biostudies-literatureUnknownHujoel MLANIEHS NIH HHSNHLBI NIH HHSNIMH NIH HHSNHGRI NIH HHSNIH HHSStructural variants (SVs) comprise the largest genetic variants, altering from 50 base pairs to megabases of DNA. However, SVs have not been effectively ascertained in most genetic association studies, leaving a key gap in our understanding of human complex trait genetics. We ascertained protein-altering SVs from UK Biobank whole-exome sequencing data (<i>n</i>=468,570) using haplotype-informed methods capable of detecting sub-exonic SVs and variation within segmental duplications. Incorporating SVs into analyses of rare variants predicted to cause gene loss-of-function (pLoF) identified 100 associations of pLoF variants with 41 quantitative traits. A low-frequency partial deletion of <i>RGL3</i> exon 6 appeared to confer one of the strongest protective effects of gene LoF on hypertension bioRxiv : the preprint server for biology2023.06.07.544066https://www.ebi.ac.uk/biostudies/studies/S-EPMC10274781biostudies-literatureHidden protein-altering variants influence diverse human phenotypes.PMC10274781OT2 OD026548OT2 OD025315OT2 OD025337OT2 OD026549F31 HL154537OT2 OD025277OT2 OD025276R56 HG006855U24 OD023121K25 HL150334F32 HL160061U24 OD023163U2C OD023196OT2 OD026555OT2 OD026554F31 MH124393OT2 OD026557OT2 OD026556OT2 OD023205OT2 OD023206OT2 OD026551OT2 OD026550OT2 OD026553OT2 OD026552R01 HG006855U24 OD023176T32 HG002295DP2 ES030554Kamitaki NLoh PRHujoel MLAMcCarroll SAMukamel RETerao CBarton ARHandsaker RESherman MAfalseHidden protein-altering variants influence diverse human phenotypes.Structural variants (SVs) comprise the largest genetic variants, altering from 50 base pairs to megabases of DNA. However, SVs have not been effectively ascertained in most genetic association studies, leaving a key gap in our understanding of human complex trait genetics. We ascertained protein-altering SVs from UK Biobank whole-exome sequencing data (<i>n</i>=468,570) using haplotype-informed methods capable of detecting sub-exonic SVs and variation within segmental duplications. Incorporating SVs into analyses of rare variants predicted to cause gene loss-of-function (pLoF) identified 100 associations of pLoF variants with 41 quantitative traits. A low-frequency partial deletion of <i>RGL3</i> exon 6 appeared to confer one of the strongest protective effects of gene LoF on hypertension 2023-01-01T00:00:00Z2023 Jun2026-04-08T15:34:03.368Z2025-04-06T17:40:15.243ZS-EPMC102747813733324410.1101/2023.06.07.544066