Analysis of high-risk pedigrees identifies 11 candidate variants for Alzheimer's disease

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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.

Original languageEnglish
Pages (from-to)307-317
Number of pages11
JournalAlzheimer's and Dementia
Volume18
Issue number2
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
Acknowledgment is made to the donors of Alzheimer's Disease Research, a program of the BrightFocus Foundation for support of this research through grant #A2020118F (PI: Miller).

Funding Information:
This study is part of the NHLBI Grand Opportunity Exome Sequencing Project (GO‐ESP). Funding for GO‐ESP was provided by NHLBI grants RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). HeartGO gratefully acknowledges the following groups and individuals who provided biological samples or data for this study. DNA samples and phenotypic data were obtained from the following studies supported by the NHLBI: the Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), and the Multi‐Ethnic Study of Atherosclerosis (MESA).

Funding Information:
Partial support for all data sets within the Utah Population Database (UPDB) was provided by Huntsman Cancer Institute, University of Utah and the Huntsman Cancer Institute's Cancer Center Support grant, P30 CA42014 from National Cancer Institute. LACA receives partial support from the Huntsman Cancer Institute's Cancer Center Support grant, P30 CA42014 from National Cancer Institute.

Publisher Copyright:
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Keywords

  • ABCA7
  • Alzheimer's disease
  • NOTCH3
  • TTR
  • Utah Population Database
  • genetic analysis
  • high-risk pedigree
  • rare variant analysis
  • whole exome sequence

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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