Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease

被引：21

作者：

Baker, Emily ^{[1
,2
]}

Sims, Rebecca ^{[1
]}

Leonenko, Ganna ^{[1
]}

Frizzati, Aura ^{[1
]}

Harwood, Janet C. ^{[1
]}

Grozeva, Detelina ^{[1
]}

Morgan, Kevin ^{[3
]}

Passmore, Peter ^{[4
]}

Holmes, Clive ^{[5
]}

Powell, John ^{[6
,7
]}

Brayne, Carol ^{[8
]}

Gill, Michael ^{[9
,10
,11
]}

Mead, Simon ^{[12
]}

Bossu, Paola ^{[13
]}

Spalletta, Gianfranco ^{[14
]}

Cruchaga, Carlos ^{[15
,16
]}

Maier, Wolfgang ^{[16
,17
]}

Heun, Reinhard ^{[18
]}

Jessen, Frank ^{[18
,19
]}

Peters, Oliver ^{[21
,22
]}

Dichgans, Martin ^{[23
,24
,25
]}

FroeLich, Lutz ^{[26
]}

Ramirez, Alfredo ^{[20
,27
]}

Jones, Lesley ^{[1
]}

Hardy, John ^{[28
]}

Ivanov, Dobril ^{[2
]}

Hill, Matthew ^{[2
]}

Holmans, Peter ^{[1
]}

Allen, Nicholas D. ^{[2
]}

Morgan, B. Paul ^{[2
]}

Seshadri, Sudha ^{[29
]}

Schellenberg, Gerard D. ^{[30
]}

Amouyel, Philippe ^{[31
]}

Williams, Julie ^{[1
,2
]}

Escott-Price, Valentina ^{[1
,2
]}

机构：

[1] Cardiff Univ, Div Psychol Med & Clin Neurosci, Ctr Neuropsychiat Genet & Genom, Med Res Council, Cardiff, S Glam, Wales

[2] Cardiff Univ, UK Dementia Res Inst, Cardiff, S Glam, Wales

[3] Univ Nottingham, Sch Life Sci, Human Genet, Life Sci Bldg A27,Univ Pk, Nottingham NG7 2RD, England

[4] Queens Univ, Sch Med Dent & Biomed Sci, Ctr Publ Hlth, Belfast, Antrim, North Ireland

[5] Univ Southampton, Sch Med, Div Clin Neurosci, Southampton, Hants, England

[6] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, London, England

[7] QIMR Berghofer Med Res Inst, Genet Epidemiol, Herston, Qld, Australia

[8] Univ Cambridge, Inst Publ Hlth, Cambridge, England

[9] St James Hosp, Mercers Inst Res Ageing, Dublin, Ireland

[10] James Hosp, Dublin, Ireland

[11] Trinity Coll Dublin, Dublin, Ireland

[12] UCL, Inst Prion Dis, MRC Prion Unit, London, England

[13] IRCCS Santa Lucia Fdn, Dept Clin & Behav Neurol, Expt Neuropsychobiol Lab, Rome, Italy

[14] IRCCS Santa Lucia Fdn, Lab Neuropsychiat, Rome, Italy

[15] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[16] Washington Univ, Sch Med, Hope Ctr Program Prot Aggregat & Neurodegenerat, St Louis, MO USA

[17] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[18] German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany

[19] Univ Bonn, Dept Psychiat & Psychotherapy, D-53127 Bonn, Germany

[20] Univ Cologne, Dept Psychiat & Psychotherapy, D-50937 Cologne, Germany

[21] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany

[22] German Ctr Neurodegenerat Dis DZNE, Berlin, Germany

[23] Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany

[24] German Ctr Neurodegenerat Dis DZNE, D-80336 Munich, Germany

[25] Munich Cluster Syst Neurol SyNergy, Munich, Germany

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

[27] Univ Hosp Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany

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

[29] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

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

[31] Univ Lille, CHU Lille, Univ Hosp,INSERM,Inst Pasteur Lille, LabEx DISTALZ,UMR1167,RID,AGE Risk Factors & Mol, F-59000 Lille, France

来源：

PLOS ONE | 2019年 / 14卷 / 07期

关键词：

COMMON VARIANTS; PGC-1-ALPHA; DIFFERENTIATION; ZNF423; ALPHA; ANNOTATION; GENERATION; IMMUNITY; BRAIN; CD2AP;

D O I：

10.1371/journal.pone.0218111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 x 10(-6)), RORA (p = 7.4 x 10(-7)) and ZNF423 (p = 2.1 x 10(-6)). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

引用

页数：11

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