Grupo de Medicina Xenómica

The identification of genetic susceptibility to common diseases is one of the great challenges of human genetics nowadays. The investigation is focused on identifying common variants of susceptibility, following the assumption that the predisposition to suffer from common diseases is due to alleles at high frequencies (common variant\ ommon disease hypothesis). This search has produced few results because, in general, the common variations identified explain a very low percentage of the difference in susceptibility. There is an increasing interest in an alternative hypothesis, which suggests that the main factors of genetic susceptibility to common diseases are low-frequency variants (rare variant common disease hypothesis). This hypothesis is supported by several studies of population genetics.

The objectives of the project are: 1) to check if the accumulation of rare variants in functional candidate genes causes an increase in susceptibility to schizophrenia considerably higher than the different common variants currently known. Specifically, we will analyze nsSNPs (i.e., single nucleotide polymorphisms that change the amino acid sequence) and haplotypes of nsSNPs at frequencies lower than 5%. 2) to check the putative existence of specific rare variants that by themselves cause a substantial increase in susceptibility to schizophrenia in general population or some families. This goal is aimed at finding allelic variants that provide an early diagnosis of the disease. 3) to identify functional pathways or protein complexes presenting an accumulation of rare variants predisposing to schizophrenia. This would be very useful in order to identify possible subtypes of schizophrenia with molecular basis.

Finding rare variants of susceptibility to schizophrenia by analyzing nsSNPs in DISC1 and its interactome. Project supported by Xunta de Galicia. PI: Javier Costas

The clearest example of the existence of rare variants with great impact on the onset of schizophrenia is a translocation that affects the gene DISC1 (Disrupted in schizophrenia 1), identified in a Scottish family, which cosegregates with schizophrenia and other mental disorders. DISC1 protein is a hub protein, a central part of its network of protein interactions (interactome). The main objective of the project is the identification of rare variants in the interactome of DISC1, both individually and in combination, conferring a significant increase in risk for developing schizophrenia. This may be of interest in the identification of subtypes of the disorder with its own molecular basis.