Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
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Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. / Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.
In: PLOS Genetics, Vol. 12, No. 10, e1006327, 10.2016.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
AU - Jakobsdottir, Johanna
AU - van der Lee, Sven J
AU - Bis, Joshua C
AU - Chouraki, Vincent
AU - Li-Kroeger, David
AU - Yamamoto, Shinya
AU - Grove, Megan L
AU - Naj, Adam
AU - Vronskaya, Maria
AU - Salazar, Jose L
AU - DeStefano, Anita L
AU - Brody, Jennifer A
AU - Smith, Albert V
AU - Amin, Najaf
AU - Sims, Rebecca
AU - Ibrahim-Verbaas, Carla A
AU - Choi, Seung-Hoan
AU - Satizabal, Claudia L
AU - Lopez, Oscar L
AU - Beiser, Alexa
AU - Ikram, M Arfan
AU - Garcia, Melissa E
AU - Hayward, Caroline
AU - Varga, Tibor V
AU - Ripatti, Samuli
AU - Franks, Paul W
AU - Hallmans, Göran
AU - Rolandsson, Olov
AU - Jansson, Jan-Håkon
AU - Porteous, David J
AU - Salomaa, Veikko
AU - Eiriksdottir, Gudny
AU - Rice, Kenneth M
AU - Bellen, Hugo J
AU - Levy, Daniel
AU - Uitterlinden, Andre G
AU - Emilsson, Valur
AU - Rotter, Jerome I
AU - Aspelund, Thor
AU - O'Donnell, Christopher J
AU - Fitzpatrick, Annette L
AU - Launer, Lenore J
AU - Hofman, Albert
AU - Wang, Li-San
AU - Williams, Julie
AU - Schellenberg, Gerard D
AU - Boerwinkle, Eric
AU - Psaty, Bruce M
AU - Seshadri, Sudha
AU - Shulman, Joshua M
AU - Cohorts for Heart and Aging Research in Genomic Epidemiology consortium
PY - 2016/10
Y1 - 2016/10
N2 - 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.
AB - 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.
KW - Age of Onset
KW - Aged
KW - Alleles
KW - Alzheimer Disease/genetics
KW - Amyloid beta-Protein Precursor/genetics
KW - Animals
KW - Apolipoproteins E/genetics
KW - Drosophila Proteins/genetics
KW - Drosophila melanogaster/genetics
KW - European Continental Ancestry Group
KW - Exome/genetics
KW - Female
KW - Genome-Wide Association Study
KW - Genomics
KW - Humans
KW - Iceland
KW - Intracellular Signaling Peptides and Proteins/genetics
KW - Male
KW - Membrane Proteins/genetics
KW - Mutation
KW - Phenotype
KW - Receptors, Notch/genetics
KW - Tropomyosin/genetics
U2 - 10.1371/journal.pgen.1006327
DO - 10.1371/journal.pgen.1006327
M3 - Journal article
C2 - 27764101
VL - 12
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 10
M1 - e1006327
ER -
ID: 242837320