The need for inclusion of sex and age of onset variables in genetic association studies of obsessive–compulsive disorder: Overview

Highlights

• Review of current and inconsistent genetic findings of obsessive–compulsive disorder

• Distinct subtypes based on sex and age of onset differences are evident.

• The perinatal period reflects a period of increased risk for females.

Abstract

Obsessive–compulsive disorder (OCD) is a heterogeneous mental disorder that significantly impairs an individual's functioning. The candidate gene approach has proven to be a useful tool in investigating potential risk genes for OCD, but genetic studies have been largely inconclusive. Etiologically distinct forms of obsessive–compulsive disorder based on sex and age of onset have been identified, yet many genetic studies fail to examine the association by these subtypes. Due to the sexually dimorphic nature of the disorder, positive associations have been found with OCD in males only, suggesting the potential for identifying risk genes that contribute to OCD in women, such as perinatal OCD. This review includes a brief overview of the disorder and its subtypes, with a current update on candidate genes that may contribute to OCD using single nucleotide polymorphisms (SNPs) and genome wide association studies (GWAS).

Introduction

Obsessive–compulsive disorder (OCD) is a debilitating mental disorder that involves the presence of obsessions and/or compulsions. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), obsessions are recurrent and persistent thoughts, urges, or images that the individual attempts to ignore or suppress, whereas compulsions are repetitive behaviors or mental acts that the individual performs to prevent or reduce feelings of anxiety or distress (American Psychiatric Association, 2013). Symptoms associated with the disorder can be clustered into four clinical dimensions: (1) responsibility obsessions and checking rituals, (2) contamination obsessions and decontamination rituals, (3) symmetry obsessions and ordering/arranging rituals, and (4) violent, sexual and religious obsessions and mental and reassurance-seeking rituals (Abramowitz et al., 2010). Hoarding, a symptom initially categorized as a major dimension of OCD, has since been recognized as its own separate disorder based on evidence indicating differences in cognitive and behavioral processing, course of illness, neurobiological basis and treatment response (Mataix-Cols et al., 2010).

Epidemiological studies conducted in several countries report lifetime prevalence rates of OCD in the general population to be between 1 and 3% (Fontenelle et al., 2006, Kessler et al., 2005, Ruscio et al., 2010). The Epidemiologic Catchment Area (ECA) study was the first to conduct a comprehensive report on the prevalence of OCD and other mental disorders in the US. Data collected for the study from 1980 to 1985, using the Diagnostic Interview Schedule (DIS) (Robins et al., 1981), reported a lifetime OCD prevalence rate of 2.6%, with prolonged illness duration (mean = 7.2 years) and occurring more commonly in women aged 18–44 (Robins and Regier, 1991). Recent estimations of prevalence from the US National Comorbidity Survey Replication (NCS-R) report a lifetime OCD prevalence of 1.6% (Kessler et al., 2005). A later assessment of OCD in a random subsample of the NCS-R population found a lifetime prevalence rate of 2.3%, with the highest rates found in the 18–29 and 30–44 age groups (Ruscio et al., 2010). The increased prevalence rates of onset seen during the childbearing years may reflect the increased incidence of OCD that occurs during pregnancy and postpartum in women. OCD prevalence rates in pregnancy range between 0.2–3.5%, and prevalence rates in the postpartum range between 2.7–9% (McGuinness et al., 2011), however, studies examining this reproductive period in women are limited and may not be reflective of all ethnicities.

A bimodal distribution of OCD based on age of onset has been consistently described, with early onset (mean onset = 11 years) and late onset (mean onset = 23 years) (Taylor, 2011a). Upon closer examination of these subgroups, a greater proportion of pediatric cases of OCD occur in boys, whereas data in adults have shown a preponderance of females in late onset cases in some, but not all studies (Fontenelle et al., 2006, de Mathis et al., 2011). According to the ECA study, 49% of individuals with OCD experienced symptom emergence in childhood or adolescence, whereas approximately 40% experienced onset between ages 20–40 (Robins and Regier, 1991). OCD onset distribution across ages for both sexes in the NCS-R subsample has shown that males have a greater proportion of cases observed during the early onset period (before age 10), which is followed by a rapid increase in female cases through adolescence and early adulthood, with an overall average age of onset occurring around 19.5 years of age (Ruscio et al., 2010). Studies examining cases of OCD in line with female reproductive milestones have found that women who have been pregnant have a later age of onset (mean = 20.2 years), whereas women who have never been pregnant have an earlier onset (mean = 13.3 years) (Williams and Koran, 1997). An earlier study examining childbirth status on OCD onset found that women who had given birth experienced a later age of onset (22–24 and 29–32 years), compared to nulliparous women who first experienced symptoms early on (13–15 years) (Neziroglu et al., 1992). Taken together, these results provide evidence for the existence of distinct forms of OCD based on differences in age of onset and sex.