Multi-population genome-wide association study implicates both immune and non-immune factors in the etiology of pediatric steroid sensitive nephrotic syndrome

Author:

Barry Alexandra,McNulty Michelle T.,Jia Xiaoyuan,Gupta Yask,Debiec Hanna,Luo YangORCID,Nagano China,Horinouchi Tomoko,Jung Seulgi,Colucci Manuela,Ahram Dina F.,Mitrotti Adele,Sinha Aditi,Teeninga Nynke,Jin Gina,Shril Shirlee,Caridi Gianluca,Bodria Monica,Lim Tze Y,Westland Rik,Zanoni Francesca,Marasa Maddalena,Turudic Daniel,Giordano Mario,Gesualdo Loreto,Magistroni Riccardo,Pisani Isabella,Fiaccadori Enrico,Reiterova Jana,Maringhini Silvio,Morello William,Montini GiovanniORCID,Weng Patricia L.,Scolari Francesco,Saraga Marijan,Tasic Velibor,Santoro Domenica,van Wijk Joanna A.E.,Milošević Danko,Kawai Yosuke,Kiryluk Krzysztof,Pollak Martin R.,Gharavi Ali,Lin Fangmin,Simœs e Silva Ana CristinaORCID,Loos Ruth J.F.,Kenny Eimear E.,Schreuder Michiel F.,Zurowska AleksandraORCID,Dossier Claire,Ariceta Gema,Drozynska-Duklas Magdalena,Hogan Julien,Jankauskiene Augustina,Hildebrandt Friedhelm,Prikhodina Larisa,Song Kyuyoung,Bagga Arvind,Cheong Hae Il,Ghiggeri Gian Marco,Vachvanichsanong PrayongORCID,Nozu Kandai,Vivarelli Marina,Raychaudhuri SoumyaORCID,Tokunaga Katsushi,Sanna-Cherchi Simone,Ronco Pierre,Iijima Kazumoto,Sampson Matthew G.ORCID

Abstract

ABSTRACTPediatric 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 signals. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. We conducted a multi-population GWAS meta-analysis in 38,463 participants (2,440 cases) and population specific GWAS, discovering twelve significant associations (eight novel). Fine-mapping implicated specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk signal. Non-HLA loci colocalized with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs was lacking, but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associated with earlier disease onset in two independent cohorts. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cellspecific insights into its molecular drivers.

Publisher

Cold Spring Harbor Laboratory

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