The Major Histocompatibility Complex (MHC) is a highly variable genetic region involved in immune response. Complement Component 4 (C4) is a gene involved in brain development and the immune system that lies within the MHC. C4 has many different versions due to three major reasons: 1) evolutionary inherited DNA sequences from viruses, 2) replication of DNA sequences, and 3) the high rates of DNA exchange in the MHC during egg fertilization. Thus, we are interested in how these various versions of C4 correlate with different disorders, but particularly with neuropsychiatric disorders such as Schizophrenia and Major Depressive Disorder. We will test the associations of different C4 versions across all disorders catalogued within the United Kingdom Biobank, controlling for factors such as age, sex, and ancestry (via principal component analysis, a mathematical method to find the greatest sources of variation between individuals). We will follow up this analysis by controlling for factors such as C4 versions that are correlated with each other (due to most individuals possessing two copies of the gene C4) to examine population effects,
and by examining whether different C4 versions are correlated with particular disorder categories (for example, an individual with C4 version A may be more prone to neuropsychiatric disorders, and an individual with C4 version B may be more prone to infectious disorders). Predicting C4 versions takes about 24 hours for about 300,000 individuals, and subsequent association analyses run in several hours. Overall, we expect this analysis to take about 12 months to conduct the individual analyses and combine the results. Through this, we will be able to understand how having particular C4 versions may put people at risk for various disorders, and whether those effects are from C4 itself, or due to correlated population effects. We will also be able to contribute to an understanding of C4, the MHC, and even neuropsychiatric disorder prevalence in the population.
