Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

被引：183

作者：

de Rojas, Itziar ^{[1
,2
,3
]}

Moreno-Grau, Sonia ^{[1
,2
,3
]}

Tesi, Niccolo ^{[4
,5
,6
]}

Grenier-Boley, Benjamin ^{[7
]}

Andrade, Victor ^{[8
,9
]}

Jansen, Iris E. ^{[4
,10
]}

Pedersen, Nancy L. ^{[11
]}

Stringa, Najada ^{[12
]}

Zettergren, Anna ^{[13
]}

Hernandez, Isabel ^{[1
,2
,3
]}

Montrreal, Laura ^{[1
,2
]}

Antunez, Carmen ^{[14
]}

Antonell, Anna ^{[15
]}

Tankard, Rick M. ^{[16
]}

Bis, Joshua C. ^{[17
]}

Sims, Rebecca ^{[18
]}

Bellenguez, Celine ^{[7
]}

Quintela, Ines ^{[19
]}

Gonzalez-Perez, Antonio ^{[20
]}

Calero, Miguel ^{[3
,21
,22
]}

Franco-Macias, Emilio ^{[23
]}

Macias, Juan ^{[24
]}

Blesa, Rafael ^{[3
,25
]}

Cervera-Carles, Laura ^{[3
,25
]}

Menendez-Gonzalez, Manuel ^{[26
,27
,28
]}

Frank-Garcia, Ana ^{[3
,29
,30
,31
]}

Luis Royo, Jose ^{[32
]}

Moreno, Fermin ^{[3
,33
,34
]}

Huerto Vilas, Raquel ^{[35
,36
]}

Baquero, Miquel ^{[37
]}

Diez-Fairen, Monica ^{[38
,39
]}

Lage, Carmen ^{[3
,40
,41
]}

Garcia-Madrona, Sebastian ^{[42
]}

Garcia-Gonzalez, Pablo ^{[1
,2
]}

Alarcon-Martin, Emilio ^{[1
,2
,32
]}

Valero, Sergi ^{[1
,2
,3
]}

Sotolongo-Grau, Oscar ^{[1
,2
]}

Ullgren, Abbe ^{[43
,44
]}

Naj, Adam C. ^{[45
,46
]}

Lemstra, Afina W. ^{[4
]}

Benaque, Alba ^{[1
,2
]}

Perez-Cordon, Alba ^{[1
,2
]}

Benussi, Alberto ^{[47
]}

Rabano, Alberto ^{[3
,22
,48
]}

Padovani, Alessandro ^{[47
]}

Squassina, Alessio ^{[49
]}

de Mendonca, Alexandre ^{[50
]}

Arias Pastor, Alfonso ^{[35
,36
]}

Kok, Almar A. L. ^{[12
,51
]}

Meggy, Alun ^{[52
]}

机构：

[1] Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr, Barcelona, Spain

[2] Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Memory Clin Fundacio ACE, Barcelona, Spain

[3] Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain

[4] Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands

[5] Vrije Univ Amsterdam, Sect Genom Neurodegenerat Dis & Aging, Dept Clin Genet, Amsterdam UMC, Amsterdam, Netherlands

[6] Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands

[7] Univ Lille, Inst Pasteur Lille, INSERM, CHU Lille,U1167 Labex DISTALZ RID AGE Risk Factor, Lille, France

[8] Univ Cologne, Fac Med, Div Neurogenet & Mol Psychiat, Dept Psychiat & Psychotherapy, Cologne, Germany

[9] Univ Clin Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany

[10] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, Amsterdam Neurosci, Amsterdam, Netherlands

[11] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[12] Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Publ Hlth Res Inst, Dept Epidemiol & Data Sci, Amsterdam, Netherlands

[13] Univ Gothenburg, Ctr Ageing & Hlth AgeCap, Neuropsychiat Epidemiol Unit,Sahlgrenska Acad, Dept Psychiat & Neurochem,Inst Neurosci & Physiol, Gothenburg, Sweden

[14] Hosp Clin Univ Virgen Arrixaca, Unidad Demencias, Murcia, Spain

[15] Univ Barcelona, Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Serv Neurol,Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain

[16] Murdoch Univ, Math & Stat, Perth, WA, Australia

[17] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[18] Cardiff Univ, Div Psychol Med & Clinial Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, Wales

[19] Univ Santiago de Compostela, Grp Med Xenom, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Santiago De Compostela, Spain

[20] Ctr Andaluz Estudios Bioinformat, Seville, Spain

[21] Inst Salud Carlos III, UFIEC, Madrid, Spain

[22] Queen Sofia Fdn Alzheimer Ctr, CIEN Fdn, Madrid, Spain

[23] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Unidad Demencias,Serv Neurol & Neurofisiol,Hosp U, Seville, Spain

[24] Hosp Univ Valme, Unidad Clin Enfermedades Infecciosas & Microbiol, Seville, Spain

[25] Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, II B St Pau, Barcelona, Spain

[26] Hosp Univ Cent Asturias, Serv Neurol, Oviedo, Spain

[27] Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain

[28] Univ Oviedo, Dept Med, Oviedo, Spain

[29] La Paz Univ Hosp, Dept Neurol, Inst Invest Sanitaria Hosp Univ La Paz, IdiPAZ, Madrid, Spain

[30] Hosp La Paz Inst Hlth Res, IdiPAZ, Madrid, Spain

[31] Univ Autonoma Madrid, Madrid, Spain

[32] Univ Malaga, Dept Especialidades Quirurg Bioquim & Inmunol, Sch Med, Malaga, Spain

[33] Hosp Univ Donostia, Dept Neurol, San Sebastian, Spain

[34] Inst Biodonostia, Neurosci Area, San Sebastian, Spain

[35] Hosp Univ Santa Maria Lleida, Unitat Trastorns Cognitius, Lleida, Spain

[36] Inst Recerca Biomed Lleida IRBLLeida, Lleida, Spain

[37] Hosp Univ & Politecn La Fe, Serv Neurol, Valencia, Spain

[38] Fundacio Docencia & Recerca MutuaTerrassa, Barcelona, Spain

[39] Hosp Univ Mutua Terrassa, Memory Disorders Unit, Dept Neurol, Barcelona, Spain

[40] Univ Cantabria, Univ Hosp, Neurol Serv, Marques de Valdecilla Univ Hosp, Santander, Spain

[41] IDIVAL, Santander, Spain

[42] Hosp Univ Ramon y Cajal, IRYCIS, Madrid, Spain

[43] Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Neurogeriatr, Stockholm, Sweden

[44] Karolinska Univ Hosp Solna, Unit Hereditary Dementias, Stockholm, Sweden

[45] Univ Penn, Dept Biostat Epidemiol & Informat, Perelman Sch Med, Philadelphia, PA 19104 USA

[46] Univ Penn, Dept Pathol & Lab Med, Penn Neurodegenerat Genom Ctr, Perelman Sch Med, Philadelphia, PA USA

[47] Univ Brescia, Dept Clin & Expt Sci, Ctr Neurodegenerat Disorders, Brescia, Italy

[48] BT CIEN, Madrid, Spain

[49] Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy

[50] Univ Lisbon, Fac Med, Lisbon, Portugal

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

基金：

英国经济与社会研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

SUSCEPTIBILITY LOCI; FAMILY-HISTORY; METAANALYSIS; IMMUNITY; AGE;

D O I：

10.1038/s41467-021-22491-8

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：

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n=409,435 and validation size n=58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE 4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease. Known genetic loci account for only a fraction of the genetic contribution to Alzheimer's disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer's disease polygenic risk score.

引用

页数：16

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