The genetic basis of obsessive–compulsive disorder (OCD)

The genetic basis of obsessive–compulsive disorder (OCD) There have been over 18 family studies of OCD during the past 70 years but, due to methodological differences, the familial aspects of the disorder remain controversial. Family studies look for the prevalence of the disorder among the biological relatives of the probands (i.e. individuals who are affected by OCD) and the prevalence is then compared with that seen in the general population or in a control group. The latter are usually unaffected subjects or relatives of those with OCD. Despite the limitations of the studies, most have found a significant increase in the rates of OCD among the first-degree relatives of the probands when compared with the general population. Similarly, there is evidence from family studies of patients with chronic motor tics and Tourette syndrome that the rates of these conditions, and OCD, are higher among the relatives of patients with Tourette syndrome. More recent studies have suggested that some of these cases are familial but unrelated to tics while in other cases there appears to be no family history of either OCD or tics. Twin studies comparing mono- and dizygotic twins have shown concordance rates of between 25 and 87%, depending on the study. Since none of the studies show a concordance rate of 100%, it is clear that nongenetic factors must influence the expression of OCD. Linkage analysis studies, in which the OCD is linked to a known polymorphic marker, are used to determine if there is a single gene locus causing susceptibility for the disorder. Using such an approach for a battery of candidate genes coding for receptors and enzymes involved in dopaminergic and serotonergic transmission (i.e. for the two neurotransmitters most likely to be involved in OCD), no evidence was found for a link. Association studies have proven to be more fruitful. In such studies, the allelic frequencies for specific marker genes are compared with a control population. When OCD patients were investigated for the association of tics with the dopamine receptor 2 marker it was shown that there was an increased frequency of homozygosity for the allele A2 of TaqIA at the D2 receptor locus. Not all investigators could replicate this finding however. No positive associations have been found between OCD and the D3 gene while there was some association found between OCD with tics and the D4

gene. Two other catecholaminergic markers have been investigated in
patients with OCD. Thus a positive association has been reported between
the low activity allele of catechol-O-methyl transferase in male patients and
a higher frequency of the low activity allele of monoamine oxidase type A
gene in female patients. There is also evidence that the serotonin transporter
gene is abnormal. In conclusion, evidence from genetic studies lends
support to the view that a single gene defect occurs in patients with OCD
while association studies of candidate genes, in spite of methodological
difficulties, have highlighted the loci for D2 and D4 receptor genes together
with those for catechol-O-methyl-transferase and monoamine oxidase A.