Genetics of Obsessive-Compulsive Disorder transmission was found. When diagnoses were made including information from the proband about the relative, evidence of familial OCD was found, but only when the diagnostic threshold was lowered to include cases with probable OCD or OCD symptoms. Evidence for familial trans- mission of OCD was found only when diagnoses were made using information from the affected proband about their relatives. Therefore, they concluded that their own inconsistent results suggest that OCD may be heterogeneous with regard to familial transmission. SEGREGATION ANALYSES Once familial aggregation of OCD is established by twin studies and family studies, the next step is to determine whether the patterns within families are consistent with genetic models. Although segregation analysis cannot prove the existence of genes, if the analyses reveal that the patterns within families closely follow a pattern predicted from basic Mendelian principles, genetic factors are likely an essential factor in the cause of the disorder.3 Five complex segregation an- alyses have implicated a major locus in a pro- portion of families with OCD.18-22 Nicolini et al.23 collected data from 24 OCD probands and re- ported that either an autosomal dominant or recessive model could not be rejected. Cavallini et al.20 applied a complex segregation analysis to a sample of 107 Italian families with probands with OCD using regressive logistic models to test for possible models of genetic transmission. For the 107 OCD families, the best fit was a dominant model of transmission (with a higher penetrance for females), but this did not include an expanded phenotype (OCD + Tourette's syndrome + chronic motor tics). In addition, Alsobrook et al.22 perform- ed complex segregation analyses with families ascertained through an OCD-affected proband. Their segregation analyses used four factor-an- alytic symptom dimensions to subset the family sample based upon the probands' symptom factor scores to resolve the phenotypic heterogeneity observed among individuals with OCD. Analyses limited to families' probands with high symmetry and ordering symptoms led to rejection of the polygenic model, indicating the involvement of a major locus. However, they also could not identify a specific Mendelian model. Nestadt et al.18 per- formed complex segregation analyses of the 153 families (80 case and 73 control) included in the Johns Hopkins OCD Family Study. They found strong evidence that OCD involved a major gene and conformed to a Mendelian-dominant model, with significant sex effects and residual familial effects. Recently, Hanna et al.19 studied 52 families (35 case and 17 control families) through pediatric probands (10 - 17 years). Their results of complex segregation analyses provided evidence for a major susceptibility locus in OCD when age at onset was incorporated into the model. These results suggest that the mode of inheritance may be influenced by the residual effects of an affected parent, which provides further evidence for the etiologic heterogeneity of OCD. The dominant Mendelian model provided a somewhat better fit than the other Mendelian models. In summary, the previous five segregation studies indicate that the familial transmission of OCD is caused by genetic factors. Although some studies suggested a possible dominant model, the mode of transmission is generally difficult to model. This might be due to the fact that OCD is an etiologically and clinically heterogeneous con- dition. Thus, several genes may influence the behavioral component of OCD, and a mixed model involving several genes of major effect on a multigenic background seems to fit the mode of transmission of OCD. LINKAGE ANALYSES Once it has been demonstrated that genetic transmission accounts for at least some of the familiarity of a disorder, the next logical step is to locate the susceptibility genes. The purpose of a linkage study is to demonstrate that a DNA- marker with known chromosomal localization congregates with a disease in families.3 Weissbeck et al.24 studied a three-generation family trans- mitting OCD and tic disorders and reported that the highest LOD score found was 1.3 in the 4p13 chromosome region. To date, several genome- wide linkage studies of OCD have been pub- Yonsei Med J Vol. 47, No. 4, 2006