Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. (2nd May 2023)

• Record Type: Journal Article
• Authors: Zhang, Yuankai; Liu, Xue; Wiggins, Kerri L.; Kurniansyah, Nuzulul; Guo, Xiuqing; Rodrigue, Amanda L.; Zhao, Wei; Yanek, Lisa R.; Ratliff, Scott M.; Pitsillides, Achilleas; Aguirre Patiño, Juan Sebastian; Sofer, Tamar; Arking, Dan E.; Austin, Thomas R.; Beiser, Alexa S.; Blangero, John; Boerwinkle, Eric; Bressler, Jan; Curran, Joanne E.; Hou, Lifang; Hughes, Timothy M.; Kardia, Sharon L.R.; Launer, Lenore J.; Levy, Daniel; Mosley, Thomas H.; Nasrallah, Ilya M.; Rich, Stephen S.; Rotter, Jerome I.; Seshadri, Sudha; Tarraf, Wassim; González, Kevin A.; Ramachandran, Vasan; Yaffe, Kristine; Nyquist, Paul A.; Psaty, Bruce M.; DeCarli, Charles S.; Smith, Jennifer A.; Glahn, David C.; González, Hector M.; Bis, Joshua C.; Fornage, Myriam; Heckbert, Susan R.; Fitzpatrick, Annette L.; Liu, Chunyu; Satizabal, Claudia L.;
• Other Names: author non-byline.; Aguilera Norma author non-byline.; Ament Seth author non-byline.; Ammous Farah author non-byline.; Arnett Donna K author non-byline.; Becker Diane author non-byline.; Bis Joshua author non-byline.; Blue Elizabeth author non-byline.; Boerwinkle Eric author non-byline.; Breaux Camille author non-byline.; Bressler Jan author non-byline.; Chaar Dima author non-byline.; MHI author non-byline.; Clarkson-Townsend Danielle author non-byline.; Cooper Brigidann author non-byline.; Coresh Josef author non-byline.; Correa Adolfo author non-byline.; DeStefano Anita author non-byline.; Ding Jingzhong author non-byline.; Fardo David author non-byline.; Fitzpatrick Annette author non-byline.; Fornage Myriam author non-byline.; French Jennifer author non-byline.; Glahn David author non-byline.; Gonzalez Hector author non-byline.; Granot-Hershkovitz Einat author non-byline.; Hanly Patrick author non-byline.; Hayden Kathleen author non-byline.; Heckbert Susan author non-byline.; Heemann Scott author non-byline.; Horvath Steve author non-byline.; Hoth Karin author non-byline.; Hughes Timothy author non-byline.; Jaiswal Sidd author non-byline.; Jian Xueqiu author non-byline.; Katsumata Yuriko author non-byline.; Kho Minjung author non-byline.; Kooperberg Charles author non-byline.; Launer Lenore author non-byline.; Lin Honghuang author non-byline.; Litkowski Elizabeth author non-byline.; Longstreth Will author non-byline.; Martin Alexandra author non-byline.; Mayeux Richard author non-byline.; Mikulla Julie author non-byline.; Miller Amy author non-byline.; Misra Biswapriya author non-byline.; Mosley Thomas author non-byline.; Nyquist Paul author non-byline.; O'Connell Jeff author non-byline.; Olivier Michael author non-byline.; Peloso Gina author non-byline.; Perry James author non-byline.; Psaty Bruce author non-byline.; Purcell Shaun author non-byline.; Raffield Laura author non-byline.; Ranaweera Yugandi author non-byline.; Reiner Alex author non-byline.; Rotter Jerome author non-byline.; Sargurupremraj Muralidharan author non-byline.; Sarnowski Chloé author non-byline.; Satizabal Claudia author non-byline.; Schellenberg Gerard author non-byline.; Schoenbein Bonnie L author non-byline.; Seshadri Sudha author non-byline.; Shade Lincoln author non-byline.; Short Meghan I author non-byline.; Simino Jeannette author non-byline.; Smith Jennifer author non-byline.; Smith Mallorie author non-byline.; Smoller Sylvia author non-byline.; Snively Beverly author non-byline.; Soemedi Rachel author non-byline.; Sokolow Sophie author non-byline.; Thorington Daune author non-byline.; Thornton Timothy A. author non-byline.; Yanek Lisa author non-byline.; Yang Qiong author non-byline.; Yu Miao author non-byline.; Zare Habil author non-byline.; Zhao Wei author non-byline.; Abecasis Goncalo author non-byline.; Abhyankar Avinash author non-byline.; Aldred Micheala author non-byline.; Arking Dan author non-byline.; Ashley-Koch Allison author non-byline.; Aviv Abraham author non-byline.; Barnes Kathleen author non-byline.; Barron-Casella Emily author non-byline.; Battle Stephanie author non-byline.; Blackwell Thomas author non-byline.; Burkardt Deepika author non-byline.; Castellani Christina A author non-byline.; Comhair Suzy author non-byline.; Cooper Brigidann author non-byline.; Correa Adolfo author non-byline.; Crockett Phyllis author non-byline.; de Andrade Mariza author non-byline.; DeMeo Dawn author non-byline.; DePaoli Maria Rizzo author non-byline.; Ding Jun author non-byline.; Dobski Christine author non-byline.; Erzurum Serpil author non-byline.; Farha Samar author non-byline.; Fetterman Jessica author non-byline.; Floyd Caitlin author non-byline.; Fu Mao author non-byline.; Gist Amber author non-byline.; Granot-Hershkovitz Einat author non-byline.; Gu C. Charles author non-byline.; Heemann Scott author non-byline.; Hernandez Ryan author non-byline.; Hong Yun Soo author non-byline.; Hsu Yi-Hsiang author non-byline.; Justice Anne author non-byline.; Lange Leslie author non-byline.; Levy Dan author non-byline.; Lin Honghuang author non-byline.; Liu Chunyu author non-byline.; Longchamps Ryan author non-byline.; Ma Jiantao author non-byline.; Manson JoAnn author non-byline.; Markus Tammy author non-byline.; McDonald Merry-Lynn author non-byline.; McGarvey Stephen author non-byline.; Mikulla Julie author non-byline.; Montgomery Courtney author non-byline.; Musunuri Rajeeva Lochan author non-byline.; O'Connell Jeff author non-byline.; Oppong Richard author non-byline.; Pankratz Nathan author non-byline.; Qian Yong author non-byline.; Rotter Jerome author non-byline.; Shaw Jessica R author non-byline.; Smith Albert Vernon author non-byline.; Sofer Tamar author non-byline.; Streeten Elizabeth author non-byline.; Tang Weihong author non-byline.; Taylor Kent D. author non-byline.; Telen Marilyn author non-byline.; Thompson Shelby author non-byline.; Thorington Daune author non-byline.; Tiwari Hemant author non-byline.; Walsh Ann author non-byline.; Wan Emily author non-byline.; Wang Cuicui author non-byline.; Wang Heming author non-byline.; Wang Penglong author non-byline.; Weir Bruce author non-byline.; Williams L. Keoki author non-byline.; Wilson James author non-byline.; Xiao Shujie author non-byline.; Xu Weiling author non-byline.; Yang Yu-Chung author non-byline.; Zhao Wei author non-byline.;
• Is Part Of: Neurology. Volume 100:Number 18(2023)
• Page Start: e1930
• Page End: e1943
• Publication Date: 2023-05-02
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000207157
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : Background and Objectives: Previous 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. Methods: We 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. Results: We 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. Discussion: Higher 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.