The effect of LRRK2 loss-of-function variants in humans.

Adult Aged Aged, 80 and over Biological Specimen Banks Cell Line Embryonic Stem Cells / metabolism Female Gain of Function Mutation / genetics Heterozygote Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors Longevity / genetics Loss of Function Mutation / genetics Lymphocytes / metabolism Male Middle Aged Myocytes, Cardiac / metabolism Parkinson Disease / drug therapy Phenotype

Journal

Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015

Informations de publication

Date de publication:
06 2020
Historique:
received: 20 03 2020
accepted: 20 04 2020
pubmed: 29 5 2020
medline: 9 9 2020
entrez: 29 5 2020
Statut: ppublish

Résumé

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes

Identifiants

DOI: 10.1038/s41591-020-0893-5 PMID: 32461697 PMC: PMC7303015
pubmed: 32461697
doi: 10.1038/s41591-020-0893-5
pii: 10.1038/s41591-020-0893-5
pmc: PMC7303015
doi:

Substances chimiques

LRRK2 protein, human EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 EC 2.7.11.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

869-877

Subventions

Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1102/20
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107469/Z/15/Z
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH085548
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH123451
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK105566
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM104371
Pays : United States
Organisme : NIGMS NIH HHS
ID : F32 GM115208
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/10/33842
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH104964
Pays : United States
Organisme : British Heart Foundation
ID : CS/14/2/30841
Pays : United Kingdom

Investigateurs

Irina M Armean (IM)
Eric Banks (E)
Louis Bergelson (L)
Kristian Cibulskis (K)
Ryan L Collins (RL)
Kristen M Connolly (KM)
Miguel Covarrubias (M)
Beryl Cummings (B)
Mark J Daly (MJ)
Stacey Donnelly (S)
Yossi Farjoun (Y)
Steven Ferriera (S)
Stacey Gabriel (S)
Laura D Gauthier (LD)
Jeff Gentry (J)
Namrata Gupta (N)
Thibault Jeandet (T)
Diane Kaplan (D)
Kristen M Laricchia (KM)
Christopher Llanwarne (C)
Ruchi Munshi (R)
Benjamin M Neale (BM)
Sam Novod (S)
Anne H O'Donnell-Luria (AH)
Nikelle Petrillo (N)
Timothy Poterba (T)
David Roazen (D)
Valentin Ruano-Rubio (V)
Andrea Saltzman (A)
Kaitlin E Samocha (KE)
Molly Schleicher (M)
Cotton Seed (C)
Matthew Solomonson (M)
Jose Soto (J)
Grace Tiao (G)
Kathleen Tibbetts (K)
Charlotte Tolonen (C)
Christopher Vittal (C)
Gordon Wade (G)
Arcturus Wang (A)
Nicholas A Watts (NA)
Ben Weisburd (B)
Carlos A Aguilar-Salinas (CA)
Tariq Ahmad (T)
Christine M Albert (CM)
Diego Ardissino (D)
Gil Atzmon (G)
John Barnard (J)
Laurent Beaugerie (L)
Emelia J Benjamin (EJ)
Michael Boehnke (M)
Lori L Bonnycastle (LL)
Erwin P Bottinger (EP)
Donald W Bowden (DW)
Matthew J Bown (MJ)
John C Chambers (JC)
Juliana C Chan (JC)
Daniel Chasman (D)
Judy Cho (J)
Mina K Chung (MK)
Bruce Cohen (B)
Adolfo Correa (A)
Dana Dabelea (D)
Dawood Darbar (D)
Ravindranath Duggirala (R)
Josée Dupuis (J)
Patrick T Ellinor (PT)
Roberto Elosua (R)
Jeanette Erdmann (J)
Martti Färkkilä (M)
Jose Florez (J)
Andre Franke (A)
Gad Getz (G)
Benjamin Glaser (B)
Stephen J Glatt (SJ)
David Goldstein (D)
Clicerio Gonzalez (C)
Leif Groop (L)
Christopher Haiman (C)
Craig Hanis (C)
Matthew Harms (M)
Mikko Hiltunen (M)
Matti M Holi (MM)
Christina M Hultman (CM)
Mikko Kallela (M)
Jaakko Kaprio (J)
Sekar Kathiresan (S)
Bong-Jo Kim (BJ)
Young Jin Kim (YJ)
George Kirov (G)
Jaspal Kooner (J)
Seppo Koskinen (S)
Harlan M Krumholz (HM)
Subra Kugathasan (S)
Soo Heon Kwak (SH)
Markku Laakso (M)
Terho Lehtimäki (T)
Ruth J F Loos (RJF)
Steven A Lubitz (SA)
Ronald C W Ma (RCW)
Daniel G MacArthur (DG)
Jaume Marrugat (J)
Kari M Mattila (KM)
Steven McCarroll (S)
Mark I McCarthy (MI)
Dermot McGovern (D)
Ruth McPherson (R)
James B Meigs (JB)
Olle Melander (O)
Andres Metspalu (A)
Peter M Nilsson (PM)
Michael C O'Donovan (MC)
Dost Ongur (D)
Lorena Orozco (L)
Michael J Owen (MJ)
Colin N A Palmer (CNA)
Aarno Palotie (A)
Kyong Soo Park (KS)
Carlos Pato (C)
Ann E Pulver (AE)
Nazneen Rahman (N)
Anne M Remes (AM)
John D Riou (JD)
Samuli Ripatti (S)
Dan M Roden (DM)
Danish Saleheen (D)
Veikko Salomaa (V)
Nilesh J Samani (NJ)
Jeremiah Scharf (J)
Heribert Schunkert (H)
Moore B Shoemaker (MB)
Pamela Sklar (P)
Hilkka Soininen (H)
Harry Sokol (H)
Tim Spector (T)
Patrick F Sullivan (PF)
Jaana Suvisaari (J)
E Shyong Tai (ES)
Yik Ying Teo (YY)
Tuomi Tiinamaija (T)
Ming Tsuang (M)
Dan Turner (D)
Teresa Tusie-Luna (T)
Erkki Vartiainen (E)
Marquis P Vawter (MP)
James S Ware (JS)
Hugh Watkins (H)
Rinse K Weersma (RK)
Maija Wessman (M)
James G Wilson (JG)
Ramnik J Xavier (RJ)
Michelle Agee (M)
Adam Auton (A)
Robert K Bell (RK)
Katarzyna Bryc (K)
Sarah L Elson (SL)
Pierre Fontanillas (P)
Nicholas A Furlotte (NA)
Barry Hicks (B)
David A Hinds (DA)
Karen E Huber (KE)
Ethan M Jewett (EM)
Yunxuan Jiang (Y)
Keng-Han Lin (KH)
Nadia K Litterman (NK)
Matthew H McIntyre (MH)
Kimberly F McManus (KF)
Joanna L Mountain (JL)
Elizabeth S Noblin (ES)
Carrie A M Northover (CAM)
Steven J Pitts (SJ)
G David Poznik (GD)
J Fah Sathirapongsasuti (JF)
Janie F Shelton (JF)
Suyash Shringarpure (S)
Chao Tian (C)
Joyce Y Tung (JY)
Vladimir Vacic (V)
Xin Wang (X)
Catherine H Wilson (CH)

Commentaires et corrections

Type : CommentIn
Type : CommentIn
Type : ErratumIn

Références

Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015).
doi: 10.1038/ng.3314 pubmed: 26121088
Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013).
pubmed: 23868113 doi: 10.1038/nrd4051
Greggio, E. et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23, 329–341 (2006).
pubmed: 16750377 doi: 10.1016/j.nbd.2006.04.001
West, A. B. et al. Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl Acad. Sci. USA 102, 16842–16847 (2005).
pubmed: 16269541 doi: 10.1073/pnas.0507360102 pmcid: 1283829
Andersen, M. A. et al. PFE-360-induced LRRK2 inhibition induces reversible, non-adverse renal changes in rats. Toxicology 395, 15–22 (2018).
pubmed: 29307545 doi: 10.1016/j.tox.2018.01.003
Fuji, R. N. et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl. Med. 7, 273ra15 (2015).
pubmed: 25653221 doi: 10.1126/scitranslmed.aaa3634
Baptista, M. A. S. et al. Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. PLoS ONE 8, e80705 (2013).
pubmed: 24244710 pmcid: 3828242 doi: 10.1371/journal.pone.0080705
Hinkle, K. M. et al. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol. Neurodegener. 7, 25 (2012).
pubmed: 22647713 pmcid: 3441373 doi: 10.1186/1750-1326-7-25
Karczewski, K. J. et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. Preprint at bioRxiv https://doi.org/10.1101/531210 (2019).
Blauwendraat, C. et al. Frequency of loss of function variants in LRRK2 in Parkinson disease. JAMA Neurol. 75, 1416–1422 (2018).
pubmed: 30039155 pmcid: 6248108 doi: 10.1001/jamaneurol.2018.1885
de Lau, L. M. L. & Breteler, M. M. B. Epidemiology of Parkinson’s disease. Lancet Neurol. 5, 525–535 (2006).
pubmed: 16713924 doi: 10.1016/S1474-4422(06)70471-9
Polymeropoulos, M. H. et al. Mapping of a gene for Parkinson’s disease to chromosome 4q21–q23. Science 274, 1197–1199 (1996).
pubmed: 8895469 doi: 10.1126/science.274.5290.1197
Klein, C. & Westenberger, A. Genetics of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, a008888 (2012).
pubmed: 22315721 pmcid: 3253033 doi: 10.1101/cshperspect.a008888
Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607 (2004).
pubmed: 15541309 doi: 10.1016/j.neuron.2004.11.005
Goldwurm, S. et al. Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurology 68, 1141–1143 (2007).
pubmed: 17215492 doi: 10.1212/01.wnl.0000254483.19854.ef
Do, C. B. et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet. 7, e1002141 (2011).
pubmed: 21738487 pmcid: 3121750 doi: 10.1371/journal.pgen.1002141
MacLeod, D. et al. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52, 587–593 (2006).
pubmed: 17114044 doi: 10.1016/j.neuron.2006.10.008
West, A. B. et al. Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16, 223–232 (2007).
pubmed: 17200152 doi: 10.1093/hmg/ddl471
Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5, e12813 (2016).
pubmed: 26824392 pmcid: 4769169 doi: 10.7554/eLife.12813
Roosen, D. A. & Cookson, M. R. LRRK2 at the interface of autophagosomes, endosomes and lysosomes. Mol. Neurodegener. 11, 73 (2016).
pubmed: 27927216 pmcid: 5142374 doi: 10.1186/s13024-016-0140-1
Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson’s disease. Sci. Transl. Med. 10, eaar5429 (2018).
pubmed: 30045977 pmcid: 6344941 doi: 10.1126/scitranslmed.aar5429
Zhao, H. T. et al. LRRK2 antisense oligonucleotides ameliorate α-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol. Ther. Nucleic Acids 8, 508–519 (2017).
pubmed: 28918051 pmcid: 5573879 doi: 10.1016/j.omtn.2017.08.002
Chen, Z. C. et al. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease. Sci. Signal. 10, eaam6790 (2017).
pubmed: 28720718 doi: 10.1126/scisignal.aam6790
Chen, J., Chen, Y. & Pu, J. Leucine-rich repeat kinase 2 in Parkinson’s disease: updated from pathogenesis to potential therapeutic target. Eur. Neurol. 79, 256–265 (2018).
pubmed: 29705795 doi: 10.1159/000488938
Daniel, G. & Moore, D. J. in Behavioral Neurobiology of Huntington’s Disease and Parkinson’s Disease (eds Nguyen, H. H. P. & Cenci, M. A.) 331–368 (Springer Berlin Heidelberg, 2015).
Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med 354, 1264–1272 (2006).
pubmed: 16554528 doi: 10.1056/NEJMoa054013
TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung and Blood Institute et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med 371, 22–31 (2014).
doi: 10.1056/NEJMoa1307095
Myocardial Infarction Genetics Consortium Investigators et al. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med 371, 2072–2082 (2014).
doi: 10.1056/NEJMoa1405386
Minikel, E. V. et al. Quantifying prion disease penetrance using large population control cohorts. Sci. Transl. Med. 8, 322ra9 (2016).
pubmed: 26791950 pmcid: 4774245
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
pubmed: 27535533 pmcid: 5018207 doi: 10.1038/nature19057
MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012).
pubmed: 22344438 pmcid: 3299548 doi: 10.1126/science.1215040
Minikel, E. V. et al. Evaluating potential drug targets through human loss-of-function genetic variation. Preprint at bioRxiv https://doi.org/10.1101/530881 (2019).
Van Hout, C. V. et al. Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank. Preprint at bioRxiv https://doi.org/10.1101/572347 (2019).
Mir, R. et al. The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochem. J. 475, 1861–1883 (2018).
pubmed: 29743203 doi: 10.1042/BCJ20180248
Berndsen, K. et al. PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. eLife 8, e50416 (2019).
pubmed: 31663853 pmcid: 6850886 doi: 10.7554/eLife.50416
Gupta, R. P. & Strachan, D. P. Ventilatory function as a predictor of mortality in lifelong non-smokers: evidence from large British cohort studies. BMJ Open 7, e015381 (2017).
pubmed: 28706094 pmcid: 5734388 doi: 10.1136/bmjopen-2016-015381
McLaren, W. et al. The Ensembl variant effect predictor. Genome Biol. 17, 122 (2016).
pubmed: 27268795 pmcid: 4893825 doi: 10.1186/s13059-016-0974-4
Cummings, B. B. et al. Transcript expression-aware annotation improves rare variant discovery and interpretation. Preprint at bioRxiv https://doi.org/10.1101/554444 (2019).
Pato, M. T. et al. The genomic psychiatry cohort: partners in discovery. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B, 306–312 (2013).
pubmed: 23650244 doi: 10.1002/ajmg.b.32160
Saleheen, D. et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544, 235–239 (2017).
pubmed: 28406212 pmcid: 5600291 doi: 10.1038/nature22034
Ripke, S. et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150–1159 (2013).
pubmed: 23974872 pmcid: 3827979 doi: 10.1038/ng.2742
Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell 173, 1705–1715 (2018).
pmcid: 6432650 doi: 10.1016/j.cell.2018.05.046
Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016).
pubmed: 27694994 pmcid: 5104192 doi: 10.1038/nn.4402
Borodulin, K. et al. Cohort profile: the national FINRISK study. Int. J. Epidemiol. 47, 696 (2018).
pubmed: 29165699 doi: 10.1093/ije/dyx239
Leitsalu, L. et al. Cohort profile: Estonian biobank of the Estonian Genome Center, University of Tartu. Int. J. Epidemiol. 44, 1137–1147 (2015).
pubmed: 24518929 doi: 10.1093/ije/dyt268
1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
doi: 10.1038/nature15393
Bellenguez, C. et al. A robust clustering algorithm for identifying problematic samples in genome-wide association studies. Bioinformatics 28, 134–135 (2012).
pubmed: 22057162 doi: 10.1093/bioinformatics/btr599
Levey, A. S. & Stevens, L. A. Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates and better risk predictions. Am. J. Kidney Dis. 55, 622–627 (2010).
pubmed: 20338463 pmcid: 2846308 doi: 10.1053/j.ajkd.2010.02.337
UK10K Consortium et al. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).
doi: 10.1038/nature14962
Freidlin, B., Zheng, G., Li, Z. & Gastwirth, J. L. Trend tests for case-control studies of genetic markers: power, sample size and robustness. Hum. Hered. 53, 146–152 (2002).
pubmed: 12145550 doi: 10.1159/000064976
Lian, X. et al. Cozzarelli Prize Winner: robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc. Natl Acad. Sci. USA 109, E1848–E1857 (2012).
pubmed: 22645348 doi: 10.1073/pnas.1200250109 pmcid: 3390875
McKenna, A. et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).
pubmed: 20644199 pmcid: 2928508 doi: 10.1101/gr.107524.110
Dale, R. K., Pedersen, B. S. & Quinlan, A. R. Pybedtools: a flexible Python library for manipulating genomic datasets and annotations. Bioinformatics 27, 3423–3424 (2011).
pubmed: 21949271 pmcid: 3232365 doi: 10.1093/bioinformatics/btr539
Naito, Y., Hino, K., Bono, H. & Ui-Tei, K. CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites. Bioinformatics 31, 1120–1123 (2015).
pubmed: 25414360 doi: 10.1093/bioinformatics/btu743

Auteurs

Nicola Whiffin (N)

National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK. n.whiffin@imperial.ac.uk.
Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK. n.whiffin@imperial.ac.uk.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. n.whiffin@imperial.ac.uk.
ORCID: 0000-0003-1554-6594

Irina M Armean (IM)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-1043-4756

Aaron Kleinman (A)

23andMe, Inc., Sunnyvale, CA, USA.

Jamie L Marshall (JL)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0002-2364-391X

Eric V Minikel (EV)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Julia K Goodrich (JK)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Nicholas M Quaife (NM)

National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK.
ORCID: 0000-0003-2755-2086

Joanne B Cole (JB)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Program in Metabolism, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
ORCID: 0000-0001-9520-2788

Qingbo Wang (Q)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-9110-5830

Konrad J Karczewski (KJ)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0003-2878-4671

Beryl B Cummings (BB)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0001-6346-1646

Laurent Francioli (L)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-3039-8895

Kristen Laricchia (K)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Anna Guan (A)

23andMe, Inc., Sunnyvale, CA, USA.

Babak Alipanahi (B)

23andMe, Inc., Sunnyvale, CA, USA.
Google, Inc., Mountain View, CA, USA.
ORCID: 0000-0001-8216-7178

Peter Morrison (P)

23andMe, Inc., Sunnyvale, CA, USA.

Marco A S Baptista (MAS)

Michael J. Fox Foundation, New York, NY, USA.

Kalpana M Merchant (KM)

Michael J. Fox Foundation, New York, NY, USA.

James S Ware (JS)

National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0002-6110-5880

Aki S Havulinna (AS)

National Institute for Health and Welfare, Helsinki, Finland.
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-4787-8959

Bozenna Iliadou (B)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Jung-Jin Lee (JJ)

Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Girish N Nadkarni (GN)

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Cole Whiteman (C)

Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, NY, USA.

Mark Daly (M)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Tõnu Esko (T)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
ORCID: 0000-0003-1982-6569

Christina Hultman (C)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ruth J F Loos (RJF)

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
ORCID: 0000-0002-8532-5087

Lili Milani (L)

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
ORCID: 0000-0002-5323-3102

Aarno Palotie (A)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Carlos Pato (C)

Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, NY, USA.

Michele Pato (M)

Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, NY, USA.

Danish Saleheen (D)

Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Center for Non-Communicable Diseases, Karachi, Pakistan.
ORCID: 0000-0001-6193-020X

Patrick F Sullivan (PF)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.

Jessica Alföldi (J)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0001-9713-6200

Paul Cannon (P)

23andMe, Inc., Sunnyvale, CA, USA.

Daniel G MacArthur (DG)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. d.macarthur@garvan.org.au.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. d.macarthur@garvan.org.au.
Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia. d.macarthur@garvan.org.au.
Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia. d.macarthur@garvan.org.au.
ORCID: 0000-0002-5771-2290

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Établissements, main d'oeuvre et services de soins de santé › Établissements de santé › Biobanques › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches embryonnaires › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Hétérozygote › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › Leucine-rich repeat serine-threonine protein kinase-2 › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Phénomènes physiologiques › Longévité › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation perte de fonction › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Cellules › Cellules musculaires › Myocytes cardiaques › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › The effect of LRRK2 loss-of-function variants...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › The effect of LRRK2 loss-of-function variants...