دورية أكاديمية
GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.
| العنوان: | GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health. |
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| المؤلفون: | Zhao, Yajie, Stankovic, Stasa, Koprulu, Mine, Wheeler, Eleanor, Day, Felix R, Lango Allen, Hana, Kerrison, Nicola D, Pietzner, Maik, Loh, Po-Ru, Wareham, Nicholas J, Langenberg, Claudia, Ong, Ken K, Perry, John R B |
| المصدر: | nlmid: 101528555 ; essn: 2041-1723 |
| بيانات النشر: | Nature communications |
| سنة النشر: | 2021 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Leukocytes, Chromosomes, Human, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Insulin, Receptor, IGF Type 1, Carrier Proteins, Case-Control Studies, DNA Mutational Analysis, Signal Transduction, Mosaicism, Adult, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, Whole Exome Sequencing, Loss of Function Mutation |
| الوصف: | Funder: Department of Health ; 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/326577Test |
| DOI: | 10.17863/CAM.74026 |
| الإتاحة: | https://doi.org/10.17863/CAM.74026Test https://www.repository.cam.ac.uk/handle/1810/326577Test |
| حقوق: | Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.537C745A |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.74026 |
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