The aim of our study was to discover genomic variations related to variant Creutzfeldt-Jakob disease (vCJD) susceptibility. A genome-wide association analysis with most vCJD samples available in the world was performed. A series of 93 vCJD UK patients and 1504 UK controls were included in the discovery stage. Our best findings were replicated in an independent population of 22 UK and 20 French vCJD cases. Post hoc analysis to assess our main results included 5711 French controls, 445 Dutch controls, and 446 sporadic Creutzfeldt-Jakob disease (CJD) cases. We found 2 genome wide significant variants tagging PRNP: rs6107516 (p = 2.6 x 10(-18)) and rs2065706 (p = 8.8 x 10(-14)). Two other single nucleotide polymorphisms (SNPs) (rs4921542 and rs7565981) were successfully replicated in independent samples and reached genome-wide significance after pooling discovery and replication populations. Rs4921542 (p = 1.6 x 10(-8)) is an intronic variant in the myotubularin related protein 7 gene (MTMR7), which is specifically expressed in the central nervous system (CNS) and dephosphorylates phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate. Rs7565981 (p = 4.2 x 10(-8)) is in an intergenic region upstream of the neuronal PAS (per-ARNT-sim) domain-containing protein 2 gene (NPAS2), a regulatory gene belonging to a family of transcription factors that has been implicated in memory, seasonal affective disorder, and the molecular clock in the mammalian forebrain. A proxy of rs7565981 (rs17024792; r(2) = 1.0) has been found to regulate the phospholipase C-delta-3 gene (PLCD3) in trans. This enzyme catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate. Our study reveals 2 new genome-wide significant markers for vCJD outside PRNP and provides evidence supporting a role of the phosphatidylinositol pathway in vCJD susceptibility. (C) 2012 Elsevier Inc. All rights reserved.