| Title: |
Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease |
| Authors: |
Xicota, Laura; Cosentino, Stephanie; Vardarajan, Badri; Mayeux, Richard; Perls, Thomas T; Andersen, Stacy L; Zmuda, Joseph M; Thyagarajan, Bharat; Yashin, Anatoli; Wojczynski, Mary K; Krinsky‐McHale, Sharon; Handen, Benjamin L; Christian, Bradley T; Head, Elizabeth; Mapstone, Mark E; Schupf, Nicole; Lee, Joseph H; Barral, Sandra; Study, the Long‐Life Family; Abner, Erin; Adams, Perrie M; Aguirre, Alyssa; Albert, Marilyn S; Albin, Roger L; Allen, Mariet; Alvarez, Lisa; Andrews, Howard; Apostolova, Liana G; Arnold, Steven E; Asthana, Sanjay; Atwood, Craig S; Ayres, Gayle; Barber, Robert C; Barnes, Lisa L; Bartlett, Jackie; Beach, Thomas G; Becker, James T; Beecham, Gary W; Benchek, Penelope; Bennett, David A; Bertelson, John; Biber, Sarah A; Bird, Thomas D; Blacker, Deborah; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Brewer, James B; Burke, James R; Burns, Jeffrey M; Bush, William S; Buxbaum, Joseph D; Byrd, Goldie; Cantwell, Laura B; Cao, Chuanhai; Carlsson, Cynthia M; Carrasquillo, Minerva M; Chan, Kwun C; Chasse, Scott; Chen, Yen‐Chi; Chesselet, Marie‐Francoise; Chin, Nathaniel A; Chui, Helena C; Chung, Jaeyoon; Craft, Suzanne; Crane, Paul K; Cranney, Marissa; Cruchaga, Carlos; Cuccaro, Michael L; Culhane, Jessica; Cullum, C Munro; Darby, Eveleen; Davis, Barbara; De Jager, Philip L; DeCarli, Charles; DeToledo, John C; Dickson, Dennis W; Dobbins, Nic; Duara, Ranjan; Ertekin‐Taner, Nilufer; Evans, Denis A; Faber, Kelley M; Fairchild, Thomas J; Fallin, Daniele; Fallon, Kenneth B; Fardo, David W; Farlow, Martin R; Farrell, John; Farrer, Lindsay A; Fernandez‐Hernandez, Victoria; Foroud, Tatiana M; Frosch, Matthew P; Galasko, Douglas R; Gamboa, Adriana; Gauthreaux, Kathryn M; Gefen, Tamar; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R |
| Source: |
Alzheimer's & Dementia, vol 20, iss 4 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
32 Biomedical and Clinical Sciences (for-2020); 5202 Biological Psychology (for-2020); 3202 Clinical Sciences (for-2020); 3209 Neurosciences (for-2020); 52 Psychology (for-2020); Neurosciences (rcdc); Human Genome (rcdc); Genetics (rcdc); Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc); Brain Disorders (rcdc); Alzheimer's Disease (rcdc); Neurodegenerative (rcdc); Aging (rcdc); Prevention (rcdc); Acquired Cognitive Impairment (rcdc); Dementia (rcdc); 2.1 Biological and endogenous factors (hrcs-rac); Neurological (hrcs-hc); Humans (mesh); Alzheimer Disease (mesh); Amyloid beta-Peptides (mesh); Genetic Predisposition to Disease (mesh); Genome-Wide Association Study (mesh); Microtubule-Associated Proteins (mesh); Polymorphism; Single Nucleotide (mesh); Sequence Analysis (mesh); genetic risk; late-onset Alzheimer's disease; microtubule protein |
| Time: |
2670 - 2679 |
| Description: |
INTRODUCTION: Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. METHODS: We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N=14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N=1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels. RESULTS: We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p=7.6×10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid. DISCUSSION: MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology. HIGHLIGHTS: Long-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt8h4405s2; https://escholarship.org/uc/item/8h4405s2; https://escholarship.org/content/qt8h4405s2/qt8h4405s2.pdf |
| DOI: |
10.1002/alz.13718 |
| Availability: |
https://escholarship.org/uc/item/8h4405s2; https://escholarship.org/content/qt8h4405s2/qt8h4405s2.pdf; https://doi.org/10.1002/alz.13718 |
| Rights: |
CC-BY-NC |
| Accession Number: |
edsbas.1983D33B |
| Database: |
BASE |