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

Ken Y. Hui, Heriberto Fernandez-Hernandez, Jianzhong Hu, Adam Schaffner, Nathan Pankratz, Nai Yun Hsu, Ling Shiang Chuang, Shai Carmi, Nicole Villaverde, Xianting Li, Manual Rivas, Adam P. Levine, Xiuliang Bao, Philippe R. Labrias, Talin Haritunians, Darren Ruane, Kyle Gettler, Ernie Chen, Dalin Li, Elena R. Schiff & 31 others Nikolas Pontikos, Nir Barzilai, Steven R. Brant, Susan Bressman, Adam S. Cheifetz, Lorraine N. Clark, Mark J. Daly, Robert J. Desnick, Richard H. Duerr, Seymour Katz, Todd Lencz, Richard H. Myers, Harry Ostrer, Laurie Ozelius, Haydeh Payami, Yakov Peter, John D. Rioux, Anthony W. Segal, William K. Scott, Mark S. Silverberg, Jeffery M. Vance, Iban Ubarretxena-Belandia, Tatiana Foroud, Gil Atzmon, Itsik Pe'er, Yiannis Ioannou, Dermot P.B. McGovern, Zhenyu Yue, Eric E. Schadt, Judy H. Cho, Inga Peter

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbereaai7795
JournalScience Translational Medicine
Volume10
Issue number423
DOIs
StatePublished - Jan 10 2018

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Crohn Disease
Parkinson Disease
Genes
Phosphotransferases
Haplotypes
Mutation
Alleles
Exome
Bayes Theorem
GTP Phosphohydrolases
Autophagy
Guanosine Triphosphate
Inflammatory Bowel Diseases
Age of Onset

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hui, K. Y., Fernandez-Hernandez, H., Hu, J., Schaffner, A., Pankratz, N., Hsu, N. Y., ... Peter, I. (2018). Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Science Translational Medicine, 10(423), [eaai7795]. https://doi.org/10.1126/scitranslmed.aai7795

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. / Hui, Ken Y.; Fernandez-Hernandez, Heriberto; Hu, Jianzhong; Schaffner, Adam; Pankratz, Nathan; Hsu, Nai Yun; Chuang, Ling Shiang; Carmi, Shai; Villaverde, Nicole; Li, Xianting; Rivas, Manual; Levine, Adam P.; Bao, Xiuliang; Labrias, Philippe R.; Haritunians, Talin; Ruane, Darren; Gettler, Kyle; Chen, Ernie; Li, Dalin; Schiff, Elena R.; Pontikos, Nikolas; Barzilai, Nir; Brant, Steven R.; Bressman, Susan; Cheifetz, Adam S.; Clark, Lorraine N.; Daly, Mark J.; Desnick, Robert J.; Duerr, Richard H.; Katz, Seymour; Lencz, Todd; Myers, Richard H.; Ostrer, Harry; Ozelius, Laurie; Payami, Haydeh; Peter, Yakov; Rioux, John D.; Segal, Anthony W.; Scott, William K.; Silverberg, Mark S.; Vance, Jeffery M.; Ubarretxena-Belandia, Iban; Foroud, Tatiana; Atzmon, Gil; Pe'er, Itsik; Ioannou, Yiannis; McGovern, Dermot P.B.; Yue, Zhenyu; Schadt, Eric E.; Cho, Judy H.; Peter, Inga.

In: Science Translational Medicine, Vol. 10, No. 423, eaai7795, 10.01.2018.

Research output: Contribution to journalArticle

Hui, KY, Fernandez-Hernandez, H, Hu, J, Schaffner, A, Pankratz, N, Hsu, NY, Chuang, LS, Carmi, S, Villaverde, N, Li, X, Rivas, M, Levine, AP, Bao, X, Labrias, PR, Haritunians, T, Ruane, D, Gettler, K, Chen, E, Li, D, Schiff, ER, Pontikos, N, Barzilai, N, Brant, SR, Bressman, S, Cheifetz, AS, Clark, LN, Daly, MJ, Desnick, RJ, Duerr, RH, Katz, S, Lencz, T, Myers, RH, Ostrer, H, Ozelius, L, Payami, H, Peter, Y, Rioux, JD, Segal, AW, Scott, WK, Silverberg, MS, Vance, JM, Ubarretxena-Belandia, I, Foroud, T, Atzmon, G, Pe'er, I, Ioannou, Y, McGovern, DPB, Yue, Z, Schadt, EE, Cho, JH & Peter, I 2018, 'Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease', Science Translational Medicine, vol. 10, no. 423, eaai7795. https://doi.org/10.1126/scitranslmed.aai7795
Hui, Ken Y. ; Fernandez-Hernandez, Heriberto ; Hu, Jianzhong ; Schaffner, Adam ; Pankratz, Nathan ; Hsu, Nai Yun ; Chuang, Ling Shiang ; Carmi, Shai ; Villaverde, Nicole ; Li, Xianting ; Rivas, Manual ; Levine, Adam P. ; Bao, Xiuliang ; Labrias, Philippe R. ; Haritunians, Talin ; Ruane, Darren ; Gettler, Kyle ; Chen, Ernie ; Li, Dalin ; Schiff, Elena R. ; Pontikos, Nikolas ; Barzilai, Nir ; Brant, Steven R. ; Bressman, Susan ; Cheifetz, Adam S. ; Clark, Lorraine N. ; Daly, Mark J. ; Desnick, Robert J. ; Duerr, Richard H. ; Katz, Seymour ; Lencz, Todd ; Myers, Richard H. ; Ostrer, Harry ; Ozelius, Laurie ; Payami, Haydeh ; Peter, Yakov ; Rioux, John D. ; Segal, Anthony W. ; Scott, William K. ; Silverberg, Mark S. ; Vance, Jeffery M. ; Ubarretxena-Belandia, Iban ; Foroud, Tatiana ; Atzmon, Gil ; Pe'er, Itsik ; Ioannou, Yiannis ; McGovern, Dermot P.B. ; Yue, Zhenyu ; Schadt, Eric E. ; Cho, Judy H. ; Peter, Inga. / Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. In: Science Translational Medicine. 2018 ; Vol. 10, No. 423.
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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.",
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T1 - Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease

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

PY - 2018/1/10

Y1 - 2018/1/10

N2 - 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.

AB - 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.

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