title: A high-density genome-wide association screen of sporadic ALS in US veterans.
abstract: Following reports of an increased incidence of amyotrophic lateral sclerosis (ALS) in U.S. veterans, we have conducted a high-density genome-wide association study (GWAS) of ALS outcome and survival time in a sample of U.S. veterans. We tested ∼1.3 million single nucleotide polymorphisms (SNPs) for association with ALS outcome in 442 incident Caucasian veteran cases diagnosed with definite or probable ALS and 348 Caucasian veteran controls. To increase power, we also included genotypes from 5909 publicly-available non-veteran controls in the analysis. In the survival analysis, we tested for association between SNPs and post-diagnosis survival time in 639 Caucasian veteran cases with definite or probable ALS. After this discovery phase, we performed follow-up genotyping of 299 SNPs in an independent replication sample of Caucasian veterans and non-veterans (ALS outcome: 183 cases and 961 controls; survival: 118 cases). Although no SNPs reached genome-wide significance in the discovery phase for either phenotype, three SNPs were statistically significant in the replication analysis of ALS outcome: rs6080539 (177 kb from PCSK2), rs7000234 (4 kb from ZNF704), and rs3113494 (13 kb from LOC100506746). Two SNPs located in genes that were implicated by previous GWA studies of ALS were marginally significant in the pooled analysis of discovery and replication samples: rs17174381 in DPP6 (p = 4.4×10(-4)) and rs6985069 near ELP3 (p = 4.8×10(-4)). Our results underscore the difficulty of identifying and convincingly replicating genetic associations with a rare and genetically heterogeneous disorder such as ALS, and suggest that common SNPs are unlikely to account for a substantial proportion of patients affected by this devastating disorder.
authors.affiliation: Durham Veterans Affairs Medical Center, Durham, North Carolina, United States of America.
authors.forename: Lydia Coulter
authors.initials: LC
authors.lastname: Kwee
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gibson
authors.forename: Annjanette
authors.initials: A
authors.lastname: Stone
authors.forename: Steven A
authors.initials: SA
authors.lastname: Schichman
authors.forename: Freya
authors.initials: F
authors.lastname: Kamel
authors.forename: Lorene M
authors.initials: LM
authors.lastname: Nelson
authors.forename: Barbara
authors.initials: B
authors.lastname: Topol
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Van den Eeden
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Tanner
authors.forename: Merit E
authors.initials: ME
authors.lastname: Cudkowicz
authors.forename: Daniela L
authors.initials: DL
authors.lastname: Grasso
authors.forename: Robert
authors.initials: R
authors.lastname: Lawson
authors.forename: Sumitra
authors.initials: S
authors.lastname: Muralidhar
authors.forename: Eugene Z
authors.initials: EZ
authors.lastname: Oddone
authors.forename: Silke
authors.initials: S
authors.lastname: Schmidt
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics; D016016:Proportional Hazards Models; D016019:Survival Analysis; D014481:United States; D014728:Veterans; D044465:White People / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases