The biomedical landscape of genomic structural variation in the qatari population

We present a large-scale study of structural variation (SV) in the Qatari population, based on short-read whole-genome sequencing (WGS) of 6,141 individuals, identifying 153,946 variants across 5 classes reflecting the region's diversity and evolutionary history. Leveraging consanguinity and biobank phenotypes, we identify >180 putative gene knockouts, and use proteomics to show functional consequences in homozygotes. Conversely, 52 genes show significant depletion of homozygous deletions, eight of which cause severe pediatric disease or murine embryonic lethality. Examining phenotypic extremes uncovers several non-exonic homozygous deletions with large effect, including in SPIRE2 (creatinine), MAGI2 (leanness) and a chr19 microRNA cluster (extreme obesity). Further, SV-GWAS reveals gene-trait associations independent of SNPs, including at ACY1 (acetylation), SLC2A9 (uric acid), UGT1A8 (bilirubin) and ZNF251 (alanine aminotransferase). Notably, 3.2% of Qataris carry findings in medically actionable genes, one-third attributable to SVs. Our findings offer a rich SV reference for a globally understudied population, and demonstrate the utility of consanguineous biobanks for studying SVs in health and disease. All common SVs and tag-SNPs are provided as imputation resource.