Research Interests:

The genetics of complex common brain disorders, including epilepsy, bipolar disorder, anorexia nervosa and heroin dependence.

Keywords:

Epilepsy, genetics, bipolar disorder, Anorexia nervosa, heroin dependence.

Research Summary:

The Center for Neurobiology and Behavior (CNB) is a group of interdisciplinary investigators who study biologic influences on behavior, including human behavioral disorders and relevant animal models. Dr. Berrettini's group has several projects designed to identify susceptibility genes for common behavioral disorders, including idiopathic epilepsy, bipolar disorder, schizophrenia, anorexia nervosa and heroin dependence. These studies typically proceed from gene mapping research in the mouse to susceptibility gene investigations in DNA samples from affected human populations. In our genetic studies of idiopathic epilepsy, murine gene mapping research revealed a susceptibility locus on chromosome one. Congenic investigations and comparative sequencing suggested an inwardly-rectifying potassium ion channel gene as a probable candidate. This gene is now being studied in human epileptic populations to determine whether sequence variations are associated with increased risk for seizure disorders.

Regarding genetic studies of heroin dependence, murine gene mapping investigations implicated the mu opioid receptor gene. Subsequent human studies indicated that sequence variation in the mu opioid receptor gene promoter may increase risk for heroin dependence. This hypothesis is being explored through functional studies of these mu promoter variants in tissue culture. In the genetic studies of bipolar disorder and schizophrenia, we are investigating a novel intronless gene (located in a linkage-nominated region, 18p11.2), encoding a secreted neuropeptide as a susceptibility gene. This gene is brain-specific, and is expressed at high levels in hippocampus and entorhinal cortex.

For the genetic studies of anorexia nervosa, we have identified a region of human chromosome one which may contain a susceptibility gene. Investigations of a candidate gene in this region, the serotonin 1D receptor gene, appear promising.

Rotation projects:

Studying the expression pattern of a novel brain-specific gene which may increase risk for bipolar disorder and schizophrenia.

Testing polymorphisms in a potassium ion channel gene to determine whether they increase risk for idiopathic epilepsy.

Key References:

Ferraro TN, Golden GT, Smith GG, Longman RL, Synder RL, DeMuth D, Szpilzak I, Mulholland N, Eng E, Lohoff FW, Buono RJ, Berrettini WH: Quantitative genetic study of maximal electroshock seizure threshold in mice: further evidence for a major seizure susceptibility locus on distal chromosome 1. Genomics 75: 1-8, 2001.

Buono RJ, Ferraro TN, O'Connor MJ, Sperling MR, Ryan SG, Scattergood T, Mulholland N, Gilmore J, Lohoff FW, Berrettini WH: Lack of Association Between an Interleukin 1 Beta (IL-1B) Gene Variation and Refractory Temporal Lobe Epilepsy. Epilepsia 42:782-785, 2001.

Detera-Wadleigh SD, Badner, JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G, Rolins DY, Moses T, Sanders AR, Karkera JD, Esterling LE, Zeng J, Guroff JJ, Kazuba D, Maxwell ME, Nurnberger JI, Jr., Gershon ES: Evidence for a bipolar susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. PNAS 96: 96: 5604-9, 1999.

Rojas K, Liang L, Hohnson EI, Berrettini WH, Overhauser J: Identification of candidate genes for affective disorder on 18p11. Molecular Psychiatry 5:389-95, 2000.

Grice DE, Halmi KA, Fichter MM, Strober M, Woodside DB, Treasure JT, Kaplan AS, Magistretti PJ, Goldman D, Kaye WH, Bulik CM, Berrettini WH: Evidence for a susceptibility gene for restricting anorexia nervosa on chromosome 1. Am J Hum Genet 70:787-92, 2002.

Devlin B, Bacanu S-A, Klump KL, Bulik CM, Fichter MM, Halmi KA, Kaplan AS, Strober M, Treasure J, Woodside DB, Berrettini WH, Kaye WH: Linkage analysis of anorexia nervosa incorporating behavioral covariates. Human Molecular Genetics 11:689-696, 2002 .