Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population
<p dir="ltr">Natural human knockouts of genes associated with desirable outcomes, such as <i>PCSK9</i> with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homoz...
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| مؤلفون آخرون: | , , , , , |
| منشور في: |
2023
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| _version_ | 1864513507219734528 |
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| author | Aziz Belkadi (779313) |
| author2 | Gaurav Thareja (459188) Fatemeh Abbaszadeh (13841344) Ramin Badii (491543) Eric Fauman (3900379) Omar M.E. Albagha (18508167) Karsten Suhre (67967) |
| author2_role | author author author author author author |
| author_facet | Aziz Belkadi (779313) Gaurav Thareja (459188) Fatemeh Abbaszadeh (13841344) Ramin Badii (491543) Eric Fauman (3900379) Omar M.E. Albagha (18508167) Karsten Suhre (67967) |
| author_role | author |
| dc.creator.none.fl_str_mv | Aziz Belkadi (779313) Gaurav Thareja (459188) Fatemeh Abbaszadeh (13841344) Ramin Badii (491543) Eric Fauman (3900379) Omar M.E. Albagha (18508167) Karsten Suhre (67967) |
| dc.date.none.fl_str_mv | 2023-01-11T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.xgen.2022.100218 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Identification_of_PCSK9-like_human_gene_knockouts_using_metabolomics_proteomics_and_whole-genome_sequencing_in_a_consanguineous_population/26808559 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Medical biochemistry and metabolomics Pharmacology and pharmaceutical sciences human gene knockouts metabolomicsproteomics whole-genome sequencing consanguineous population drug target validation drug target identification |
| dc.title.none.fl_str_mv | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Natural human knockouts of genes associated with desirable outcomes, such as <i>PCSK9</i> with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare<i> PCSK9</i> variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Genomics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.xgen.2022.100218" target="_blank">https://dx.doi.org/10.1016/j.xgen.2022.100218</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_f270865c67a9f3de3a5e7b11a9d06d65 |
| identifier_str_mv | 10.1016/j.xgen.2022.100218 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26808559 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous populationAziz Belkadi (779313)Gaurav Thareja (459188)Fatemeh Abbaszadeh (13841344)Ramin Badii (491543)Eric Fauman (3900379)Omar M.E. Albagha (18508167)Karsten Suhre (67967)Biological sciencesGeneticsBiomedical and clinical sciencesMedical biochemistry and metabolomicsPharmacology and pharmaceutical scienceshuman gene knockoutsmetabolomicsproteomicswhole-genome sequencingconsanguineous populationdrug target validationdrug target identification<p dir="ltr">Natural human knockouts of genes associated with desirable outcomes, such as <i>PCSK9</i> with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare<i> PCSK9</i> variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Genomics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.xgen.2022.100218" target="_blank">https://dx.doi.org/10.1016/j.xgen.2022.100218</a></p>2023-01-11T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.xgen.2022.100218https://figshare.com/articles/journal_contribution/Identification_of_PCSK9-like_human_gene_knockouts_using_metabolomics_proteomics_and_whole-genome_sequencing_in_a_consanguineous_population/26808559CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/268085592023-01-11T09:00:00Z |
| spellingShingle | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population Aziz Belkadi (779313) Biological sciences Genetics Biomedical and clinical sciences Medical biochemistry and metabolomics Pharmacology and pharmaceutical sciences human gene knockouts metabolomicsproteomics whole-genome sequencing consanguineous population drug target validation drug target identification |
| status_str | publishedVersion |
| title | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population |
| title_full | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population |
| title_fullStr | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population |
| title_full_unstemmed | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population |
| title_short | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population |
| title_sort | Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population |
| topic | Biological sciences Genetics Biomedical and clinical sciences Medical biochemistry and metabolomics Pharmacology and pharmaceutical sciences human gene knockouts metabolomicsproteomics whole-genome sequencing consanguineous population drug target validation drug target identification |