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

Michael A. van Es; Jan H. Veldink; Christiaan G. J. Saris; Hylke M. Blauw; Paul W. J. van Vught; Anna Birve; Robin Lemmens; Helenius J. Schelhaas; Ewout J. N. Groen; Mark H. B. Huisman; Anneke J. van der Kooi; Marianne de Visser; Caroline Dahlberg; Karol Estrada; Fernando Rivadeneira; Albert Hofman; Machiel J. Zwarts; Perry T. C. van Doormaal; Dan Rujescu; Eric Strengman; Ina Giegling; Pierandrea Muglia; Barbara Tomik; Agnieszka Slowik; Andre G. Uitterlinden; Corinna Hendrich; Stefan Waibel; Thomas Meyer; Albert C. Ludolph; Jonathan D. Glass; Shaun Purcell; Sven Cichon; Markus M. Noethen; H-Erich Wichmann; Stefan Schreiber; Sita H. H. M. Vermeulen; Lambertus A. Kiemeney; John H. J. Wokke; Simon Cronin; Russell L. McLaughlin; Orla Hardiman; Katsumi Fumoto; R. Jeroen Pasterkamp; Vincent Meininger; Judith Melki; P. Nigel Leigh; Christopher E. Shaw; John E. Landers; Ammar Al-Chalabi; Robert H. Brown; Wim Robberecht; Peter M. Andersen; Roel A. Ophoff; Leonard H. 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

Michael A. van Es, Jan H. Veldink, Christiaan G. J. Saris, Hylke M. Blauw, Paul W. J. van Vught, Anna Birve, Robin Lemmens, Helenius J. Schelhaas, Ewout J. N. Groen, Mark H. B. Huisman, Anneke J. van der Kooi, Marianne de Visser, Caroline Dahlberg, Karol Estrada, Fernando Rivadeneira, Albert Hofman, Machiel J. Zwarts, Perry T. C. van Doormaal, Dan Rujescu, Eric StrengmanIna Giegling, Pierandrea Muglia, Barbara Tomik, Agnieszka Slowik, Andre G. Uitterlinden, Corinna Hendrich, Stefan Waibel, Thomas Meyer, Albert C. Ludolph, Jonathan D. Glass, Shaun Purcell, Sven Cichon, Markus M. Noethen, H-Erich Wichmann, Stefan Schreiber, Sita H. H. M. Vermeulen, Lambertus A. Kiemeney, John H. J. Wokke, Simon Cronin, Russell L. McLaughlin, Orla Hardiman, Katsumi Fumoto, R. Jeroen Pasterkamp, Vincent Meininger, Judith Melki, P. Nigel Leigh, Christopher E. Shaw, John E. Landers, Ammar Al-Chalabi, Robert H. Brown, Wim Robberecht, Peter M. Andersen, Roel A. Ophoff, Leonard H. van den Berg^*

^*Corresponding author for this work

Deanery of Biomedical Sciences

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

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	English
Pages (from-to)	1083-7
Number of pages	6
Journal	Nature Genetics
Volume	41
Issue number	10
DOIs	https://doi.org/10.1038/ng.442
Publication status	Published - Oct 2009

Keywords / Materials (for Non-textual outputs)

FRONTOTEMPORAL DEMENTIA
CONFERS SUSCEPTIBILITY
CHROMOSOME 9P
POPULATION
DISEASE
VARIANTS
RELEASE
LINKAGE
HAPMAP
DESIGN

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https://www.nature.com/articles/ng.442

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van Es, M. A., Veldink, J. H., Saris, C. G. J., Blauw, H. M., van Vught, P. W. J., Birve, A., Lemmens, R., Schelhaas, H. J., Groen, E. J. N., Huisman, M. H. B., van der Kooi, A. J., de Visser, M., Dahlberg, C., Estrada, K., Rivadeneira, F., Hofman, A., Zwarts, M. J., van Doormaal, P. T. C., Rujescu, D., ... van den Berg, L. H. (2009). Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature Genetics, 41(10), 1083-7. 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.",

keywords = "FRONTOTEMPORAL DEMENTIA, CONFERS SUSCEPTIBILITY, CHROMOSOME 9P, POPULATION, DISEASE, VARIANTS, RELEASE, LINKAGE, HAPMAP, DESIGN",

author = "{van Es}, {Michael A.} and Veldink, {Jan H.} and Saris, {Christiaan G. J.} and Blauw, {Hylke M.} and {van Vught}, {Paul W. J.} and Anna Birve and Robin Lemmens and Schelhaas, {Helenius J.} and Groen, {Ewout J. N.} and Huisman, {Mark H. B.} and {van der Kooi}, {Anneke J.} and {de Visser}, Marianne and Caroline Dahlberg and Karol Estrada and Fernando Rivadeneira and Albert Hofman and Zwarts, {Machiel J.} and {van Doormaal}, {Perry T. C.} and Dan Rujescu and Eric Strengman and Ina Giegling and Pierandrea Muglia and Barbara Tomik and Agnieszka Slowik and Uitterlinden, {Andre G.} and Corinna Hendrich and Stefan Waibel and Thomas Meyer and Ludolph, {Albert C.} and Glass, {Jonathan D.} and Shaun Purcell and Sven Cichon and Noethen, {Markus M.} and H-Erich Wichmann and Stefan Schreiber and Vermeulen, {Sita H. H. M.} and Kiemeney, {Lambertus A.} and Wokke, {John H. J.} and Simon Cronin and McLaughlin, {Russell L.} and Orla Hardiman and Katsumi Fumoto and Pasterkamp, {R. Jeroen} and Vincent Meininger and Judith Melki and Leigh, {P. Nigel} and Shaw, {Christopher E.} and Landers, {John E.} and Ammar Al-Chalabi and Brown, {Robert H.} and Wim Robberecht and Andersen, {Peter M.} and Ophoff, {Roel A.} and {van den Berg}, {Leonard H.}",

year = "2009",

month = oct,

doi = "10.1038/ng.442",

language = "English",

volume = "41",

pages = "1083--7",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

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, de Visser, M, Dahlberg, C, Estrada, K, Rivadeneira, F, Hofman, A, Zwarts, MJ, van Doormaal, PTC, Rujescu, D, Strengman, E, Giegling, I, Muglia, P, Tomik, B, Slowik, A, Uitterlinden, AG, Hendrich, C, Waibel, S, Meyer, T, Ludolph, AC, Glass, JD, Purcell, S, Cichon, S, Noethen, MM, Wichmann, H-E, 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. 1083-7. 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, Michael A.

AU - Veldink, Jan H.

AU - Saris, Christiaan G. J.

AU - Blauw, Hylke M.

AU - van Vught, Paul W. J.

AU - Birve, Anna

AU - Lemmens, Robin

AU - Schelhaas, Helenius J.

AU - Groen, Ewout J. N.

AU - Huisman, Mark H. B.

AU - van der Kooi, Anneke J.

AU - de Visser, Marianne

AU - Dahlberg, Caroline

AU - Estrada, Karol

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Zwarts, Machiel J.

AU - van Doormaal, Perry T. C.

AU - Rujescu, Dan

AU - Strengman, Eric

AU - Giegling, Ina

AU - Muglia, Pierandrea

AU - Tomik, Barbara

AU - Slowik, Agnieszka

AU - Uitterlinden, Andre G.

AU - Hendrich, Corinna

AU - Waibel, Stefan

AU - Meyer, Thomas

AU - Ludolph, Albert C.

AU - Glass, Jonathan D.

AU - Purcell, Shaun

AU - Cichon, Sven

AU - Noethen, Markus M.

AU - Wichmann, H-Erich

AU - Schreiber, Stefan

AU - Vermeulen, Sita H. H. M.

AU - Kiemeney, Lambertus A.

AU - Wokke, John H. J.

AU - Cronin, Simon

AU - McLaughlin, Russell L.

AU - Hardiman, Orla

AU - Fumoto, Katsumi

AU - Pasterkamp, R. Jeroen

AU - Meininger, Vincent

AU - Melki, Judith

AU - Leigh, P. Nigel

AU - Shaw, Christopher E.

AU - Landers, John E.

AU - Al-Chalabi, Ammar

AU - Brown, Robert H.

AU - Robberecht, Wim

AU - Andersen, Peter M.

AU - Ophoff, Roel A.

AU - van den Berg, Leonard H.

PY - 2009/10

Y1 - 2009/10

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.

KW - FRONTOTEMPORAL DEMENTIA

KW - CONFERS SUSCEPTIBILITY

KW - CHROMOSOME 9P

KW - POPULATION

KW - DISEASE

KW - VARIANTS

KW - RELEASE

KW - LINKAGE

KW - HAPMAP

KW - DESIGN

U2 - 10.1038/ng.442

DO - 10.1038/ng.442

M3 - Letter

SN - 1061-4036

VL - 41

SP - 1083

EP - 1087

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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