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Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

TitleRare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsCruchaga, C, Karch, CM, Jin, SChih, Benitez, BA, Cai, Y, Guerreiro, R, Harari, O, Norton, J, Budde, J, Bertelsen, S, Jeng, AT, Cooper, B, Skorupa, T, Carrell, D, Levitch, D, Hsu, S, Choi, J, Ryten, M, Sassi, C, Brás, J, Gibbs, RJ, Hernandez, DG, Lupton, MK, Powell, J, Forabosco, P, Ridge, PG, Corcoran, CD, Tschanz, JAT, Norton, MC, Munger, RG, Schmutz, C, Leary, M, F Demirci, Y, Bamne, MN, Wang, X, Lopez, OL, Ganguli, M, Medway, C, Turton, J, Lord, J, Braae, A, Barber, I, Brown, K, Pastor, P, Lorenzo-Betancor, O, Brkanac, Z, Scott, E, Topol, E, Morgan, K, Rogaeva, E, Singleton, A, Hardy, J, M Kamboh, I, St George-Hyslop, P, Cairns, N, Morris, JC, Kauwe, JSK, Goate, AM
Corporate AuthorsAlzheimer's Research UK (ARUK) Consortium
JournalNature
Volume505
Issue7484
Pagination550-554
Date Published2014 Jan 23
ISSN1476-4687
KeywordsAfrican Americans, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Brain, Case-Control Studies, Europe, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Peptide Fragments, Phospholipase D, Protein Processing, Post-Translational, Proteolysis
Abstract

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

DOI10.1038/nature12825
Alternate JournalNature
PubMed ID24336208
PubMed Central IDPMC4050701
Grant ListG0901254 / / Medical Research Council / United Kingdom
ZO1AG000950-11 / AG / NIA NIH HHS / United States
R01AG21136 / AG / NIA NIH HHS / United States
R01-AG042611 / AG / NIA NIH HHS / United States
R01-AG11380 / AG / NIA NIH HHS / United States
AG07562 / AG / NIA NIH HHS / United States
1R01AG041797 / AG / NIA NIH HHS / United States
R01 AG044546 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
G0802189 / / Medical Research Council / United Kingdom
R01 AG042611 / AG / NIA NIH HHS / United States
ZO1 AG000950-10 / AG / NIA NIH HHS / United States
ZIA AG000950-11 / / Intramural NIH HHS / United States
MR/L016400/1 / / Medical Research Council / United Kingdom
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
P30-NS069329 / NS / NINDS NIH HHS / United States
R01-AG21136 / AG / NIA NIH HHS / United States
5U24AG026395 / AG / NIA NIH HHS / United States
U24AG21886 / AG / NIA NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
MC_G1000735 / / Medical Research Council / United Kingdom
NIH R01039700 / / PHS HHS / United States
089703 / / Wellcome Trust / United Kingdom
AG041718 / AG / NIA NIH HHS / United States
G1100695 / / Medical Research Council / United Kingdom
G0802462 / / Medical Research Council / United Kingdom
NIH P50 AG05681 / AG / NIA NIH HHS / United States
089698 / / Wellcome Trust / United Kingdom
R01-AG18712 / AG / NIA NIH HHS / United States
K01 AG046374 / AG / NIA NIH HHS / United States
AG023652 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01-AG035083 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
Z01 AG000950 / AG / NIA NIH HHS / United States
R01-AG044546 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
R01 AG021136 / AG / NIA NIH HHS / United States
R01 AG041718 / AG / NIA NIH HHS / United States
R25 DA027995 / DA / NIDA NIH HHS / United States
P30 NS069329 / NS / NINDS NIH HHS / United States
AG005133 / AG / NIA NIH HHS / United States
100140 / / Wellcome Trust / United Kingdom
081864 / / Wellcome Trust / United Kingdom
R01 AG011380 / AG / NIA NIH HHS / United States
R01 AG039700 / AG / NIA NIH HHS / United States
MC_G1000734 / / Medical Research Council / United Kingdom
R01 AG035083 / AG / NIA NIH HHS / United States
R01 AG018712 / AG / NIA NIH HHS / United States