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

doi:10.1002/alz.12397

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 language	English
Pages (from-to)	307-317
Number of pages	11
Journal	Alzheimer's and Dementia
Volume	18
Issue number	2
DOIs	https://doi.org/10.1002/alz.12397
State	Published - Feb 2022

Bibliographical note

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

Funding

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). 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). 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.

Funders	Funder number
Alzheimer's Disease Research Center
HeartGO	RC2 HL102924, RC2 HL102923
National Heart, Lung, and Blood Institute (NHLBI)	RC2 HL103010, RC2HL102923
National Heart, Lung, and Blood Institute (NHLBI)
National Childhood Cancer Registry – National Cancer Institute
BrightFocus Foundation	2020118F
BrightFocus Foundation
University of Utah Health	P30 CA42014
University of Utah Health
Huntsman Cancer Institute

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/alz.12397

Cite this

@article{05f07f7adf4a4fbaa0e4ff1ca3590a47,

title = "Analysis of high-risk pedigrees identifies 11 candidate variants for Alzheimer's disease",

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.",

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

author = "Teerlink, {Craig C.} and Miller, {Justin B.} and Vance, {Elizabeth L.} and Staley, {Lyndsay A.} and Jeffrey Stevens and Tavana, {Justina P.} and Cloward, {Matthew E.} and Page, {Madeline L.} and Louisa Dayton and Cannon-Albright, {Lisa A.} and Kauwe, {John S.K.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2022",

month = feb,

doi = "10.1002/alz.12397",

language = "English",

volume = "18",

pages = "307--317",

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TY - JOUR

T1 - Analysis of high-risk pedigrees identifies 11 candidate variants for Alzheimer's disease

AU - Teerlink, Craig C.

AU - Miller, Justin B.

AU - Vance, Elizabeth L.

AU - Staley, Lyndsay A.

AU - Stevens, Jeffrey

AU - Tavana, Justina P.

AU - Cloward, Matthew E.

AU - Page, Madeline L.

AU - Dayton, Louisa

AU - Cannon-Albright, Lisa A.

AU - Kauwe, John S.K.

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

KW - ABCA7

KW - Alzheimer's disease

KW - NOTCH3

KW - TTR

KW - Utah Population Database

KW - genetic analysis

KW - high-risk pedigree

KW - rare variant analysis

KW - whole exome sequence

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UR - http://www.scopus.com/inward/citedby.url?scp=85126389502&partnerID=8YFLogxK

U2 - 10.1002/alz.12397

DO - 10.1002/alz.12397

M3 - Article

C2 - 34151536

AN - SCOPUS:85126389502

SN - 1552-5260

VL - 18

SP - 307

EP - 317

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 2

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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