Extended Data Fig. 8: Cis-regulatory effects at the CARD9 locus.

a, The CARD9 gene model depicting 13 exons of CARD9 and the splicing events from GTEx blood RNA-seq. The top IgAN risk allele (rs4077515-T) encodes S12N substitution in the second exon of CARD9. This SNP also exhibits a strong and statistically significant blood sQTL effect, wherein the risk allele is associated with higher rates of the chr9:136372094:136373532:clu_47895 splicing event, leading to the retention of exon 2 (red) in the coding sequence of CARD9 (isoform A), while the protective (rs4077515-C) allele is associated with the alternative splicing event that truncates exon 2 (isoform B). The functional CARD domain (green) maps to a portion of exon 2 that is intact in isoform A, but truncated in isoform B. b, Blood splice QTL violin plots of normalized intron excision ratios (corresponding to the ratio of isoform A to isoform B) by the genotype of rs10870077 (top blood sQTL in GTEx) and rs4077515 (top SNP in GWAS for IgAN). These two SNPs are in near perfect linkage disequilibrium (r² > 0.98). The white bar represents a median, the thick gray bar represents an interquartile range, and the blue shape reflects the distribution kernel density estimation. Numbers in parentheses under the x-axis indicate n independent samples per each genotype group. c, Both rs10870077 and rs4077515 are also associated with a significant cis-eQTL effect on CARD9 mRNA levels in GTEx blood (violin plots with similar definitions as in b). d, The blood eQTL signal for CARD9 significantly co-localizes with the GWAS signal (PP4 of 0.86). The top panel represents a regional plot for the GWAS signal (Immunochip data excluded). The bottom panel represents a blood cis-eQTL signal for CARD9 from the QTLGen Consortium meta-analysis (y-axis truncated at P < 1 × 10⁻³¹⁰); rs10870077 and rs4077515 are indicated in red. All P-values are two-sided, correspond to a logistic regression Wald test under an additive genetic model, and are not corrected for multiple testing.