Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

被引：4

作者：

Kucukali, Fahri ^{[1
,2
]}

Neumann, Alexander ^{[1
,2
]}

Van Dongen, Jasper ^{[1
,2
]}

De Pooter, Tim ^{[2
,3
]}

Joris, Geert ^{[2
,3
]}

De Rijk, Peter ^{[2
,3
]}

Ohlei, Olena ^{[4
]}

Dobricic, Valerija ^{[4
]}

Bos, Isabelle ^{[5
]}

Vos, Stephanie J. B. ^{[6
]}

Engelborghs, Sebastiaan ^{[2
,7
,8
,9
]}

De Roeck, Ellen ^{[2
,10
,11
]}

Vandenberghe, Rik ^{[12
,13
]}

Gabel, Silvy ^{[12
,13
]}

Meersmans, Karen ^{[12
,13
]}

Tsolaki, Magda ^{[14
]}

Verhey, Frans ^{[6
,15
,16
]}

Martinez-Lage, Pablo ^{[17
]}

Tainta, Mikel ^{[17
]}

Frisoni, Giovanni ^{[18
,19
]}

Blin, Oliver ^{[20
]}

Richardson, Jill C. ^{[21
]}

Bordet, Regis ^{[22
]}

Scheltens, Philip ^{[23
,24
]}

Popp, Julius ^{[25
,26
]}

Peyratout, Gwendoline ^{[27
]}

Johannsen, Peter ^{[28
]}

Frolich, Lutz ^{[29
]}

Freund-Levi, Yvonne ^{[30
,31
,32
]}

Streffer, Johannes ^{[2
]}

Lovestone, Simon ^{[33
,34
]}

Legido-Quigley, Cristina ^{[35
,36
]}

Ten Kate, Mara ^{[23
,24
,37
]}

Barkhof, Frederik ^{[37
,38
,39
]}

Zetterberg, Henrik ^{[40
,41
,42
,43
,44
]}

Bertram, Lars ^{[4
,45
]}

Strazisar, Mojca ^{[2
,3
]}

Visser, Pieter Jelle ^{[6
,23
,24
]}

Van Broeckhoven, Christine ^{[2
,46
]}

Sleegers, Kristel ^{[1
,2
]}

机构：

[1] VIB, VIB Ctr Mol Neurol, Complex Genet Alzheimers Dis Grp, Antwerp, Belgium

[2] Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium

[3] VIB, VIB Ctr Mol Neurol, Neur Support Facil, Antwerp, Belgium

[4] Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany

[5] Netherlands Inst Hlth Serv Res, Utrecht, Netherlands

[6] Maastricht Univ, Alzheimer Ctr Limburg, Maastricht, Netherlands

[7] Univ Ziekenhuis Brussel UZ Brussel, Dept Neurol, Brussels, Belgium

[8] Univ Ziekenhuis Brussel UZ Brussel, Brussels Integrated Ctr Brain & Memory Bru BRAIN, Brussels, Belgium

[9] Vrije Univ Brussel VUB, Ctr Neurosci C4N, Brussels, Belgium

[10] Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Dept Neurol, Antwerp, Belgium

[11] Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Memory Clin, Antwerp, Belgium

[12] Univ Hosp Leuven, Leuven, Belgium

[13] Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium

[14] Aristotle Univ Thessaloniki, Fac Hlth Sci, Sch Med, Dept Neurol 1, Thessaloniki, Greece

[15] Maastricht Univ, Dept Psychiat & Neuropsychol, Maastricht, Netherlands

[16] Maastricht Univ, Sch Mental Hlth & Neurosci, Maastricht, Netherlands

[17] CITA Alzheimer Fdn, Ctr Res & Adv Therapies, San Sebastian, Spain

[18] Geneva Univ Hosp, Fac Med, Dept Psychiat, Geneva, Switzerland

[19] RCCS Inst Ctr San Giovanni di Dio Fatebenefratell, Brescia, Italy

[20] Marseille Univ Hosp, Clin Pharmacol & Pharmacovigilance Dept, Marseille, France

[21] GlaxoSmithKline R&D, Neurosci Therapeut Area, Stevanage, England

[22] Univ Lille, INSERM, CHU Lille, Neurosci & Cognit, Lille, France

[23] Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands

[24] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands

[25] Univ Hosp Psychiat Zurich, Dept Geriatr Psychiat, Zurich, Switzerland

[26] Univ Hosp Lausanne, Dept Psychiat, Old Age Psychiat, Lausanne, Switzerland

[27] Univ Hosp Lausanne, Dept Psychiat, Lausanne, Switzerland

[28] Novo Nordisk, Clin Drug Dev, Copenhagen, Denmark

[29] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Geriatr Psychiat, Mannheim, Germany

[30] Orebro Univ, Sch Med Sci, Orebro, Sweden

[31] Univ Hosp Orebro, Dept Geriatr, Orebro, Sweden

[32] Sodertalje Hosp, Sodersjukhuset Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden

[33] Univ Oxford, Dept Psychiat, Oxford, England

[34] Janssen Med Ltd, High Wycombe, Bucks, England

[35] Steno Diabet Ctr, Copenhagen, Denmark

[36] Kings Coll London, Inst Pharmaceut Sci, London, England

[37] Vrije Univ Amsterdam Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands

[38] UCL, Queen Sq Inst Neurol, London, England

[39] UCL, Ctr Med Image Comp, London, England

[40] Univ Gothenburg, Dept Psychiat & Neurochem, Gothenburg, Sweden

[41] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England

[42] Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden

[43] UCL, UK Dementia Res Inst, London, England

[44] Hong Kong Ctr Neurodegenerat Dis, Hong Kong, Peoples R China

[45] Univ Oslo, Ctr Lifespan Changes Brain & Cognit, Oslo, Norway

[46] VIB, VIB Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Antwerp, Belgium

来源：

ALZHEIMERS & DEMENTIA | 2022年

基金：

加拿大健康研究院; 新加坡国家研究基金会; 美国国家卫生研究院; 欧洲研究理事会; 瑞典研究理事会;

关键词：

Alzheimer's disease; biomarkers; endophenotypes; rare coding variants; whole-exome sequencing; GENOME-WIDE ASSOCIATION; COGNITIVE DECLINE; D-RIBOSE; MUTATIONS; ENDOPHENOTYPES; METAANALYSIS; FRAMEWORK; ABCA7; GWAS;

D O I：

10.1002/alz.12842

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

IntroductionDespite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. MethodsWe performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). ResultsMutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DiscussionThe identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

引用

页码：2317 / 2331

页数：15

共 50 条

[1] UK Biobank Whole-Exome Sequence Binary Phenome Analysis with Robust Region-Based Rare-Variant Test
Zhao, Zhangchen
Bi, Wenjian
Zhou, Wei
VandeHaar, Peter
Fritsche, Lars G.
Lee, Seunggeun
[J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2020, 106 (01) : 3 - 12
[2] Human whole-exome genotype data for Alzheimer’s disease
Yuk Yee Leung
Adam C. Naj
Yi-Fan Chou
Otto Valladares
Michael Schmidt
Kara Hamilton-Nelson
Nicholas Wheeler
Honghuang Lin
Prabhakaran Gangadharan
Liming Qu
Kaylyn Clark
Amanda B. Kuzma
Wan-Ping Lee
Laura Cantwell
Heather Nicaretta
Jonathan Haines
Lindsay Farrer
Sudha Seshadri
Zoran Brkanac
Carlos Cruchaga
Margaret Pericak-Vance
Richard P. Mayeux
William S. Bush
Anita Destefano
Eden Martin
Gerard D. Schellenberg
Li-San Wang
[J]. Nature Communications, 15
[3] Human whole-exome genotype data for Alzheimer's disease
Leung, Yuk Yee
Naj, Adam C.
Chou, Yi-Fan
Valladares, Otto
Schmidt, Michael
Hamilton-Nelson, Kara
Wheeler, Nicholas
Lin, Honghuang
Gangadharan, Prabhakaran
Qu, Liming
Clark, Kaylyn
Kuzma, Amanda B.
Lee, Wan-Ping
Cantwell, Laura
Nicaretta, Heather
van der Lee, Sven
English, Adam
Kalra, Divya
Muzny, Donna
Skinner, Evette
Doddapeneni, Harsha
Dinh, Huyen
Hu, Jianhong
Santibanez, Jireh
Jayaseelan, Joy
Worley, Kim
Gibbs, Richard A.
Lee, Sandra
Dugan-Perez, Shannon
Korchina, Viktoriya
Nasser, Waleed
Liu, Xiuping
Han, Yi
Zhu, Yiming
Liu, Yue
Khan, Ziad
Zhu, Congcong
Sun, Fangui Jenny
Jun, Gyungah R.
Chung, Jaeyoon
Farrell, John
Zhang, Xiaoling
Banks, Eric
Gupta, Namrata
Gabriel, Stacey
Butkiewicz, Mariusz
Benchek, Penelope
Smieszek, Sandra
Song, Yeunjoo
Vardarajan, Badri
[J]. NATURE COMMUNICATIONS, 2024, 15 (01)
[4] Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease
Raghavan, Neha S.
Brickman, Adam M.
Andrews, Howard
Manly, Jennifer J.
Schupf, Nicole
Lantigua, Rafael
Wolock, Charles J.
Kamalakaran, Sitharthan
Petrovski, Slave
Tosto, Giuseppe
Vardarajan, Badri N.
Goldstein, David B.
Mayeux, Richard
[J]. ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 2018, 5 (07): : 832 - 842
[5] Whole-exome sequencing detected a novel APP variant in a Han-Chinese family with Alzheimer’s disease
Wang Zhaoxia
Wang Chenyu
Yuan ZhuangZhuang
Fan Liangliang
Lin Xue
Tang Tieyu
[J]. Molecular Biology Reports, 2023, 50 : 5267 - 5271
[6] Whole-exome sequencing detected a novel APP variant in a Han-Chinese family with Alzheimer's disease
Wang, Zhaoxia
Wang, Chenyu
Yuan, ZhuangZhuang
Fan, Liangliang
Xue, Lin
Tang, Tieyu
[J]. MOLECULAR BIOLOGY REPORTS, 2023, 50 (06) : 5267 - 5271
[7] Whole-Exome Sequencing Analysis of Alzheimer's Disease in Non-APOE*4 Carriers
Fan, Kang-Hsien
Feingold, Eleanor
Rosenthal, Samantha L.
Demirci, F. Yesim
Ganguli, Mary
Lopez, Oscar L.
Kamboh, M. Ilyas
[J]. JOURNAL OF ALZHEIMERS DISEASE, 2020, 76 (04) : 1553 - 1565
[8] Search for rare-variant risks of Parkinson's disease by sequencing of candidate genes and exome sequencing
Satake, W.
Ando, Y.
Tomiyama, H.
Takeda, A.
Hasegawa, K.
Yamamoto, M.
Murata, M.
Hattori, N.
Toda, T.
[J]. MOVEMENT DISORDERS, 2013, 28 : S402 - S403
[9] Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype
Ma, Yiyi
Jun, Gyungah R.
Zhang, Xiaoling
Chung, Jaeyoon
No, Adam C.
Chen, Yuning
Bellenguez, Celine
Hamilton-Nelson, Kara
Martin, Eden R.
Kunkle, Brian W.
Bis, Joshua C.
Debette, Stephanie
DeStefano, Anita L.
Fornage, Myriam
Nicolas, Gael
van Duijn, Cornelia
Bennett, David A.
De Jager, Philip L.
Mayeux, Richard
Haines, Jonathan L.
Pericak-Vance, Margaret A.
Seshadri, Sudha
Lambert, Jean-Charles
Schellenberg, Gerard D.
Lunetta, Kathryn L.
Farrer, Lindsay A.
Grenier-Boley, Benjamin
Charbonnier, Camille
Quenez, Olivier
Chauhan, Ganesh
Wallon, David
Rousseau, Stephan
Richard, Anne Claire
Boland, Anne
Bourque, Guillaume
Munter, Hans Markus
Olaso, Robert
Meyer, Vincent
Rollin-Sillaire, Adeline
Pasquier, Florence
Letenneur, Luc
Redon, Richard
Dartigues, Jean-Francois
Tzourio, Christophe
Lathrop, Mark
Deleuze, Jean-Francois
Hannequin, Didier
Genin, Emmanuelle
Amouyel, Philippe
Campion, Dominique
[J]. JAMA NEUROLOGY, 2019, 76 (09) : 1099 - 1108
[10] Gene-based rare variant analysis of whole-exome sequencing in relation to eosinophil counts
Hoglund, J. R.
Ek, W. E.
Karlsson, T.
Johansson, A.
[J]. EUROPEAN JOURNAL OF HUMAN GENETICS, 2020, 28 (SUPPL 1) : 712 - 713

← 1 2 3 4 5 →