Cutting-edge genetics in obsessive-compulsive disorder

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.


Introduction
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions) 1 . With a lifetime prevalence of 2-3% and a typically chronic course 2 , OCD is associated with considerable role impairment 3 , reduced quality of life 4 , and morbidity 5 . Moreover, individuals with OCD have an elevated mortality risk independently of the effects of comorbidities 6 .
First-line treatments for OCD include both pharmacological and cognitive-behavioral approaches 7 ; alone or combined, these can help about half of patients to achieve minimal symptoms 8 . The development of more targeted and effective treatment interventions may benefit from further understanding of the underlying etiology of OCD, including underlying genetic mechanisms. Here we review recent advances in OCD genetics research, including genome-wide association studies (GWAS), whole-exome sequencing (WES) studies, copy number variation (CNV) studies; gene expression, polygenic risk score (PRS), gene-environment interactions, experimental animal systems, human cell models, imaging genetics, pharmacogenetics, and studies of endophenotypes. We suggest that recent work converges in pointing out that genes involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems are involved in the pathophysiology of OCD (Figure 1). Given the genetic overlap between OCD and related disorders, further work is needed to assess the specificity of this involvement.

From genetic epidemiology to genetic architecture
Family and twin studies are useful for exploring genetic and environmental contributions to a disease. In this context, familiality refers to increased clustering of a disorder amongst families 9 . Consistent with multiple previous studies 10-12 , a recent family study in Sweden provided further evidence for the familiality of OCD, especially when associated with tics 13 .
Heritability can be defined as the proportion of variance in a phenotypic trait attributable to additive genetic effects (i.e. narrow-sense heritability, h 2 ) or to total genetic effects (i.e. broad-sense heritability, H 2 ) 14 . Henceforth in this article, narrow-sense heritability (h 2 ) will be referred to as heritability. Past twin studies have estimated the heritability of OCD to range from 27 to 65% 15 , and a recent heritability estimate of 74% was reported for obsessive-compulsive traits in a pediatric nonclinical twin cohort 16 .
The heritability of OCD encourages further work on the genetics of this disorder, with the hope that this will, in turn, contribute to the development of more precise diagnostic and therapeutic approaches 17 . The term "genetic architecture" refers to the overall number, effect size, population frequency, and interactions of genetic variants associated with a phenotype 18 . Genetic studies that contribute to elucidating genetic architecture include GWAS, WES studies, CNV studies, gene expression analysis, gene-environment interaction studies, experimental models with animal and human cells, imaging genetics studies, pharmacogenetic studies, and studies of endophenotypes. We consider each in turn, presenting a summary of all of the cited studies after the section describing an exploratory model of the genetic architecture of OCD (Table 1).

Genome variants
Early studies on the genetics of OCD focused on candidate gene association studies 15 . Because of their insufficient power and biased a priori hypotheses, these studies produced rather inconsistent findings and are now considered obsolete 19 . The development of novel methods capable of assessing the entire genome, coupled with the recruitment of larger samples, allowed the undertaking of unbiased and powerful genetic investigations 19 . In this regard, cumulative evidence supports the idea that both common and rare genome variants contribute to the polygenic architecture of psychiatric disorders 20 . 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.

Den Braber et al.(2016)
Obsessive-compulsive symptoms of 8,267 subjects GWAS A genome-wide significant SNP was detected at MEF2BNB. Gene-based testing revealed four genes significantly associated with obsessive-compulsive symptoms located in the 19p13.11 chromosomal region, which has been associated with brain and immune processes.
Costas et al. PGC OCD workgroup (2018) 2,688 OCD probands and 7,037 control subjects GWAS No genome-wide significant SNP was detected. Most significant SNPs were in LD with GRID2 and KIT. PRSs estimated based on the first and second OCD GWASs significantly predicted case-control status in the second and the first OCD GWASs case-control samples, respectively. SNP-based heritability was estimated at 0.28.

Khramtsova et al.
(2018) PGC-OCD GWAS sample GWAS SNP-based heritability estimates were similar for male and female OCD, and significant genetic correlation between them was reported. GRID2 and GRP135 were associated only with female OCD in gene-based tests. SNPs with sex-specific effects were significantly enriched for regions regulating gene expression in brain and immune tissues. Whole-exome sequencing study A significantly higher prevalence of de novo damaging variants (33.9%) was found among probands. These variants were estimated to be present in 22.2% of overall OCD cases.
SCUBE1 and CHD8 were identified as high-confidence risk genes for OCD. Genes carrying these variants significantly overlap among ASD and TS probands and were associated with immune system-related processes.
307 pediatric OCD probands and 3,861 control subjects Copy number variants study A similar rate of rare copy number variants (CNVs) in early onset OCD probands and controls was observed. In 5.9% of probands, structural variants were detected in genes associated with brain function. Particularly, CNVs were found in three targets of fragile X mental retardation protein (FMRP), including DLGAP1 and PTPRD.

Grünblatt et al. (2017) 121 pediatric OCD probands and 123 control subjects
Copy number variants study Although no significant difference in number and size of rare CNVs between pediatric OCD patients and controls was detected, the number of CNVs encompassing genes involved in neurological function was higher among the former.

Zarrei et al.
(2019) 2,691 probands diagnosed with OCD, SCZ, ASD, or ADHD and 1,769 family members Copy number variants study Clinically relevant CNVs were found in 5.6% of OCD probands. Multiple brain-expressed genes impacted by CNVs in at least two probands were found. An increased burden of rare CNVs impacting genes involved in genomic stability was found in probands.

OCD probands
Gene-environment interaction Although not predicting treatment response, a PRS estimate based on OCD risk variants predicted pretreatment symptom severity.

Mahjani et al.
(2020) 822,843 individuals, including 7,184 probands diagnosed with OCD Maternal effects Genetic maternal effects (i.e. the influence of the maternal genotype on the phenotype of the offspring) accounted for 7.6% of the liability for OCD, whereas additive genetic effects accounted for 35%.

Experimental
animal system Targeted deletion of Hoxb8-lineage microglia led to significant grooming and anxietylike behaviors and stress-response among female rodents, which were ameliorated by suppressing female sex hormones.

Delgado-Acevedo et al.
Experimental animal system Overexpression of EAAT3 in the frontal cortex, hippocampus, and striatum increased anxious and grooming behaviors and prolonged spontaneous recovery of conditioned fear among rodents. Moreover, alterations in NMDA receptor constitution and corticostriatal synaptic plasticity were observed.

Author
Experimental animal system Rodent with microglia-restricted progranulin (PGRN) inactivation exhibited increased selfgrooming and marble-burying behaviors, which were normalized with suppression of nuclear factor κB (NF-κB) signaling.
Ullrich et al.
Experimental animal system SPRED2 knockout mice displayed severe grooming and anxiety behaviors, dysfunctional thalamo-amygdala synapses, and altered expression of synaptic proteins in the amygdala.

Van de
Vondervoort et al.
Experimental animal system TALLYHO/JngJ rodents, which are a model of human type 2 diabetes mellitus, exhibited increased compulsive and anxious behaviors in addition to structural brain abnormalities in midline corpus callosum, dorsomedial striatum, and superior cerebellar peduncles. Human cell models Significant differences were detected in the neutrophil: lymphocyte ratio and white blood cell, neutrophil, and platelet counts among OCD probands with comorbid anxiety disorder, OCD probands with no comorbidities, and control subjects, which remained after controlling for age and sex.

Noh
Hibar et al. Accordingly, distinct methods have been recently used to detect genome variants associated with OCD, as described below.

Common variants
GWASs employ a case-control design to detect single nucleotide polymorphisms (SNPs) (Figure 2) associated with a disorder 21 , with significance thresholds set at P = 5 × 10 -822 . A range of secondary analyses of GWAS data can be conducted to further probe the relevant genetic architecture 23 . Such analyses include determining the portion of heritability conferred by the SNPs investigated in a GWAS, defined as SNP-based heritability (h 2 SNP ) 24 , estimating the degree of shared genetic architecture between disorders by determining their genetic correlation 25,26 , calculating PRSs based on risk variants for a disorder identified in a GWAS 27 , and undertaking enrichment analysis to assess clustering of detected variants within functionally related genomic regions and biological pathways 28 .
To date, GWASs of OCD have not revealed any genome-wide significant SNPs associated with this disorder in case-control analyses 15 . Recently, the Psychiatric Genomics Consortium OCD (PGC-OCD) workgroup combined data from the first two OCD GWASs 29,30 to yield a sample of 2,688 OCD cases and 7,037 controls. The top-ranked detected SNP (i.e. strongest association) was in the P = 10 -7 significance range 31 . Nonetheless, SNP-based heritability was estimated at 28% in this sample 31 , among the highest reported for neuropsychiatric disorders. These findings indicate the need for still larger samples for sufficient statistical power.
The top-ranked SNPs detected in the PGC-OCD GWAS were in linkage disequilibrium with genes previously associated with autism spectrum disorders (ASD) 31 : GRID2, involved in cerebellar synaptic processes 32 , and KIT, implicated in neurodevelopment 33 . Moreover, a sex-stratified GWAS of the PGC-OCD sample revealed that SNPs with sex-specific effects were significantly enriched for genome regions influencing gene expression (i.e. expression quantitative trait loci, eQTLs) in brain and immune tissues 34 . In line with the findings of an earlier GWAS of obsessive-compulsive symptoms 35 , a recent meta-analysis of the PGC-OCD GWAS and a GWAS of 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%) 18 . SNVs that occur in at least 1% of the population are called single nucleotide polymorphisms (SNPs) 18 . 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.
compulsive symptoms in 8,267 nonclinical subjects revealed the most significant enrichment for genes expressed in brain regions associated with the neurocircuitry of OCD, i.e. the cingulate cortex, nucleus accumbens, and amygdala 36 . Taken together, the aforementioned GWASs suggest a role for synaptic, neurodevelopmental, and immune processes in the etiology of OCD.
Genetic correlation analyses using data from the PGC-OCD GWAS have suggested a shared genetic architecture between OCD and related conditions. In this respect, two studies found a significant genetic correlation between OCD and anorexia nervosa (AN) 37,38 , consistent with the hypothesis that obsessive and compulsive traits in these conditions have shared etiology 39 . Furthermore, PRSs for other neuropsychiatric disorders were able to significantly predict case-control status in previous OCD GWAS samples, indicating a shared genetic liability 40 . In smaller studies, a PRS for schizophrenia (SCZ) significantly predicted case-control status in a Spanish sample comprising 370 OCD patients and 443 controls 41 , and a PRS for ASD significantly predicted case-control status in a sample of 2,535 OCD cases and controls 42 . PRS may, in the future, have applications in clinical practice, ranging from improving diagnostic precision to predicting treatment response 20 . However, it needs to be emphasized that such applications are not currently possible and that translation of PRSs from a population of one ancestry to a population of different ancestry is problematic 43 .

Rare variants
WES is a technique employed to detect single nucleotide variants in the exome (i.e. all of the genome exons) 20 , among which de novo variants (Figure 2) have the most pathogenic effect for neuropsychiatric disorders 44 . De novo variants refer to genome variants that occur in the proband but not in the parents. WES studies are usually performed in trios composed of healthy parents and an affected child in order to detect de novo variants driving pathology 20,44 .
Two recent studies reported an increased genome-wide burden of gene-disrupting de novo mutations in patients with OCD. In the first WES study 45 , 20 nonsynonymous de novo variants were detected among 17 OCD probands at a rate similar to that reported for other neuropsychiatric disorders. Moreover, these variants were enriched for pathways related to the immune system and neurodevelopment.
The second WES study was conducted on a sample of 184 OCD and 777 control parent-child trios 46 . De novo damaging variants were significantly more frequent among probands, achieving a prevalence of 33.9%. Such findings were used to estimate the rate of these variants among overall OCD cases at 22.2%. Two high-confidence risk genes for OCD were further identified: SCUBE1, potentially involved in endothelial inflammatory responses 47 , and CHD8, implicated in chromatin metabolism 48 , neurogenesis 49 , and synaptic transmission 50 and extensively associated with ASD 51-53 . Additionally, genes carrying de novo damaging variants in OCD probands significantly overlapped with genes associated with ASD, Tourette's syndrome (TS), and other neurodevelopmental disorders and were enriched for immune system pathways. Similar findings were reported in another study which found a significant overlap between genes associated with OCD and genes associated with ASD; in addition, the overlapping genes were significantly enriched for biological pathways related to brain function 54 .

Copy number variants
The most common type of structural variants in the human genome are CNVs (Figure 2), which comprise duplications and deletions 55 . The prevalence of CNVs can be assessed across the whole genome using array methods 56 .
In an earlier CNV study in OCD, a 4.4-fold increase in deletions encompassing loci associated with neurodevelopmental disorders (including 16p13.11) was found among OCD probands 57 . More recently, two CNV studies were conducted on samples comprising 307 and 121 individuals with pediatric OCD and 3,861 and 124 healthy controls, respectively 58,59 . The number of CNVs in genes involved in brain function was higher among OCD probands in both studies. In the first study, CNVs were found in three targets of the fragile X mental retardation protein (FMRP). Consistent with FMRP involvement in several processes related to synaptic plasticity 60 , CNVs encompassing FMRP targets have been associated with SCZ 61 , ASD 62 , and attention deficit hyperactivity disorder (ADHD) 63 . In the second study, CNVs were found in genes implicated in SCZ, ASD, and TS. Finally, a recent study of 2,691 individuals diagnosed with OCD, SCZ, ASD, or ADHD found clinically relevant CNVs in 5.6% of OCD cases and multiple brain-expressed genes impacted by CNVs overlapping across those disorders 64 .
Taken together, these WES and CNV findings again support a role for synaptic, neurodevelopmental, and immune processes in the etiology of OCD. Moreover, these findings indicate the existence of a shared genetic etiology between OCD and related disorders, suggesting that their current diagnostic categories may not reflect distinct clinical entities. In line with this, a recent study used a machine learning approach to cluster patients with OCD, ASD, and ADHD into homogenous groups based on neuroimaging measures of cortical thickness and behavioral measures and found that those diagnostic categories were not reflected in the groups formed 65 .

Variation in gene expression
Complex regulatory mechanisms govern the way in which genotype and environment together lead to distinctive patterns of gene expression in different tissues at different developmental stages 20,66,67 . Methods are now available to explore tissue-specific gene expression and environmental regulatory mechanisms in OCD.

Gene expression in specific tissue
As a proxy of gene expression, the measurement of transcript levels (i.e. mRNA) (Figure 3) in post-mortem brain specimens of patients with psychiatric disorders is useful for genetic investigations 68 . Furthermore, the discovery of differential transcript levels in the peripheral blood of patients with psychiatric disorders may provide additional insight into mechanisms underlying gene expression 69 .
Recently, reduced expression of genes related to excitatory glutamatergic synapses has been identified in the lateral and frontal regions of the orbitofrontal cortex (OFC) of individuals with OCD 70 . Speculatively, such findings may be relevant to understanding alterations in OFC volume 71 and activity in neuroimaging studies of OCD 72 .
Gene expression profiling in the peripheral blood has been employed to compare individuals with OCD, major depressive disorder (MDD), and SCZ and healthy controls 73 . A six-gene panel was able to diagnose OCD cases with 88% sensitivity and 85% specificity 73 . Among the genes included in the panel, FKBP1A encodes an enzyme involved in immune regulation 74 and COPS7A encodes a subunit of a protein complex involved in protein degradation 75 .

Gene expression and the environment
The reciprocal interactions between gene expression and the environment have been investigated through diverse methods, ranging from basic science to epidemiological approaches 76,77 . Importantly, epigenetic mechanisms ( Figure 3) provide a pathway whereby the environment can modulate gene expression through alterations in chromatin and DNA structure 78 .
In one recent study, no difference was found in blood DNA methylation levels of candidate genes previously implicated in OCD among 21 pediatric cases and 12 controls 79 . Conversely, in another study using a genome-wide approach, multiple genes with different methylation levels were detected among 65 pediatric OCD cases and 96 controls 80 . These findings emphasize the importance of an unbiased approach for studying the genomics of OCD.
A study of gene-environment interactions in a cohort of 103 patients with OCD revealed that neither PRS for OCD nor the presence of a stressful life event at the onset of the disorder predicted treatment response 81 . Nonetheless, PRS was able to predict illness severity. Moreover, environmental factors, such as perinatal complications 82,83 and maternal effects (i.e. the influence of maternal genetic and environmental factors on the phenotype of the offspring) 84 , have been shown to increase the risk for OCD. Further work is needed to determine whether PRSs, taken together with a range of environmental factors, may be useful in predicting OCD severity and treatment response. As a complement to the gene-environment interaction approach, in-depth environmental research in psychiatry, known as the exposome 85 , should add to the understanding of the interplay between genetics and the exposure to multiple internal and external stimuli in the prevention and treatment of psychiatric disorders.

Modeling genetic architecture
Laboratory-based experimental models may be used to study genes which appear to be important in clinical studies of the genomics of OCD 86 . We focus here on work done in animals and in human cells.

Experimental animal systems
Excessive grooming, hoarding behaviors (e.g. marble-burying), and stereotyped behaviors have been studied in rodent models of OCD 87 . Such work is not intended to replicate the disease in an animal system but may rather provide insight into the biological mechanisms relevant to OCD, which may foster the development of novel treatment approaches 88 .
Overexpression of the excitatory amino acid transporter 3 (EAAT3), involved in glutamate neurotransmission, in the frontal cortex, hippocampus, and striatum of rodents resulted in increasing grooming and disturbed cortical-striatal excitatory synapse plasticity 89 . Furthermore, a protective effect against the induction of stereotyped behaviors by dopaminergic challenge was obtained by constitutive EAAT3 reduced expression in mice 90 .
Immunity-and neuroinflammation-related processes have been consistently associated with OCD 91 . In this respect, mice with microglia-restricted progranulin inactivation exhibited increased self-grooming and marble-burying, which was normalized after suppression of nuclear factor κB signaling in the microglia 92 . Also suggesting a potential role for the microglia in the etiology of OCD, targeted deletion of Hoxb8-lineage microglia yielded severe grooming, especially in female mice 93 . Furthermore, restoring tropomyosin receptor kinase B/ERK-MAPK signaling in mice normalized severe grooming behaviors induced by ablation of SPRED2 94 , which pertain to a family of proteins that has been implicated in neurodevelopment 95 .
Recent investigations of gene pathway analysis 96 and PRSs 97 using GWAS data support the association of disturbances in insulin signaling with the pathophysiology of OCD. These findings were further validated in a rodent model of type 2 diabetes mellitus, which revealed increased compulsive-like behaviors and brain abnormalities previously associated with OCD 98 .
Findings from experimental animal systems may inform clinical studies 99 . A large set of candidate genes potentially associated with OCD in previous human, rodent, and canine studies was investigated using a target-sequencing approach for the detection of regulatory and coding variants (i.e. functional variants) in 592 OCD cases and 560 controls 100 . Among the four genes significantly enriched for functional variants in OCD cases (i.e. NRXN1, HTR2A, CTTNBP2, and REEP3), all were involved in brain biological pathways implicated in OCD 100 . Additionally, NRXN1 achieved genome-wide significance when OCD cases were compared to 33,370 controls 100 .
Human cell models Investigations using human-derived cells as models may be useful in studying OCD at the molecular and cellular levels 101 . Higher ratios of immune cells in the peripheral blood 102,103 and abnormal production of inflammatory cytokines upon stimulation by those cells 102 have been reported in OCD. Future work on pluripotent stem cells derived from somatic cells of patients with OCD could be useful in extending this preliminary work.

Genetic variations underlying relevant phenotypes
There is growing interest in determining the genetic basis of OCD-associated neuroimaging abnormalities, cognitive dysfunction, and treatment response, as outlined below.

Neuroimaging
The Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium is the largest collaboration working to integrate genetic and neuroimaging findings; it combines findings from sites across the globe 104 . The combination of data from the first OCD GWAS and the ENIGMA GWAS of subcortical brain structure 105 allowed for the detection of a significant overlap between the SNPs associated with increases in the risk for OCD and in the volumes of the putamen, a component of the cortical-striatal-thalamic-cortical circuitry implicated in OCD 106 , and the nucleus accumbens, a treatment target for deep brain stimulation in treatment-refractory OCD 107 . Moreover, the SNP associated with both the increased risk for OCD and the increased putamen volume is located near the RSPO4, a gene implicated in pathways related to neurodevelopment 108 .

Cognitive dysfunction
Cognitive deficits have been frequently explored as OCD endophenotypes 109 , defined as heritable quantitative traits found at higher rates in unaffected relatives of patients and associated with increased genetic susceptibility to the disorder 110,111 . The findings of investigations on cognitive deficits as endophenotypes of OCD have been recently meta-analyzed 112 ; this study found significant impairment in global executive functioning among unaffected relatives, with specific deficits in planning, visuospatial working memory, and verbal fluency. Since these endophenotypes may be more proximally related to genetic mechanisms than OCD itself 111 , further investigation of these deficits may be useful.

Treatment response
Pharmacogenetic studies address the association of genetic variation with drug response 113 . Although earlier pharmacogenetic studies in psychiatric disorders have focused mainly on candidate genes and on genes related to the cytochrome P450 system 114 , genome-wide approaches have been recently employed in OCD research.
The association of the response to serotonin reuptake inhibitors (SRIs) treatment with common variants was assessed in a GWAS of 804 OCD cases, including 514 responders and 290 non-responders 115 . A genome-wide significant SNP was detected near the gene DISP1, within a chromosomal region associated with neurodevelopment. Further enrichment analysis revealed that the most significant SNPs were enriched for biological pathways related to glutamate and serotonin neurotransmission. However, a follow-up study with 112 OCD cases found no association between the SNP located near DISP1 and the response to SRIs treatment 116 . Further investigation in larger samples is warranted to determine the clinical utility of pharmacogenetic data in OCD.

OCD genetic architecture: an exploratory model
The data described in the previous sections suggest that genes involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems are involved in the pathophysiology of OCD (Figure 1). Based on these data, an exploratory analysis was undertaken with GeneNets in order to investigate whether genes associated with risk for OCD, identified in studies assessing common and rare variants, would form communities (i.e. clusters of functionally connected genes involved in a particular biological process) 117 . Three communities were significantly enriched for biological processes: related to glutamate neurotransmission, to cell adhesion, and to the immune system (Figure 4). These findings are consistent with a model in which multiple genes and biological pathways play a role in the pathogenesis of OCD and in which synaptic, neurodevelopmental, and immune pathways may be particularly important.

OCD genetics: current insights and future prospects
This review shows how several recent developments in genomics have contributed to understanding the genetic architecture of OCD. The use of cutting-edge methods has moved the field from a focus on candidate genes in underpowered samples to unbiased approaches in larger cohorts. At the same time, a great deal more work is needed to fully understand the role of common and rare gene variants in OCD. Work on gene methylation and expression has provided proof-of-principle demonstrations of the value of such studies and deserves expansion. Such work, taken together with careful phenotyping and comparison of individuals with different disorders, may lead to a better understanding of transdiagnostic genetic mechanisms.
The question of how advances in the genomics of OCD will become clinically useful remains to be answered. First-line pharmacological treatments for OCD target mostly serotonergic neurotransmission; biological pathways implicated in recent . 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] [29][30][31]35,36,41,42 , two whole-exome sequencing [WES] studies 45,46 , two copy number variant [CNV] studies 58,59 , and one functional variants study 100 ) 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 118 ( Figure 4A); the cell adhesion-related processes (P <10 -9 ), involved in synaptic processes 119 and neurodevelopment 120,121 ( Figure 4B); the regulation of kit signaling (P <10 -4 ), associated with immune function 122 ( Figure 4C); and the activation of GABAA receptors (P <10 -12 ), implicated in neuropsychiatric disorders 123 . For the pathways displayed in the figure, the type of study from which their respective genes were selected is highlighted in the figure. genomic studies, such as those related to glutamatergic, neurodevelopmental, and the immune and inflammatory systems, may be useful targets in the future. More robust pharmacogenetic evidence may ultimately improve the prediction of response to pharmacological treatments, advancing precision medicine for OCD. Shared genetic liability among OCD, ASD, and SCZ may suggest new approaches to transdiagnostic assessment of patients. That said, to date, genetic studies have not demonstrated clinical utility, suggesting that OCD is not a simple homogeneous entity but rather that the underlying biological pathways are complex, variable, and heterogeneous. 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.