Published online before print March 25, 2009, doi:10.1212/WNL.0b013e3181a18674)

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NEUROLOGY 2009;73:16-24
© 2009 American Academy of Neurology

A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS

A. -M. Wills, MD, S. Cronin, PhD, MRCPI, A. Slowik, MD, D. Kasperaviciute, PhD, M. A. Van Es, MD, J. M. Morahan, PhD, P. N. Valdmanis, BSc, V. Meininger, MD, PhD, J. Melki, MD, PhD, C. E. Shaw, MD, FRACP, FRCP, G. A. Rouleau, MD, PhD, E.M.C. Fisher, PhD, P. J. Shaw, MD, K. E. Morrison, DPhil, R. Pamphlett, MD, FRACP, L. H. Van den Berg, MD, PhD, D. A. Figlewicz, PhD, P. M. Andersen, MD, PhD, A. Al-Chalabi, PhD, FRCP, O. Hardiman, MD, FRCPI, S. Purcell, PhD, J. E. Landers, PhD and R. H. Brown, Jr, MD, DPhil

Authors' affiliations are listed at the end of the article.
From the Cecil B. Day Neuromuscular Research Laboratory (A.-M.W., J.E.L., R.H.B.), Massachusetts General Hospital, Charlestown; Department of Neurology (S.C., O.H.), Beaumont Hospital, Dublin, Ireland; Department of Neurology (A.S.), Jagiellonian University, Krakow, Poland; Department of Neurodegenerative Disease (D.K., E.M.C.F.), UCL Institute of Neurology, London, UK; Netherlands ALS Center Department of Neurology (M.A.V.E., L.H.V.d.B.), Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands; The Stacey MND Laboratory (J.M.M., R.P.), Department of Pathology, The University of Sydney, Australia; Department of Molecular and Clinical Genetics (J.M.M.), Royal Prince Alfred Hospital, Australia; Center of Excellence in Neuromics (P.N.V., G.A.R.), University of Montreal, CHUM Research Center, and the Department of Medicine, University of Montreal, Canada; Centre Référent SLA (V.M.), Hôpital Salpêtrière, Paris, France; Department of Human Genetics (J.M.), Hadassah University Hospital, Jerusalem, Israel; MRC Centre for Neurodegeneration Research (C.E.S., A.A.-C.), King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, London, UK; Academic Neurology Unit (P.J.S,), Medical School, University of Sheffield, UK; Department of Clinical Neurosciences (K.E.M.), Institute of Biomedical Research, The Medical School, University of Birmingham, UK; University of Michigan (D.A.F.), Ann Arbor, MI and the ALS Society of Canada; Department of Neurology (P.M.A.), Umeå University Hospital, Sweden; Trinity College Institute of Neuroscience (O.H.), Trinity College, Dublin, Ireland; and Center for Human Genetics Research, Richard B. Simches Research Building (S.P.), Massachusetts General Hospital, Boston, MA.

Address correspondence and reprint requests to Dr. Wills, CNY 114-3125, 114 16th St, Charlestown, MA 02129 awills{at}partners.org.

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.

Abbreviations: ALS = amyotrophic lateral sclerosis; CI = confidence interval; GWAS = genome-wide association studies; OR = odds ratio; SALS = sporadic ALS; SNP = single nucleotide polymorphism.

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Supplemental data at www.neurology.org

Editorial, page 11.

e-Pub ahead of print on March 25, 2009, at www.neurology.org.

Support information is provided at the end of the article.

Disclosure: The authors report no disclosures.

Devices: GoldenGate assay, Illumina BeadArray station, Infinium II SNP Chip assays, Human Hap550K SNP chips, HumanHap 300K SNP chips (Illumina, San Diego, CA); KASPar PCR system (KBiosciences, Hertfordshire, UK); SNaPshot® assay (Applied Biosystems, Foster City, CA).

Received September 12, 2008. Accepted in final form January 5, 2009.

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