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 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene 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, 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 shared 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 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 triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.
Bibliographical noteFunding Information:
We thank A. Diaz of the University of Miami for the technical assistance. Funding: We acknowledge financial support from the NIH [research grants GM007205 and DK098927 (to K.Y.H.); DK62429, DK062422, DK092235, and DK106593 (to J.H.C.); DK062413, DK046763-19, AI067068, and HS021747 (to D.P.B.M.); DK062431 (to S.R.B.); AG042188 (to G.A.); NS050487 and NS060113 (to L.N.C.); MH089964, MH095458, and MH084098 (to T.L.); AG618381, AG021654, and AG038072 (to N.B.); NS071674 (to J.M.V.); NS37167 and NS036711 (to T.F.); NS076843 (to R.H.M.); NS036960 (to H.P.); DK062420 and CA141743 (to R.H.D.); CA121852 (to I. Pe'er); and NS060809 (to Z.Y.)]; the NSF [research grants 08929882 and 0845677 (to I. Pe'er)]; the Human Frontier Science Program (to S.C.); the Lewis and Rachel Rudin Foundation (to H.O.); the Northwell Health Foundation, the Brain & Behaviour Foundation, and the United States-Israel Binational Science Foundation (to T.L.); the Nathan Shock Center of Excellence for the Biology of Aging and the Glenn Center for the Biology of Human Aging (to N.B.); the New York Crohn's Foundation (to R.J.D., I. Peter, and Y.P.); Edwin and Caroline Levy and Joseph and Carol Reich (to S.B.); Sinai Ulcerative Colitis: Experimental and Systems Studies (SUCCESS) grant (to J.H.C. and I. Peter); the Sanford J. Grossman Charitable Trust (to J.H.C.); the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds (European Union grant no. IBD-BIOM 305479); the Crohn's and Colitis Foundation and the Joshua L. and Lisa Z. Greer Chair in IBD Genetics (to D.P.B.M.); The Leona M. and Harry B. Helmsley Charitable Trust (to D.P.B.M and I. Peter); the Parkinson's Disease Foundation (to L.N.C.); the Meyerhoff Inflammatory Bowel Disease Center and the Atran Foundation (to S.R.B.); the University of Pittsburgh Inflammatory Bowel Disease Genetic Research Chair (to R.H.D.); the Robert P. & Judith N. Goldberg Foundation, the Bumpus Foundation, and the Harvard NeuroDiscovery Center (to T.F.); and The Charles Wolfson Charitable Trust (to A.W.S., A.P.L., E.R.S., and N. Pontikos). Genotyping services for selected PD cohorts were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to Johns Hopkins University (contract no. HHSN268200782096C). Author contributions: K.Y.H. conducted the primary analysis and wrote the manuscript. I. Peter, J.H.C., R.J.D., and D.P.B.M. conceptualized and designed the project. N.B., S.R.B., A.S.C., R.H.D., S.K., D.P.B.M., J.D.R., A.S., N. Pontikos, A.P.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., A.W.S., and P.R.L. recruited the patients, acquired the samples, and collected the phenotype data for CD, PD, and control data sets (for a total of >24,000 study subjects). K.Y.H., N. Pankratz, M.R., K.G., S.C., H.O., T.H., D.L., M.J.D., I. Pe'er, and E.E.S. processed, prepared, and analyzed the data. J.H., Z.Y., Y.P., Y.I., and I.U.-B. provided the model for functional studies. H.F.-H., A.S., J.H., X.B., X.L., D.R., N.V., N.-Y.H., L.-S.C., and E.C. performed the experiments. K.Y.H., I. Peter, J.H.C., J.H., S.C., H.F.-H., and E.E.S. wrote the manuscript. Competing interests: R.J.D. has consulted for Amicus Therapeutics, Alexion Pharmaceuticals, Genzyme-Sanofi, Kiniksa Pharmaceuticals, Mitsubishi-Tanabe, Synageva Pharmaceuticals, Recordati Rare Diseases, and Sangamo Therapeutics and has received royalties from Shire. Y.I. has consulted for Neurotrope Inc. and Amathus Therapeutics Inc. S.C. has consulted for MyHeritage. A.S.C. has consulted for AbbVie Pharmaceuticals, Janssen Pharmaceuticals, Takeda Pharmaceuticals, Pfizer Pharmaceuticals, Ferring Pharmaceuticals, and Miraca Life Sciences. D.P.B.M. has consulted for Janssen Pharmaceuticals, UCB, Merck, Cidara, and Qu Biologics. All other authors declare that they have no competing interests. Data and materials availability: Samples from the Ashkenazi Genome Consortium are available from member institutions through a material transfer agreement.