Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly

Area of Science:

• Genetics
• Hematology
• Aging

Background:

• Clonal hematopoiesis (CH) is the expansion of a single hematopoietic stem cell lineage due to somatic mutations.
• Candidate driver (CD) genes are implicated in CH, but the full spectrum of its causes and consequences is not well understood.

Purpose of the Study:

• To investigate the prevalence, genetic underpinnings, and phenotypic associations of clonal hematopoiesis in a large population.
• To explore potential mechanisms for CH development, including those independent of known CD mutations.

Main Methods:

• Whole-genome sequencing of 11,262 Icelanders to identify mosaic somatic mutations indicative of CH.
• Statistical analysis to associate CH with genetic factors, mortality, and various phenotypic characteristics.

Main Results:

• CH is highly prevalent in the elderly, approaching inevitability.
• Somatic mutations in TET2, DNMT3A, ASXL1, and PPM1D are significantly associated with CH, yet only a fraction of CH cases harbor known CD mutations.
• CH is linked to increased mortality, hematological malignancy risk, smoking, shorter telomere length, and Y-chromosome loss.
• A germline deletion in the TERT gene (rs34002450) predisposes individuals to CH.

Conclusions:

• Clonal hematopoiesis is a widespread phenomenon in aging, with significant health implications.
• CH can arise through mechanisms beyond mutations in known CD genes, possibly involving neutral drift.
• Genetic predisposition, including germline variants like the TERT deletion, plays a role in CH development.