Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies <i>MTUS2</i> gene associated with late‐onset Alzheimer's disease
Laura Xicota, Stephanie Cosentino, Badri N. Vardarajan, Richard Mayeux, Thomas T. Perls, Stacy L. Andersen, Joseph M. Zmuda, Bharat Thyagarajan, Anatoli I. Yashin, Mary K. Wojczynski, Sharon J. Krinsky‐McHale, Benjamin L. Handen, Bradley T. Christian, Elizabeth Head, Mark Mapstone, Nicole Schupf, Joseph H. Lee, Sandra Barral, the Long‐Life Family Study (LLFS)
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: ). 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.