Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis

被引：19

作者：

Stacey, Simon N. ^{[1
]}

Zink, Florian ^{[1
]}

Halldorsson, Gisli H. ^{[1
,2
]}

Stefansdottir, Lilja ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Einarsson, Gudmundur ^{[1
]}

Hjorleifsson, Grimur ^{[1
]}

Eiriksdottir, Thjodbjorg ^{[1
]}

Helgadottir, Anna ^{[1
]}

Bjornsdottir, Gyda ^{[1
]}

Thorgeirsson, Thorgeir E. ^{[1
]}

Olafsdottir, Thorunn A. ^{[1
,3
]}

Jonsdottir, Ingileif ^{[1
,3
,4
]}

Gretarsdottir, Solveig ^{[1
]}

Tragante, Vinicius ^{[1
]}

Magnusson, Magnus K. ^{[1
,3
]}

Jonsson, Hakon ^{[1
]}

Gudmundsson, Julius ^{[1
]}

Olafsson, Sigurgeir ^{[1
]}

Holm, Hilma ^{[1
]}

Gudbjartsson, Daniel F. ^{[1
,2
]}

Sulem, Patrick ^{[1
]}

Helgason, Agnar ^{[1
,5
]}

Thorsteinsdottir, Unnur ^{[1
,3
]}

Tryggvadottir, Laufey ^{[6
]}

Rafnar, Thorunn ^{[1
]}

Melsted, Pall ^{[1
,2
]}

Ulfarsson, Magnus O. ^{[1
,2
]}

Vidarsson, Brynjar ^{[3
,7
]}

Thorleifsson, Gudmar ^{[1
]}

Stefansson, Kari ^{[1
,3
]}

机构：

[1] deCODE Genet Amgen Inc, Reykjavik, Iceland

[2] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[3] Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland

[4] Landspitali Univ Hosp, Dept Immunol, Reykjavik, Iceland

[5] Univ Iceland, Dept Anthropol, Reykjavik, Iceland

[6] Icelandic Canc Registry, Reykjavik, Iceland

[7] Landspitali Univ Hosp, Dept Hematol, Reykjavik, Iceland

来源：

NATURE GENETICS | 2023年 / 55卷 / 12期

关键词：

Y-CHROMOSOME LOSS; TELOMERE LENGTH; VARIANTS; RISK; COMMON; ASSOCIATION; EXPRESSION; CANCER; TRAIT; LOCI;

D O I：

10.1038/s41588-023-01555-z

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A. A barcode-based approach applied to UK Biobank and an Icelandic cohort identifies drivers of clonal hematopoiesis (CH) and finds associations between CH and multiple diseases. Genome-wide association analyses identify 25 loci associated with CH susceptibility.

引用

页码：2149 / 2159

页数：11