Medical Genetics

L. Erlenmeyer-Kimling, Ph.D., Chief of Psychiatric Research
Miron Baron, M.D., Psychiatrist (Research) II
David Friedman, Ph.D., Research Scientist VI
Jill Harkavy-Friedman, Ph.D., Assistant Professor of Clinical Psychiatry
Charles A. Kaufmann, M.D., Ph.D., Psychiatrist (Research) II
James A. Knowles, M.D., Ph.D., Psychiatrist (Research) II
Dolores Malaspina, M.D., Psychiatrist (Research) II
Nancy S. Wexler, Ph.D., Head, Division of Neurology

Cognitive Electrophysiology Laboratory (Dr. David Friedman, Head)
The laboratory is involved in a series of interlocking investigations on cognitive event-related brain potentials (ERPs), memory and attention in normal development, aging, schizophrenia, and Alzheimer's disease (AD). The cognitive aging project is directed at understanding basic memory processes and their changes, in brain activity, with normal aging. The lab’s ERP studies confirm the hypothesis that age-related deficits in recognition and free recall memory tasks are due to a relative inefficiency of frontal-lobe function: in young but not elderly subjects, retrieval of information about the source of initial learning is accomplished by brain activity over the frontal regions. ERP studies of working memory also implicate poor frontal lobe deficits in both cognitive aging and the poorer performance of children compared with young adults (Dr. Yale Cycowicz). Studies of AD (Dr. Helen Gaeta) and schizophrenia (in collaboration with Drs. Gerard Bruder and Elizabeth Squires-Wheeler) also aim at understanding how basic memory processes are either maintained or deteriorate in these devastating illnesses. Studies of attention suggest that the more complex function of attentional capture, as indexed by the P3a, also is somewhat compromised with increasing age. Studies of sensory memory, measured by the mismatch negativity component of the ERP, suggest that sensory memory is relatively intact at least in the early stages of AD.

Psychogenetics Division (Dr. Miron Baron, Head)
A project on “Molecular Genetics of Bipolar Disorder” (in collaboration with Drs. Jean Endicott and T. Conrad Gilliam) continues on two fronts: (1) An ongoing nationwide collection of pedigrees and cell lines as part of the “Healthy People 2000” initiative of the U.S. Public Health Service to assemble one of the largest genetic datasets for identifying genes for bipolar and related mood disorders. (2) Continued systematic genome scans and studies of candidate chromosomal regions. A recently completed genome scan of a previously obtained pedigree sample points to several genomic regions as potential sites of susceptibility genes, including chromosomes 2p, 4q, 7q, 8q, 10q, 13q, 14p and 17q. A follow-up linkage study supports prior evidence for a gene on 21q.

Molecular Genetics Laboratories
Gilliam Laboratory (Dr. T. Conrad Gilliam, Head)
This lab continues to study autism and celiac disease, having completed whole genome scans for susceptibility alleles. For autism, based on 160 pedigrees with 2 or more affected individuals, the scan yielded suggestive evidence for linkage on chromosomes 5, 19, and X, and with stronger evidence (lod score > 3.5) for linked regions when X and 19 were considered jointly. For celiac disease, 65 Finnish families provided evidence for a very strong HLA component on chromosome 6 (lod score exceeding > 20), but only nominal evidence for non-HLA related linkage.

The lab is studying (with Drs. Jack Gorman and Eric Kandel) the molecular genetic basis of working memory, which is conceptualized as an endophenotype for schizophrenia and which can be analyzed in transgenic and control mice. Simultaneously, a collaboration with Dr. Gerry Bruder seeks to identify (human) individuals who test at the upper and lower deciles for working memory. A similar project with Dr. Kandel’s group studies the molecular genetic basis of fear conditioning as a possible endophenotype for various anxiety disorders or personality traits.

With Dr. Ruth Ottman, a linked region has been identified that harbors a gene for generalized epilepsy spanning 4 million base pairs on chromosome 10. The lab has identified over 40 genes in this region and has sequenced most of the segments of 7 of these genes, without identifying any unambiguous mutations. Other work with Dr. David Greenberg uses linkage disequilibrium analyses to distinguish among several candidate genes in a small segment of chromosome 6 that segregates with juvenile onset epilepsy.

Knowles Laboratory (Dr. James Knowles, Head)
The Knowles Laboratory is working on the genetic basis to several human diseases. Since finding the gene for Primary Pulmonary Hypertension in 2000, the lab continues collaboration with Dr. Jane Morse on determining how mutations in the bone morphogenetic protein receptor 2 gene cause the disorder. Studies of several candidate genes for panic disorder have recently been published (collaborating with Drs. Weissman, Hodge and Fyer). One of these, catechol-O-methyltransferase, appears to play a role in the development of the disorder. Work on AD continues (collaborating with Dr. Richard Mayeux), with the finding of a potential gene on chromosome 12 that predisposes individuals of Caribbean Hispanics descent to the disorder. Work on the genetics of obsessive-compulsive disorder (OCD) continues in populations from both South Africa (with Dr. Dan Stein, University of Stellenbosch, Tygerberg, South Africa and University of Florida, Gainesville) and North America (with Dr. Abby Fyer). Lastly, the genetics of substance abuse are being explored by the collection of pedigrees with nicotine addiction (in collaboration with Drs. Glassman and Covey) and separately, pedigrees with opiate dependence (in collaboration with Drs. Nunes and Lachman).

Huntington’s Disease Research Group (Dr. Nancy Wexler, Head)
For the past 22 years, Dr. Wexler’s study in Venezuela (the U.S.-Venezuela Collaborative Research Project) has examined members of the world’s largest Huntington’s disease family. With a pedigree of about 14,000 individuals this extended family led to the localization of the HD gene region (at the tip of human chromosome 4) in 1983 and to the isolation of the gene itself in 1993. This research and multiple collaborations on the family helped to define the natural progression of the illness from a neurological and neuropsychological perspective and, in the process of isolating of the HD gene, helped to characterize the mechanism of the newly discovered tri-nucleotide repeats. Currently, the group here, together with collaborators at MIT and Oxford University, searches for genetic and environmental modifying factors influencing age of onset and other phenotypic characteristics of HD. The search for these factors will entail a genome-wide scan and combined new genetic strategies, including the use of single nucleotide polymorphisms (SNPs), as well as an intensified search for environmental factors.

Division of Developmental Behavioral Studies (Dr. L. Erlenmeyer-Kimling, Head)
The Division continues its longitudinal prospective study (now in year 31) following offspring of schizophrenic, affectively ill and psychiatrically normal parents. Deficits in at least three neurobehavioral measures (verbal short-term memory, attention, and gross motor skills) tested in mid-childhood were found to be strong predictors of adulthood schizophrenia-related psychoses in offspring of schizophrenic parents and to be highly specific to this latter group, thus suggesting that the neurobehavioral measures may be indicators of the schizophrenia genotype. Currently, data analyses focus on (1) delineation of other childhood dysfunctions that may, independently or additively with the three already identified, also predict to adulthood schizophrenia, as suggested in ongoing work by Dr. Salome Ott on negative symptoms and thought disorder exhibited in childhood videotaped interviews; (2) a search for environmental or genetic potentiators and/or buffers; and (3) characterization of the prodromal stage of illness in subjects who have developed schizophrenia-related vs affective disorder psychoses.

Other work in this Division continues to carry out a genome-wide scan of a collection of European schizophrenia-pedigrees, in collaboration with Dr. Knowles and Dr. Dieter Wildenauer (Bonn, Germany); to conduct collaborative analyses with pooled data from several now inactive U.S. high-risk studies on children of schizophrenic parents; and to analyze sensory-gating data collected on schizophrenic patients, normal controls, and first-degree relatives of each group.

Laboratory of Clinical Neurobiology (Dr. Dolores Malaspina, Head)
The group continues to examine genetic and environmental factors and their interaction with respect to the liability to schizophrenia. Further analyses continues on data from a birth cohort in Jerusalem, in which Dr. Malaspina had previously identified a significant effect of paternal age on risk for schizophrenia. In the past year, this study has been supplemented by awards from NIMH to collect DNA samples of study participants and from NARSAD to examine “de novo mutations.” The study was also recognized in the New York State Office of Mental Health Research Award, given to Dr. Malaspina in fall 2001.

Dr. Cheryl Corcoran (mentored by Dr. Malaspina) received a pilot grant to examine elements of the stress cascade in schizophrenia and the Pisetsky Award to study estrogen and cortisol in psychosis relapse. Dr. Corcoran received awards from NARSAD to investigate aspects of the schizophrenia prodrome and the Sackler Institute to open a prodromal clinic at NYSPI. Dr. Lilianne Mujica-Parodi (also mentored by Dr. Malaspina) has received funding from the Office of Naval Research to study neural (fMRI), cardiac, endocrine and cognitive mechanisms of stress/arousal-vulnerability in healthy adults, as a prelude to work on psychotic delusions in schizophrenia.

Suicide in Schizophrenia (Dr. Jill Harkavy-Friedman, Head)
Dr. Harkavy-Friedman continues with an NIMH grant to investigate psychological, social, and biological factors related to suicidal behavior in schizophrenia and is collaborating (as Co-PI) with Dr. John Mann (PI) on a grant to test a diathesis-stress model for suicidal behavior. She continues to assist in training of research interviewers for projects throughout the Institute.

Molecular Neurobiology (Dr. Charles A. Kaufmann, Head)
Continuing efforts to identify psychosis-susceptibility genes, Dr. Kaufmann has focused on novel statistical approaches, including scan statistics and neural networks, to compare genetically linked regions in schizophrenia and bipolar disorder.