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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.
Document Type
Article
Publication Date
6-20-2021
Digital Object Identifier (DOI)
https://doi.org/10.1002/alz.12397
Funding Information
National Cancer Institute. Grant Number: P30 CA42014
NHLBI. Grant Number: RC2 HL103010
BrightFocus Foundation and the National Institute on Aging in the list of funders
Related Content
Data from Alzheimer’s Disease Genetics Consortium (ADGC) were appropriately downloaded from dbGaP (accession: phs000372.v1.p1). We acknowledge the contributions of the members of the ADGC listed in Appendix: Alzheimer’s Disease Genetics Consortium Collaborators.
Repository Citation
Teerlink, Craig C.; Miller, Justin B.; Vance, Elizabeth L.; Staley, Lyndsay A.; Stevens, Jeffrey; Tavana, Justina P.; Cloward, Matthew E.; Page, Madeline L.; Dayton, Louisa; Alzheimer's Disease Genetics Consortium; Cannon-Albright, Lisa A.; and Kauwe, John S. K., "Analysis of High-Risk Pedigrees Identifies 12 Candidate Variants for Alzheimer's Disease" (2021). Institute for Biomedical Informatics Faculty Publications. 14.
https://uknowledge.uky.edu/bmi_facpub/14
Supporting Information
alz12397-sup-0002-suppmat.docx (847 kB)
Supporting Information
alz12397-sup-0003-tables1.xlsx (23 kB)
Supporting Information
Notes/Citation Information
Published in Alzheimer's & Dementia.
© 2021 The Authors
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.