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S. Evelyn Stewart, MD; Jill Platko, PhD; Jesen Fagerness, BS; Julie Birns, BA; Eric Jenike, BA; Jordan W. Smoller, MD; Roy Perlis, MD; Marion Leboyer, MD; Richard Delorme, PhD; Nadia Chabane, PhD; Scott L. Rauch, MD; Michael A. Jenike, MD; David L. Pauls, PhD

Arch Gen Psychiatry. 2007;64(2):209-214.

Context  Obsessive-compulsive disorder (OCD) is a debilitating familial psychiatric illness with associated brain abnormalities in the white matter. The gene for oligodendrocyte lineage transcription factor 2 (OLIG2) is an essential regulator in the development of cells that produce white matter (myelin). The OLIG2 gene is also highly expressed in brain regions implicated in OCD.

Objectives  To examine OLIG2 as a candidate gene for OCD susceptibility and to explore whether comorbidity subtypes of OCD have distinct associations with OLIG2 and the functionally related OLIG1 gene. It was hypothesized a priori that OLIG2 and OLIG1 were associated with OCD regardless of the presence of comorbid Tourette disorder (TD), but not with TD alone.

Design  Family-based association candidate gene study.

Setting  Participants and their family members were recruited from tertiary care OCD and TD specialty clinics.

Participants  Families of 66 probands with OCD with and without TD and 31 probands with TD without OCD.

Main Outcome Measures  Genotypes of single nucleotide polymorphism markers and related haplotypes.

Results  The following 3 single nucleotide polymorphism markers on OLIG2 were associated with the OCD without TD phenotype: rs762178 (minor allele frequency, 35%; P<.001), rs1059004 (minor allele frequency, 44%; P = .005), and rs9653711 (minor allele frequency, 44%; P = .004). A 5-marker haplotype (A/C/T/T/G) constituting these single nucleotide polymorphisms and exonic single nucleotide polymorphisms rs6517137 and rs13046814 was undertransmitted (frequency, 32%; permuted P=.004), whereas the G/A/T/T/C haplotype (frequency, 22%; permuted P=.02) was overtransmitted to probands with OCD alone, with a significant global P value (permuted P=.008).

Conclusions  This is the first study reporting an association between OLIG2 and OCD, specifically when TD comorbidity is absent. The findings support a role for white matter abnormalities in the etiology of the disorder.

Author Affiliations: Psychiatric Neurodevelopmental and Genetics Unit (Drs Stewart, Platko, Jenike, Smoller, Perlis, and Pauls; Mr Fagerness; and Ms Birns), Psychiatric Neuroscience Research Division (Dr Rauch), and Obsessive-compulsive Disorder Clinic, Harvard Medical School (Drs Stewart and Jenike), Massachusetts General Hospital, Boston; and Departments of Psychiatry, Mondor-Chenevier Hospital, University of Paris (Dr Leboyer), and Robert Debré Hospital (Drs Delorme and Chabane), Paris, France.

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