AbstractIdiopathic Parkinson's disease is a common movement disorder characterized by a loss of dopaminergic neurons in the substantia nigra. Its pathogenesis is postulated to involve complex interactions between genetic susceptibility and environmental exposures. The IGF2‐INS‐TH gene cluster on the telomeric end of human chromosome 11 is a gene rich region expressing several proteins important for dopamine neuron homeostasis. We used a haplotyping approach to determine whether common genetic variation in the IGF2‐INS‐TH cluster influences the risk of idiopathic Parkinson's disease in a Caucasian case–control group recruited from Brisbane, Australia. Three tagging polymorphisms, the SNPs, rs680 and rs689 and the microsatellite, HUMTH01, were genotyped in 215 cases and 215 age‐ and gender‐matched controls. Eight common haplotypes accounted for 91% of the genetic variation in our control group and one haplotype, IGF2‐INS‐TH*6, was significantly under‐represented among the cases with idiopathic Parkinson's disease (OR = 0.42, 95% CI = 0.25–0.72, P‐value = 0.001). Analysis of the individual polymorphisms showed that the IGF2‐rs680 alternate ‘A’ allele accounted for the majority of the protective effect. Our findings suggest that common genetic variants in the IGF2‐INS‐TH cluster modify susceptibility to idiopathic Parkinson's disease. © 2007 Wiley‐Liss, Inc.