Unknown

Dataset Information

0

Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.


ABSTRACT: 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.

SUBMITTER: Barry A 

PROVIDER: S-EPMC10148875 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.

Barry Alexandra A   McNulty Michelle T MT   Jia Xiaoyuan X   Gupta Yask Y   Debiec Hanna H   Luo Yang Y   Nagano China C   Horinouchi Tomoko T   Jung Seulgi S   Colucci Manuela M   Ahram Dina F DF   Mitrotti Adele A   Sinha Aditi A   Teeninga Nynke N   Jin Gina G   Shril Shirlee S   Caridi Gianluca G   Bodria Monica M   Lim Tze Y TY   Westland Rik R   Zanoni Francesca F   Marasa Maddalena M   Turudic Daniel D   Giordano Mario M   Gesualdo Loreto L   Magistroni Riccardo R   Pisani Isabella I   Fiaccadori Enrico E   Reiterova Jana J   Maringhini Silvio S   Morello William W   Montini Giovanni G   Weng Patricia L PL   Scolari Francesco F   Saraga Marijan M   Tasic Velibor V   Santoro Domenica D   van Wijk Joanna A E JAE   Milošević Danko D   Kawai Yosuke Y   Kiryluk Krzysztof K   Pollak Martin R MR   Gharavi Ali A   Lin Fangmin F   Simœs E Silva Ana Cristina AC   Loos Ruth J F RJF   Kenny Eimear E EE   Schreuder Michiel F MF   Zurowska Aleksandra A   Dossier Claire C   Ariceta Gema G   Drozynska-Duklas Magdalena M   Hogan Julien J   Jankauskiene Augustina A   Hildebrandt Friedhelm F   Prikhodina Larisa L   Song Kyuyoung K   Bagga Arvind A   Cheong Hae H   Ghiggeri Gian Marco GM   Vachvanichsanong Prayong P   Nozu Kandai K   Lee Dongwon D   Vivarelli Marina M   Raychaudhuri Soumya S   Tokunaga Katsushi K   Sanna-Cherchi Simone S   Ronco Pierre P   Iijima Kazumoto K   Sampson Matthew G MG  

Nature communications 20230429 1


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  ...[more]

Similar Datasets

| S-EPMC6050942 | biostudies-literature
| EGAS00001003607 | EGA
| S-EPMC4541972 | biostudies-literature
| S-EPMC5276801 | biostudies-literature
| S-EPMC4089737 | biostudies-literature
| S-EPMC7896825 | biostudies-literature
| S-EPMC6361778 | biostudies-literature
| S-EPMC6061657 | biostudies-literature
| S-EPMC9307535 | biostudies-literature
| S-EPMC7160055 | biostudies-literature