Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation

被引：14

作者：

Neumann, Alexander ^{[1
,2
]}

Kucukali, Fahri ^{[1
,2
]}

Bos, Isabelle ^{[3
]}

Vos, Stephanie J. B. ^{[4
]}

Engelborghs, Sebastiaan ^{[2
,5
,6
,7
]}

De Pooter, Tim ^{[2
,8
]}

Joris, Geert ^{[2
,8
]}

De Rijk, Peter ^{[2
,8
]}

De Roeck, Ellen ^{[2
,9
,10
]}

Tsolaki, Magda ^{[11
]}

Verhey, Frans ^{[4
,12
,13
]}

Martinez-Lage, Pablo ^{[14
]}

Tainta, Mikel ^{[14
]}

Frisoni, Giovanni ^{[15
,16
]}

Blin, Oliver ^{[17
]}

Richardson, Jill ^{[18
]}

Bordet, Regis ^{[19
]}

Scheltens, Philip ^{[20
,21
]}

Popp, Julius ^{[22
,23
]}

Peyratout, Gwendoline ^{[24
]}

Johannsen, Peter ^{[25
]}

Froelich, Lutz ^{[26
]}

Vandenberghe, Rik ^{[27
]}

Freund-Levi, Yvonne ^{[28
,29
]}

Streffer, Johannes ^{[2
]}

Lovestone, Simon ^{[30
,31
]}

Legido-Quigley, Cristina ^{[32
,33
]}

ten Kate, Mara ^{[20
,21
,34
]}

Barkhof, Frederik ^{[34
,35
]}

Strazisar, Mojca ^{[2
,8
]}

Zetterberg, Henrik ^{[36
,37
,38
,39
,40
]}

Bertram, Lars ^{[41
,42
]}

Visser, Pieter Jelle ^{[4
,20
,21
]}

van Broeckhoven, Christine ^{[2
,43
]}

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] Netherlands Inst Hlth Serv Res, Utrecht, Netherlands

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

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

[6] Univ Ziekenhuis Brussel UZ Brussel, Memory Clin, Brussels, Belgium

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

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

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

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

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

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

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

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

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

[16] RCCS Inst Ctr San Giovanni Dio Fatebenefratelli, Brescia, Italy

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

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

[19] Univ Lille, INSERM, CHU Lille, Neurosci & Cognit, Inserm, France

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

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

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

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

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

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

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

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

[28] Karolinska Inst Stockholm Sweden, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden

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

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

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

[32] Steno Diabet Ctr, Copenhagen, Denmark

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

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

[35] UCL, Inst Neurol, London, England

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

[37] UCL Inst Neurol, Dept Mol Neurosci, London, England

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

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

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

[41] Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany

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

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

来源：

MOLECULAR PSYCHIATRY | 2022年 / 27卷 / 04期

基金：

新加坡国家研究基金会; 欧盟地平线“2020”; 瑞典研究理事会; 加拿大健康研究院; 欧洲研究理事会; 美国国家卫生研究院;

关键词：

MINI-MENTAL-STATE; METAANALYSIS; BIOMARKERS; GENETICS;

D O I：

10.1038/s41380-022-01437-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (beta-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.

引用

页码：1990 / 1999

页数：10

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