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

Xiaoling Zhang, John Farrell, Alzheimer's Disease Sequencing Project, Tong Tong, Junming Hu, Congcong Zhu, Li San Wang, Richard Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Kathy Lunetta, Lindsay Farrer, Yi Han, Xiuping Liu

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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 variant (rs28709356 C>T; minor allele frequency = 0.002; P = 7.3 × 10 −5) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10 −5). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10 −5). 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.

Original languageEnglish
Pages (from-to)294-306
Number of pages13
JournalAlzheimer's and Dementia
Volume18
Issue number2
Early online date20 Jun 2021
DOIs
Publication statusPublished - Feb 2022

Bibliographical note

Funding Information:
The Alzheimer's Disease Sequencing Project (ADSP) is comprised of two Alzheimer's Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer's Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non‐governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak‐Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate, U01AG052410 to Dr. Pericak‐Vance and U01 AG052409 to Drs. Seshadri and Fornage. Data generation and harmonization in the Follow‐up Phases is supported by U54AG052427 (to Drs. Schellenberg and Wang). This work was also supported by NIA grants R01‐AG048927 (to Dr. Farrer), RF1‐AG057519 (to Drs. Farrer and Jun), U19‐AG068753 (to Drs. Farrer and Au), U54‐AG052427 (to Drs. Schellenberg and Wang), U01‐AG058654 (to Drs. Bush, Farrer, Haines, Martin and Pericak‐Vance), and U01‐AG062602 (to Dr. Farrer).

Funding Information:
The CHARGE cohorts are supported in part by National Heart, Lung, and Blood Institute (NHLBI) infrastructure grant HL105756 (Psaty), RC2HL102419 (Boerwinkle), and the neurology working group is supported by the National Institute on Aging (NIA) R01 grant AG033193. The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS‐Family study, and the Prospective Dementia Registry‐Austria (ASPS/PRODEM‐Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fond (FWF) grant number P20545‐P05 and P13180 and the Medical University of Graz. The ASPS‐Fam is funded by the Austrian Science Fund (FWF) project I904), the EU Joint Programme‐Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM‐Austria is supported by the Austrian Research Promotion agency (FFG) (Project No. 827462) and by the Austrian National Bank (Anniversary Fund, project 15435. ARIC research is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA, and NIDCD), and with previous brain MRI examinations funded by R01‐HL70825 from the NHLBI. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the NIA. FHS research is supported by NHLBI contracts N01‐HC‐25195 and HHSN268201500001I. This study was also supported by additional grants from the NIA (R01s AG054076, AG049607 and AG033040 and NINDS (R01 NS017950). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG‐CT‐2006‐01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007‐2013)/grant agreement HEALTH‐F4‐2007‐201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2‐CT‐2002‐01254). High‐throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO‐RFBR 047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911‐03‐012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014‐93‐015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project 050‐060‐810. All studies are grateful to their participants, faculty, and staff. The content of these manuscripts is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. Department of Health and Human Services.

Funding Information:
Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions, and at the National Cell Repository for Alzheimer's Disease (NCRAD, U24AG021886) at Indiana University funded by NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA funded Alzheimer's Disease Centers (ADCs), and the National Alzheimer's Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA, and at the Database for Genotypes and Phenotypes (dbGaP) funded by NIH. This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations.

Publisher Copyright:
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

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