Invited Speaker

Endophenotypes as Drug Targets in Psychiatric Disorders: Connecting Genetics to Pathophysiology
Mihály Hajós
USA

The underlying genetic and neuronal abnormalities in psychiatric disorders, such as schizophrenia and bipolar disorder are largely unknown, making it challenging to measure the severity of clinical symptoms objectively, or to design and evaluate psychotherapeutic interventions. Considering schizophrenia, it is recognized that it is a genetically predisposed disease, and twin studies show unequivocally that schizophrenia is predominantly a genetic disorder, with estimates of heritability of risk of around 80%. However, it is suggested that, like other complex disorders, schizophrenia is characterized by the contribution of multiple risk genes, which could contribute in combination with epigenetic and environmental processes to the development of the disease. In addition, most recent findings provide strong support for a model of schizophrenia and other psychiatric disorders pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci, including rare copy number variations. Recent advances in neurophysiological techniques provide new opportunities to measure abnormal brain functions in patients with psychiatric disorders. These pathophysiological markers, called endophenotypes show heritability, and could be linked to genetic variants. Moreover, many of these neurophysiological processes are phylogenetically conserved and can be modeled in preclinical studies, offering unique opportunities for use as translational biomarkers in psychotherapeutic drug discovery. For example, a genetic linkage of the 15q13-15 region of chromosome 15 containing the α7 nicotinic acetylcholine receptors (nAChR) subunit gene CHRNA7 has been established to impaired auditory gating (P50), a presumed indicator of dysfunctional sensory processing in schizophrenia. The association between CHRNA7 gene and impaired P50 auditory gating provided a very attractive endophenotype not only for genetic research in schizophrenia but also for antipsychotic drug discovery. Although the biological connection of α7 nAChRs to schizophrenia is prominent, association between CHRNA7 gene alterations and other psychiatric disorders has been also revealed, indicating that alteration in CHRNA7 gene or its α7 nAChR expression might contribute to psychotic or delusional symptoms in various psychiatric disorders, and not specifically linked to development of schizophrenia. As a case study, current preclinical and clinical findings on α7 nAChRs ligands, and auditory gating as a translational biomarker will be reviewed.