A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease

Alzheimer's Disease Sequencing Project

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood. Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome–sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. Results: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10 −10 ) which improved when combined with results from stage 2 data sets (P = 1.92 × 10 −10 ). Discussion: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

Original languageEnglish (US)
Pages (from-to)441-452
Number of pages12
JournalAlzheimer's and Dementia
Volume15
Issue number3
DOIs
StatePublished - Mar 1 2019

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Alzheimer Disease
Hispanic Americans
Genome-Wide Association Study
Case-Control Studies
Alzheimer disease type 2
Datasets

Keywords

  • Association study
  • Enriched case-control
  • Gene-based analyses
  • Genome-wide association studies
  • Whole exome sequencing

ASJC Scopus subject areas

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

Cite this

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. / Alzheimer's Disease Sequencing Project.

In: Alzheimer's and Dementia, Vol. 15, No. 3, 01.03.2019, p. 441-452.

Research output: Contribution to journalArticle

Alzheimer's Disease Sequencing Project. / A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. In: Alzheimer's and Dementia. 2019 ; Vol. 15, No. 3. pp. 441-452.
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abstract = "Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood. Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome–sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. Results: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10 −10 ) which improved when combined with results from stage 2 data sets (P = 1.92 × 10 −10 ). Discussion: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.",
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AU - Zhang, Xiaoling

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AU - Vardarajan, Badri N.

AU - Ma, Yiyi

AU - Lancour, Daniel

AU - Farrell, John J.

AU - Chung, Jaeyoon

AU - Bellair, Michelle

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AU - Doddapeneni, Harsha

AU - Dugan-Perez, Shannon

AU - English, Adam

AU - Gibbs, Richard A.

AU - Han, Yi

AU - Hu, Jianhong

AU - Jayaseelan, Joy

AU - Kalra, Divya

AU - Khan, Ziad

AU - Korchina, Viktoriya

AU - Lee, Sandra

AU - Liu, Yue

AU - Liu, Xiuping

AU - Muzny, Donna

AU - Nasser, Waleed

AU - Salerno, William

AU - Santibanez, Jireh

AU - Skinner, Evette

AU - White, Simon

AU - Worley, Kim

AU - Zhu, Yiming

AU - Beiser, Alexa

AU - Chen, Yuning

AU - Cupples, L. Adrienne

AU - DeStefano, Anita

AU - Dupuis, Josee

AU - Farrell, John

AU - Farrer, Lindsay

AU - Lin, Honghuang

AU - Liu, Ching Ti

AU - Lunetta, Kathy

AU - Patel, Devanshi

AU - Sarnowski, Chloe

AU - Satizabal, Claudia

AU - Seshadri, Sudha

AU - Sun, Fangui Jenny

AU - Choi, Seung Hoan

AU - Banks, Eric

AU - Gabriel, Stacey

AU - Foroud, Tatiana

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N2 - Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood. Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome–sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. Results: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10 −10 ) which improved when combined with results from stage 2 data sets (P = 1.92 × 10 −10 ). Discussion: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

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