Genetic variation in lim homeobox genes and hippocampal morphology

Hippocampal dysmorphology has been implicated in the pathophysiology of schizophrenia. The molecular under-pinnings of this dysmorphology, however, are unknown. Recently, two genes, LHX2 and LHX5, in the LIM homeobox family have been identified as critical for hippocampal morphogenesis in rodents. LHX2 knockout mice exhibit agenesis of the hippocampal anlagen whereas LHX5 knockout mice have significant defects in hippocampal morphogenesis. Therefore, the LHX2 and LHX5 genes may represent candidate genes for disruptions in hippocampal development in schizophrenia. We are using dHPLC to identify genetic variation in the coding region of the LHX2 and LHX5 genes in a panel of over 100 ethnically diverse subjects with various clinical diagnoses. Moreover, we are collecting DNA and conducting hippocampal volumetric measurements in over 100 antipsychotic drug-naïve subjects in order to examine the relationship between LHX2 and LHX5 genetic variation and inter-individual differences in bilateral hippocampal morphology. Thus far, we have scanned over 50% of the coding region of the LHX2 gene. Preliminary data reveals several SNP's of which at least one represents an amino acid substitution. The relationship of these SNP's to hippocampal dysmorphology will be explored upon collection of the entire MRI data set and completion of the LHX2 and LHX5 gene scans.