Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population

• DOI: 10.1016/j.xgen.2022.100218
• Publication Date: 2022-11-16T05:06:00Z
• Authors: Aziz Belkadi; Gaurav Thareja; Fatemeh Abbaszadeh; Ramin Badii; Eric Fauman; Omar M.E. Albagha; Karsten Suhre
• Keywords: PCSK9; Gene knockout

Natural human knockouts of genes associated with desirable outcomes, such as PCSK9 low levels LDL-cholesterol, can lead to the discovery new drug targets and treatments. Rare loss-of-function variants are more likely be found in homozygous state consanguineous populations, deep molecular phenotyping blood samples from carriers help discriminate between silent functional variants. Here, we combined whole-genome sequencing proteomics metabolomics for 2,935 individuals Qatar Biobank (QBB) evaluate power this approach finding clinical pharmaceutical interest. As proof-of-concept, identified a carrier very rare variant extremely circulating LDL. Our study demonstrates that chances about 168 times higher QBB compared GnomAD emphasizes potential populations discovery.