title: A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.
abstract: BACKGROUND
  Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding.
  
  
  METHODS
  We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls.
  
  
  RESULTS
  The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02-1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07-1.45, p = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86-1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92-1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97-1.16, p = 0.22).
  
  
  CONCLUSIONS
  In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS.
authors.affiliation: Cecil B Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, MA 02129, USA. awills@partners.org
authors.forename: A-M
authors.initials: AM
authors.lastname: Wills
authors.forename: S
authors.initials: S
authors.lastname: Cronin
authors.forename: A
authors.initials: A
authors.lastname: Slowik
authors.forename: D
authors.initials: D
authors.lastname: Kasperaviciute
authors.forename: M A
authors.initials: MA
authors.lastname: Van Es
authors.forename: J M
authors.initials: JM
authors.lastname: Morahan
authors.forename: P N
authors.initials: PN
authors.lastname: Valdmanis
authors.forename: V
authors.initials: V
authors.lastname: Meininger
authors.forename: J
authors.initials: J
authors.lastname: Melki
authors.forename: C E
authors.initials: CE
authors.lastname: Shaw
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: E M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: P J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: K E
authors.initials: KE
authors.lastname: Morrison
authors.forename: R
authors.initials: R
authors.lastname: Pamphlett
authors.forename: L H
authors.initials: LH
authors.lastname: Van den Berg
authors.forename: D A
authors.initials: DA
authors.lastname: Figlewicz
authors.forename: P M
authors.initials: PM
authors.lastname: Andersen
authors.forename: A
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: O
authors.initials: O
authors.lastname: Hardiman
authors.forename: S
authors.initials: S
authors.lastname: Purcell
authors.forename: J E
authors.initials: JE
authors.lastname: Landers
authors.forename: R H
authors.initials: RH
authors.lastname: Brown