Interaction between PGRN gene and the early trauma on clinical characteristics in patients with obsessive-compulsive disorder

Background: Emerging evidence suggests that obsessive-compulsive disorder (OCD) is caused by a combination of genetic predisposition and environmental factors. In this regard, abnormity of progranulin (PGRN, a key regulator of brain inflammation) and a history of childhood trauma have both been linked to an increased risk of developing OCD. This study is aimed to investigate the association between PGRN and childhood trauma in the development of OCD.

Methods: We genotyped four single nucleotide polymorphisms (SNPs) covering PGRN in 484 OCD patients and 368 healthy controls. Among the OCD patients, 335 of them accepted clinical assessments in details. Generalized multifactor dimensionality reduction (GDMR) analysis and a general linear model were used to identify gene-environment interactions. The Braineac expression Quantitative Trait Loci (eQTL) dataset was used to analyze the differences in PGRN expression in various brain regions among different genotypes.

Results: Our linkage disequilibrium analysis revealed that rs3859268-rs2879096-rs3785817 combined OCD and control groups constructed one haplotype block. The haplotype analysis suggested that TCA haplotype frequency was associated with the risk of developing OCD (Padj=0.03). The Braineac eQTL database revealed that rs2879096 and rs3785817 might be associated with PGRN expression in the hippocampus (Padj=0.00085, Padj=0.007). Emotional abuse was positively correlated with the obsession subscale and Y-BOCS total scores. Except for common trauma, physical abuse, emotional abuse and sexual trauma were all positively correlated with the BAI and BDI-II scores of OCD patients (all P<0.05). The interaction between emotional abuse and PGRN haplotype was associated with the development of depression symptoms in OCD patients corrected by age (Padj=0.043).

Conclusions: The PGRN gene and childhood trauma may be closely related to the incidence of OCD, and OCD patients who have experienced more childhood trauma may exhibit a more severe clinical symptom. The interaction between PGRN and the early trauma may play a critical role in the development of depression symptom in OCD patients.