Background: SERT I425V, an uncommon missense single nucleotide polymorphism producing a gain-of-function of the serotonin transporter (SERT), was originally found to segregate with a primarily obsessive-compulsive disorder (OCD) but complexly comorbid phenotype in two unrelated families.
Objective: As two individuals with SERT I425V and OCD also had Asperger syndrome (AS), an autism spectrum disorder, and as other rare SERT variants have recently shown significant associations with autism, we set out to extend our original OCD study by genotyping additional autism/AS and OCD samples.
Methods: Case-control association study of SERT I425V in 210 AS/autism probands and 215 controls, plus 335 OCD probands and their family members.
Results: SERT I425V was not found in any of the individuals with AS/autism, OCD alone or OCD comorbid with AS and other disorders, or in controls. This results in new estimates of SERT I425V having a 1.5% prevalence in 530 individuals with OCD from five unrelated families genotyped by us and by one other group and a 0.23% frequency in four control populations totaling 1300 individuals, yielding a continuing significant OCD-control difference (Fisher's exact test corrected for family coefficient of identity P=0.004, odds ratio=6.54).
Conclusion: As several other uncommon, less well quantitated genetic variations occur with an OCD phenotype, including chromosomal anomalies and some other rare gene variants (SGCE, GCH1 and SLITRK1), a tentative conclusion is that OCD resembles other complex disorders in being etiologically heterogeneous and in having both highly penetrant familial subtypes associated with rare alleles or chromosomal anomalies, as well as having a more common, polygenetic form that may involve polymorphisms in such genes as BDNF, COMT, GRIN2β, TPH2, HTR2A and SLC1A1.