Title | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Jakobsdottir, 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 Authors | Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium |
Journal | PLoS Genet |
Volume | 12 |
Issue | 10 |
Pagination | e1006327 |
Date Published | 2016 Oct |
ISSN | 1553-7404 |
Keywords | Age 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. |
DOI | 10.1371/journal.pgen.1006327 |
Alternate Journal | PLoS Genet |
PubMed ID | 27764101 |
PubMed Central ID | PMC5072721 |
Grant List | P30 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 |
Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
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