Fig. 4: HCM locus-to-gene mapping, prioritization and rare LoF association testing identifies SVIL as a new HCM disease gene.

a, HCM locus-to-gene mapping and prioritization based on cardiac expression. Locus-to-gene mapping was done using the OpenTargets¹³ V2G pipeline (release of 12 October 2022) for all 68 lead variants at the HCM MTAG loci and using FUMA¹⁴ for the HCM MTAG summary statistics (see Methods for detailed parameters). Of 164 genes mapped using both FUMA and OpenTargets (top 3 genes per locus), 26 were prioritized because of either high specificity of LV expression using the bulk RNA-seq data of the GTEx project³⁸ release v.8 and/or high expression in cardiomyocytes using snRNA-seq data¹⁵. See Methods and Supplementary Tables 12 and 13 for details. b, Rare (MAF < 10⁻⁴) LoF variant association analyses with HCM versus controls performed for all 26 genes using sequencing data in up to 2,502 unrelated HCM cases and 486,217 controls from four datasets followed by IVW meta-analysis. Association of rare synonymous (SYN) variants was also performed as a negative control. Results shown restricted to two genes (ALPK3 and SVIL) reaching the Bonferroni-corrected threshold of P < 0.0019 (0.05/26) in the IVW meta-analysis. Filled circles and error bars represent the OR and their 95% CI, respectively, from the meta-analysis for LoF (blue) and SYN (red). P values shown are not corrected for multiple testing. Full results appear in Supplementary Table 16. c, Schematic of the rare LoF SVIL variants in HCM cases (top) and controls (bottom) along the linear structure of SVIL, showing the Gelsolin-like and headpiece (HP) domains. The coordinates reflect the codon numbers, and the colored bars are the exons. Detailed variant annotation appears in Supplementary Table 19. Panel a was created using BioRender.com.