A large genome scan for rare CNVs in amyotrophic lateral sclerosis

被引：48

作者：

Blauw, Hylke M. ^{[1
]}

Al-Chalabi, Ammar ^{[4
]}

Andersen, Peter M. ^{[5
,6
]}

van Vught, Paul W. J. ^{[1
]}

Diekstra, Frank P. ^{[1
]}

van Es, Michael A. ^{[1
]}

Saris, Christiaan G. J. ^{[1
]}

Groen, Ewout J. N. ^{[1
]}

van Rheenen, Wouter ^{[1
]}

Koppers, Max ^{[1
]}

van't Slot, Ruben ^{[2
]}

Strengman, Eric ^{[2
]}

Estrada, Karol ^{[7
]}

Rivadeneira, Fernando ^{[7
,8
]}

Hofman, Albert ^{[8
]}

Uitterlinden, Andre G. ^{[7
,8
]}

Kiemeney, Lambertus A. ^{[9
]}

Vermeulen, Sita H. M. ^{[9
]}

Birve, Anna ^{[5
]}

Waibel, Stefan ^{[6
]}

Meyer, Thomas ^{[10
]}

Cronin, Simon ^{[11
]}

McLaughlin, Russell L. ^{[11
]}

Hardiman, Orla ^{[11
,12
]}

Sapp, Peter C. ^{[13
,14
,15
,16
]}

Tobin, Martin D. ^{[17
,18
]}

Wain, Louise V. ^{[17
,18
]}

Tomik, Barbara ^{[19
]}

Slowik, Agnieszka ^{[19
]}

Lemmens, Robin ^{[20
,21
]}

Rujescu, Dan ^{[22
]}

Schulte, Claudia ^{[23
,24
]}

Gasser, Thomas ^{[23
,24
]}

Brown, Robert H., Jr. ^{[13
,14
]}

Landers, John E. ^{[13
,14
]}

Robberecht, Wim ^{[20
,21
]}

Ludolph, Albert C. ^{[6
]}

Ophoff, Roel A. ^{[3
,25
]}

Veldink, Jan H. ^{[1
]}

van den Berg, Leonard H. ^{[1
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Neurol, Rudolf Magnus Inst Neurosci, NL-3584 CX Utrecht, Netherlands

[2] Univ Med Ctr Utrecht, Complex Genet Sect, Div Biomed Genet, Dept Med Genet, NL-3584 CX Utrecht, Netherlands

[3] Rudolf Magnus Inst Pharmacol, NL-3584 CX Utrecht, Netherlands

[4] Kings Coll London, Inst Psychiat, Dept Clin Neurosci, MRC,Ctr Neurodegenerat Res, London SE5 8AF, England

[5] Umea Univ, Inst Pharmacol & Clin Neurosci, SE-90185 Umea, Sweden

[6] Univ Ulm, Dept Neurol, D-89081 Ulm, Germany

[7] Erasmus Univ, Med Ctr Rotterdam, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands

[8] Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands

[9] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6500 HB Nijmegen, Netherlands

[10] Humboldt Univ, Charite Univ Hosp, Dept Neurol, D-13353 Berlin, Germany

[11] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland

[12] Univ Dublin Trinity Coll, Trinity Coll Inst Neurosci, Dublin 2, Ireland

[13] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA

[14] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA

[15] Howard Hughes Med Inst, Cambridge, MA 01605 USA

[16] MIT, Dept Biol, Cambridge, MA 01605 USA

[17] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England

[18] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[19] Jagiellonian Univ, Dept Neurol, PL-31007 Krakow, Poland

[20] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Neurol, B-3000 Leuven, Belgium

[21] Katholieke Univ Leuven VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium

[22] Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, D-80336 Munich, Germany

[23] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, D-72074 Tubingen, Germany

[24] German Ctr Neurodegenerat Dis, D-72074 Tubingen, Germany

[25] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 20期

关键词：

COPY-NUMBER VARIATION; WIDE ASSOCIATION; RECURRENT MICRODELETIONS; STRUCTURAL VARIATION; SPORADIC ALS; NIPA1; GENE; SUSCEPTIBILITY; MUTATIONS; DPP6; POPULATION;

D O I：

10.1093/hmg/ddq323

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19 000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 x 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 x 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 x 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 x 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.

引用

页码：4091 / 4099

页数：9

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