

volume = "100",

pages = "E1930--E1943",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "18",

}

Zhang, Y, Liu, X, Wiggins, KL, Kurniansyah, N, Guo, X, Rodrigue, AL, Zhao, W, Yanek, LR, Ratliff, SM, Pitsillides, A, Patiño, JSA, Sofer, T, Arking, DE, Austin, TR, Beiser, AS, Blangero, J, Boerwinkle, E, Bressler, J, Curran, JE, Hou, L, Hughes, TM, Kardia, SLR, Launer, LJ, Levy, D, Mosley, TH, Nasrallah, IM, Rich, SS, Rotter, JI, Seshadri, S, Tarraf, W, González, KA, Ramachandran, V, Yaffe, K, Nyquist, PA, Psaty, BM, Decarli, CS, Smith, JA, Glahn, DC, González, HM, Bis, JC, Fornage, M, Heckbert, SR, Fitzpatrick, AL, Liu, C & Satizabal, CL 2023, 'Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts', Neurology, vol. 100, no. 18, pp. E1930-E1943. https://doi.org/10.1212/WNL.0000000000207157

TY - JOUR

T1 - Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function

T2 - A Meta-analysis of Community-Based Cohorts

AU - Zhang, Yuankai

AU - Liu, Xue

AU - Wiggins, Kerri L.

AU - Kurniansyah, Nuzulul

AU - Guo, Xiuqing

AU - Rodrigue, Amanda L.

AU - Zhao, Wei

AU - Yanek, Lisa R.

AU - Ratliff, Scott M.

AU - Pitsillides, Achilleas

AU - Patiño, Juan Sebastian Aguirre

AU - Sofer, Tamar

AU - Arking, Dan E.

AU - Austin, Thomas R.

AU - Beiser, Alexa S.

AU - Blangero, John

AU - Boerwinkle, Eric

AU - Bressler, Jan

AU - Curran, Joanne E.

AU - Hou, Lifang

AU - Hughes, Timothy M.

AU - Kardia, Sharon L.R.

AU - Launer, Lenore J.

AU - Levy, Daniel

AU - Mosley, Thomas H.

AU - Nasrallah, Ilya M.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Seshadri, Sudha

AU - Tarraf, Wassim

AU - González, Kevin A.

AU - Ramachandran, Vasan

AU - Yaffe, Kristine

AU - Nyquist, Paul A.

AU - Psaty, Bruce M.

AU - Decarli, Charles S.

AU - Smith, Jennifer A.

AU - Glahn, David C.

AU - González, Hector M.

AU - Bis, Joshua C.

AU - Fornage, Myriam

AU - Heckbert, Susan R.

AU - Fitzpatrick, Annette L.

AU - Liu, Chunyu

AU - Satizabal, Claudia L.

PY - 2023/5/2

Y1 - 2023/5/2

N2 - Background and ObjectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality.ResultsWe included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.DiscussionHigher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

AB - Background and ObjectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality.ResultsWe included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.DiscussionHigher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

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DO - 10.1212/WNL.0000000000207157

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VL - 100

SP - E1930-E1943

JO - Neurology

JF - Neurology

IS - 18

ER -

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts

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