A large genome scan for rare CNVs in amyotrophic lateral sclerosis

HM Blauw; A Al-Chalabi; PM Andersen; PWJ Van Vught; FP Diekstra; MA van Es; CGJ Saris; EJN Groen; W van Rheenen; M Koppers; R van 't Slot; E Strengman; Karol Estrada Gil; Fernando Rivadeneira; Bert Hofman; André Uitterlinden; LA Kiemeney; SHM Vermeulen; A Birve; S Waibel; T Meyer; S Cronin; RL McLaughlin; O Hardiman; PC Sapp; MD Tobin; LV Wain; B Tomik; A Slowik; R Lemmens; D Rujescu; C Schulte; T Gasser; RH Brown; JE Landers; W Robberecht; AC Ludolph; RA Ophoff; JH Veldink; LH van den Berg

doi:10.1093/hmg/ddq323

A large genome scan for rare CNVs in amyotrophic lateral sclerosis

HM Blauw, A Al-Chalabi, PM Andersen, PWJ Van Vught, FP Diekstra, MA van Es, CGJ Saris, EJN Groen, W van Rheenen, M Koppers, R van 't Slot, E Strengman, Karol Estrada Gil, Fernando Rivadeneira, Bert Hofman, André Uitterlinden, LA Kiemeney, SHM Vermeulen, A Birve, S WaibelT Meyer, S Cronin, RL McLaughlin, O Hardiman, PC Sapp, MD Tobin, LV Wain, B Tomik, A Slowik, R Lemmens, D Rujescu, C Schulte, T Gasser, RH Brown, JE Landers, W Robberecht, AC Ludolph, RA Ophoff, JH Veldink, LH van den Berg

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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	Undefined/Unknown
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 - 2010

Research programs

EMC MM-01-39-02
EMC NIHES-01-64-01

Access to Document

10.1093/hmg/ddq323

http://hdl.handle.net/1765/21314

Cite this

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 Gil, K., Rivadeneira, F., Hofman, B., Uitterlinden, A., Kiemeney, LA., Vermeulen, SHM., Birve, A., ... van den Berg, LH. (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

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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.",

author = "HM Blauw and A Al-Chalabi and PM Andersen and {Van Vught}, PWJ and FP Diekstra and {van Es}, MA and CGJ Saris and EJN Groen and {van Rheenen}, W and M Koppers and {van 't Slot}, R and E Strengman and {Estrada Gil}, Karol and Fernando Rivadeneira and Bert Hofman and Andr{\'e} Uitterlinden and LA Kiemeney and SHM Vermeulen and A Birve and S Waibel and T Meyer and S Cronin and RL McLaughlin and O Hardiman and PC Sapp and MD Tobin and LV Wain and B Tomik and A Slowik and R Lemmens and D Rujescu and C Schulte and T Gasser and RH Brown and JE Landers and W Robberecht and AC Ludolph and RA Ophoff and JH Veldink and {van den Berg}, LH",

year = "2010",

doi = "10.1093/hmg/ddq323",

language = "Undefined/Unknown",

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 Gil, K, Rivadeneira, F , Hofman, B , Uitterlinden, A, 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, HM

AU - Al-Chalabi, A

AU - Andersen, PM

AU - Van Vught, PWJ

AU - Diekstra, FP

AU - van Es, MA

AU - Saris, CGJ

AU - Groen, EJN

AU - van Rheenen, W

AU - Koppers, M

AU - van 't Slot, R

AU - Strengman, E

AU - Estrada Gil, Karol

AU - Rivadeneira, Fernando

AU - Hofman, Bert

AU - Uitterlinden, André

AU - Kiemeney, LA

AU - Vermeulen, SHM

AU - Birve, A

AU - Waibel, S

AU - Meyer, T

AU - Cronin, S

AU - McLaughlin, RL

AU - Hardiman, O

AU - Sapp, PC

AU - Tobin, MD

AU - Wain, LV

AU - Tomik, B

AU - Slowik, A

AU - Lemmens, R

AU - Rujescu, D

AU - Schulte, C

AU - Gasser, T

AU - Brown, RH

AU - Landers, JE

AU - Robberecht, W

AU - Ludolph, AC

AU - Ophoff, RA

AU - Veldink, JH

AU - van den Berg, LH

PY - 2010

Y1 - 2010

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.

U2 - 10.1093/hmg/ddq323

DO - 10.1093/hmg/ddq323

M3 - Article

C2 - 20685689

SN - 0964-6906

VL - 19

SP - 4091

EP - 4099

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 20

ER -