Ethnicity-independent Vulnerability to Functional Psychoses

Our quantitative approach to ethnicity is based on the genotypic differences in genetic similarity between individuals, that is, we evaluate high-dimensional feature vectors made up of the allelic information of 20 uncorrelated, polymorphic markers ("ethnicity markers"). The genetic similarity between first-degree relatives is then one half, and the genetic similarity between subjects of the same ethnic group is higher than that between subjects of different ethnic groups. Thus, it also becomes possible to structurally decompose ethnically diverse populations. Principal component analysis leads to a representation of the multivariate feature vectors in such a way that the (orthogonal) axes of the transformed vector space optimally account for the variance of the underlying features ("genetic diversity").

Figure 3: Genetic vector space spanned by 20 polymorphic markers on chromosomes 6, 11, and 22 reveals differences between ethnic groups: circles designate Afro-Americans (n=141), triangles designate NonAfro-Americans (n=111), and squares designate Swiss subjects (n=257). Subjects are projected onto the hyperplane defined through the eigenvectors associated with the two largest eigenvalues.

The functional psychoses "schizophrenia", "schizoaffective disorder", and "bipolar illness" represent complex clinical syndromes that are characterized by phenotypic heterogeneity. Yet evidence from numerous studies suggests that (1) the prevalence of schizophrenia and bipolar illness is with 1% very similar across ethnicities, and (2) a strong genetic component is involved in the disorders’ pathogenesis. Using data from different US-American ethnicities (77 families with a total of 17 unaffected and 170 affected sib pairs; 276 marker loci) we searched for ethnicity-independent oligogenic susceptibility loci for which the between-sib genetic similarity in affected sib pairs deviated from the expected values. Specifically, we addressed the question of the extent to which genetic risk factors and their interactions constitute multigenic inheritance of functional psychoses across populations and might constitute universal targets for treatment. Our genotype-to-phenotype search strategy was based on a genetic similarity function that allowed us to quantify the inter-individual genetic distances d(x_i,x_j) between the allelic genotype patterns x_i, x_j of any two subjects i, j with respect to n loci l₁, l₂, .. l_n. Thus, we were able to assess the between-ethnicity, the within-ethnicity, and the within-family genetic similarities. The problem of ethnicity-independent vulnerability was addressed by treating the Afro-American families as "training" samples, while the NonAfro-American families served as independent "test" samples. 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 genes. The reference value "0.5" was derived from the parent-offspring similarities that are always "0.5", irrespective of the affection status of parents and offspring.

We found 12 vulnerability loci on chromosomes 1, 4, 5, 6, 13, 14, 18 and 20, which were reproducible across the two samples under comparison and may constitute an ethnicity-independent oligogenic model of vulnerability to functional psychoses. Families of all index-case related diagnostic categories contributed to these signals. The elevated vulnerability appeared to be unspecific and to act in such a way that exogenous factors become more likely to trigger the onset of psychiatric illnesses. This view was further supported by the fact that some of the genomic regions identified through this study also showed up with other psychiatric and somatic conditions, such as alcohol dependence and psoriasis. Derived through a method of approach different from standard linkage analyses, our results displayed some remarkable overlap with previous findings in the literature, in particular, for the D13S779 locus along with the well-known candidate region at D6S1009. Compared to the results of previous linkage analyses of the NIMH data our analysis yielded the same signals at the D6S462 and D13S797 loci, while the α-7 nicotinic receptor CNRNA7 on chromosome 15 did not show up among the NonAfro-Americans, suggesting that ethnical differences might influence, to some extent, susceptibility to "schizophrenia", "schizoaffective disorder", and "bipolar illness".

References

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