Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease

被引：250

作者：

Steinberg, Stacy ^{[1
]}

Stefansson, Hreinn ^{[1
]}

Jonsson, Thorlakur ^{[1
]}

Johannsdottir, Hrefna ^{[1
]}

Ingason, Andres ^{[1
]}

Helgason, Hannes ^{[1
]}

Sulem, Patrick ^{[1
]}

Magnusson, Olafur Th ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Unnsteinsdottir, Unnur ^{[1
]}

Kong, Augustine ^{[1
]}

Helisalmi, Seppo ^{[2
,3
]}

Soininen, Hilkka ^{[2
,3
]}

Lah, James J. ^{[4
]}

Aarsland, Dag ^{[5
,6
,7
]}

Fladby, Tormod ^{[7
,8
]}

Ulstein, Ingun D. ^{[9
,10
]}

Djurovic, Srdjan ^{[11
,12
]}

Sando, Sigrid B. ^{[13
,14
]}

White, Linda R. ^{[13
,14
]}

Knudsen, Gun-Peggy ^{[15
]}

Westlye, Lars T. ^{[16
,17
]}

Selbaek, Geir ^{[18
]}

Giegling, Ina ^{[19
]}

Hampel, Harald ^{[20
]}

Hiltunen, Mikko ^{[2
,3
,21
]}

Levey, Allan I. ^{[4
]}

Andreassen, Ole A. ^{[16
,22
]}

Rujescu, Dan ^{[19
]}

Jonsson, Palmi V. ^{[23
,24
]}

Bjornsson, Sigurbjorn ^{[24
]}

Snaedal, Jon ^{[24
]}

Stefansson, Kari ^{[1
,23
]}

机构：

[1] DeCODE Genet, Reykjavik, Iceland

[2] Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland

[3] Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland

[4] Emory Univ, Sch Med, Atlanta, GA USA

[5] Karolinska Inst, Alzheimers Dis Res Ctr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden

[6] Stavanger Univ Hosp, Ctr Age Related Dis, Stavanger, Norway

[7] Univ Oslo, Div Med & Lab Sci, Inst Clin Med, Oslo, Norway

[8] Akershus Univ Hosp, Dept Neurol, Lorenskog, Norway

[9] Oslo Univ Hosp, Dept Psychiat Old Age, Oslo, Norway

[10] Univ Oslo, Inst Clin Med, Oslo, Norway

[11] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[12] Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr, Bergen, Norway

[13] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway

[14] Univ Trondheim Hosp, St Olavs Hosp, Dept Neurol, Trondheim, Norway

[15] Norwegian Inst Publ Hlth, Div Mental Hlth, Oslo, Norway

[16] Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr Psychosis Res, Oslo, Norway

[17] Univ Oslo, Dept Psychol, Oslo, Norway

[18] Vestfold Hosp Trust, Norwegian Ctr Res Educ & Serv Dev, Ageing & Hlth, Tonsberg, Norway

[19] Univ Halle Wittenberg, Dept Psychiat, D-06108 Halle, Germany

[20] Univ Paris 06, Sorbonne Univ, Dept Neurol, Hop Pitie Salpetriere, Paris, France

[21] Univ Eastern Finland, Inst Biomed, Kuopio, Finland

[22] Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway

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

[24] Landspitali Univ Hosp, Dept Geriatr Med, Reykjavik, Iceland

来源：

NATURE GENETICS | 2015年 / 47卷 / 05期

基金：

芬兰科学院;

关键词：

CELLULAR CHOLESTEROL; APOLIPOPROTEIN-E; AMYLOID-BETA; ASSOCIATION; BINDING; EXPRESSION; MUTATION; GENE; PHAGOCYTOSIS; DIAGNOSIS;

D O I：

10.1038/ng.3246

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 x 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 x 10(-15)).

引用

页码：445 / U24

页数：4

共 29 条

[1] Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate high density lipoprotein [J].

Abe-Dohmae, S ;

Ikeda, Y ;

Matsuo, M ;

Hayashi, M ;

Okuhira, K ;

Ueda, K ;

Yokoyama, S .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (01) :604-611

[2] A method and server for predicting damaging missense mutations [J].

Adzhubei, Ivan A. ;

Schmidt, Steffen ;

Peshkin, Leonid ;

Ramensky, Vasily E. ;

Gerasimova, Anna ;

Bork, Peer ;

Kondrashov, Alexey S. ;

Sunyaev, Shamil R. .

NATURE METHODS, 2010, 7 (04) :248-249

[3] Novel late-onset Alzheimer disease loci variants associate with brain gene expression [J].

Allen, Mariet ;

Zou, Fanggeng ;

Chai, High Seng ;

Younkin, Curtis S. ;

Crook, Julia ;

Pankratz, V. Shane ;

Carrasquillo, Minerva M. ;

Rowley, Christopher N. ;

Nair, Asha A. ;

Middha, Sumit ;

Maharjan, Sooraj ;

Thuy Nguyen ;

Ma, Li ;

Malphrus, Kimberly G. ;

Palusak, Ryan ;

Lincoln, Sarah ;

Bisceglio, Gina ;

Georgescu, Constantin ;

Schultz, Debra ;

Rakhshan, Fariborz ;

Kolbert, Christopher P. ;

Jen, Jin ;

Haines, Jonathan L. ;

Mayeux, Richard ;

Pericak-Vance, Margaret A. ;

Farrer, Lindsay A. ;

Schellenberg, Gerard D. ;

Petersen, Ronald C. ;

Graff-Radford, Neill R. ;

Dickson, Dennis W. ;

Younkin, Steven G. ;

Ertekin-Taner, Niluefer .

NEUROLOGY, 2012, 79 (03) :221-228

[4]

[Anonymous], 1992, The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines

[5] Locus-specific mutation databases for neurodegenerative brain diseases [J].

Cruts, Marc ;

Theuns, Jessie ;

Van Broeckhoven, Christine .

HUMAN MUTATION, 2012, 33 (09) :1340-1344

[6] Genomic control for association studies [J].

Devlin, B ;

Roeder, K .

BIOMETRICS, 1999, 55 (04) :997-1004

[7] Alzheimer's Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta [J].

Griciuc, Ana ;

Serrano-Pozo, Alberto ;

Parrado, Antonio R. ;

Lesinski, Andrea N. ;

Asselin, Caroline N. ;

Mullin, Kristina ;

Hooli, Basavaraj ;

Choi, Se Hoon ;

Hyman, Bradley T. ;

Tanzil, Rudolph E. .

NEURON, 2013, 78 (04) :631-643

[8] TREM2 Variants in Alzheimer's Disease [J].

Guerreiro, Rita ;

Wojtas, Aleksandra ;

Bras, Jose ;

Carrasquillo, Minerva ;

Rogaeva, Ekaterina ;

Majounie, Elisa ;

Cruchaga, Carlos ;

Sassi, Celeste ;

Kauwe, John S. K. ;

Lupton, Michelle K. ;

Ryten, Mina ;

Brown, Kristelle ;

Lowe, James ;

Ridge, Perry G. ;

Hammer, Monia B. ;

Wakutani, Yosuke ;

Proitsi, Petroula ;

Newhouse, Stephen ;

Lohmann, Ebba ;

Erginel-Unaltuna, Nihan ;

Medway, Christopher ;

Hanagasi, Hasmet ;

Troakes, Claire ;

Gurvit, Hakan ;

Bilgic, Basar ;

Al-Sarraj, Safa ;

Benitez, Bruno ;

Cooper, Breanna ;

Carrell, David ;

Emre, Murat ;

Zou, Fanggeng ;

Ma, Li ;

Murray, Melissa E. ;

Dickson, Dennis W. ;

Younkin, Steven ;

Hazrati, Lilinaz ;

Petersen, Ronald C. ;

Corcoran, Christopher D. ;

Cai, Yefei ;

Oliveira, Catarina ;

Ribeiro, Maria Helena ;

Santana, Isabel ;

Tschanz, JoAnn T. ;

Gibbs, J. Raphael ;

Norton, Maria C. ;

Kloszewska, Iwona ;

Mecocci, Patrizia ;

Soininen, Hilkka ;

Tsolaki, Magda ;

Vellas, Bruno .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (02) :117-127

[9] ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis [J].

Iwamoto, Noriyuki ;

Abe-Dohmae, Sumiko ;

Sato, Ryuichiro ;

Yokoyama, Shinji .

JOURNAL OF LIPID RESEARCH, 2006, 47 (09) :1915-1927

[10] ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages [J].

Jehle, Andreas W. ;

Gardai, Shyra J. ;

Li, Suzhao ;

Linsel-Nitschke, Patrick ;

Morimoto, Konosuke ;

Janssen, William J. ;

Vandivier, R. William ;

Wang, Nan ;

Greenberg, Steven ;

Dale, Benjamin M. ;

Qin, Chunbo ;

Henson, Peter M. ;

Tall, Alan R. .

JOURNAL OF CELL BIOLOGY, 2006, 174 (04) :547-556

← 1 2 3 →