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Obsessive–compulsive disorder: an integrative genetic and neurobiological perspective

Key Points

  • Obsessive–compulsive disorder (OCD) is a phenotypically complex multidimensional neuropsychiatric disorder.

  • Family and twin studies provide definitive evidence that genetic and environmental factors can increase risk of the disorder.

  • Candidate gene and genome-wide association studies provide strong suggestive evidence that genes in the serotonergic, dopaminergic and glutamatergic systems confer risk for the manifestation of OCD.

  • Imaging studies as well as neuropsychological and treatment studies have implicated frontal–subcortical circuits in the pathophysiology of OCD.

  • A cortico–striato–thalamo–cortical circuit is the prevailing model regarding the neural and pathophysiological underpinnings of OCD.

  • The prevailing treatments include both pharmacological agents (selective serotonin-reuptake inhibitors) and cognitive behavioural therapy (CBT), with CBT and/or a combination of pharmacological and CBT being the most efficacious.

  • Animal studies provide strong evidence for the involvement of the glutamatergic system in the expression of OCD-like behaviours.

  • A model incorporating both genetic and epigenetic mechanisms in the manifestation of OCD is suggested as a heuristic for the pathophysiology of OCD.

Abstract

Obsessive–compulsive disorder (OCD) is characterized by repetitive thoughts and behaviours that are experienced as unwanted. Family and twin studies have demonstrated that OCD is a multifactorial familial condition that involves both polygenic and environmental risk factors. Neuroimaging studies have implicated the cortico–striato–thalamo–cortical circuit in the pathophysiology of the disorder, which is supported by the observation of specific neuropsychological impairments in patients with OCD, mainly in executive functions. Genetic studies indicate that genes affecting the serotonergic, dopaminergic and glutamatergic systems, and the interaction between them, play a crucial part in the functioning of this circuit. Environmental factors such as adverse perinatal events, psychological trauma and neurological trauma may modify the expression of risk genes and, hence, trigger the manifestation of obsessive–compulsive behaviours.

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Figure 1: The theoretical basis of obsessive–compulsive behaviour.
Figure 2: The cortico–striato–thalamo–cortical circuitry.
Figure 3: An integrative model of genetics, environment and neurobiology for the expression of OCD.

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Acknowledgements

This work was supported in part by US National Institutes of Health (NIH) grants NS16648 (to D.L.P.), NS40024 (to D.L.P.) and MH079489 (to D.L.P.).

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Correspondence to David L. Pauls or Daniel A. Geller.

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Competing interests

D.L.P., S.L.R. and D.A.G have received funds from US National Institutes of Health (NIH) grants. D.A.G. has received funds for lectures at the American Association of Child and Adolescent Psychiatry and at the Massachusetts General Hospital Psychiatry Academy. S.L.R. has received research funding from Cyberonics and Medtronic. A.A. declares no competing interests.

PowerPoint slides

Glossary

Exposure and response prevention

The first-line behavioural therapeutic technique for the treatment of obsessive–compulsive disorder, anxiety disorders and phobias. This technique involves exposing the patient to stimuli that the patient perceives as threatening, anxiety-provoking or dangerous. This gradual exposure accompanies the prevention of responses that the patient usually undertakes in order to avoid or decrease anxiety. This technique is theoretically anchored in the Pavlovian extinction of conditioned fear.

Probands

People who serve as the starting point of a genetic study.

Enuresis

Involuntary control of urination, such as bed-wetting.

Odds ratios

Measures of effect size, defined as the ratio of the odds of an event occurring in one group to the odds of it occurring in another group. In the context of a genetic-association study, this might be the odds of obsessive–compulsive disorder occurring in one genotype group against the odds of it occurring in another genotype group.

Genetic linkage studies

Studies that explore the possibility that a risk gene for a particular disorder is located near a gene or DNA marker localized to a specific chromosomal region and is thus inherited together with that locus during meiosis. These studies are based on the observation that genes that are close to each other on the same chromosome are less likely to be separated during chromosomal crossover and are therefore said to be genetically linked.

Single-nucleotide polymorphisms

(SNPs). DNA sequence variations that occur when a single nucleotide at a specific site in the genome differs between paired chromosomes.

Candidate gene studies

Studies that assess whether specific 'candidate' genes are involved in the variation observed for a particular trait based on prior knowledge, such as the function of the gene and polymorphisms in the gene that are known to alter its function.

Genome-wide association studies

(GWASs). Studies in which many common genetic variants are examined to determine whether they are associated with a trait. These studies typically focus on associations between single-nucleotide polymorphism and commonly occurring disorders.

Genome-wide significance

A statistical threshold (P = 5 × 10−8) based on the testing of one million single-nucleotide polymorphisms in a genome-wide association study and on the use of a Bonferroni correction for multiple testing (that is, 0.05/1,000,000).

Cingulotomy

A form of a neurosurgical procedure, usually performed in psychiatric patients, that involves surgical severing of the anterior cingulum.

Optogenetics

A novel technique that combines genetics and optics to enable manipulation of specific cells in living organisms, utilizing light to activate genetically sensitized neurons.

Endophenotype

(Also known as an intermediate phenotype). A quantifiable construct that mediates low-level genetic variability and high-level phenotypic expression.

Go–no-go task

A task of response inhibition in which stimuli (for example, coloured squares) are continuously presented and the individual is asked to respond as fast as possible to all coloured squares (that is, go stimuli) except for one type of no-go stimulus (for example, a red square). Responding to a no-go stimulus is considered to be a commission error — a strong indicator for response inhibition impairments.

Stroop task

A task in which participants are presented with colour names printed in different font colour. In one trial block, the colour name and font colour are incongruent. The difference in performance or reaction time between congruent and incongruent blocks is defined as the Stroop effect.

Stop signal task

A response-inhibition task in which participants are asked to respond as fast as possible to a certain feature of a specific stimulus. On some trials, the go stimulus is followed by a signal indicating that the response should be withheld.

Iowa gambling task

A decision-making task in which the goal is to earn as much money as possible. Participants are faced with four decks of cards. Each card may earn or lose the participant a monetary reward. The decks vary in the percentage of non-rewarding cards. Healthy controls will tend to quickly focus on a 'good' deck, whereas patients with orbitofrontal dysfunction will tend to persevere on 'bad' decks.

Monetary incentive delayed task

A reward task in which participants are required to respond within a time window and be potentially rewarded depending on their response time.

Wisconsin card sorting test

A test in which participants are presented with stimulus cards that differ in the number, form and colour of shapes they show. Participants are required match each card to one of four target cards according to a dimensional rule that is not explicitly articulated. Participants may understand the rule only by either a 'correct' or 'wrong' feedback from the experimenter, who changes the sorting rules throughout the task. The participant is required to discover the rules in order to succeed in this task.

Object alternation test

A test in which participants are presented with two objects, and a target stimulus that may be located under one of the objects. The examiner covers the objects and changes the location of the target stimulus. This task assesses working memory and set shifting.

Set-shifting task

In set-shifting tasks, participants are required to alternate between two judgements within a set of stimuli, as fast as and as accurately as possible.

Trail-making test

In the first part of this test, which assesses psychomotor functioning and processing speed, participants are asked to connect the dots between numbered circles as fast as possible. In the second part, which assesses set shifting, participants are asked to connect the dots according to an ascending order of a series of letters and numbers.

Tower of London test

A task that assesses planning. It consists of three coloured discs placed on pegs. Participants are required to arrange the discs according to specific models using the fewest possible moves. The number of excess moves is an indicator for deficient planning ability.

Wechsler memory scale logical memory

A subtest of the Wechsler memory scale test battery in which participants are asked to remember a short, detailed story.

Rey auditory verbal learning test

A verbal memory test in which participants are asked to memorize a list of words read aloud by the examiner.

Copy number variants

Copy number variants correspond to regions of the genome that have been deleted or duplicated on certain chromosomes. The deletions and/or duplications can result in gene expression changes that can elucidate specific aetiological pathways.

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Pauls, D., Abramovitch, A., Rauch, S. et al. Obsessive–compulsive disorder: an integrative genetic and neurobiological perspective. Nat Rev Neurosci 15, 410–424 (2014). https://doi.org/10.1038/nrn3746

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