Looking into the genetic bases of OCD dimensions: a pilot genome-wide association study

Abstract

The multidimensional nature of obsessive-compulsive disorder (OCD) has been consistently reported. Clinical and biological characteristics have been associated with OCD dimensions in different ways. Studies suggest the existence of specific genetic bases for the different OCD dimensions. In this study, we analyze the genomic markers, genes, gene ontology and biological pathways associated with the presence of aggressive/checking, symmetry/order, contamination/cleaning, hoarding, and sexual/religious symptoms, as assessed via the Dimensional Yale-Brown Obsessive Compulsive Scale (DY-BOCS) in 399 probands. Logistic regression analyses were performed at the singlenucleotide polymorphism (SNP) level. Gene-based and enrichment analyses were carried out for common (SNPs) and rare variants. No SNP was associated with any dimension at a genome-wide level (p < 5 × 10 −8). Gene-based analyses showed one gene to be associated with hoarding (SETD3, p = 1.89 × 10 −08); a gene highly expressed in the brain and which plays a role in apoptotic processes and transcriptomic changes, and another gene associated with aggressive symptoms (CPE; p = 4.42 × 10 −6), which is involved in neurotrophic functions and the synthesis of peptide hormones and neurotransmitters. Different pathways or biological processes were represented by genes associated with aggressive (zinc ion response and lipid metabolism), order (lipid metabolism), sexual/religious (G protein-mediated processes) and hoarding (metabolic processes and anion transport) symptoms after FDR correction; while no pathway was associated with contamination. Specific genomic bases were found for each dimension assessed, especially in the enrichment analyses. Further research with larger samples and different techniques, such as next-generation sequencing, are needed to better understand the differential genetics of OCD dimensions.

The polygenic risk for obsessive‐compulsive disorder is associated with the personality trait harm avoidance

“…A general PRS for OCD lumps all of these hypothetical dimension‐specific SNPs together, so that a lack of an association is not surprising. A recent GWAS of obsessive‐compulsive symptom dimensions also supports the notion that divergent genes and pathways may be involved in the expression of different symptom dimensions, although no genome‐wide significant SNPs have been found, so far (71).…”

Genetics of obsessive-compulsive disorder

“…Focusing on compulsive symptoms only also increased the ability to identify genome-wide significant genes. Recently, a smaller study of 399 patients with OCD using a gene-based analysis has reported that SETD3 was associated with hoarding symptoms only ( p = 1.89 × 10 −8 ) and that biological pathways and processes were differentially associated across symptom dimensions (Alemany-Navarro et al, 2020 ).…”

A dimensional perspective on the genetics of obsessive-compulsive disorder

“…Approaches to identify genes associated with OCD typically take advantage of these frameworks and often attempt to either narrow the phenotypic definition to reduce heterogeneity or broaden the phenotypic definition to leverage observed genetic or clinical relationships between OCD and other traits. Methodologies aimed at narrowing the phenotypic definition may use a strict case definition or only include cases with clinically diagnosed OCD [ 1 , 17 , 18 ], childhood-onset OCD [ 4 , 7 ], OCD from multiplex families [ 19 , 20 ], OCD with tics [ 21 ], severe OCD, or specific OC symptoms [ 22 ] (Fig. 1 ).…”

“…Only two GWAS studies to date have examined the unique and shared genetic architecture of OC symptom factors, one of which used data from clinical OCD patients [ 22 ], and the other of which used data collected in the general population [ 25 ]. These studies, while suggesting some genetic sharing between symptom subtypes, still require replication.…”