Alzheimer disease pathology-associated polymorphism in a complex variable number of tandem repeat region within the MUC6 gene, near the AP2A2 gene

Yuriko Katsumata, David W. Fardo, Adam D. Bachstetter, Sergey C. Artiushin, Wang Xia Wang, Angela Wei, Lena J. Brzezinski, Bela G. Nelson, Qingwei Huang, Erin L. Abner, Sonya Anderson, Indumati Patel, Benjamin C. Shaw, Douglas A. Price, Dana M. Niedowicz, Donna W. Wilcock, Gregory A. Jicha, Janna H. Neltner, Linda J. Van Eldik, Steven EstusPeter T. Nelson

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n=119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n=173), more pTau pathology was again observed in subjects with longer VNTR regions (p=0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p=0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.

Original languageEnglish
Pages (from-to)3-21
Number of pages19
JournalJournal of Neuropathology and Experimental Neurology
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2020

Bibliographical note

Funding Information:
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 Steierma€rkische 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, HHSN26820 1100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neuro-cognitive data in ARIC are 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 NIH or the U.S. Department of Health and Human Services. The 4 LSACs are: The Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), The American Genome Center at the Uniformed Services University of the Health Sciences (U01AG057659), and the Washington University Genome Institute (U54HG003079). Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions, and at the National Cell Repository for AD (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 ADCs, and the National Alzheimer’s Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of AD 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 US organizations, or foreign governmental or nongovernmental organizations.

Funding Information:
We are deeply grateful to all of the study participants, clinical workers, and researchers who made this study possible. Thanks to Drs Peter Davies, Edward Lee, and Virginia Lee for providing antibodies. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The ADSP is composed of 2 AD genetics consortia and 3 National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the ADGC funded by NIA (U01 AG032984), and CHARGE consortium funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes and other foreign governmental and nongovernmental 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 Boer-winkle; 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). The ADGC cohorts include: Adult Changes in Thought (ACT), the ADCs, the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic (MAYO), Mayo Parkinson’s Disease controls, University of Miami, the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE), the National Cell Repository for AD (NCRAD), the NIA Late Onset AD Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer’s Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic-Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA), the University of Toronto (UT), and Genetic Differences (GD). The CHARGE cohorts are supported in part by 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/PRO-DEM-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

Funding Information:
Send correspondence to: Peter T. Nelson, MD, PhD, Sanders-Brown Center on Aging, University of Kentucky, 311, 800 S. Limestone Ave., Lexing-ton, KY 40536; E-mail: peter.nelson@uky.edu Funding included grants P30 AG028383, R01 AG057187, R01 AG042475, and U01 AG016976 from the National Institute on Aging (NIA)/National Institutes of Health (NIH). Please see the additional Acknowledgment section at the end of the Discussion section.

Publisher Copyright:
© 2019 American Association of Neuropathologists, Inc.

Keywords

  • ADSP
  • AP-2
  • Digital pathology
  • GWAS
  • ScanScope
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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