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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.
* To whom correspondence should be addressed. E-mail: 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Methods: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425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.
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  D. A. Greenberg, W. C.L. Stewart, and L. P. Rowland Paraoxonase genes and susceptibility to ALS Neurology, July 7, 2009; 73(1): 11 - 12. [Full Text] [PDF]
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