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Identification of candidate causal variants and target genes at 41 breast cancer risk loci through differential allelic expression analysis

2024-09-28Journal article Open access
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dc.contributor.authorGonçalves de Gouveia Maia Xavier, Joana
dc.contributor.authorMagno, Ramiro
dc.contributor.authorRussell, Roslin
dc.contributor.authorAlmeida, Bernardo P. de
dc.contributor.authorJacinta-Fernandes, Ana
dc.contributor.authorDuarte, André
dc.contributor.authorBesouro-Duarte, André
dc.contributor.authorDunning, Mark
dc.contributor.authorSamarajiwa, Shamith
dc.contributor.authorO’Reilly, Martin
dc.contributor.authorMARQUES MAIA DE ALMEIDA, JOSE ANTONIO
dc.contributor.authorRocha, Cátia L.
dc.contributor.authorRosli, Nordiana
dc.contributor.authorPonder, Bruce A. J.
dc.contributor.authorMaia, Ana-Teresa
dc.date.accessioned2024-10-24T13:17:07Z
dc.date.available2024-10-24T13:17:07Z
dc.date.issued2024-09-28
dc.description.abstractUnderstanding breast cancer genetic risk relies on identifying causal variants and candidate target genes in risk loci identified by genome-wide association studies (GWAS), which remains challenging. Since most loci fall in active gene regulatory regions, we developed a novel approach facilitated by pinpointing the variants with greater regulatory potential in the disease’s tissue of origin. Through genome-wide differential allelic expression (DAE) analysis, using microarray data from 64 normal breast tissue samples, we mapped the variants associated with DAE (daeQTLs). Then, we intersected these with GWAS data to reveal candidate risk regulatory variants and analysed their cis-acting regulatory potential. Finally, we validated our approach by extensive functional analysis of the 5q14.1 breast cancer risk locus. We observed widespread gene expression regulation by cis-acting variants in breast tissue, with 65% of coding and noncoding expressed genes displaying DAE (daeGenes). We identified over 54 K daeQTLs for 6761 (26%) daeGenes, including 385 daeGenes harbouring variants previously associated with BC risk. We found 1431 daeQTLs mapped to 93 different loci in strong linkage disequilibrium with risk-associated variants (risk-daeQTLs), suggesting a link between risk-causing variants and cis-regulation. There were 122 risk-daeQTL with stronger cis-acting potential in active regulatory regions with protein binding evidence. These variants mapped to 41 risk loci, of which 29 had no previous report of target genes and were candidates for regulating the expression levels of 65 genes. As validation, we identified and functionally characterised five candidate causal variants at the 5q14.1 risk locus targeting the ATG10 and ATP6AP1L genes, likely acting via modulation of alternative transcription and transcription factor binding. Our study demonstrates the power of DAE analysis and daeQTL mapping to identify causal regulatory variants and target genes at breast cancer risk loci, including those with complex regulatory landscapes. It additionally provides a genome-wide resource of variants associated with DAE for future functional studies.eng
dc.description.sponsorshipPOCI "01-0145; EDER-022184; DL 57/2016/CP1361/CT0042; FP7/2007-2013; 303745
dc.identifier.doi10.1038/s41598-024-72163-y
dc.identifier.issn2045-2322
dc.identifier.urihttp://hdl.handle.net/10400.1/26144
dc.language.isoeng
dc.peerreviewedyes
dc.publisherSpringer Science and Business Media
dc.relationCentre for Biomedical Research
dc.relationHealth Research Network: From Lab to Community Health
dc.relationResearch Centre for Tourism, Sustainability and Well-being
dc.relationUnveiling cis-regulatory variants role in breast cancer aetiology
dc.relation.ispartofScientific Reports
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleIdentification of candidate causal variants and target genes at 41 breast cancer risk loci through differential allelic expression analysiseng
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentre for Biomedical Research
oaire.awardTitleHealth Research Network: From Lab to Community Health
oaire.awardTitleResearch Centre for Tourism, Sustainability and Well-being
oaire.awardTitleUnveiling cis-regulatory variants role in breast cancer aetiology
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F04773%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0053%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04020%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F99502%2F2014/PT
oaire.citation.issue1
oaire.citation.startPage22526
oaire.citation.titleScientific Reports
oaire.citation.volume14
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameGonçalves de Gouveia Maia Xavier
person.familyNameMagno
person.familyNameDuarte
person.familyNameMARQUES MAIA DE ALMEIDA
person.familyNameMaia
person.givenNameJoana
person.givenNameRamiro
person.givenNameAndré
person.givenNameJOSE ANTONIO
person.givenNameAna-Teresa
person.identifier1489493
person.identifier.ciencia-idEE13-176A-5613
person.identifier.orcid0000-0002-0702-6700
person.identifier.orcid0000-0001-5226-3441
person.identifier.orcid0000-0002-4773-4621
person.identifier.orcid0000-0003-0511-2813
person.identifier.orcid0000-0002-0454-9207
person.identifier.ridI-4676-2014
person.identifier.ridF-4404-2012
person.identifier.scopus-author-id36061472900
person.identifier.scopus-author-id14319300100
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
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