Genotype-Phenotype Associations in Functional Psychoses

Scharfetter C. and Stassen H.H. (SNF32-61578.00)

Background
Schizophrenia, schizoaffective disorder, and bipolar illness are complex traits with a strong genetic component that does not follow simple Mendelian or near Mendelian modes of inheritance. There is considerable overlap between the clinical syndromes of these diagnostic entities, and the lifetime prevalences of schizophrenia and bipolar illness are each 1% across ethnically diverse populations. This suggests the existence of ethnicity-independent vulnerability and protection factors. So far, results of linkage and association studies have been inconclusive and difficult to reproduce. As there may exist genetically different pathways to the phenotype in ethnically different populations, unknown population admixture is likely to substantially reduce the power of studies that aim to link phenotype to genotype. The more so, since current knowledge about how susceptibility genes of small effect --such as modifier genes and redundant genes-- may interact to give rise to a multifactorial phenotype is marginal. We have recently proposed a novel research strategy that allows one to quantify the between-ethnicity, the within-ethnicity, and the within-family genetic similarities, thus enabling the search for ethnicity-independent vulnerability and protection factors. The underlying genotype-to-phenotype research strategy involves multilocus, interacting genes. Once an oligogenic model has been identified, the genotypic variation is correlated with the phenotypic characteristics of the disorders using quantitative, syndrome-oriented measures of psychopathology.
 
Research Project
Functional psychoses are complex traits influenced by multiple genes of small effect, as well as by non- genetic factors. Evidence from twin, family and adoption studies suggests a significant genetic component, while segregation analyses have revealed non-Mendelian inheritance. Accordingly, it is not surprising that standard molecular-genetic studies have turned out to be inconclusive and difficult to reproduce [Antonarakis 1994; Plomin et al. 1994; Baron 1995; Reich 1995; DeLisi 1997; Comings 1998; Gershon et al. 1998; Nothen et al. 1999; Bailer et al. 2000; Berretti 2000; Brzustowicz et al. 2000; Foroud et al. 2000; Levinston et al. 2000; Mowry et al. 2000; Nurnberger and Foroud 2000; Vuoristo et al 2000; Cichon et al 2001; Greenwood et al. 2001; Gurling et al. 2001; Kelsoe et al. 2001; Nurnberger et al. 2001].
Standard phenotype-to-genotype research strategies enable the localization of genes coding for traits influenced by a few major genes. These strategies have not been successful in elucidating the genetic background of complex disorders. Thus, if (1) the contributions of single loci are small, (2) the single loci are, by themselves, neither necessary nor sufficient for developing the phenotype, (3) significant interactions between the loci are involved, and (4) there exist genetically different pathways to the phenotype in ethnically different populations, detecting genes by these strategies may be very difficult or impossible. Unknown population admixture can also substantially reduce the power of studies that aim to link phenotype to genotype.
For complex traits, a genotype-to-phenotype research strategy with multilocus, interacting genes may be more successful [Burghes et al. 2001]. This strategy evaluates high-dimensional genetic "feature vectors" with respect to between-population, within-population, and within-family similarities. The analysis of within- population similarities allows one to structurally decompose an ethnically diverse population, while the analysis of within-family similarities allows one to detect differences between affected and unaffected sib pairs. Once a genetic model has been identified, the observed genotypic variation is correlated with the phenotype of the disorder, using a quantitative syndrome-oriented approach to psychopathology [Stassen et al. 1999].
 
Material and Methods
Zurich study of functional psychoses: Our study comprised 77 nuclear families ascertained through an index case with a diagnosis of schizophrenia (n=50), schizoaffective disorder (n=2), or bipolar illness (n=15), and a Swiss case-control sample of 128 patients suffering from functional psychoses together with 128 healthy control subjects. The families were genotyped with respect to 430 polymorphic markers for a genome scan at a 10cM resolution, while the fine mapping of the candidate regions revealed by the genome scan is being accomplished on the basis of our case-control subsample.
Clinical assessments: The patients were clinically interviewed on the basis of the SADS syndrome check lists SSCL-16, SSCL-16 Supplement [Angst et al. 1988]. Clinical diagnoses were made by the principal investigator (C.S.) according to ICD-10 diagnostic criteria. From the SSCL-16, severity scores were computed with respect to 16 psychopathology syndromes and Axis V overall social functioning. The healthy subjects were asked to fill out the Zurich Health Questionnaire ZGF that comprised 63 items addressing regular tobacco consumption, regular alcohol consumption, regular use of medicine, illegal drugs, state of physical health, psychosomatic disturbances, and state of mental health (lifetime). The US-American patients' and their first-degree relatives' psychopathology was documented in a standardized way using the DIGS or FIGS rating instruments. Written informed consent was obtained from all subjects.
Statistical analysis: Using data from diverse US- and European ethnic groups we have searched for a configuration of 5-25 ethnicity-independent susceptibility and protection loci for which the between-sib genetic similarity in affected and unaffected sib pairs deviated from the genetic similarity between parents and offspring. Our multivariate search was based on a genetic similarity function that allowed us to quantify the inter-individual genetic distances d(xi,xj) between feature vectors xi, xj made up by the allelic genotype patterns of any two subjects i, j with respect to n loci l1, l2, .. ln. The iterative search involved all 430 markers in such a way that nonlinear interactions between any 2 loci were detected.
The question of ethnicity-independent vulnerability was addressed by treating all Afro-American families as "training" samples, while the NonAfro-American families served as independent "test" samples. Thus, the reproducibility of results across ethnicities could be tested. We evaluated the between-sib similarities which were expected to deviate from "0.5" in affected sib pairs if the region of interest contained markers close to vulnerability or protection genes. The reference value "0.5" was derived from the parents-offspring similarities which are always 0.5, irrespective of the affection status of parents and offspring.
Our concept of protective factors assumes etiologic and phenotypic heterogeneity in such a way that only a certain proportion of the affected sib pairs (typically 10%-30%) exhibit an elevated IBD/IBS score at a locus within an oligogenic configuration. The weight of that locus is proportional to the number of affected sib pairs who show an elevated IBD/IBS score at the locus. There also exist subsets of affected sib pairs with a significant genetic dissimilarity at a locus within an oligogenic configuration as well. Since a "dissimilarity locus" interacts with at least one of the vulnerability loci, it is likely that it modifies the genetic risk of the phenotype. We conjecture that affected siblings who are dissimilar on the genotype level also exhibit differences on the phenotype level, perhaps, in terms of onset and severity of illness. Consequently, "dissimilarity loci" may be "protective".

Key words: complex traits, genetic predisposition, genetic diversity, population admixture, vulnerability, syndromes, psychopathology

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