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


ABSTRACT: 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.

SUBMITTER: Hui KY 

PROVIDER: S-EPMC6028002 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Functional variants in the <i>LRRK2</i> gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

Hui Ken Y KY   Fernandez-Hernandez Heriberto H   Hu Jianzhong J   Schaffner Adam A   Pankratz Nathan N   Hsu Nai-Yun NY   Chuang Ling-Shiang LS   Carmi Shai S   Villaverde Nicole N   Li Xianting X   Rivas Manual M   Levine Adam P AP   Bao Xiuliang X   Labrias Philippe R PR   Haritunians Talin T   Ruane Darren D   Gettler Kyle K   Chen Ernie E   Li Dalin D   Schiff Elena R ER   Pontikos Nikolas N   Barzilai Nir N   Brant Steven R SR   Bressman Susan S   Cheifetz Adam S AS   Clark Lorraine N LN   Daly Mark J MJ   Desnick Robert J RJ   Duerr Richard H RH   Katz Seymour S   Lencz Todd T   Myers Richard H RH   Ostrer Harry H   Ozelius Laurie L   Payami Haydeh H   Peter Yakov Y   Rioux John D JD   Segal Anthony W AW   Scott William K WK   Silverberg Mark S MS   Vance Jeffery M JM   Ubarretxena-Belandia Iban I   Foroud Tatiana T   Atzmon Gil G   Pe'er Itsik I   Ioannou Yiannis Y   McGovern Dermot P B DPB   Yue Zhenyu Z   Schadt Eric E EE   Cho Judy H JH   Peter Inga I  

Science translational medicine 20180101 423


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 <i>LRRK2</i> gene that conferred risk for CD (N2081D variant, <i>P</i> = 9.5 × 10<sup>-10</sup>)  ...[more]

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