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Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome
A. Barry, MT. McNulty, X. Jia, Y. Gupta, H. Debiec, Y. Luo, C. Nagano, T. Horinouchi, S. Jung, M. Colucci, DF. Ahram, A. Mitrotti, A. Sinha, N. Teeninga, G. Jin, S. Shril, G. Caridi, M. Bodria, TY. Lim, R. Westland, F. Zanoni, M. Marasa, D....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu metaanalýza, časopisecké články, Research Support, U.S. Gov't, Non-P.H.S., práce podpořená grantem, Research Support, N.I.H., Extramural
Grantová podpora
U54 DK083912
NIDDK NIH HHS - United States
RC2 DK122397
NIDDK NIH HHS - United States
U2C TR002818
NCATS NIH HHS - United States
R01 DK119380
NIDDK NIH HHS - United States
UL1 TR001873
NCATS NIH HHS - United States
NLK
Directory of Open Access Journals
od 2015
Free Medical Journals
od 2010
Nature Open Access
od 2010-12-01
PubMed Central
od 2012
Europe PubMed Central
od 2012
ProQuest Central
od 2010-01-01
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
Medline Complete (EBSCOhost)
od 2012-11-01
Health & Medicine (ProQuest)
od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2010
Springer Nature OA/Free Journals
od 2010-12-01
- MeSH
- celogenomová asociační studie * MeSH
- dítě MeSH
- genetická predispozice k nemoci MeSH
- haplotypy MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- nefrotický syndrom * genetika MeSH
- rizikové faktory MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
AP HP Pediatric Nephrology Department Hôpital Robert Debré Paris France
Center for Data Sciences Brigham and Women's Hospital Harvard Medical School Boston MA USA
Centre for Genetics and Genomics Versus Arthritis University of Manchester Manchester UK
Croatian Academy of Medical Sciences Praska 2 3 p p 27 10000 Zagreb Croatia
Department of Advanced Pediatric Medicine Kobe University Graduate School of Medicine Kobe Japan
Department of Biomedical Informatics Harvard Medical School Boston MA USA
Department of Clinical Sciences and Community Health University of Milan Milan Italy
Department of Human Genetics Graduate School of Medicine The University of Tokyo Tokyo Japan
Department of Medicine Boston Children's Hospital Boston MA USA
Department of Nephrology and Renal Transplantation IRCCS Instituto Giannina Gaslini Genoa Italy
Department of Nephrology Centre Hospitalier du Mans Le Mans France
Department of Nephrology Dialysis and Transplant Unit University Hospital of Modena Modena Italy
Department of Pediatric Nephrology University Children's Hospital Skopje Macedonia
Department of Pediatric Nephrology VU University Medical Center Amsterdam The Netherlands
Department of Pediatrics AIIMS New Delhi India
Department of Pediatrics Harvard Medical School Boston MA USA
Department of Pediatrics ISMETT Palermo Italy
Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan
Department of Pediatrics Nephrology and Hypertension Medical University Gdansk Gdansk Poland
Department of Pediatrics University of Split Split Croatia
Division of Nephrology and Dialysis Unit University of Messina Sicily Italy
Division of Nephrology Beth Israel Deaconess Medical Center Boston MA USA
Division of Nephrology Boston Children's Hospital Boston MA USA
Division of Transplantation Department of Surgery University of Pennsylvania Philadelphia PA USA
Genome Medical Science Project Tokyo Japan
Hyogo Prefectural Kobe Children's Hospital Kobe Japan
Institute for Genomic Health Icahn School of Medicine at Mount Sinai New York NY USA
Institute of Clinical Medicine Faculty of Medicine Vilnius University Vilnius Lithuania
Laboratory on Molecular Nephrology IRCCS Instituto Giannina Gaslini Genoa Italy
Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA
Citace poskytuje Crossref.org
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