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.
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Christiaan G J
authors.initials: CG
authors.lastname: Saris
authors.forename: Hylke M
authors.initials: HM
authors.lastname: Blauw
authors.forename: Paul W J
authors.initials: PW
authors.lastname: van Vught
authors.forename: Anna
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authors.lastname: Birve
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: Helenius J
authors.initials: HJ
authors.lastname: Schelhaas
authors.forename: Ewout J N
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authors.lastname: Huisman
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authors.lastname: van der Kooi
authors.forename: Marianne
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authors.lastname: de Visser
authors.forename: Caroline
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authors.lastname: Dahlberg
authors.forename: Karol
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authors.forename: Fernando
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authors.lastname: Rivadeneira
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Machiel J
authors.initials: MJ
authors.lastname: Zwarts
authors.forename: Perry T C
authors.initials: PT
authors.lastname: van Doormaal
authors.forename: Dan
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authors.lastname: Rujescu
authors.forename: Eric
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authors.lastname: Strengman
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Muglia
authors.forename: Barbara
authors.initials: B
authors.lastname: Tomik
authors.forename: Agnieszka
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authors.lastname: Slowik
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Corinna
authors.initials: C
authors.lastname: Hendrich
authors.forename: Stefan
authors.initials: S
authors.lastname: Waibel
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.forename: Shaun
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authors.lastname: Purcell
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Sita H H M
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: John H J
authors.initials: JH
authors.lastname: Wokke
authors.forename: Simon
authors.initials: S
authors.lastname: Cronin
authors.forename: Russell L
authors.initials: RL
authors.lastname: McLaughlin
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fumoto
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D002899:Chromosomes, Human, Pair 9; D004198:Disease Susceptibility; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide