Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.

TitleWhole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsRaghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S, Petrovski S, Tosto G, Vardarajan BN, Goldstein DB, Mayeux R
Corporate AuthorsAlzheimer's Disease Sequencing Project
JournalAnn Clin Transl Neurol
Volume5
Issue7
Pagination832-842
Date Published2018 Jul
ISSN2328-9503
Abstract

Objective: The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals.

Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.

Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 × 10; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.

Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.

DOI10.1002/acn3.582
Alternate JournalAnn Clin Transl Neurol
PubMed ID30009200
PubMed Central IDPMC6043775
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
U54 AG052427 / AG / NIA NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
K01 MH098126 / MH / NIMH NIH HHS / United States
U01 AG049507 / AG / NIA NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
R56 AG051876 / AG / NIA NIH HHS / United States
U54 NS078059 / NS / NINDS NIH HHS / United States
UF1 AG047133 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
RF1 AG054023 / AG / NIA NIH HHS / United States
R01 HD048805 / HD / NICHD NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01 HG007672 / HG / NHGRI NIH HHS / United States
U01 NS053998 / NS / NINDS NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
P01 HD080642 / HD / NICHD NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
R01 MH097971 / MH / NIMH NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
R37 AG015473 / AG / NIA NIH HHS / United States
U01 NS077303 / NS / NINDS NIH HHS / United States
U01 AG049508 / AG / NIA NIH HHS / United States
U01 AG052410 / AG / NIA NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
TL1 TR001875 / TR / NCATS NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
RF1 AG015473 / AG / NIA NIH HHS / United States
U01 AG049506 / AG / NIA NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States