PT  - JOURNAL ARTICLE
AU  - Hui, Ken Y.
AU  - Fernandez-Hernandez, Heriberto
AU  - Hu, Jianzhong
AU  - Schaffner, Adam
AU  - Pankratz, Nathan
AU  - Hsu, Nai-Yun
AU  - Chuang, Ling-Shiang
AU  - Carmi, Shai
AU  - Villaverde, Nicole
AU  - Li, Xianting
AU  - Rivas, Manual
AU  - Levine, Adam P.
AU  - Bao, Xiuliang
AU  - Labrias, Philippe R.
AU  - Haritunians, Talin
AU  - Ruane, Darren
AU  - Gettler, Kyle
AU  - Chen, Ernie
AU  - Li, Dalin
AU  - Schiff, Elena R.
AU  - Pontikos, Nikolas
AU  - Barzilai, Nir
AU  - Brant, Steven R.
AU  - Bressman, Susan
AU  - Cheifetz, Adam S.
AU  - Clark, Lorraine N.
AU  - Daly, Mark J.
AU  - Desnick, Robert J.
AU  - Duerr, Richard H.
AU  - Katz, Seymour
AU  - Lencz, Todd
AU  - Myers, Richard H.
AU  - Ostrer, Harry
AU  - Ozelius, Laurie
AU  - Payami, Haydeh
AU  - Peter, Yakov
AU  - Rioux, John D.
AU  - Segal, Anthony W.
AU  - Scott, William K.
AU  - Silverberg, Mark S.
AU  - Vance, Jeffery M.
AU  - Ubarretxena-Belandia, Iban
AU  - Foroud, Tatiana
AU  - Atzmon, Gil
AU  - Pe’er, Itsik
AU  - Ioannou, Yiannis
AU  - McGovern, Dermot P. B.
AU  - Yue, Zhenyu
AU  - Schadt, Eric E.
AU  - Cho, Judy H.
AU  - Peter, Inga
TI  - Functional variants in the <em>LRRK2</em> gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease
AID  - 10.1126/scitranslmed.aai7795
DP  - 2018 Jan 10
TA  - Science Translational Medicine
PG  - eaai7795
VI  - 10
IP  - 423
4099  - http://stm.sciencemag.org/content/10/423/eaai7795.short
4100  - http://stm.sciencemag.org/content/10/423/eaai7795.full
AB  - Crohn’s disease (CD), an inflammatory bowel disease, has a relatively high prevalence in Ashkenazi Jewish populations. Hui et al. conducted genome-wide association analysis in 2066 CD patients and 3633 healthy control individuals of Ashkenazi Jewish ancestry and identified two functional variants in the LRRK2 gene. The LRRK2 gene has been previously linked to the development of Parkinson’s disease (PD). The new LRRK2 variants conferred risk for CD (N2081D) or protection from CD (N551K/R1398H). Analysis of other variants within the LRRK2 locus in 24,570 individuals revealed similar genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The presence of shared LRRK2 alleles in CD and PD provides insight into disease mechanisms and potential treatments.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.