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Ann Clin Transl Neurol. 2018 Mar 13;5(4):406-417. doi: 10.1002/acn3.537. eCollection 2018 Apr.

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease.

Author information

1
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain New York.
2
The Gertrude H. Sergievsky Center Columbia University The New York Presbyterian Hospital New York New York.
3
Department of Systems Biology Columbia University The New York Presbyterian Hospital New York New York.
4
The Department of Neurology Columbia University The New York Presbyterian Hospital New York New York.
5
Dr. John T. Macdonald Foundation Department of Human Genetics The John P. Hussman Institute for Human Genomics Miami Florida.
6
Division of Medical Genetics Department of Medicine University of Washington Seattle Washington.
7
School of Medicine Mother and Teacher Pontifical Catholic University Santiago Dominican Republic.
8
Department of Medicine Columbia University The New York Presbyterian Hospital New York New York.
9
School of Medicine University of Pennsylvania Philadelphia Pennsylvania.
10
Department of Biostatistics University of Washington Seattle Washington.
11
Boston University School of Medicine Boston Massachusetts.
12
Department of Biostatistics and Epidemiology Case Western Reserve University Cleveland Ohio.
13
Erasmus University Medical Center Rotterdam Netherlands.
14
Mount Sinai School of Medicine New York New York.
15
University of Texas Houston Texas.
16
Department of Psychiatry Columbia University The New York Presbyterian Hospital New York New York.
17
The Department of Epidemiology School of Public Health Columbia University New York New York.

Abstract

Objective:

To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.

Methods:

We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results:

A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).

Conclusions and Relevance:

Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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