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Once sufficient evidence for the familial transmission of OCD has been attained, the next step is to determine whether genetic factors are responsible for the observed familiality, and, if so, what the mode of genetic transmission is. Complex segregation analysis (CSA) is a method designed to evaluate the transmission of a trait within a pedigree, to determine whether the segregation of a major gene occurs in the presence of familial resemblance of the disorder.

The analysis also tests the magnitude of the genetic sources of variation in the trait.

Parameters that are usually estimated in the CSA include transmission probabilities, allele frequencies, penetrances for each genotype (for qualitative traits) and genotype means (quantitative traits), variance within genotypes and residual correlations not explained by Mendelian inheritance (Jarvik, 1998).

The success of a genetic association study depends critically upon the allelic architecture of the disease. Allelic architecture refers to the number of alleles involved in a disorder, and their respective penetrances (Pritchard and Cox, 2002). It follows that, in order to detect a significantly increased frequency in disease alleles in a group of affected individuals, the

allelic spectrum should be simple – in other words, a few predominant alleles should account for the phenotype (Reich and Lander, 2001). Assumptions regarding the allelic spectrum provide insight into the most efficient strategy to employ when searching for genetic contributions to complex disorders.

In order to understand the allelic architecture of a disorder, it is important to comprehend how the disease causing alleles are (and have been) affected by factors such as population growth, mutation rate, genetic drift, and to appreciate the role of selection against disease alleles (Reich and Lander, 2001; Pritchard and Cox, 2002). The common disease/common variant (CD/CV) hypothesis maintains that the genetic variation underlying complex disorders arose within the founding population of contemporary humans; hence the disease alleles are common, usually with frequencies in excess of 1% in the general population (Collins et al., 1997; Lander, 1996; Risch and Merikangas, 1996). The disease allele remains within the population at a relatively moderate frequency due to their selective neutrality (Wright and Hastie, 2001). If the CD/CV hypothesis is assumed, it is possible for the disease-causing alleles to be sought using indirect methods, such as linkage disequilibrium (LD) mapping.

The alternative hypothesis is known as the common disease/rare allele (CD/RA), or genetic heterogeneity, model. This model posits that rare alleles at numerous loci, each with a large number of alleles, can comprise the genetic contribution to the disorder. In contrast to the CD/CV hypothesis, the CD/RA hypothesis suggests that disease susceptibility alleles arose independently, in various geographically distinct, dispersed populations (Smith and Lusis, 2002), with the result that a disease allele in one population may not be evident in another. If one adopts this hypothesis, it is important to note that, although the susceptibility alleles comprise a large proportion of the genetic risk for the disease, they will not be conducive to indirect genetic association methods.

Clearly, it is in the investigator’s best interest to identify the disorder’s underlying allelic architecture; indeed, numerous segregation analyses have been conducted in an attempt to elucidate the mode of genetic transmission of OCD (Table I.2). In the first published segregation analysis, Nicolini et al. (1991) investigated the mode of transmission in OCD probands. Their segregation analysis included all affected individuals with a diagnosis of OCD, chronic motor tics (CMT) or TS. The investigators found that the autosomal dominant model was most compatible with the observed levels of segregation, although, due to the

small numbers of probands included in the study, neither the autosomal dominant nor autosomal recessive models could be rejected, indicating that OCD cannot be explained by a simple mode of transmission.

Cavallini et al. (1999) confirmed the presence of a major locus, with Mendelian properties accounting for most of the liability to OCD. They could not, however, exclude the possibility of the existence of potential heterogeneity in their model when the phenotypic boundaries were widened to include OCD, TS and CMT. They also noted differential penetrance values for OCD phenotypes between males and females, with females exhibiting slightly higher penetrance values.

In an attempt to limit the phenotypic heterogeneity of OCD, Alsobrook et al. (1999) categorised families in the sample according to four factor analytic symptom dimensions of OCD (section I.4.2.2.5). Segregation analysis of 96 families allowed only rejection of the no-transmission model, providing evidence that OCD is indeed genetically transmitted, although no specific mode of transmission could be specified. In the most recent, and only controlled, segregation analyses conducted, Nestadt et al. (2000[b]) found that neither Mendelian dominant nor codominant models could be rejected, indicating the presence of a major locus.

However, unexplained familial factors were also observed to be important in the expression of OCD: for example, significant heterogeneity on the basis of gender of the proband was detected. This prompted separate segregation analyses of families with male and female probands. The transmission of OCD in female proband families was compatible with the Mendelian major locus (either dominant or codominant) model. In the male proband families, although a Mendelian mode of transmission was found to be the most compatible, the details of this model were found to be less evident than for the female group.

Collective evidence from the segregation analyses indicates that the familial transmission of OCD is indeed due, in part at least, to genetic factors, and that this mode of inheritance is not simple. The genetic contribution to the disorder is more than likely complex, representing a mixed mode of transmission, involving genes of major effect with appreciable impact, operating against a milieu of polygenic inheritance.

Once it has been proven that genetic transmission accounts for at least some of the familiality of a disorder, the next logical step is to locate the susceptibility gene(s). This can be achieved

using a number of molecular genetic methodologies that are broadly categorised into parametric (model-based) and non-parametric (non-model-based) strategies.

Table I.2: Complex segregation analyses in OCD

aNo additional information available

bThe dominant model was found to be more parsimonious than the co-dominant model