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Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
K. Kiryluk, E. Sanchez-Rodriguez, XJ. Zhou, F. Zanoni, L. Liu, N. Mladkova, A. Khan, M. Marasa, JY. Zhang, O. Balderes, S. Sanna-Cherchi, AS. Bomback, PA. Canetta, GB. Appel, J. Radhakrishnan, H. Trimarchi, B. Sprangers, DC. Cattran, H. Reich, Y....
Language English Country United States
Document type Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
R01 DK105124
NIDDK NIH HHS - United States
R01 DK082753
NIDDK NIH HHS - United States
RC2 DK116690
NIDDK NIH HHS - United States
R01 LM013061
NLM NIH HHS - United States
U01 HG008680
NHGRI NIH HHS - United States
U01 AI152960
NIAID NIH HHS - United States
R01 DK078244
NIDDK NIH HHS - United States
R01 AI149431
NIAID NIH HHS - United States
R01 HG010730
NHGRI NIH HHS - United States
U01 AI130830
NIAID NIH HHS - United States
R01 NS099068
NINDS NIH HHS - United States
R01 AI024717
NIAID NIH HHS - United States
R01 AR073228
NIAMS NIH HHS - United States
U01 AI150748
NIAID NIH HHS - United States
R01 AI148276
NIAID NIH HHS - United States
P01 AI150585
NIAID NIH HHS - United States
P41 GM103311
NIGMS NIH HHS - United States
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- Genome-Wide Association Study MeSH
- Glomerulonephritis, IGA * drug therapy genetics diagnosis MeSH
- Immunoglobulin A genetics MeSH
- Mice MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic
Amsterdam University Medical Centre VU University Medical Center Amsterdam the Netherlands
Azienda Unità Sanitaria Locale Rimini Rimini Italy
Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK
Belcolle Hospital Viterbo Italy
Biomedical Science Seoul National University College of Medicine Seoul Republic of Korea
CBP American Hospital Dubai United Arab Emirates
Center for Population Genomic Health Icahn School of Medicine at Mount Sinai New York City NY USA
Center for Research on Inflammation University of Paris INSERM and CNRS Paris France
Children's Foundation Research Center Le Bonheur Children's Hospital Memphis TN USA
Cincinnati Children's Hospital Medical Center Cincinnati OH USA
CRTI Nantes University Nantes France
Department of Biostatistics Mailman School of Public Health Columbia University New York City NY USA
Department of Clinical Immunology Medical University of Warsaw Warsaw Poland
Department of Genetics and Genomic Sciences Mount Sinai Health System New York City NY USA
Department of Genetics Medical University of Poznan Poznan Poland
Department of Genetics Yale School of Medicine New Haven CT USA
Department of Medical Sciences University of Turin Turin Italy
Department of Medicine and Surgery University of Parma Parma Italy
Department of Nephrology and Dialysis ASST Lariana Como Italy
Department of Nephrology and Dialysis G Brotzu Hospital Cagliari Italy
Department of Nephrology Juntendo University Faculty of Medicine Tokyo Japan
Department of Nephrology Karol Marcinkowski Hospital Zielona Góra Poland
Department of Nephrology University of Toronto Toronto General Hospital Toronto Ontario Canada
Department of Pathology Medical University of Warsaw Warsaw Poland
Department of Pediatric Nephrology Medical University of Lublin Lublin Poland
Department of Pediatrics and Nephrology Medical University of Warsaw Warsaw Poland
Department of Pediatrics University of Zielona Góra Zielona Góra Poland
Department of Renal Medicine University College London London UK
Departments of Microbiology and Medicine University of Alabama at Birmingham Birmingham AL USA
Departments of Neurology and Genetics Yale University New Haven CT USA
Division of Nephrology and Clinical Immunology RWTH Aachen University Aachen Germany
Division of Nephrology and Dialysis Gorizia Hospital Gorizia Italy
Division of Nephrology and Renal Transplantation Carreggi Hospital Florence Italy
Division of Nephrology Department of Internal Medicine University of Calgary Calgary Alberta Canada
Division of Nephrology Dialysis and Renal Transplantation Riuniti Hospital Ancona Italy
Division of Nephrology Dialysis and Transplantation IRCCS Giannina Gaslini Institute Genova Italy
Division of Nephrology Saint Louis University Saint Louis MO USA
Division of Nephrology University Hospitals Leuven Leuven Belgium
Division of Pediatric Nephrology Baylor College of Medicine Texas Children's Hospital Houston TX USA
Division of Pediatric Nephrology Boston Children's Hospital Boston MA USA
Division of Pediatric Nephrology Department of Pediatrics University of Kentucky Lexington KY USA
Division of Pediatric Nephrology Department of Pediatrics University of Utah Salt Lake City UT USA
Division of Pediatric Nephrology Driscoll Children's Hospital Corpus Christi TX USA
Division of Pediatric Nephrology Helen DeVos Children's Hospital Grand Rapids MI USA
Division of Pediatric Nephrology Mattel Children's Hospital Los Angeles CA USA
Division of Pediatric Nephrology Medical College of Wisconsin Milwaukee WI USA
Division of Pediatric Nephrology Mott Children's Hospital Ann Arbor MI USA
Division of Pediatric Nephrology Nationwide Children's Hospital Columbus OH USA
Division of Pediatric Nephrology SUNY Buffalo Buffalo NY USA
Division of Pediatric Nephrology University of Kentucky Lexington KY USA
Division of Pediatric Nephrology University of Minnesota Minneapolis MN USA
Division of Pediatric Nephrology University of Tennessee Health Sciences Center Memphis TN USA
Hospital Universitario Puerta del Hierro Majadahonda REDINREN IISCIII Madrid Spain
ICS Maugeri SpA University of Pavia Pavia Italy
Institute for Genomic Medicine Columbia University New York City NY USA
Institute of Biochemistry and Biophysics Polish Academy of Sciences Warsaw Poland
Institute of Clinical Molecular Biology Christian Albrechts University of Kiel Kiel Germany
Institute of Human Genetics Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany
Institute on Aging Seoul National University College of Medicine Seoul Republic of Korea
Internal Medicine Seoul National University College of Medicine Seoul Republic of Korea
John Walls Renal Unit University Hospitals of Leicester Leicester UK
Laboratory of Human Genetics and Genomics The Rockefeller University New York City NY USA
Nephrology and Dialysis A R N A S Civico and Benfratelli Palermo Italy
Nephrology and Dialysis Ospedale Maggiore Milan Italy
Nephrology and Dialysis Unit G Bosco Hub Hospital and University of Torino Torino Italy
Nephrology Dialysis and Renal Transplant Unit S Maria della Misericordia Hospital ASUFC Udine Italy
Nephrology Division San Marco Hospital Catania Italy
Nephrology Service Hospital Británico de Buenos Aires Buenos Aires Argentina
Regina Margherita Children's Hospital Torino Italy
Renal Division DMCO San Paolo Hospital School of Medicine University of Milan Milan Italy
Renal Unit Department of Medicine University of Verona Verona Italy
S Andrea Hospital La Spezia Italy
Salford Royal Hospital Salford UK
San Raffaele Hospital Milan Italy
Sandro Pertini Hospital Rome Italy
The Aristotle University of Thessaloniki Thessaloniki Greece
Unit of Nephrology and Dialysis AOU G Martino University of Messina Messina Italy
Unit of Nephrology and Dialysis ASL TO4 Consultorio Cirié Turin Italy
Unità Operativa di Nefrologia e Dialisi Ospedale di Acireale Acireale Italy
Université de Paris Hôpital Necker Enfants Malades Paris France
University of Cincinnati College of Medicine Cincinnati OH USA
University of Groningen Groningen the Netherlands
University of Hamburg Hamburg Germany
References provided by Crossref.org
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- $a Magnano, Andrea $u Department of Medicine and Surgery, University of Parma, Parma, Italy
- 700 1_
- $a Marcantoni, Carmelita $u Nephrology Division, San Marco Hospital, Catania, Italy
- 700 1_
- $a Messa, Piergiorgio $u Nephrology Dialysis and Kidney Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
- 700 1_
- $a Mignani, Renzo $u Azienda Unità Sanitaria Locale Rimini, Rimini, Italy
- 700 1_
- $a Pani, Antonello $u Department of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy
- 700 1_
- $a Ponticelli, Claudio $u Nephrology and Dialysis, Ospedale Maggiore, Milan, Italy
- 700 1_
- $a Roccatello, Dario $u Nephrology and Dialysis Unit, G. Bosco Hub Hospital (ERK-net Member) and University of Torino, Torino, Italy $1 https://orcid.org/0000000244196813
- 700 1_
- $a Salvadori, Maurizio $u Division of Nephrology and Renal Transplantation, Carreggi Hospital, Florence, Italy
- 700 1_
- $a Salvi, Erica $u Renal Division, DMCO (Dipartimento di Medicina, Chirurgia e Odontoiatria), San Paolo Hospital, School of Medicine, University of Milan, Milan, Italy
- 700 1_
- $a Santoro, Domenico $u Unit of Nephrology and Dialysis, AOU G Martino, University of Messina, Messina, Italy
- 700 1_
- $a Gembillo, Guido $u Unit of Nephrology and Dialysis, AOU G Martino, University of Messina, Messina, Italy
- 700 1_
- $a Savoldi, Silvana $u Unit of Nephrology and Dialysis, ASL TO4-Consultorio Cirié, Turin, Italy
- 700 1_
- $a Spotti, Donatella $u San Raffaele Hospital, Milan, Italy
- 700 1_
- $a Zamboli, Pasquale $u NephroCare Italy, Naples, Italy
- 700 1_
- $a Izzi, Claudia $u Department of Medical and Surgical Specialties and Nephrology Unit, University of Brescia-ASST Spedali Civili, Brescia, Italy
- 700 1_
- $a Alberici, Federico $u Department of Medical and Surgical Specialties and Nephrology Unit, University of Brescia-ASST Spedali Civili, Brescia, Italy
- 700 1_
- $a Delbarba, Elisa $u Department of Medical and Surgical Specialties and Nephrology Unit, University of Brescia-ASST Spedali Civili, Brescia, Italy
- 700 1_
- $a Florczak, Michał $u Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- 700 1_
- $a Krata, Natalia $u Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland $1 https://orcid.org/0000000305640819
- 700 1_
- $a Mucha, Krzysztof $u Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland $u Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland $1 https://orcid.org/0000000266137638
- 700 1_
- $a Pączek, Leszek $u Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland $u Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
- 700 1_
- $a Niemczyk, Stanisław $u Department of Internal Disease, Nephrology and Dialysotherapy, Military Institute of Medicine, Warsaw, Poland
- 700 1_
- $a Moszczuk, Barbara $u Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland $u Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland
- 700 1_
- $a Pańczyk-Tomaszewska, Malgorzata $u Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
- 700 1_
- $a Mizerska-Wasiak, Malgorzata $u Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
- 700 1_
- $a Perkowska-Ptasińska, Agnieszka $u Department of Pathology, Medical University of Warsaw, Warsaw, Poland
- 700 1_
- $a Bączkowska, Teresa $u Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- 700 1_
- $a Durlik, Magdalena $u Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- 700 1_
- $a Pawlaczyk, Krzysztof $u Department of Nephrology, Transplantology and Internal Medicine, Poznan Medical University, Poznan, Poland
- 700 1_
- $a Sikora, Przemyslaw $u Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland
- 700 1_
- $a Zaniew, Marcin $u Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland
- 700 1_
- $a Kaminska, Dorota $u Clinical Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
- 700 1_
- $a Krajewska, Magdalena $u Clinical Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland $1 https://orcid.org/0000000226322409
- 700 1_
- $a Kuzmiuk-Glembin, Izabella $u Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland $1 https://orcid.org/000000020625148X
- 700 1_
- $a Heleniak, Zbigniew $u Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland
- 700 1_
- $a Bullo-Piontecka, Barbara $u Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland
- 700 1_
- $a Liberek, Tomasz $u Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland
- 700 1_
- $a Dębska-Slizien, Alicja $u Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland
- 700 1_
- $a Hryszko, Tomasz $u 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Bialystok, Poland $1 https://orcid.org/0000000201453103
- 700 1_
- $a Materna-Kiryluk, Anna $u Department of Genetics, Medical University of Poznan, Poznan, Poland
- 700 1_
- $a Miklaszewska, Monika $u Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland
- 700 1_
- $a Szczepańska, Maria $u Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland $1 https://orcid.org/000000015336261X
- 700 1_
- $a Dyga, Katarzyna $u Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland
- 700 1_
- $a Machura, Edyta $u Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland
- 700 1_
- $a Siniewicz-Luzeńczyk, Katarzyna $u Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
- 700 1_
- $a Pawlak-Bratkowska, Monika $u Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
- 700 1_
- $a Tkaczyk, Marcin $u Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Harley, John B $u US Department of Veterans Affairs Medical Center and Cincinnati Education and Research for Veterans Foundation, Cincinnati, OH, USA
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Park, Jin-Ho $u Department of Family Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea $1 https://orcid.org/0000000239426813
- 700 1_
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- 700 1_
- $a Choi, Murim $u Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea $1 https://orcid.org/0000000291951455
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Ballarin, Jose $u Molecular Biology Laboratory and Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau, Universitat Autònoma de Barcelona, REDINREN, IISCIII, Barcelona, Spain
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Abeygunaratne, Thilini $u Salford Royal Hospital, Salford, UK
- 700 1_
- $a Kalra, Philip A $u Salford Royal Hospital, Salford, UK
- 700 1_
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- 700 1_
- $a Panzer, Ulf $u University of Hamburg, Hamburg, Germany
- 700 1_
- $a Rauen, Thomas $u Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
- 700 1_
- $a Floege, Jürgen $u Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
- 700 1_
- $a Schlosser, Pascal $u Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany $1 https://orcid.org/0000000284600462
- 700 1_
- $a Ekici, Arif B $u Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany $1 https://orcid.org/0000000160997066
- 700 1_
- $a Eckardt, Kai-Uwe $u Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany $u Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany $1 https://orcid.org/0000000338230920
- 700 1_
- $a Chen, Nan $u Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- 700 1_
- $a Xie, Jingyuan $u Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- 700 1_
- $a Lifton, Richard P $u Department of Genetics, Yale School of Medicine, New Haven, CT, USA $u Laboratory of Human Genetics and Genomics, The Rockefeller University, New York City, NY, USA
- 700 1_
- $a Loos, Ruth J F $u The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA $u Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark $1 https://orcid.org/0000000285325087
- 700 1_
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- 700 1_
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- 700 1_
- $a Köttgen, Anna $u Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany $1 https://orcid.org/0000000246713714
- 700 1_
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- 700 1_
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