1. Analysis of high-risk pedigrees identifies 11 candidate variants for Alzheimer's disease.
- Author
-
Teerlink CC, Miller JB, Vance EL, Staley LA, Stevens J, Tavana JP, Cloward ME, Page ML, Dayton L, Cannon-Albright LA, and Kauwe JSK
- Subjects
- ATP-Binding Cassette Transporters genetics, Genetic Predisposition to Disease genetics, Genotype, Humans, Longevity, Membrane Proteins genetics, Pedigree, Alzheimer Disease genetics
- Abstract
Introduction: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants., Methods: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer's disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members., Results: AD-affected high-risk cousin pairs contained 564 shared rare variants. Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously implicated in AD pathology; rs141402160 (NOTCH3) and rs140914494 (NOTCH3) were previously reported; rs200290640 (PIDD1) and rs199752248 (PIDD1) were present in more than one cousin pair; rs61729902 (SNAP91), rs140129800 (COX6A2, AC026471), and rs191804178 (MUC16) were not present in a longevity cohort; and rs148294193 (PELI3) and rs147599881 (FCHO1) approached significance from analysis of AD-related phenotypes. Three variants were validated via evidence of co-segregation to additional relatives (PELI3, ABCA7, and SNAP91)., Discussion: These analyses support ABCA7 and TTR as AD risk genes, expand on previously reported NOTCH3 variant identification, and prioritize seven additional candidate variants., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
- Published
- 2022
- Full Text
- View/download PDF