Approach to depressogenic genes from QTL analysis

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Human depression or mood disorder is defined as acomplex disease, making positional cloning of susceptibility genes a formidable task. We have undertaken genetic analyses of animal models for depression, comparing our results with advanced database resources.1.We performed quantitative trait loci(QTL) analysis on two mouse models of "despair", namely the forced swim test(FST) and tail suspension test(TST), and detected multiple chromosomal loci that control immobility time in these test. One QTL detected on mouse chromosome 11 harbors the GABAA receptor subunit genes, α1 and α6 as candidates genes. Sequence and expression analyses of α1 and α6 revealed significantly difference in the frontal cortex of two strains parents mice.2.We tested these genes for association in human mood disorder patients. A linkage study has detected chromosomal area 5q34,where GABA type A receptor subunit genes are mapped, as a susceptibility region for mood disorders, making these genes compelling candidates for such diseases. We obtained significant associations of the α1 and α6 subunit genes with the disease on 5q34,particularly in females. This result was striking, because we had previously detected an epistatic interaction between mouse chromosome 11 and X that regulates immobility time in these animals.3.These data offer genetic support for a role of GABA-A receptor genes in susceptibility to mood disorders.