Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking.

Leukemia
Ahmed A Z DawoudNicholas C P Cross

Abstract

We sought to determine the significance of myeloid clonal hematopoiesis (CH) in the UK Biobank cohort (n = 502,524, median age = 58 years). Utilizing SNP array (n = 486,941) and whole exome sequencing data (n = 49,956), we identified 1166 participants with myeloid CH, defined by myeloid-associated mosaic chromosome abnormalities (mCA) and/or likely somatic driver mutations in DNMT3A, TET2, ASXL1, JAK2, SRSF2, or PPM1D. Myeloid CH increased by 1.1-fold per annum (myeloid mCA, P = 1.57 × 10-38; driver mutations, P = 5.89 × 10-47). Genome-wide association analysis identified two distinct signals within TERT that predisposed to myeloid CH, plus a weaker signal corresponding to the JAK2 46/1 haplotype. Specific subtypes of myeloid CH were associated with several blood features and clinical phenotypes, including TET2 mutations and chronic obstructive pulmonary disease. Smoking history was significantly associated with myeloid CH: 53% of myeloid CH cases were smokers compared to 44% of controls (P = 3.38 × 10-6), a difference principally due to current (OR = 1.10; P = 6.14 × 10-6) rather than past smoking (P = 0.08). Breakdown of CH by specific mutation type revealed that ASXL1 loss of function mutations were most strongly associated ...Continue Reading

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Citations

Jul 30, 2020·Cancers·Gajalakshmi RamanathanAngela G Fleischman
Dec 12, 2020·Neurobiology of Disease·Cornelis BlauwendraatAndrew B Singleton
Jan 10, 2021·American Journal of Human Genetics·Gabriella GalatàWilliam J Tapper
Mar 10, 2021·Pathology·Danielle Hammond, Sanam Loghavi
Mar 7, 2021·Pathology·David M RossPiers Blombery
Apr 24, 2021·Trends in Cardiovascular Medicine·Nicholas W ChavkinKenneth Walsh
Apr 21, 2021·Blood Advances·Isabelle A van ZeventerGerwin Huls
May 11, 2021·The Journal of Experimental Medicine·Jung-Yeon LimMinji Byun
May 15, 2021·Nature Reviews. Genetics·Alexander J SilverMichael R Savona
Jun 16, 2021·The Journal of Experimental Medicine·Francisco CaiadoMarkus G Manz
Jul 24, 2021·Journal of Molecular and Cellular Cardiology·Christopher S MarnellPradeep Natarajan
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Sep 2, 2021·Current Atherosclerosis Reports·Romit Bhattacharya, Alexander G Bick
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Dec 3, 2021·Blood·Peter G MillerUNKNOWN COPDGene Study Investigators, National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Consortium
Jan 21, 2022·Blood·Gerwin Huls

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Methods Mentioned

BETA
exome sequencing
genotyping

Software Mentioned

PHEnome Scan ANalysis Tool ( PHESANT )
BWA
Picard
Annovar
SPSS
lubridate
Affymetrix
PHESANT
SAMtools
WeCall

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