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Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease.

TitleAssociation of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsZhang X, Farrell JJ, Tong T, Hu J, Zhu C, San Wang L-, Mayeux R, Haines JL, Pericak-Vance MA, Schellenberg GD, Lunetta KL, Farrer LA
Corporate AuthorsAlzheimer's Disease Sequencing Project
JournalAlzheimers Dement
Date Published2021 Jun 20
ISSN1552-5279
Abstract

INTRODUCTION: Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent.

METHODS: We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O.

RESULTS: Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L missense variant (rs28709356; minor allele frequency = 0.002; P = 7.3 × 10 ) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10 ). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03).

DISCUSSION: Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.

DOI10.1002/alz.12396
Alternate JournalAlzheimers Dement
PubMed ID34152079
Grant ListR01-AG048927 / AG / NIA NIH HHS / United States
RF1-AG057519 / AG / NIA NIH HHS / United States
U19-AG068753 / AG / NIA NIH HHS / United States
U54-AG052247 / AG / NIA NIH HHS / United States
U01-AG058654 / AG / NIA NIH HHS / United States
U01-AG062602 / AG / NIA NIH HHS / United States
UF1AG047133 / / National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through /
HL105756 / HL / NHLBI NIH HHS / United States
RC2HL102419 / HL / NHLBI NIH HHS / United States
AG033193 / / National Institute on Aging (NIA) /
P20545-P05 / / Austrian Science Fond (FWF) /
P13180 / / Austrian Science Fond (FWF) /
HHSN268201100005C / HB / NHLBI NIH HHS / United States
HHSN268201100006C / HB / NHLBI NIH HHS / United States
HHSN268201100007C / HB / NHLBI NIH HHS / United States
HHSN268201100008C / HB / NHLBI NIH HHS / United States
HHSN268201100009C / HB / NHLBI NIH HHS / United States
HHSN268201100010C / HB / NHLBI NIH HHS / United States
HHSN268201100011C / HB / NHLBI NIH HHS / United States
HHSN268201100012C / HB / NHLBI NIH HHS / United States
U01 2U01HL096812 / / Neurocognitive data in ARIC is collected /
2U01HL096814 / / Neurocognitive data in ARIC is collected /
2U01HL096899 / / Neurocognitive data in ARIC is collected /
2U01HL096902 / / Neurocognitive data in ARIC is collected /
2U01HL096917 / / Neurocognitive data in ARIC is collected /
R01-HL70825 / / MRI examinations /
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
U01HL080295 / / CHS research /
U01HL130114 / / CHS research /
R01AG023629 / NS / NINDS NIH HHS / United States
R01AG15928 / NS / NINDS NIH HHS / United States
R01AG20098 / NS / NINDS NIH HHS / United States
N01-HC-25195 / NS / NINDS NIH HHS / United States
HHSN268201500001I / NS / NINDS NIH HHS / United States
R01s AG054076 / AG / NIA NIH HHS / United States
AG049607 / AG / NIA NIH HHS / United States
AG033040 / AG / NIA NIH HHS / United States
018947 / / European Commission FP6 STRP /