Max Planck Institute of Psychiatry, Germany
Ludwig Czibere has completed his Ph.D in biology 2009 at the Ludwig Maximilians University in Munich, and has further conducted his postdoctoral studies at the Max Planck Institute of Psychiatry, first as a Max Planck postdoctoral fellow, then as a pos tdoctoral scientist. His research is focused on neurogenomics and neurotranscriptomics of anxiety- and depres sionlike disorders. He published about 8 papers and was awarded the Ernst and Berta Scharrer Prize of the German Society of Endocrinology (DGE) in 2009.
Despite years of extensive research on a common final pathway of anxiety and depression-related disorders, it is still a major issue to pinpoint the candidate genes involved in modulating the relevant phenotypes, among others, due to the complexity of the respective t raits. Therefore, even large-sample clinical patient-control genome-wide association studies encounter difficulties to highlight genes that contribute a small, but nevertheless significant, effect to a specific phenotype. To circumvent the pitfalls of analyzing a population with vast amounts of heterogenous variants, including rare ones, we followed a breeding strategy to select for genetic variants based on trait anxiety in mice. A commonly used parameter in antidepressant research, the percentage of time animals spend on the arms of the elevated plus-maze, was applied to select for high (HAB) and low (LAB) anxiety-related behavior mice over generations, starting from the outbred CD-1 mouse str ain. After accumulating some of the genetic determinants, we crossbred HABxLAB animals to generate a population of HABxLAB-derived F2 mice that would already show free segregation of the previously inbred alleles, thus allowing us to calculate linkages based on the phenotypes of interest. Applying genomic single-nucleotide polymorphism (SNP) screening in 521 of these F2 mice, with subsequent linkage analyses, we succeeded in highlighting a very strong effect of a 7.5cM locus on mouse chromosome 3 on HPA-axis responsiveness, which is known to be connected with anxiety and depression scale disorders. Indeed, the locus harbors genes relevant to corticosteroid synthesis, e.g. Hsd3b1. Using this bottleneck breeding and subsequent segregating approach, we could also demonstrate that the effect sizes can be increased to a well-measurable size of true effects in complex traits, which seems to be acceptable even at the price of losing other potential loci.