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dc.contributor.authorZhao, Yajie
dc.contributor.authorStankovic, Stasa
dc.contributor.authorKoprulu, Mine
dc.contributor.authorWheeler, Eleanor
dc.contributor.authorDay, Felix R.
dc.contributor.authorLango Allen, Hana
dc.contributor.authorKerrison, Nicola D.
dc.contributor.authorPietzner, Maik
dc.contributor.authorLoh, Po-Ru
dc.contributor.authorWareham, Nicholas J.
dc.contributor.authorLangenberg, Claudia
dc.contributor.authorOng, Ken K.
dc.contributor.authorPerry, John R. B.
dc.date.accessioned2021-07-07T15:46:16Z
dc.date.available2021-07-07T15:46:16Z
dc.date.issued2021-07-07
dc.date.submitted2021-02-24
dc.identifier.others41467-021-24504-y
dc.identifier.other24504
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/324926
dc.description.abstractAbstract: Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes—CHEK2 and GIGYF1—reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04–11.81], p = 1.3 × 10−10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51–10.61], p = 1.8 × 10−12), 4 kg higher fat mass (p = 1.3 × 10−4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10−4) and 4.5 kg lower handgrip strength (p = 4.7 × 10−7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.
dc.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/631/208/205/2138
dc.subject/631/208/211
dc.subject/692/163/2743/137/773
dc.subject/45
dc.subject/45/43
dc.subjectarticle
dc.titleGIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health
dc.typeArticle
dc.date.updated2021-07-07T15:46:15Z
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.volume12
dc.identifier.doi10.17863/CAM.72379
dcterms.dateAccepted2021-06-21
rioxxterms.versionofrecord10.1038/s41467-021-24504-y
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidZhao, Yajie [0000-0002-2747-0219]
dc.contributor.orcidStankovic, Stasa [0000-0002-6602-1379]
dc.contributor.orcidWheeler, Eleanor [0000-0002-8616-6444]
dc.contributor.orcidDay, Felix R. [0000-0003-3789-7651]
dc.contributor.orcidPietzner, Maik [0000-0003-3437-9963]
dc.contributor.orcidLoh, Po-Ru [0000-0001-5542-9064]
dc.contributor.orcidWareham, Nicholas J. [0000-0003-1422-2993]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.contributor.orcidOng, Ken K. [0000-0003-4689-7530]
dc.contributor.orcidPerry, John R. B. [0000-0001-6483-3771]
dc.identifier.eissn2041-1723
pubs.funder-project-idRCUK | Medical Research Council (MRC) (MC_UU_00006/2)


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