Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

MA van Es; JH Veldink; CGJ Saris; HM Blauw; PWJ Van Vught; A Birve; R Lemmens; HJ Schelhaas; EJN Groen; MHB Huisman; AJ van der Kooi; Martje Visser; C Dahlberg; Karol Estrada Gil; Fernando Rivadeneira; Bert Hofman; MJ Zwarts; PTC van Doormaal; D Rujescu; E Strengman; I Giegling; P Muglia; B Tomik; A Slowik; André Uitterlinden; C Hendrich; S Waibel; T Meyer; AC Ludolph; JD Glass; S Purcell; S Cichon; MM Nothen; HE Wichmann; S Schreiber; SHHM Vermeulen; LA Kiemeney; JHJ Wokke; S Cronin; RL McLaughlin; O Hardiman; K Fumoto; RJ Pasterkamp; V Meininger; J Melki; PN Leigh; CE Shaw; JE Landers; A Al-Chalabi; RH Brown; W Robberecht; PM Andersen; RA Ophoff; LH van den Berg

doi:10.1038/ng.442

Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

MA van Es, JH Veldink, CGJ Saris, HM Blauw, PWJ Van Vught, A Birve, R Lemmens, HJ Schelhaas, EJN Groen, MHB Huisman, AJ van der Kooi, Martje Visser, C Dahlberg, Karol Estrada Gil, Fernando Rivadeneira, Bert Hofman, MJ Zwarts, PTC van Doormaal, D Rujescu, E StrengmanI Giegling, P Muglia, B Tomik, A Slowik, André Uitterlinden, C Hendrich, S Waibel, T Meyer, AC Ludolph, JD Glass, S Purcell, S Cichon, MM Nothen, HE Wichmann, S Schreiber, SHHM Vermeulen, LA Kiemeney, JHJ Wokke, S Cronin, RL McLaughlin, O Hardiman, K Fumoto, RJ Pasterkamp, V Meininger, J Melki, PN Leigh, CE Shaw, JE Landers, A Al-Chalabi, RH Brown, W Robberecht, PM Andersen, RA Ophoff, LH van den Berg

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Abstract

We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.

Original language	Undefined/Unknown
Pages (from-to)	1083-U53
Journal	Nature Genetics
Volume	41
Issue number	10
DOIs	https://doi.org/10.1038/ng.442
Publication status	Published - 2009

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Cite this

van Es, MA., Veldink, JH., Saris, CGJ., Blauw, HM., Van Vught, PWJ., Birve, A., Lemmens, R., Schelhaas, HJ., Groen, EJN., Huisman, MHB., van der Kooi, AJ., Visser, M., Dahlberg, C., Estrada Gil, K., Rivadeneira, F., Hofman, B., Zwarts, MJ., van Doormaal, PTC., Rujescu, D., ... van den Berg, LH. (2009). Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature Genetics, 41(10), 1083-U53. https://doi.org/10.1038/ng.442

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title = "Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis",

abstract = "We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.",

author = "{van Es}, MA and JH Veldink and CGJ Saris and HM Blauw and {Van Vught}, PWJ and A Birve and R Lemmens and HJ Schelhaas and EJN Groen and MHB Huisman and {van der Kooi}, AJ and Martje Visser and C Dahlberg and {Estrada Gil}, Karol and Fernando Rivadeneira and Bert Hofman and MJ Zwarts and {van Doormaal}, PTC and D Rujescu and E Strengman and I Giegling and P Muglia and B Tomik and A Slowik and Andr{\'e} Uitterlinden and C Hendrich and S Waibel and T Meyer and AC Ludolph and JD Glass and S Purcell and S Cichon and MM Nothen and HE Wichmann and S Schreiber and SHHM Vermeulen and LA Kiemeney and JHJ Wokke and S Cronin and RL McLaughlin and O Hardiman and K Fumoto and RJ Pasterkamp and V Meininger and J Melki and PN Leigh and CE Shaw and JE Landers and A Al-Chalabi and RH Brown and W Robberecht and PM Andersen and RA Ophoff and {van den Berg}, LH",

year = "2009",

doi = "10.1038/ng.442",

language = "Undefined/Unknown",

volume = "41",

pages = "1083--U53",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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van Es, MA, Veldink, JH, Saris, CGJ, Blauw, HM, Van Vught, PWJ, Birve, A, Lemmens, R, Schelhaas, HJ, Groen, EJN, Huisman, MHB, van der Kooi, AJ, Visser, M, Dahlberg, C, Estrada Gil, K, Rivadeneira, F , Hofman, B, Zwarts, MJ, van Doormaal, PTC, Rujescu, D, Strengman, E, Giegling, I, Muglia, P, Tomik, B, Slowik, A, Uitterlinden, A, Hendrich, C, Waibel, S, Meyer, T, Ludolph, AC, Glass, JD, Purcell, S, Cichon, S, Nothen, MM, Wichmann, HE, Schreiber, S, Vermeulen, SHHM, Kiemeney, LA, Wokke, JHJ, Cronin, S, McLaughlin, RL, Hardiman, O, Fumoto, K, Pasterkamp, RJ, Meininger, V, Melki, J, Leigh, PN, Shaw, CE, Landers, JE, Al-Chalabi, A, Brown, RH, Robberecht, W, Andersen, PM, Ophoff, RA & van den Berg, LH 2009, 'Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis', Nature Genetics, vol. 41, no. 10, pp. 1083-U53. https://doi.org/10.1038/ng.442

TY - JOUR

T1 - Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

AU - van Es, MA

AU - Veldink, JH

AU - Saris, CGJ

AU - Blauw, HM

AU - Van Vught, PWJ

AU - Birve, A

AU - Lemmens, R

AU - Schelhaas, HJ

AU - Groen, EJN

AU - Huisman, MHB

AU - van der Kooi, AJ

AU - Visser, Martje

AU - Dahlberg, C

AU - Estrada Gil, Karol

AU - Rivadeneira, Fernando

AU - Hofman, Bert

AU - Zwarts, MJ

AU - van Doormaal, PTC

AU - Rujescu, D

AU - Strengman, E

AU - Giegling, I

AU - Muglia, P

AU - Tomik, B

AU - Slowik, A

AU - Uitterlinden, André

AU - Hendrich, C

AU - Waibel, S

AU - Meyer, T

AU - Ludolph, AC

AU - Glass, JD

AU - Purcell, S

AU - Cichon, S

AU - Nothen, MM

AU - Wichmann, HE

AU - Schreiber, S

AU - Vermeulen, SHHM

AU - Kiemeney, LA

AU - Wokke, JHJ

AU - Cronin, S

AU - McLaughlin, RL

AU - Hardiman, O

AU - Fumoto, K

AU - Pasterkamp, RJ

AU - Meininger, V

AU - Melki, J

AU - Leigh, PN

AU - Shaw, CE

AU - Landers, JE

AU - Al-Chalabi, A

AU - Brown, RH

AU - Robberecht, W

AU - Andersen, PM

AU - Ophoff, RA

AU - van den Berg, LH

PY - 2009

Y1 - 2009

N2 - We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.

AB - We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.

U2 - 10.1038/ng.442

DO - 10.1038/ng.442

M3 - Article

C2 - 19734901

SN - 1061-4036

VL - 41

SP - 1083-U53

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -