Schizophrenia is a highly heritable polygenic psychiatric disorder. Characterization of its genetic architecture may lead to a better understanding of the overall burden of risk variants and how they determine susceptibility to disease. A major goal of this project was to develop a modeling approach to compare and quantify the relative effects of single nucleotide polymorphisms (SNPs), copy number variants (CNVs) and other factors. We derived a mathematical model for the various genetic

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... tions based on the probability of expressing a combination of risk variants at a frequency that matched disease prevalence. The model included estimated risk variant allele outputs (VAOs) adjusted for population allele frequency. We hypothesized that schizophrenia risk genes would be more interactive than random genes and we confirmed this relationship. Gene-gene interactions may cause network ripple effects that spread and amplify small individual effects of risk variants. The modeling revealed that the number of risk alleles required to achieve threshold for susceptibility will be determined by the average functional locus output (FLO) associated with a risk allele, the risk allele frequency (RAF), the number of protective variants present and the extent of gene interactions within and between risk loci. The model can account for the quantitative impact of protective variants as well as CNVs on disease susceptibility. The fact that non-affected individuals must carry a non-trivial burden of risk alleles suggests that genetic susceptibility will inevitably reach threshold for schizophrenia at a recurring frequency in the population.