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, Stephanie Cosentino, Badri Vardarajan, Richard Mayeux, Thomas T. Perls, Stacy L. Andersen, Joseph M. Zmuda, Bharat Thyagarajan, Anatoli Yashin, Mary K. Wojczynski, Sharon Krinsky-McHale, Benjamin L. Handen, Bradley T. Christian, Elizabeth Head, Mark E. Mapstone, Nicole Schupf, Joseph H. Lee, Sandra Barral

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2670-2679
Number of pages10
JournalAlzheimer's and Dementia
Volume20
Issue number4
DOIs
StatePublished - Apr 2024

Keywords

  • MTUS2 gene
  • genetic risk
  • late-onset Alzheimer's disease
  • microtubule protein
  • whole genome sequence

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