A Rare Truncating Mutation in ADH1C (G78Stop) Shows Significant Association With Parkinson Disease in a Large International Sample

Patients: The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls. Results:ThepreviouslyidentifiedassociationwithanADH class IV allele remained significant (P.02) in the extended Swedish study. Furthermore, in the international collaboration,theG78stopmutationinADH1Cwasfound in22(2.0%)ofthePDpatientsbutonlyin6controls(0.6%). Thisassociationwasstatisticallysignificant( 2 1=7.5;2-sided P=.007; odds ratio, 3.25 [95% confidence interval, 1.318.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder. Conclusion: Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD. Arch Neurol. 2005;62:74-78