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. 2024 Apr;20(4):2670-2679.
doi: 10.1002/alz.13718. Epub 2024 Feb 21.

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

Laura Xicota  1   2 , Stephanie Cosentino  1   2 , Badri Vardarajan  1   2   3 , Richard Mayeux  1   2   3 , Thomas T Perls  4 , Stacy L Andersen  4 , Joseph M Zmuda  5 , Bharat Thyagarajan  6 , Anatoli Yashin  7 , Mary K Wojczynski  8 , Sharon Krinsky-McHale  3   9 , Benjamin L Handen  10 , Bradley T Christian  11   12 , Elizabeth Head  13 , Mark E Mapstone  14 , Nicole Schupf  2 , Joseph H Lee  1   2   3 , Sandra Barral  1   2   3 ; Long‐Life Family Study (LLFS); Alzheimer's Disease Genetic Consortium (ADGC); Alzheimer's Biomarkers Consortium‐Down Syndrome (ABC‐DS)
Collaborators, Affiliations

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

Laura Xicota et al. Alzheimers Dement. 2024 Apr.

Abstract

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.

Keywords: MTUS2 gene; genetic risk; late‐onset Alzheimer's disease; microtubule protein; whole genome sequence.

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Conflict of interest statement

Bradley Christian receives PET precursor and compounds from Avid Radiopharmaceuticals Inc and equipment from Cerveau Technologies. Handen receives funding from National Institute of Child Health and Human Development, Autism Speaks, and Roche Pharmaceuticals. Mapstone is an inventor on patents related to biomarkers of neurodegenerative diseases owned by Georgetown University and the University of Rochester. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Manhattan plot of Seq‐GWAS results in LLFS cohort. The X‐axis represents the genomic position for each of the SNPs analyzed; Y‐axis represents the ‐log10 transformed p‐values. The red line indicates the genome‐wide significance threshold (p < 5 × 10−8). GWAS, genome‐wide association studies; LLFS, Long‐Life Family Study; SNP, single nucleotide polymorphism.
FIGURE 2
FIGURE 2
Q‐Q plot of Seq‐GWAS results in LLFS cohort. The X‐axis represents the expected ‐log10 transformed p‐values for each SNP association; the Y‐axis represents the observed ‐log10 transformed p‐values. GWAS, genome‐wide association studies; LLFS, Long‐Life Family Study; SNP, single nucleotide polymorphism.
See this image and copyright information in PMC

References

    1. Harman D. Alzheimer's disease pathogenesis: role of aging. Ann N Y Acad Sci. 2006;1067:454‐460. - PubMed
    1. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168‐174. - PubMed
    1. Ibanez L, Cruchaga C, Fernandez MV. Advances in genetic and molecular understanding of Alzheimer's disease. Genes (Basel). 2021;12(8):1247. - PMC - PubMed
    1. Karlsson IK, Escott‐Price V, Gatz M, et al. Measuring heritable contributions to Alzheimer's disease: polygenic risk score analysis with twins. Brain Commun. 2022;4:fcab308. - PMC - PubMed
    1. Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(10):a006296. - PMC - PubMed

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