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Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease
- Xicota, Laura;
- Cosentino, Stephanie;
- Vardarajan, Badri;
- Mayeux, Richard;
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- 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;
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- Wisniewski, Thomas;
- Woltjer, Randall L;
- Woon, Martin;
- Younkin, Steven G;
- Yu, Lei;
- Zhao, Yi;
- Zhou, Xiongwei;
- Zhu, Congcong;
- Aizenstein, Howard J;
- Ances, Beau M;
- Andrews, Howard F;
- Bell, Karen;
- Birn, Rasmus M;
- Brickman, Adam M;
- Bulova, Peter;
- Cheema, Amrita;
- Chen, Kewei;
- Christian, Bradley T;
- Clare, Isabel;
- Cohen, Ann D;
- Constantino, John N;
- Doran, Eric W;
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- Feingold, Eleanor;
- Foroud, Tatiana M;
- Handen, Benjamin L;
- Harp, Jordan;
- Hartley, Sigan L;
- Head, Elizabeth;
- Henson, Rachel;
- Hom, Christy;
- Honig, Lawrence;
- Ikonomovic, Milos D;
- Johnson, Sterling C;
- Jordan, Courtney;
- Kamboh, M Ilyas;
- Keator, David;
- Klunk, William E;
- Kofler, Julia K;
- Krinsky‐McHale, Sharon J;
- Lai, Florence;
- Lao, Patrick;
- Laymon, Charles;
- Lee, Joseph;
- Lott, Ira T;
- Lupson, Victoria;
- Mapstone, Mark;
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- Minhas, Davneet Singh;
- Nadkarni, Neelesh;
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- Reiman, Eric;
- Rizvi, Batool;
- Rosas, Herminia Diana;
- Ryan, Laurie;
- Schmitt, Frederick;
- Schupf, Nicole;
- Silverman, Wayne P;
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- et al.
Published Web Location
https://doi.org/10.1002/alz.13718Abstract
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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
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