Format

Send to

Choose Destination
Sci Transl Med. 2018 Jan 10;10(423). pii: eaai7795. doi: 10.1126/scitranslmed.aai7795.

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

Author information

1
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
7
Braun School of Public Health and Community Medicine, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
8
Department of Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
9
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
10
Centre for Molecular Medicine, Division of Medicine, University College, London WC1E 6JF, UK.
11
Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
12
Department of Immunology and Inflammation, Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
13
Department of Genetics, Yale University, New Haven, CT 06520, USA.
14
Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
15
Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
16
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA.
17
Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, NY 10003, USA.
18
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
19
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
20
Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
21
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
22
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
23
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
24
New York University School of Medicine, New York City, NY 10016, USA.
25
North Shore University-Long Island Jewish Medical Center, Manhasset, NY, USA.
26
St. Francis Hospital, Roslyn, NY 11576, USA.
27
Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA.
28
Department of Neurology, Boston University School of Medicine, Boston, MA 02114, USA.
29
Departments of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
30
Deparment of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
31
Departments of Neurology and Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
32
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35805, USA.
33
Department of Biology, Touro College, Queens, NY 10033, USA.
34
Department of Pulmonary Medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10033, USA.
35
Research Center, Montreal Heart Institute, Montreal, Quebec H1T1C8, Canada.
36
Faculté de Médecine, Université de Montréal, Montreal, Quebec H1T1C8, Canada.
37
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
38
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario M5T3L9, USA.
39
Department of Medicine, University of Toronto, Toronto, Ontario M5G1X5, Canada.
40
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
41
Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel.
42
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
43
Institute for Genetics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
44
Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.
45
Section of Gastroenterology and Hepatology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
46
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. inga.peter@mssm.edu.

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.

Comment in

PMID:
29321258
PMCID:
PMC6028002
DOI:
10.1126/scitranslmed.aai7795
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substance, Grant support

Publication types

MeSH terms

Substance

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center