Complex Segregation Analysis Provides Compelling Evidence for a Major Gene Underlying Obsessive-Compulsive Disorder and for Heterogeneity by Sex

Nestadt, Gerald; Lan, Tsuo Hung; Samuels, Jack; Riddle, Mark A.; Bienvenu, O. Joseph; Liang, Kung‐Yee; Hoehn‐Saric, Rudolf; Cullen, Bernadette; Grados, Marco A.; Beaty, Terri H.; Shugart, Yin Yao

doi:10.1086/316898

Cited by 122 publications

(101 citation statements)

References 24 publications

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“…In contrast, this is the first report to our knowledge to describe the same abnormalities in unaffected parents of OCD patients. As OCD displays a complex pattern of inheritance (Nestadt et al, 2000a), these abnormalities of peripheral serotonergic parameters could represent the genetic liability of unaffected relatives of probands for the disorder. The highly significant intrafamilial correlation observed for whole blood 5-HT concentration suggests that the heritability of this marker is high.…”

Section: Discussionmentioning

confidence: 99%

“…OCD is a common disorder, affecting between 2 and 3% of the population (Weissman et al, 1994). Although the precise etiology of the disorder remains unknown, the results of twin studies (Jonnal et al, 2000), family genetic studies (Nestadt et al, 2000b;Pauls et al, 1995), and segregation analyses (Alsobrook et al, 1999;Nestadt et al, 2000a) have provided compelling evidence that OCD has a strong genetic component. However, like other major psychiatric disorders, OCD fails to follow Mendelian patterns of inheritance and is considered as a complex genetic disorder.…”

Section: Introductionmentioning

confidence: 99%

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Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Delorme

Betancur

Crinon

et al. 2005

Neuropsychopharmacol

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Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT 2A receptorbinding characteristics, and platelet inositol trisphosphate (IP 3 ) content in a sample of OCD probands (n ¼ 48) and their unaffected parents (n ¼ 65), and compared them with sex-and age-matched controls (n ¼ 113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP 3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (po0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT 2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Delorme

Betancur

Crinon

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Family and twin studies have provided evidence for the involvement of a genetic factor in OCD (Nestadt et al, 2000;Pauls et al, 1995). Although very little is known about the disorder's pathogenesis, both serotonergic and dopaminergic pathways may be implicated.…”

Section: Introductionmentioning

confidence: 99%

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

Denys

Nieuwerburgh

Deforce

et al. 2006

European Neuropsychopharmacology

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Background: Mounting evidence suggests the involvement of the dopamine system in the pathophysiology of obsessive-compulsive disorder. Method: The relationship of the dopamine D 2 receptor (DRD2) TaqI A, and catechol-O-methyltransferase (COMT) NlaIII High/Low activity polymorphism to obsessive-compulsive disorder (OCD) was examined in a sample of 150 patients and 150 controls. Results: OCD patients did not show significant differences in genotype distribution and allele frequency for polymorphisms investigated relative to controls. However, when the sample was stratified by gender, there was a trend to a significant predominance of the DRD2 A2A2 genotype ( p = 0.049), and a higher frequency of the DRD2 A2 allele ( p = 0.020) and low-activity COMT allele ( p = 0.035) in male OCD patients compared to male controls. In addition, we observed an association of the DRD2 A2A2 genotype in patients with an early onset of disease (V15 years) ( p = 0.033). Conclusions: Our findings replicate previous reports and provide support for a potential role of the COMT and DRD2 locus in subgroup of male, early onset patients with OCD.

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“…[1][2][3][4][5][6] Nevertheless, molecular genetic studies failed to individuate genes with minor or major effect in the susceptibility to OCD, 7,8 or reported contrasting results. [9][10][11][12] This could be due to the paucity of genes studied to date.…”

Section: Introductionmentioning

confidence: 99%

Obsessive-Compulsive Disorder, 5-HTTLPR polymorphism and treatment response

et al. 2002

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Recently, a role for a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR) in conferring susceptibility to Obsessive Compulsive Disorder (OCD) has been suggested. The aim of this study was to test the hypothesis that allelic variation of the 5-HTTLPR could be associated with OCD susceptibility or influence the drug response in OCD. One hundred and eighty-one OCD patients were recruited; 92 patients underwent a standardized treatment with fluvoxamine. No significant differences in allele/genotype distribution of the 5-HTTLPR were found between 191 controls and OCD. No differences in fluvoxamine response in the three genotypes groups in OCD were found, considering Yale-Brown Obsessive Compulsive Scale (YBOCS) total scores. Nevertheless, a significant time per genotype interaction was found for the YBOCS subtotal compulsion scores. Considering patients without tic disorder co-diagnosis, a significant time per genotype interaction for both YBOCS total scores and compulsion scores was found

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Complex Segregation Analysis Provides Compelling Evidence for a Major Gene Underlying Obsessive-Compulsive Disorder and for Heterogeneity by Sex

Cited by 122 publications

References 24 publications

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

Obsessive-Compulsive Disorder, 5-HTTLPR polymorphism and treatment response

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