Extended Data Fig. 7. gnomAD-SV can augment disease association studies.

a, Functional enrichments of 2,307 common SVs in strong linkage disequilibrium (R² ≥ 0.8) with an SNV associated with a trait or disease in the GWAS catalogue or the UK Biobank^33,34. Points represent odds ratios of SVs being in strong linkage disequilibrium with at least one GWAS-significant SNV among all SVs in strong linkage disequilibrium with at least one SNV (total n = 15,634 SVs). Single and triple asterisks correspond to nominal (P < 0.05) and Bonferroni-corrected (P < 0.0083) significance thresholds from a two-sided Fisher’s exact test, respectively. Bars represent 95% confidence intervals. Test statistics, SV counts, and P values are provided in Supplementary Table 6. b, Example locus at 16q22.1, where we identified a 336-bp deletion in strong linkage disequilibrium with SNVs significantly associated with hypothyroidism in the UK Biobank³⁴. Top, the GWAS signal among genotyped SNVs in the UK Biobank, coloured by strength of linkage disequilibrium (Pearson’s R² value) with the 336-bp deletion identified in gnomAD-SV. Bottom, the local genomic context of this deletion, which overlaps an annotated intronic Alu element near (<1 kb) the first exon of a highly constrained, thyroid-expressed gene, ATP6V0D1. The deletion lies amidst histone mark peaks commonly found at active enhancers (H3K27ac and H3K4me1) based on publicly available chromatin data from adult thyroid samples, a phenotype-relevant tissue⁴⁸. Human Alu elements are known to frequently act as enhancers, and the sentinel hypothyroidism SNV from the UK Biobank GWAS is a significant expression-modifying variant (that is, eQTL) for ATP6V0D1 and other nearby genes across many tissues, which indicates that the hypothyroidism risk haplotype modifies expression of ATP6V0D1 and/or other genes, potentially through the deletion of an intronic enhancer^4,49.