Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene
Year: 2019
Type: article
Study design: Observational Study
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.
DOI: 10.1093/jnen/nlz116
Authors: 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 Estus, Peter T Nelson
Institution: University of Kentucky
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,036
Funders: Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, National Center for Research Resources
Awards: G1002540797, G100543330, G1052397333, G1135917780, G1194337659, G1220223050, G1224480130, G1243299691, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1309605592, G1343836163, G1353455142, G1379949353, G1527150935, G1609525565, CORONARY HEART DISEASE AND STROKE, G1691174148, G173303992, G1871439151, G1941623656, Large Scale Sequencing and Analysis of Genomes, G2110643723, G2194386449, G2195207551, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G2391884931, G247538147, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G2682171662, G272783259, G2742075923, G278200998, G2818629771, G3045517347, G3114902838, G3220743633, National Alzheimer's Coordinating Center, G3405256882, G3410686264, G3462919067, CHS research resources for the cardiovascular health of older adults, G36433118, G36881302, ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems, G3839646794, G384347443, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Predictors of Alheimers Disease in Mild Cognitive Impairment, G4290615481, G4365567135, G4429312988, Replication and Extension of ADSP Discoveries in African-Americans, The Human Genome Sequencing Center, G457330776, ARIC Neurocognitive Study (ARIC-NCS) Renewal UNC 4 of 5, Genomic Architecture of a Key Alzheimer's Disease Mimic: CARTS, G4702044304, G4728428359, G494123624, G5164707915, Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS), Alzheimer's Disease Genetics Consortium, G5364873420, G5370164845, G5479317095, G5652732059, MRI, Cognitive, Genetic and Biomarker Precursors of AD & Dementia in Young Adults, G567847597, G5681130674, G581887176, G583528397, CHS Events Follow-up Study, G6226795708, The Framingham Heart Study, G6548750934, CHS-Transition Phase, ARIC Neurocognitive Study (ARIC-NCS) Renewal 2 of 5, ARIC Neurocognitive Study (ARIC-NCS), G6978868085, G7176672723, G740377980, G7786438869, Aperio ScanScope XT Digital Slide Scanner System, Identification and characterization of AD risk networks using multi-dimensional "omics" data, Novel misfolded proteins in ADRD: proteomics, genetics, and clinical-pathological correlations, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W2991004684