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 -