A large genome scan for rare CNVs in amyotrophic lateral sclerosis

Hylke M. Blauw; Ammar Al-Chalabi; Peter M. Andersen; Paul W. J. van Vught; Frank P. Diekstra; Michael A. van Es; Christiaan G. J. Saris; Ewout J. N. Groen; Wouter van Rheenen; Max Koppers; Ruben van't Slot; Eric Strengman; Karol Estrada; Fernando Rivadeneira; Albert Hofman; Andre G. Uitterlinden; Lambertus A. Kiemeney; Sita H. M. Vermeulen; Anna Birve; Stefan Waibel; Thomas Meyer; Simon Cronin; Russell L. McLaughlin; Orla Hardiman; Peter C. Sapp; Martin D. Tobin; Louise V. Wain; Barbara Tomik; Agnieszka Slowik; Robin Lemmens; Dan Rujescu; Claudia Schulte; Thomas Gasser; Robert H. Brown; John E. Landers; Wim Robberecht; Albert C. Ludolph; Roel A. Ophoff; Jan H. Veldink; Leonard H. van den Berg

doi:10.1093/hmg/ddq323

A large genome scan for rare CNVs in amyotrophic lateral sclerosis

Hylke M. Blauw, Ammar Al-Chalabi, Peter M. Andersen, Paul W. J. van Vught, Frank P. Diekstra, Michael A. van Es, Christiaan G. J. Saris, Ewout J. N. Groen, Wouter van Rheenen, Max Koppers, Ruben van't Slot, Eric Strengman, Karol Estrada, Fernando Rivadeneira, Albert Hofman, Andre G. Uitterlinden, Lambertus A. Kiemeney, Sita H. M. Vermeulen, Anna Birve, Stefan WaibelThomas Meyer, Simon Cronin, Russell L. McLaughlin, Orla Hardiman, Peter C. Sapp, Martin D. Tobin, Louise V. Wain, Barbara Tomik, Agnieszka Slowik, Robin Lemmens, Dan Rujescu, Claudia Schulte, Thomas Gasser, Robert H. Brown, John E. Landers, Wim Robberecht, Albert C. Ludolph, Roel A. Ophoff, Jan H. Veldink, Leonard H. van den Berg^*

^*Corresponding author for this work

School of Neurological and Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	4091-4099
Number of pages	9
Journal	Human Molecular Genetics
Volume	19
Issue number	20
DOIs	https://doi.org/10.1093/hmg/ddq323
Publication status	Published - 15 Oct 2010

Keywords / Materials (for Non-textual outputs)

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

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10.1093/hmg/ddq323

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Blauw, H. M., Al-Chalabi, A., Andersen, P. M., van Vught, P. W. J., Diekstra, F. P., van Es, M. A., Saris, C. G. J., Groen, E. J. N., van Rheenen, W., Koppers, M., van't Slot, R., Strengman, E., Estrada, K., Rivadeneira, F., Hofman, A., Uitterlinden, A. G., Kiemeney, L. A., Vermeulen, S. H. M., Birve, A., ... van den Berg, L. H. (2010). A large genome scan for rare CNVs in amyotrophic lateral sclerosis. Human Molecular Genetics, 19(20), 4091-4099. https://doi.org/10.1093/hmg/ddq323

@article{82fa6be3f6e64eb0bdc0f43feca96418,

title = "A large genome scan for rare CNVs in amyotrophic lateral sclerosis",

abstract = "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.",

keywords = "COPY-NUMBER VARIATION, WIDE ASSOCIATION, RECURRENT MICRODELETIONS, STRUCTURAL VARIATION, SPORADIC ALS, NIPA1 GENE, SUSCEPTIBILITY, MUTATIONS, DPP6, POPULATION",

author = "Blauw, \{Hylke M.\} and Ammar Al-Chalabi and Andersen, \{Peter M.\} and \{van Vught\}, \{Paul W. J.\} and Diekstra, \{Frank P.\} and \{van Es\}, \{Michael A.\} and Saris, \{Christiaan G. J.\} and Groen, \{Ewout J. N.\} and \{van Rheenen\}, Wouter and Max Koppers and \{van't Slot\}, Ruben and Eric Strengman and Karol Estrada and Fernando Rivadeneira and Albert Hofman and Uitterlinden, \{Andre G.\} and Kiemeney, \{Lambertus A.\} and Vermeulen, \{Sita H. M.\} and Anna Birve and Stefan Waibel and Thomas Meyer and Simon Cronin and McLaughlin, \{Russell L.\} and Orla Hardiman and Sapp, \{Peter C.\} and Tobin, \{Martin D.\} and Wain, \{Louise V.\} and Barbara Tomik and Agnieszka Slowik and Robin Lemmens and Dan Rujescu and Claudia Schulte and Thomas Gasser and Brown, \{Robert H.\} and Landers, \{John E.\} and Wim Robberecht and Ludolph, \{Albert C.\} and Ophoff, \{Roel A.\} and Veldink, \{Jan H.\} and \{van den Berg\}, \{Leonard H.\}",

year = "2010",

month = oct,

day = "15",

doi = "10.1093/hmg/ddq323",

language = "English",

volume = "19",

pages = "4091--4099",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "20",

}

Blauw, HM, Al-Chalabi, A, Andersen, PM, van Vught, PWJ, Diekstra, FP, van Es, MA, Saris, CGJ, Groen, EJN, van Rheenen, W, Koppers, M, van't Slot, R, Strengman, E, Estrada, K, Rivadeneira, F, Hofman, A, Uitterlinden, AG, Kiemeney, LA, Vermeulen, SHM, Birve, A, Waibel, S, Meyer, T, Cronin, S, McLaughlin, RL, Hardiman, O, Sapp, PC, Tobin, MD, Wain, LV, Tomik, B, Slowik, A, Lemmens, R, Rujescu, D, Schulte, C, Gasser, T, Brown, RH, Landers, JE, Robberecht, W, Ludolph, AC, Ophoff, RA, Veldink, JH & van den Berg, LH 2010, 'A large genome scan for rare CNVs in amyotrophic lateral sclerosis', Human Molecular Genetics, vol. 19, no. 20, pp. 4091-4099. https://doi.org/10.1093/hmg/ddq323

TY - JOUR

T1 - A large genome scan for rare CNVs in amyotrophic lateral sclerosis

AU - Blauw, Hylke M.

AU - Al-Chalabi, Ammar

AU - Andersen, Peter M.

AU - van Vught, Paul W. J.

AU - Diekstra, Frank P.

AU - van Es, Michael A.

AU - Saris, Christiaan G. J.

AU - Groen, Ewout J. N.

AU - van Rheenen, Wouter

AU - Koppers, Max

AU - van't Slot, Ruben

AU - Strengman, Eric

AU - Estrada, Karol

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

AU - Kiemeney, Lambertus A.

AU - Vermeulen, Sita H. M.

AU - Birve, Anna

AU - Waibel, Stefan

AU - Meyer, Thomas

AU - Cronin, Simon

AU - McLaughlin, Russell L.

AU - Hardiman, Orla

AU - Sapp, Peter C.

AU - Tobin, Martin D.

AU - Wain, Louise V.

AU - Tomik, Barbara

AU - Slowik, Agnieszka

AU - Lemmens, Robin

AU - Rujescu, Dan

AU - Schulte, Claudia

AU - Gasser, Thomas

AU - Brown, Robert H.

AU - Landers, John E.

AU - Robberecht, Wim

AU - Ludolph, Albert C.

AU - Ophoff, Roel A.

AU - Veldink, Jan H.

AU - van den Berg, Leonard H.

PY - 2010/10/15

Y1 - 2010/10/15

N2 - 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.

AB - 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.

KW - COPY-NUMBER VARIATION

KW - WIDE ASSOCIATION

KW - RECURRENT MICRODELETIONS

KW - STRUCTURAL VARIATION

KW - SPORADIC ALS

KW - NIPA1 GENE

KW - SUSCEPTIBILITY

KW - MUTATIONS

KW - DPP6

KW - POPULATION

U2 - 10.1093/hmg/ddq323

DO - 10.1093/hmg/ddq323

M3 - Article

SN - 0964-6906

VL - 19

SP - 4091

EP - 4099

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 20

ER -

A large genome scan for rare CNVs in amyotrophic lateral sclerosis

Abstract

Keywords / Materials (for Non-textual outputs)

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