Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

TitleRare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsJakobsdottir, J, van der Lee, SJ, Bis, JC, Chouraki, V, Li-Kroeger, D, Yamamoto, S, Grove, ML, Naj, A, Vronskaya, M, Salazar, JL, DeStefano, AL, Brody, JA, Smith, AV, Amin, N, Sims, R, Ibrahim-Verbaas, CA, Choi, S-H, Satizabal, CL, Lopez, OL, Beiser, A, M Ikram, A, Garcia, ME, Hayward, C, Varga, TV, Ripatti, S, Franks, PW, Hallmans, G, Rolandsson, O, Jansson, J-H, Porteous, DJ, Salomaa, V, Eiriksdottir, G, Rice, KM, Bellen, HJ, Levy, D, Uitterlinden, AG, Emilsson, V, Rotter, JI, Aspelund, T, O'Donnell, CJ, Fitzpatrick, AL, Launer, LJ, Hofman, A, San Wang, L-, Williams, J, Schellenberg, GD, Boerwinkle, E, Psaty, BM, Seshadri, S, Shulman, JM, Gudnason, V, van Duijn, CM
Corporate AuthorsCohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium
JournalPLoS Genet
Volume12
Issue10
Paginatione1006327
Date Published2016 Oct
ISSN1553-7404
KeywordsAge of Onset, Aged, Alleles, Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Apolipoproteins E, Drosophila melanogaster, Drosophila Proteins, Exome, Female, Genome-Wide Association Study, Genomics, Humans, Iceland, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mutation, Phenotype, Receptors, Notch, Tropomyosin, White People
Abstract

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

DOI10.1371/journal.pgen.1006327
Alternate JournalPLoS Genet
PubMed ID27764101
PubMed Central IDPMC5072721
Grant ListP30 AG010124 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
G0902227 / MRC_ / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
HHSN271201200022C / DA / NIDA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG050631 / AG / NIA NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
G0300429 / MRC_ / Medical Research Council / United Kingdom
U01 AG016976 / AG / NIA NIH HHS / United States
C06 RR029965 / RR / NCRR NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
R25 GM056929 / GM / NIGMS NIH HHS / United States
MR/L023784/1 / MRC_ / Medical Research Council / United Kingdom
CZD/16/6/4 / CSO_ / Chief Scientist Office / United Kingdom
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
U01 AG049506 / AG / NIA NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom
MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom

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