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

被引：44

作者：

Jakobsdottir, Johanna ^{[1
]}

van der Lee, Sven J. ^{[2
]}

Bis, Joshua C. ^{[3
]}

Chouraki, Vincent ^{[4
,5
]}

Li-Kroeger, David ^{[6
,7
]}

Yamamoto, Shinya ^{[6
,7
,8
]}

Grove, Megan L. ^{[9
]}

Naj, Adam ^{[10
]}

Vronskaya, Maria ^{[11
]}

Salazar, Jose L. ^{[6
]}

DeStefano, Anita L. ^{[5
,12
]}

Brody, Jennifer A. ^{[3
]}

Smith, Albert V. ^{[1
,13
]}

Amin, Najaf ^{[2
]}

Sims, Rebecca ^{[11
]}

Ibrahim-Verbaas, Carla A. ^{[2
,14
]}

Choi, Seung-Hoan ^{[5
,12
]}

Satizabal, Claudia L. ^{[4
,5
]}

Lopez, Oscar L. ^{[15
]}

Beiser, Alexa ^{[4
,5
,12
]}

Ikram, M. Arfan ^{[2
,14
,16
]}

Garcia, Melissa E. ^{[17
]}

Hayward, Caroline ^{[18
,19
]}

Varga, Tibor V. ^{[20
]}

Ripatti, Samuli ^{[21
,22
]}

Franks, Paul W. ^{[20
,23
,24
]}

Hallmans, Goran ^{[25
]}

Rolandsson, Olov ^{[26
]}

Jansson, Jan-Hakon ^{[23
,27
]}

Porteous, David J. ^{[19
,28
]}

Salomaa, Veikko ^{[29
]}

Eiriksdottir, Gudny ^{[1
]}

Rice, Kenneth M. ^{[30
]}

Bellen, Hugo J. ^{[6
,7
,8
,31
]}

Levy, Daniel ^{[4
,5
,32
]}

Uitterlinden, Andre G. ^{[2
,33
]}

Emilsson, Valur ^{[1
,34
]}

Rotter, Jerome I. ^{[35
,36
,37
]}

Aspelund, Thor ^{[1
,38
]}

O'Donnell, Christopher J. ^{[5
,32
]}

Fitzpatrick, Annette L. ^{[39
,40
]}

Launer, Lenore J. ^{[17
]}

Hofman, Albert ^{[2
]}

Wang, Li-San ^{[41
]}

Williams, Julie ^{[11
]}

Schellenberg, Gerard D. ^{[41
]}

Boerwinkle, Eric ^{[9
,42
]}

Psaty, Bruce M. ^{[3
,39
,43
,44
]}

Seshadri, Sudha ^{[4
,5
]}

Shulman, Joshua M. ^{[6
,7
,8
]}

机构：

[1] Iceland Heart Assoc, Kopavogur, Iceland

[2] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[3] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[4] Boston Univ, Sch Med, Boston, MA 02118 USA

[5] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[6] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[7] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

[8] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA

[9] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA

[10] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[11] Cardiff Univ, Med Res Council MRC Ctr Neuropsychiat Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales

[12] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[13] Univ Iceland, Fac Med, Reykjavik, Iceland

[14] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands

[15] Univ Pittsburgh, Med Ctr, Dept Neurol, Pittsburgh, PA USA

[16] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands

[17] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA

[18] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[19] Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland

[20] Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden

[21] Univ Helsinki, FIMM, Helsinki, Finland

[22] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland

[23] Umea Univ Hosp, Dept Publ Hlth & Clin Med, Umea, Sweden

[24] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA

[25] Umea Univ, Dept Biobank Res, Umea, Sweden

[26] Umea Univ, Sect Family Med, Dept Publ Hlth & Clin Med, Umea, Sweden

[27] Skelleftea Hosp, Res Unit, Skelleftea, Sweden

[28] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland

[29] Natl Inst Hlth & Welf, Helsinki, Finland

[30] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[31] Howard Hughes Med Inst, Durham, NC USA

[32] NHLBI, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA

[33] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[34] Univ Iceland, Fac Pharmaceut Sci, Reykjavik, Iceland

[35] Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA

[36] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA

[37] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA

[38] Univ Iceland, Ctr Publ Hlth, Reykjavik, Iceland

[39] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[40] Collaborat Hlth Studies Coordinating Ctr, Seattle, WA USA

[41] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[42] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[43] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[44] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

来源：

PLOS GENETICS | 2016年 / 12卷 / 10期

关键词：

GENOME-WIDE ASSOCIATION; HAPLOTYPE RECONSTRUCTION; IDENTIFIES VARIANTS; APOLIPOPROTEIN-E; COMMON VARIANTS; DROSOPHILA; PROTEIN; GENETICS; MUTATION; ALMONDEX;

D O I：

10.1371/journal.pgen.1006327

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, 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 beta-amyloid cascade.

引用

页数：17

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