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Alzheimers Dement. 2019 Mar;15(3):441-452. doi: 10.1016/j.jalz.2018.10.005. Epub 2019 Jan 3.

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

Author information

1
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
2
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
3
Hussman Institute of Human Genetics, University of Miami, Miami, FL, USA.
4
Department of Neurology, Columbia University, New York, NY, USA.
5
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
6
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
7
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
8
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA. Electronic address: farrer@bu.edu.

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.

KEYWORDS:

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

PMID:
30503768
PMCID:
PMC6408965
[Available on 2020-03-01]
DOI:
10.1016/j.jalz.2018.10.005
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