Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.
Journal
Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060
Informations de publication
Date de publication:
02 05 2023
02 05 2023
Historique:
received:
29
06
2022
accepted:
20
01
2023
pmc-release:
02
05
2024
medline:
3
5
2023
pubmed:
18
3
2023
entrez:
17
3
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36927883
pii: WNL.0000000000207157
doi: 10.1212/WNL.0000000000207157
pmc: PMC10159770
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1930-e1943Subventions
Organisme : NINDS NIH HHS
ID : R01 NS017950
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054076
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG059421
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG048642
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD105351
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH105632
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG059727
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG052409
Pays : United States
Organisme : NIA NIH HHS
ID : R35 AG071916
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG063887
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072972
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117626
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL155569
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL120393
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB015611
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054548
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH078111
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG058464
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH083824
Pays : United States
Investigateurs
Norma Aguilera
(N)
Seth Ament
(S)
Farah Ammous
(F)
Donna K Arnett
(DK)
Diane Becker
(D)
Joshua Bis
(J)
Elizabeth Blue
(E)
Eric Boerwinkle
(E)
Camille Breaux
(C)
Jan Bressler
(J)
Dima Chaar
(D)
None Mhi
Danielle Clarkson-Townsend
(D)
Brigidann Cooper
(B)
Josef Coresh
(J)
Adolfo Correa
(A)
Anita DeStefano
(A)
Jingzhong Ding
(J)
David Fardo
(D)
Annette Fitzpatrick
(A)
Myriam Fornage
(M)
Jennifer French
(J)
David Glahn
(D)
Hector Gonzalez
(H)
Einat Granot-Hershkovitz
(E)
Patrick Hanly
(P)
Kathleen Hayden
(K)
Susan Heckbert
(S)
Scott Heemann
(S)
Steve Horvath
(S)
Karin Hoth
(K)
Timothy Hughes
(T)
Sidd Jaiswal
(S)
Xueqiu Jian
(X)
Yuriko Katsumata
(Y)
Minjung Kho
(M)
Charles Kooperberg
(C)
Lenore Launer
(L)
Honghuang Lin
(H)
Elizabeth Litkowski
(E)
Will Longstreth
(W)
Alexandra Martin
(A)
Richard Mayeux
(R)
Julie Mikulla
(J)
Amy Miller
(A)
Biswapriya Misra
(B)
Thomas Mosley
(T)
Paul Nyquist
(P)
Jeff O'Connell
(J)
Michael Olivier
(M)
Gina Peloso
(G)
James Perry
(J)
Bruce Psaty
(B)
Shaun Purcell
(S)
Laura Raffield
(L)
Yugandi Ranaweera
(Y)
Alex Reiner
(A)
Jerome Rotter
(J)
Muralidharan Sargurupremraj
(M)
Chloé Sarnowski
(C)
Claudia Satizabal
(C)
Gerard Schellenberg
(G)
Bonnie L Schoenbein
(BL)
Sudha Seshadri
(S)
Lincoln Shade
(L)
Meghan I Short
(MI)
Jeannette Simino
(J)
Jennifer Smith
(J)
Mallorie Smith
(M)
Sylvia Smoller
(S)
Beverly Snively
(B)
Rachel Soemedi
(R)
Sophie Sokolow
(S)
Daune Thorington
(D)
Timothy A Thornton
(TA)
Lisa Yanek
(L)
Qiong Yang
(Q)
Miao Yu
(M)
Habil Zare
(H)
Wei Zhao
(W)
Goncalo Abecasis
(G)
Avinash Abhyankar
(A)
Micheala Aldred
(M)
Dan Arking
(D)
Allison Ashley-Koch
(A)
Abraham Aviv
(A)
Kathleen Barnes
(K)
Emily Barron-Casella
(E)
Stephanie Battle
(S)
Thomas Blackwell
(T)
Deepika Burkardt
(D)
Christina A Castellani
(CA)
Suzy Comhair
(S)
Brigidann Cooper
(B)
Adolfo Correa
(A)
Phyllis Crockett
(P)
Mariza de Andrade
(M)
Dawn DeMeo
(D)
Maria Rizzo DePaoli
(MR)
Jun Ding
(J)
Christine Dobski
(C)
Serpil Erzurum
(S)
Samar Farha
(S)
Jessica Fetterman
(J)
Caitlin Floyd
(C)
Mao Fu
(M)
Amber Gist
(A)
Einat Granot-Hershkovitz
(E)
C Charles Gu
(CC)
Scott Heemann
(S)
Ryan Hernandez
(R)
Yun Soo Hong
(YS)
Yi-Hsiang Hsu
(YH)
Anne Justice
(A)
Leslie Lange
(L)
Dan Levy
(D)
Honghuang Lin
(H)
Chunyu Liu
(C)
Ryan Longchamps
(R)
Jiantao Ma
(J)
JoAnn Manson
(J)
Tammy Markus
(T)
Merry-Lynn McDonald
(ML)
Stephen McGarvey
(S)
Julie Mikulla
(J)
Courtney Montgomery
(C)
Rajeeva Lochan Musunuri
(RL)
Jeff O'Connell
(J)
Richard Oppong
(R)
Nathan Pankratz
(N)
Yong Qian
(Y)
Jerome Rotter
(J)
Jessica R Shaw
(JR)
Albert Vernon Smith
(AV)
Tamar Sofer
(T)
Elizabeth Streeten
(E)
Weihong Tang
(W)
Kent D Taylor
(KD)
Marilyn Telen
(M)
Shelby Thompson
(S)
Daune Thorington
(D)
Hemant Tiwari
(H)
Ann Walsh
(A)
Emily Wan
(E)
Cuicui Wang
(C)
Heming Wang
(H)
Penglong Wang
(P)
Bruce Weir
(B)
L Keoki Williams
(LK)
James Wilson
(J)
Shujie Xiao
(S)
Weiling Xu
(W)
Yu-Chung Yang
(YC)
Wei Zhao
(W)
Informations de copyright
Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
Références
Hum Genet. 2022 Jan;141(1):127-146
pubmed: 34859289
Eur J Epidemiol. 2017 May;32(5):377-389
pubmed: 28527048
Semin Cell Dev Biol. 2016 Apr;52:93-101
pubmed: 26827792
J Am Soc Nephrol. 2016 Aug;27(8):2467-73
pubmed: 26794963
Neurobiol Aging. 2008 May;29(5):676-92
pubmed: 17222480
JAMA. 2018 Apr 10;319(14):1444-1472
pubmed: 29634829
Genome Res. 2021 Mar;31(3):349-358
pubmed: 33441415
Genet Epidemiol. 2020 Apr;44(3):290-299
pubmed: 32048336
Sci Transl Med. 2016 May 11;8(338):338ra66
pubmed: 27169802
Nature. 2021 Feb;590(7845):290-299
pubmed: 33568819
Hum Genet. 2014 Sep;133(9):1149-59
pubmed: 24902542
Genet Epidemiol. 2013 Nov;37(7):658-65
pubmed: 24114802
Acta Neuropathol Commun. 2017 Feb 2;5(1):13
pubmed: 28153046
Cell Genom. 2021 Oct 13;1(1):
pubmed: 35036986
Ann Neurol. 2013 Nov;74(5):655-68
pubmed: 23794434
Neurobiol Dis. 2013 Nov;59:100-10
pubmed: 23867235
PLoS Genet. 2015 Jul 14;11(7):e1005306
pubmed: 26172475
Mol Neurobiol. 2020 Dec;57(12):5103-5120
pubmed: 32851560
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10966-71
pubmed: 11526211
Nat Commun. 2018 May 29;9(1):2098
pubmed: 29844566
Elife. 2018 May 30;7:
pubmed: 29846171
Nat Commun. 2020 Dec 8;11(1):6285
pubmed: 33293549
Stat Methods Med Res. 2017 Oct;26(5):2333-2355
pubmed: 26282889
Lancet Neurol. 2013 Feb;12(2):207-16
pubmed: 23332364
Mol Neurodegener. 2021 Nov 6;16(1):75
pubmed: 34742335
J Evol Biol. 2011 Aug;24(8):1836-41
pubmed: 21605215
Ann N Y Acad Sci. 2008 Dec;1147:180-95
pubmed: 19076441
Neurology. 2020 Dec 15;95(24):e3331-e3343
pubmed: 32913026
Alzheimers Dement. 2021 Mar;17(3):327-406
pubmed: 33756057
Mol Neurobiol. 2022 Feb;59(2):1230-1237
pubmed: 34978044
Nat Commun. 2017 Jan 18;8:13624
pubmed: 28098162
Stat Med. 2008 Apr 15;27(8):1133-63
pubmed: 17886233
JAMA. 1995 Mar 22-29;273(12):942-7
pubmed: 7884953
J Mol Med (Berl). 2015 Feb;93(2):177-186
pubmed: 25471480
Commun Biol. 2019 Aug 2;2:285
pubmed: 31396565
Elife. 2022 Jan 13;11:
pubmed: 35023831
PLoS One. 2020 Jan 31;15(1):e0228166
pubmed: 32004343
Biology (Basel). 2019 Jun 17;8(2):
pubmed: 31213034
Neurobiol Aging. 2016 Feb;38:216.e7-216.e10
pubmed: 26639155
Chest. 1992 Sep;102(3):748-52
pubmed: 1516396
J Comput Assist Tomogr. 1998 Sep-Oct;22(5):827-37
pubmed: 9754125