A novel Alzheimer disease locus located near the gene encoding tau protein

被引：203

作者：

Jun, G. ^{[1
,2
,3
]}

Ibrahim-Verbaas, C. A. ^{[4
,5
]}

Vronskaya, M. ^{[6
]}

Lambert, J-C ^{[7
,8
,9
]}

Chung, J. ^{[1
]}

Naj, A. C. ^{[10
]}

Kunkle, B. W. ^{[11
]}

Wang, L-S ^{[10
]}

Bis, J. C. ^{[12
]}

Bellenguez, C. ^{[7
,8
,9
]}

Harold, D. ^{[13
]}

Lunetta, K. L. ^{[3
]}

Destefano, A. L. ^{[3
]}

Grenier-Boley, B. ^{[7
,8
,9
]}

Sims, R. ^{[6
]}

Beecham, G. W. ^{[11
,14
]}

Smith, A. V. ^{[15
,16
]}

Chouraki, V. ^{[17
]}

Hamilton-Nelson, K. L. ^{[11
]}

Ikram, M. A. ^{[4
,18
,19
]}

Fievet, N. ^{[7
,8
,9
]}

Denning, N. ^{[6
]}

Martin, E. R. ^{[11
,14
]}

Schmidt, H. ^{[20
]}

Kamatani, Y. ^{[21
,22
]}

Dunstan, M. L. ^{[6
]}

Valladares, O. ^{[10
]}

Laza, A. R. ^{[23
]}

Zelenika, D. ^{[24
]}

Ramirez, A. ^{[25
,26
]}

Foroud, T. M. ^{[27
]}

Choi, S-H ^{[3
]}

Boland, A. ^{[24
]}

Becker, T. ^{[28
,29
]}

Kukull, W. A. ^{[30
]}

van der Lee, S. J. ^{[4
]}

Pasquier, F. ^{[8
,31
]}

Cruchaga, C. ^{[32
,33
]}

Beekly, D. ^{[34
]}

Fitzpatrick, A. L. ^{[30
,35
]}

Hanon, O. ^{[36
,37
]}

Gill, M. ^{[38
,39
]}

Barber, R. ^{[40
]}

Gudnason, V. ^{[15
,16
]}

Campion, D. ^{[41
,42
,43
]}

Love, S. ^{[43
]}

Bennett, D. A. ^{[44
,45
]}

Amin, N. ^{[4
]}

Berr, C. ^{[46
]}

Tsolaki, Magda ^{[47
]}

机构：

[1] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA

[2] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA

[3] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[4] Erasmus Univ, Erasmus, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[5] Erasmus Univ, Erasmus, Med Ctr, Dept Urol, Rotterdam, Netherlands

[6] Cardiff Univ, Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, MRC, Cardiff CF10 3AX, S Glam, Wales

[7] Inserm U744, Lille, France

[8] Univ Lille 2, Lille, France

[9] Inst Pasteur, F-59019 Lille, France

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

[11] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

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

[13] Univ Dublin Trinity Coll, Dublin 2, Ireland

[14] Univ Miami, Macdonald Fdn Dept Human Genet, Miami, FL USA

[15] Univ Iceland, Fac Med, Reykjavik, Iceland

[16] Iceland Heart Assoc, Kopavogur, Iceland

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

[18] Netherlands Consortium Hlth Aging, Leiden, Netherlands

[19] Erasmus Univ, Erasmus, Med Ctr, Dept Radiol, Rotterdam, Netherlands

[20] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria

[21] RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan

[22] Fdn Jean Dausset CEPH, Paris, France

[23] Inst Catala Neurociencies Aplicades, Memory Clin Fundacio ACE, Barcelona, Spain

[24] CEA, Inst Genom, Ctr Natl Genotypage, Evry, France

[25] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany

[26] Univ Bonn, Inst Human Genet, Bonn, Germany

[27] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN USA

[28] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany

[29] Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany

[30] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[31] CHRU Lille, CNR MAJ, F-59037 Lille, France

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

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

[34] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA

[35] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[36] Univ Paris 05, Sorbonne Paris 5, Dept Geriatr, Paris, France

[37] Broca Hosp, Geriatr Dept, Paris, France

[38] St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland

[39] Trinity Coll Dublin, Dublin, Ireland

[40] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX USA

[41] CNR MAJ, Inserm U1079, Rouen, France

[42] Univ Hosp, F-76031 Rouen, France

[43] Frenchay Hosp, Sch Clin Sci, Univ Bristol Inst Clin Neurosci, Bristol BS16 1LE, Avon, England

[44] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA

[45] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[46] Hop La Colombiere, Inserm U888, Montpellier, France

[47] Aristotle Univ Thessaloniki, Dept Neurol, GR-54006 Thessaloniki, Greece

[48] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA

[49] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA

[50] Mt Sinai Sch Med, Dept Genet, New York, NY USA

来源：

MOLECULAR PSYCHIATRY | 2016年 / 21卷 / 01期

基金：

英国医学研究理事会; 美国国家卫生研究院; 芬兰科学院; 英国惠康基金; 瑞典研究理事会;

关键词：

FRONTOTEMPORAL LOBAR DEGENERATION; COMMON VARIANTS; ASSOCIATION ANALYSIS; SUSCEPTIBILITY LOCI; KANSL1; CAUSE; RISK-FACTOR; MAPT LOCUS; HAPLOTYPE; TMEM106B; EXPRESSION;

D O I：

10.1038/mp.2015.23

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：

APOE epsilon 4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE epsilon 4+ (10 352 cases and 9207 controls) and APOE epsilon 4 - (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE e4 status. Suggestive associations (P < 1x10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE epsilon 4+: 1250 cases and 536 controls; APOE epsilon 4 -: 718 cases and 1699 controls). Among APOE epsilon 4 - subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P = 5.8 x 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE epsilon 4+ subjects (CR1 and CLU) or APOE epsilon 4 - subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P = 1.6 x 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P <= 1.3 x 10(-8)), frontal cortex (P <= 1.3 x 10(-9)) and temporal cortex (P <= 1.2 x 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P = 9.2 x 10(-6)) and temporal cortex (P = 2.6 x 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE epsilon 4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

引用

页码：108 / 117

页数：10

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