Psychiatric Genetics Laboratory

Philibert Lab: L-R (back) Harinder Kaur, Bill Adams, Dr. Rob Philibert, MD, Ph.D.,
Amanda Barkhurst, Hans Packer (front) Phil Bohle, Nancy Hollenbeck, Dianna Secrest

The Psychiatric Genetics Laboratory is located on the first-floor of the Medical Education Building. It is fully equipped for translational genetics. Major pieces of equipment include anepifluorescence microscope capable of 3-D imaging, a Biomek 3000 liquid handling robot, an Applied Biosystems 7900 HT real-time PCR (RTPCR) machine, two cell culture hoods, and a number of state-of-the-art thermal cyclers, incubators and centrifuges.

The laboratory is headed by Rob Philibert MD Ph.D., an Associate Professor of Psychiatry and a member of Neuroscience Program. The laboratory personnel are an eclectic mix of full-time research assistants, graduate students, database managers and work-study students.

The Psych Genetics laboratory group has two major foci. The first is the role of the mediator complex in human health and behavior. (Philibert, 2006). The second is the role of genetic variation and gene-environment interactions in the genesis of behavioral disorders. (Cadoret et al., 2003). Additionally, the laboratory has a number of active collaborations with members of Department of Psychiatry including Drs. Donald Black, Tracy Gunter and William Coryell and with investigators outside the University of Iowa, especially at The University of Georgia.

The Role of Med12 (HOPA) in Health and Human Behavior
The first focus of the laboratory is the role of sequence variation in Med 12 (also known as HOPA). Med12 was initially cloned and characterized by Dr. Philibert during his postdoctoral fellowship at the National Institutes of Health. In particular, a large emphasis has been placed on delineating the effects of a 4 amino acid insertional variant, known as HOPA^12bp in the C-terminal Opa domain in human health and behavior. In a series of studies, Dr. Philibert and colleagues have demonstrated that the HOPA^12bp polymorphism is a mild, sex dependent risk factor for an endophenotype of behavioral illness that includes depression, psychosis and hypothyroidism. Surprisingly, his studies have also demonstrated that this uncommon variant is a balanced polymorphism of recent evolutionary development. (Philibert et al., 2002).

Figure: the HOPA^12bp allele is the defining element f a large x-chromosome haplotype.
This large, evolutionarily conserved haploblock represents the first case of a balanced polymorphism
whose presenting outcome is aberrant behavior. From Spinks et al., 2004.

In order to fully understand the role of this variant, the laboratory is engaged in a wide variety of studies, including clinical and neuroendocrine phenotyping and the development of in vitro and murine models of Med12 dysfunction. In particular, these models are focusing on tissues known to be specifically affected by Med12 dysfunction including the brain and the pituitary.

Image: Stably transfected inducible cell lines. PC 63 cell line, 24 hours after induction.
As the photo demonstrates, expression of the construct (as shown by GFP fluorescence)
is associated with cell growth arrest, and decreased neurite outgrowth.

These findings may have a significant impact on clinical care. Since some of the deficits associated with the HOPA^12bp allele may be secondary to abnormal neuroendocrine function, laboratory is also engaged in the first genetically informed treatment trial in the history of behavioral medicine. Specifically, Drs. Philibert and Gunter have initiated a trial to determine whether levothyroxine supplementation will diminish symptoms of depression and obesity in females heterozygous for this X-chromosome polymorphism. Since one in 30 women carry the HOPA^12bp allele, this line of study could have significant implications for the treatment of certain types of depression.

Genetic Variation and Gene Environment Interactions in the Ontogeny of Behavioral Illness
The second focus of our laboratory group is the role of genetic variation and gene-environment interactions in the initiation and maintenance of depression and substance abuse in the Iowa Adoption Studies cohorts. (Cadoret et al., 2003). The Iowa Adoption Studies (IAS) were founded by the late Dr. Remi Cadoret, a peerless pioneer of the role of gene-environment (GxE) interactions in substance use disorders. The IAS are a case-control study of approximately 950 adoptees from the State of Iowa. These subjects have generously participated in a longitudinal series of interviews that characterized both their health-related behavior and their environments. These studies have generated considerable insight into the evocative and interactive role of the environment with genetic variation to alter vulnerability to health-related behavior.

Dr. Remi Cadoret, Founder of the Iowa Adoption Studies

In the latest wave of characterizations, these subjects have graciously donated biomaterial for the creation of both RNA and DNA resources. These resources are being used in combination with state-of-the-art technologies, neuroendocrine testing, and the prior treasure trove of cognitive and behavioral data, to pinpoint specific genetic variation and gene-environment interactions that alter vulnerability to behavioral illness. Through the studies, we believe that the IAS subjects and research team will create considerable insight into mechanisms that cannot only better treat, but perhaps prevent behavioral illness.