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PLoS Genet. 2016 Oct 20;12(10):e1006327. doi: 10.1371/journal.pgen.1006327. eCollection 2016 Oct.

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

Author information

1
Icelandic Heart Association, Kopavogur, Iceland.
2
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
3
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
4
Boston University School of Medicine, Boston, Massachusetts, United States of America.
5
Framingham Heart Study, Framingham, Massachusetts, United States of America.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
7
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital Houston, Texas, United States of America.
8
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
9
School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
10
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
11
Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
12
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
13
Faculty of Medicine, University of Iceland, Reykjavik, Iceland, United States of America.
14
Department of Neurology, Erasmus University Medical Center, CA Rotterdam, The Netherlands.
15
Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
16
Departments of Radiology, Erasmus University Medical Center, CA Rotterdam, The Netherlands.
17
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, United States of America.
18
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
19
Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.
20
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
21
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
22
Department of Public Health, University of Helsinki, Helsinki, Finland.
23
Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
24
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
25
Department of Biobank Research, Umeå University, Umeå, Sweden.
26
Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.
27
Research Unit, Skellefteå Hospital, Skellefteå, Sweden.
28
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
29
National Institute for Health and Welfare, Helsinki, Finland.
30
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
31
Howard Hughes Medical Institute, Durham, North Carolina, United States of America.
32
Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United states of America.
33
Department of Internal Medicine, Erasmus University Medical Center, CA Rotterdam, The Netherlands.
34
Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
35
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Departments of Medicine and Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
36
Centre for Public Health, University of Iceland, Reykjavik, Iceland.
37
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
38
Collaborative Health Studies Coordinating Center, Seattle, Washington, United States of America.
39
Department of Pathology and Laboratory of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
40
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
41
Department of Health Services, University of Washington, Seattle, Washington, United States of America.
42
Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.

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.

PMID:
27764101
PMCID:
PMC5072721
DOI:
10.1371/journal.pgen.1006327
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

PWF has been paid consultant on scientific advisory boards for Eli Lilly Inc and Sanofi Aventis. He has also recent research grants from pharmaceutical agencies as part of the EU Innovative Medicines Initiative. BMP serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. All other authors have declared that no competing interests exist.

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