Modeling activation of inflammatory response system: a molecular-genetic neural network analysis

Significant alterations of T-cell function, along with activation of the inflammatory response system, appear to be linked not only to treatment-resistant schizophrenia, but also to functional psychoses and mood disorders. Because there is a relatively high comorbidity between rheumatoid arthritis (RA), schizophrenia and major depression, the question arises whether there is a common, genetically modulated inflammatory process involved in these disorders. On the basis of three family studies from the U.S. and Europe which were ascertained through an index case suffering from RA (599 nuclear families, 1868 subjects), we aimed to predict the inter-individual variation of autoantibody IgM levels, as an unspecific indicator of inflammatory processes, through molecular-genetic factors. In a three-stage strategy, we first used nonparametric linkage (NPL) analysis to construct an initial configuration of genomic loci showing a sufficiently high NPL score in all three populations. This initial configuration was then modified by iteratively adding or removing genomic loci such that genotype-phenotype correlations were improved. Finally, neural network analysis (NNA) was applied to derive classifiers that predicted the phenotype from the multidimensional genotype. Our analysis led to an activation model that predicted individual IgM levels from the subjects' multidimensional genotypes very reliably. This allowed us to use the activation model for an analysis of the DNA of an existing sample of 1003 psychiatric patients in order to test, in a first approach, whether a deviant, genetically modulated inflammatory process is involved in the pathogenesis of major psychiatric disorders.