Cutting-edge genetics in obsessive-compulsive disorder

Abstract

This article reviews recent advances in the genetics of obsessive-compulsive disorder (OCD). We cover work on the following: genome-wide association studies, whole-exome sequencing studies, copy number variation studies, gene expression, polygenic risk scores, gene-environment interaction, experimental animal systems, human cell models, imaging genetics, pharmacogenetics, and studies of endophenotypes. Findings from this work underscore the notion that the genetic architecture of OCD is highly complex and shared with other neuropsychiatric disorders. Also, the latest evidence points to the participation of gene networks involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems in this disorder. We conclude by highlighting that further study of the genetic architecture of OCD, a great part of which remains to be elucidated, could benefit the development of diagnostic and therapeutic approaches based on the biological basis of the disorder. Studies to date revealed that OCD is not a simple homogeneous entity, but rather that the underlying biological pathways are variable and heterogenous. We can expect that translation from bench to bedside, through continuous effort and collaborative work, will ultimately transform our understanding of what causes OCD and thus how best to treat it.

Keywords: genetics; genomics; obsessive-compulsive disorder.

Figure 1.. From genetic architecture to obsessive-compulsive disorder (OCD) symptomatology.

The genetic architecture of OCD presumably underlies alterations in biological pathways, which in turn lead to disrupted brain circuits and OCD symptoms. CNV, copy number variant; SNP, single nucleotide polymorphism.

Figure 2.. Variations in the genome.

Single nucleotide variants (SNVs) constitute positions in the genome comprising a pair of bases for which different alleles (i.e. sequence variants) are found in a population. A SNV can be classified according to the frequency at which its second most common allele is found in a population, termed minor allele frequency (MAF). According to their MAF, SNVs can be classified into common (MAF≥5%), low-frequency (1%≥MAF<5%), and rare (MAF<1%). SNVs that occur in at least 1% of the population are called single nucleotide polymorphisms (SNPs). When occurring inside the exons (i.e. DNA stretches encoding protein products), SNVs can lead to the production of protein products with a normal amino acid sequence (i.e. synonymous SNVs), with an altered yet full amino acid sequence (i.e. missense SNVs), or with a truncated (i.e. incomplete) amino acid sequence (i.e. nonsense SNVs). The last two types of SNVs are termed nonsynonymous and usually have deleterious biological consequences. Copy number variants (CNVs) comprise genome deletions and duplications.

Figure 3.. Gene expression.

The gene, composed of exons (protein-coding regions) and introns (non-protein-coding regions), is transcribed into a precursor messenger ribonucleic acid (pre-mRNA), which undergoes alternative splicing to generate a messenger RNA (mRNA), called a primary transcript. Finally, mRNA undergoes translation to generate a protein product. This chain of events enables the flow of genetic information.

Figure 4.. Gene networks exploratory analysis.

The GeneNets algorithm was used to ascertain whether a set of obsessive-compulsive disorder (OCD) risk genes were more significantly connected to each other in a functional network as would be expected by chance alone. Accordingly, a total of 204 OCD-associated genes were selected from studies cited throughout the present review (more specifically, seven genome-wide association studies [GWASs]^–,,,,, two whole-exome sequencing [WES] studies^,, two copy number variant [CNV] studies^,, and one functional variants study) for the GeneNets exploratory analysis. A total of 125 of these genes were included in a significant network, in which three communities were enriched for biological pathways. More specifically, the most significant pathways detected for those communities were the ionotropic activity of kainate receptors (P <10^-6), associated with glutamate neurotransmission (Figure 4A); the cell adhesion-related processes (P <10^-9), involved in synaptic processes and neurodevelopment^, (Figure 4B); the regulation of kit signaling (P <10^-4), associated with immune function (Figure 4C); and the activation of GABAA receptors (P <10^-12), implicated in neuropsychiatric disorders. For the pathways displayed in the figure, the type of study from which their respective genes were selected is highlighted in the figure.