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; 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

doi:10.1126/scitranslmed.aai7795

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

Journal article

Open access

Peer reviewed

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, …

Science translational medicine, Vol.10(423), p.eaai7795

2018-01-10

DOI: https://doi.org/10.1126/scitranslmed.aai7795

PMID: 29321258

Abstract

Crohn Disease - enzymology

Crohn Disease - genetics

Genetic Predisposition to Disease

Reproducibility of Results

Macrophages - pathology

Gene Frequency

Humans

Risk Factors

Genetic Loci

Parkinson Disease - genetics

Gene Regulatory Networks

Open Reading Frames - genetics

Autophagy

Whole Exome Sequencing

Genetic Variation

Exome - genetics

Macrophages - metabolism

Parkinson Disease - enzymology

Alleles

Cytoskeleton - metabolism

Genome, Human

Odds Ratio

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics

Phenotype

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 gene that conferred risk for CD (N2081D variant, = 9.5 × 10 ) or protection from CD (N551K variant, tagging R1398H-associated haplotype, = 3.3 × 10 ). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated in CD pathogenesis. Analysis of the extended 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 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 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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.67 Parkinson's Disease
Web Of Science research areas: Cell Biology; Medicine, Research & Experimental
ESI research areas: Biology & Biochemistry

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Title: Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease
Creators: Ken Y Hui - Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA
Heriberto Fernandez-Hernandez - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Jianzhong Hu - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Adam Schaffner - Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Nathan Pankratz - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
Nai-Yun Hsu - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Ling-Shiang Chuang - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Shai Carmi - Braun School of Public Health and Community Medicine, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Nicole Villaverde - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Xianting Li - Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Manual Rivas - Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
Adam P Levine - Centre for Molecular Medicine, Division of Medicine, University College, London WC1E 6JF, UK
Xiuliang Bao - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Philippe R Labrias - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Talin Haritunians - Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Darren Ruane - Department of Immunology and Inflammation, Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
Kyle Gettler - Department of Genetics, Yale University, New Haven, CT 06520, USA
Ernie Chen - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Dalin Li - Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Elena R Schiff - Centre for Molecular Medicine, Division of Medicine, University College, London WC1E 6JF, UK
Nikolas Pontikos - Centre for Molecular Medicine, Division of Medicine, University College, London WC1E 6JF, UK
Nir Barzilai - Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Steven R Brant - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA
Susan Bressman - Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, NY 10003, USA
Adam S Cheifetz - Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Lorraine N Clark - Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
Mark J Daly - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Robert J Desnick - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Richard H Duerr - Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA
Seymour Katz - St. Francis Hospital, Roslyn, NY 11576, USA
Todd Lencz - Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA
Richard H Myers - Department of Neurology, Boston University School of Medicine, Boston, MA 02114, USA
Harry Ostrer - Departments of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Laurie Ozelius - Deparment of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
Haydeh Payami - HudsonAlpha Institute for Biotechnology, Huntsville, AL 35805, USA
Yakov Peter - Department of Pulmonary Medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10033, USA
John D Rioux - Faculté de Médecine, Université de Montréal, Montreal, Quebec H1T1C8, Canada
Anthony W Segal - Centre for Molecular Medicine, Division of Medicine, University College, London WC1E 6JF, UK
William K Scott - Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Mark S Silverberg - Department of Medicine, University of Toronto, Toronto, Ontario M5G1X5, Canada
Jeffery M Vance - Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Iban Ubarretxena-Belandia - Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Tatiana Foroud - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Gil Atzmon - Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel
Itsik Pe'er - Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA
Yiannis Ioannou - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Dermot P B McGovern - Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Zhenyu Yue - Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Eric E Schadt - Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
Judy H Cho - Section of Gastroenterology and Hepatology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA
Inga Peter - Institute for Genetics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Publication Details: Science translational medicine, Vol.10(423), p.eaai7795
Publisher: United States
Grant note: U01 DK062413 / NIDDK NIH HHS R01 NS036960 / NINDS NIH HHS U24 DK062429 / NIDDK NIH HHS P01 DK046763 / NIDDK NIH HHS R01 DK092235 / NIDDK NIH HHS U01 DK062429 / NIDDK NIH HHS U54 CA121852 / NCI NIH HHS U01 DK062431 / NIDDK NIH HHS R01 MH084098 / NIMH NIH HHS U01 DK062423 / NIDDK NIH HHS F30 DK098927 / NIDDK NIH HHS HHSN268200782096C / NHLBI NIH HHS P30 AG038072 / NIA NIH HHS U01 DK062420 / NIDDK NIH HHS T32 GM007205 / NIGMS NIH HHS R01 AG042188 / NIA NIH HHS R01 CA141743 / NCI NIH HHS R01 NS060809 / NINDS NIH HHS R21 NS050487 / NINDS NIH HHS R01 NS060113 / NINDS NIH HHS MR/L000261/1 / Medical Research Council P50 NS094733 / NINDS NIH HHS R01 DK106593 / NIDDK NIH HHS R01 NS037167 / NINDS NIH HHS P01 AG021654 / NIA NIH HHS U01 DK062422 / NIDDK NIH HHS R56 NS037167 / NINDS NIH HHS P50 NS071674 / NINDS NIH HHS R01 MH095458 / NIMH NIH HHS P30 DK043351 / NIDDK NIH HHS RC2 MH089964 / NIMH NIH HHS U01 AI067068 / NIAID NIH HHS R01 NS036711 / NINDS NIH HHS R01 HS021747 / AHRQ HHS R01 NS076843 / NINDS NIH HHS
Academic Unit: Miller School of Medicine; UMMG Dept of Human Genetics - Clinical and Translational Genetics; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 29321258
Record Identifier: 991031576063002976