Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease

Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study.

After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed.

A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10^-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease.

Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.