Invited Speaker

Current Pharmacogenomics & Epigenetic Studies in Neuropsychiatric Disorders
D.K. Lahiri, B. Maloney, Md. Riyaz Basha, Y.-W. Ge, N. H. Greig and N. H. Zawia
USA

Advances in human genetics research with the completion of the human genome sequence have significantly increased our understanding of genes involved in various psychiatric disorders, such as autism, affective disorders and Alzheimer’s disease. In addition to genes, environmental factors, including diet, metals and life style, play an important role in human behavior and the development of disease phenotype. The unanswered question in the current field is the nature and timing of such ‘Gene-Environment’ interaction. We have recently proposed that primary gene sequence variation is often not an immediate operator in neurobiological pathology; instead, environment acts upon the genetic substrate, producing a “somatic epitype”. Somatic epitypes are a form of epigenotype that arises through environmental influences upon a genome within a single lifetime rather than the more familiar epigenetic inheritance. These somatic epitypes would correspond to physical alterations in gene promoters, be that via (hypo)methylation, chromatin structure, or oxidative damage (as oxo-d8-guanosine). This could be instilled upon the underlying gene sequence by conditions in utero, by maternal behavior, and/or by maternal nutrition or post-natal environmental effects such as nutrition or transient exposure to heavy metals such as lead (Pb). One such example of a somatic epitype could potentially be found in the SP1 gene, which has been shown to be perturbed in a latent associated early-life regulation (LEARn) fashion after transient developmental exposure to lead. A LEARn somatic epitype would not manifest until well after exposure to an environmental effector had ended. In the case of SP1, the potentially associated neurobiological disorder would be Alzheimer's disease. Application of the LEARn model would suggest potential therapeutic strategies. This provides a mechanism of the imposition of a methylation-dependent "somatic epitype" of a promoter due to reaction to environmental stressors such as exposure to heavy metals, nutritional variation, or maternal care, resulting in a pathogenic or pathologically vulnerable phenotype. This work is supported by the NIH grants to DKL.