Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Mol Psychiatry
Authors
Keywords
Abstract

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Year of Publication
2020
Journal
Mol Psychiatry
Volume
25
Issue
8
Pages
1859-1875
Date Published
2020 08
ISSN
1476-5578
DOI
10.1038/s41380-018-0112-7
PubMed ID
30108311
PubMed Central ID
PMC6375806
Links
Grant list
R01 AG054076 / AG / NIA NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
U01 AG058635 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
P30 AG066444 / AG / NIA NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 AG054060 / AG / NIA NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
R01 AG064877 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
U01 AG058654 / AG / NIA NIH HHS / United States
U01 HL096812 / HL / NHLBI NIH HHS / United States
U54 AG052427 / AG / NIA NIH HHS / United States
R01 NS017950 / NS / NINDS 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
R03 AG054936 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
U01 AG049507 / AG / NIA NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 AG067501 / AG / NIA NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
RF1 AG053303 / 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
RF1 AG066107 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
U01 HL096902 / HL / NHLBI NIH HHS / United States
P30 AG013846 / AG / NIA 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
R01 AG049607 / AG / NIA NIH HHS / United States
RF1 AG054023 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
S10 OD018522 / OD / NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 AG058589 / AG / NIA NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
U01 AG049508 / AG / NIA NIH HHS / United States
U01 AG052410 / AG / NIA NIH HHS / United States
U01 HL096814 / HL / NHLBI NIH HHS / United States
P30 AG066509 / AG / NIA NIH HHS / United States
R01 AG033040 / AG / NIA NIH HHS / United States
R01 AG048927 / AG / NIA NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
RF1 AG044546 / AG / NIA NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
R01 HL070825 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
R01 LM012535 / LM / NLM NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
RF1 AG057519 / AG / NIA NIH HHS / United States
U01 HL096899 / 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
P30 AG010129 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States