Functional Variants in LRRK 2 Confer Pleiotropic 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 Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2,066 CD cases and 3,633 healthy controls. We detected association signals in the LRRK2 gene that conferred CD risk (N2081D variant, P=9.5×10−10) or protection (N551K variant, tagging R1398H-associated haplotype, P=3.3×10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with similar genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D 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 is associated with increased kinase activity, whereas neither N551K nor R1398H on the protective haplotype altered kinase activity. R1398H, but not N551K, increased GTPase activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined Corresponding author: inga.peter@mssm.edu. *Equal contribution Overline: Crohn’s Disease Author Contributions Primary analysis and manuscript-writing (K.Y.H.); project conception and design (I.Peter; J.H.C.; R.J.D.; D.P.B.M.); patient recruitment, sample acquisition, phenotype data collection for Crohn’s disease, Parkinson’s disease, and control datasets for a total of >24,000 study subjects (N.B.; S.R.B.; A.S.C.; R.H.D.; S.K.; D.P.B.M.; J.D.R.; A.S.; N.P.; A.L.; E.R.S.; M.S.S.; S.B.; R.H.M.; L.O.; H.P.; W.K.S.; J.M.V.; T.F., G.A.; L.N.C.; T.L.; P.R.L.); data processing, preparation, and analysis (K.Y.H.; N.P.; M.R.; K.G.; S.C.; H.O.; T.H.; D.L.; M.J.D.; I. Pe’er; E.E.S.); functional study design (J.H.; Z.Y.; Y.P.;Y.I.; I.U.B.); performing experiments (H.F.H.; A.S.;J.H.; X.B.; X.L.; D.R.; N.V.; N.Y.H; L.S.C.; E.C.); manuscript writing (K.Y.H.; I.Peter; J.H.C.; J.H.; S.C.; H.F.H.; E.E.S.). Competing Interests RJD has consulted for Amicus Therapeutics, Alexion Pharmaceuticals, Genzyme-Sanofi, Kiniksa Pharmaceuticals, Mitsubishi-Tanabe, Synageva Pharmaceuticals, Recordati Rare Diseases, Sangamo Therapeutics, and has received royalties from Shire. Shire: Royalties YI has consulted for Neurotrope, Inc and Amathus Therapeutics, Inc. SC has consulted for MyHeritage ASC has consulted for AbbVie Pharmaceuticals, Janssen Pharmaceuticals, Takeda Pharmaceuticals, Pfeizer Pharmaceuticals, Ferring Pharmaceuticals, Miraca Life Sciences DM has consulted for Janssen Pharmaceutical, UCB, Merck, Cidara, Qu Biologics. The other authors declare no competing interests. Data Availability: Samples from the Ashkenazi Genome Consortium are available from member institutions through a Material Transfer Agreement. HHS Public Access Author manuscript Sci Transl Med. Author manuscript; available in PMC 2018 July 10. Published in final edited form as: Sci Transl Med. 2018 January 10; 10(423): . doi:10.1126/scitranslmed.aai7795. A uhor M anscript