Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewishthan in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencingof Ashkenazi Jewishpatients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2gene that conferred risk for CD (N2081D variant, P = 9.5 × 10 −10 ) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10 −8 ). These variants affected CD age of onset, disease location, LRRK2activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2in CD pathogenesis. Analysis of the extended LRRK2locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewishand non-Jewish cohorts. The LRRK2N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphatebinding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.