Journal Article

Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

Schneider, Julie A., Wheeler, Nick, Kramer, Joel H., Cuccaro, Michael L., Trojanowski, John Q., Harrell, Lindy E., Mains, Douglas, Zhou, Xiongwei, Welsh‐Bohmer, Kathleen A., Marquez, David, Ory, Marcia, Manly, Jennifer, Seeley, William W., Apostolova, Liana G., Duara, Ranjan, Royall, Donald R., Frosch, Matthew P., Rajabli, Farid, Myers, Amanda J., Song, Yeunjoo, Harp, Jordan, Weintraub, Sandra, Xicota, Laura, Rosas, Herminia Diana, Ryan, Laurie, Spina, Salvatore, Atwood, Craig S., Barber, Robert C., Johnson, Leigh, Gauthreaux, Kathryn M., Van Eldik, Linda J., Zmuda, Joseph M., Lee, Joseph H., Reisch, Joan S., Buxbaum, Joseph D., Huentelman, Matthew J., Nadkarni, Neelesh, Constantino, John N., Chasse, Scott, Brewer, James B., Henson, Rachel, Vassar, Robert, Dickson, Dennis W., Paydarfar, David, Allen, Mariet, Hamilton, Ronald L., Chung, Jaeyoon, Parisi, Melissa, Paulson, Henry L., Laymon, Charles, Johnson, Sterling C, Davis, Barbara, Hakonarson, Hakon, Katz, Mindy J., Nguyen, Trung, Ormsby, Kyle, Chui, Helena C., Kowall, Neil W., Dobbins, Nic, Lunetta, Kathryn L., Woltjer, Randall L., Quiceno, Mary, Sultzer,

2024

Overview

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.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Age of onset / Aging / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Associations / Biology / Biomarkers / Candidates / Central nervous system / Cognitive ability / Consortia / Delayed / Dementia / Disease / Down syndrome / Families & family life / Genetic Predisposition to Disease / genetic risk / Genetics / Genome-Wide Association Study - methods / Genomes / Genomics / Humans / Independent study / late‐onset Alzheimer's disease / Longitudinal studies / Memory / microtubule protein / Microtubule-Associated Proteins / MTUS2 gene / Nervous system / Polymorphism, Single Nucleotide - genetics / Religious orders / Sequence Analysis / Stroke / Variants / whole genome sequence