Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases

被引：70

作者：

Chen, Jason A. ^{[1
]}

Chen, Zhongbo ^{[2
]}

Won, Hyejung ^{[3
,4
]}

Huang, Alden Y. ^{[1
]}

Lowe, Jennifer K. ^{[3
,4
]}

Wojta, Kevin ^{[5
]}

Yokoyama, Jennifer S. ^{[6
]}

Bensimon, Gilbert ^{[7
,8
,9
]}

Leigh, P. Nigel ^{[10
]}

Payan, Christine ^{[7
,8
]}

Shatunov, Aleksey ^{[2
]}

Jones, Ashley R. ^{[2
]}

Lewis, Cathryn M. ^{[11
,12
]}

Deloukas, Panagiotis ^{[13
]}

Amouyel, Philippe ^{[14
]}

Tzourio, Christophe ^{[15
]}

Dartigues, Jean-Francois ^{[15
]}

Ludolph, Albert ^{[16
]}

Boxer, Adam L. ^{[6
]}

Bronstein, Jeff M. ^{[3
,4
]}

Al-Chalabi, Ammar ^{[2
]}

Geschwind, Daniel H. ^{[1
,3
,4
]}

Coppola, Giovanni ^{[1
,3
,4
,5
,17
,18
]}

机构：

[1] Univ Calif Los Angeles, Interdept Program Bioinformat, Los Angeles, CA 90095 USA

[2] Kings Coll London, Maurice Wohl Clin Neurosci Inst, Dept Basic & Clin Neurosci, London SE5 9RX, England

[3] Univ Calif Los Angeles, David Geffen Sch Med, Program Neurogenet, Dept Neurol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA

[6] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94158 USA

[7] CHU Nimes, BESPIM, Nimes, France

[8] Hop La Pitie Salpetriere, AP PH, Dept Clin Pharmacol, Paris, France

[9] Univ Paris Sorbonne, UPMC Paris 6, Pharmacol, Paris, France

[10] Univ Sussex, Trafford Ctr Biomed Res, Brighton & Sussex Med Sch, Brighton, E Sussex, England

[11] Kings Coll London, MRC, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England

[12] Kings Coll London, Dept Med & Mol Genet, London SE5 8AF, England

[13] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Charterhouse Sq, London EC1M 6BQ, England

[14] Univ Lille, CHU Lille, Inst Pasteur Lille,Inserm,Labex Distalz, RID AGE Risk Factor & Mol Determinants Aging Dis, F-59000 Lille, France

[15] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, CHU Bordeaux, Inserm,UMR 1219, F-33000 Bordeaux, France

[16] Univ Ulm, Dept Neurol, Ulm, Germany

[17] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, 695 Charles E Young Dr South,Gonda Bldg,Rm 1524, Los Angeles, CA 90095 USA

[18] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, 695 Charles E Young Dr South,Gonda Bldg,Rm 1524, Los Angeles, CA 90095 USA

来源：

MOLECULAR NEURODEGENERATION | 2018年 / 13卷

基金：

美国国家卫生研究院; 英国经济与社会研究理事会; 欧盟地平线“2020”; 英国医学研究理事会;

关键词：

Genome-wide association study; Progressive supranuclear palsy; Neurodegeneration; FRONTOTEMPORAL DEMENTIA; VARIANTS; BRAIN; RISK; MAPT; ARCHITECTURE; PREVALENCE; DISORDERS; MUTATIONS; DIAGNOSIS;

D O I：

10.1186/s13024-018-0270-8

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood. Methods: We conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry. Results: We identified 5 associated loci at a genome-wide significance threshold P < 5 x 10(-8), including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 x 10(-6)). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson's disease and amyotrophic lateral sclerosis. Conclusions: In total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.

引用

页数：11

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