Clonal haematopoiesis of indeterminate potential and risk of incident psychiatric disorders

Exploring the association of clonal haematopoiesis of indeterminate potential (CHIP) with psychiatric disorders (PDs) may help to elucidate the biological mechanisms underlying PDs. The study aimed to identify the specific PD subtypes associated with CHIP and gene-specific CHIP for each PD subtype.

A total of 360,451 participants from UK Biobank without PDs at baseline, aged 40-69 years and recruited between 2005 and 2014, were included. CHIP status was determined from whole exome sequencing for mutations in 74 driver genes. Any CHIP (variant allele fraction (VAF) ≥ 2%), large CHIP (VAF ≥ 10%), and gene-specific CHIP were set as exposures. The primary outcomes were overall psychiatric disorder with 13 PD subtypes. Brain imaging-derived phenotypes (IDPs), derived from 40,000 individuals during follow-up, were further included.

During a median follow-up of 13.6 years, 50,074 (13.9%) participants developed at least one PD. This prospective study demonstrated that CHIP and large CHIP were independently associated with a 15% (10%-20%) and 27% (18%-36%) increased risk of PDs. Among PD subtypes, CHIP and large CHIP were associated with hazard ratios (HR) of 1.12 (1.04-1.21) and 1.27 (1.11-1.44) for major depressive disorders, and 1.27 (1.20-1.35) and 1.21 (1.09-1.34) for substance use disorders, respectively. Gene-specific analyses revealed that risk for PDs was generally increased across CHIP driven by seven genes (DNMT3A, TET2, ASXL1, PPM1D, SRSF2, NF1, SF3B1) with the highest mutation frequency. Associations of gene-specific CHIP were also heterogeneous across PD subtypes. Furthermore, CHIP carries, especially DNMT3A-CHIP carries, had significant changes in 11 brain white matter (WM) tract IDPs.

CHIP was associated with elevated risk of psychiatric disorders, specifically major depressive disorders and substance use disorders, with gene-specific associations observed with changes in brain WM tracts. These findings revealed a potential biological association between CHIP and psychiatric disorders, offering new insights into disease mechanisms and possible therapeutic targets.