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

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