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

TitleWhole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsVardarajan BN, Barral S, Jaworski J, Beecham GW, Blue E, Tosto G, Reyes-Dumeyer D, Medrano M, Lantigua R, Naj A, Thornton T, DeStefano A, Martin E, San Wang L-, Brown L, Bush W, van Duijn C, Goate A, Farrer L, Haines JL, Boerwinkle E, Schellenberg G, Wijsman E, Pericak-Vance MA, Mayeux R, San Wang L-
Corporate AuthorsAlzheimer's Disease Sequencing Project
JournalAnn Clin Transl Neurol
Volume5
Issue4
Pagination406-417
Date Published2018 Apr
ISSN2328-9503
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 p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and 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 ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 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.

DOI10.1002/acn3.537
Alternate JournalAnn Clin Transl Neurol
PubMed ID29688227
PubMed Central IDPMC5899906
Grant ListR01 AG058501 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
UF1 AG047133 / AG / NIA NIH HHS / United States
RF1 AG015473 / AG / NIA NIH HHS / United States