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
T. Conrad Gilliam, Ph.D., Research
Scientist VI
Charles A. Kaufmann, M.D., Psychiatrist
(Research) II
James Knowles, M.D.,
Psychiatrist (Research) II
Dolores Malaspina, M.D., Psychiatrist
(Research) II
Nancy S. Wexler, Ph.D., Head,
Division of Neurology
Molecular Genetics Laboratories
Gilliam Lab The lab, headed by Dr. T. Conrad Gilliam, completed whole genome scans for susceptibility alleles to autism and celiac disease. 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 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 (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 mice altered for this trait. Initial studies focus on whole genome gene expression in transgenic and control mice. Simultaneously, a collaboration with Dr. Gerry Bruder seeks to identify 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 and spans 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.
Molecular Genetics Laboratory The laboratory, headed by Dr. James Knowles, works on a number of human genetic disorders. Recently, after narrowing the genetic region containing the gene for familial Primary Pulmonary Hypertension, the lab (collaborating with Dr. Jane Morse) identified it as the bone morphogenetic protein receptor 2 gene. This discovery both enables genetic testing for the disorder and implicates the bone morphogenetic protein pathway in maintenance of vascular integrity.
The search for genes predisposing individuals to panic disorder continues (collaborating with Drs. Weissman, Hodge, and Fyer). A subtype of panic disorder with co-morbid medical conditions was reported in 2000, along with studies indicating that the genes for monoamine oxidase A, the dopamine transporter and the dopamine receptor 4 are unlikely to play a role in the disorder. Data are being analyzed from the Center for Disease Research's (CIDR) recent genotyping of 120 panic disorder and families.
The search for late-onset Alzheimer's disease-genes continues (collaborating with Dr. Richard Mayeux) by linkage and candidate gene methods. Evidence for involvement of the alpha-2-macroglobulin gene on chromosome 12, but not the presenilin-1 gene, has been published.
Collection of a DNA library from children and adolescents enrolled in NYSPI studies continues (collaborating with the Department of Child Psychiatry).
Work has begun on a recently-awarded grant concerned with genetics of nicotine addiction (collaborating with Drs. Glassman and Covey).
Cognitive Electrophysiology Laboratory This laboratory, headed by Dr. David Friedman, continues a series of interrelated investigations on cognitive event-related brain potentials (ERPs), memory, and attentional function in normal development, aging, and disease states. The cognitive aging project focuses on understanding basic memory processes and their changes in relation to brain activity, with normal aging. 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, by showing that, for young but not elderly subjects, retrieval of information about the source of initial learning is accomplished by brain activity over frontal regions. ERP studies of working memory also implicate frontal lobe deficits in cognitive aging and in the poorer performance of children, compared with young adults (work in collaboration with Dr. Yael Cycowicz, Medical Genetics). Studies of Alzheimer's disease (in collaboration with Dr. Helen Gaeta, Medical Genetics) and schizophrenia (in collaboration with Drs. Gerard Bruder, Biopsychology, and Elizabeth Squires- Wheeler, Medical Genetics) also aim at understanding how basic memory processes either are maintained or deteriorate in these illnesses. 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 Alzheimer's disease.
Psychogenetics Division
In the division, headed by Dr. Miron Baron, a project on "Molecular Genetics of Bipolar Disorder" (in collaboration with Dr. Jean Endicott) 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 in the previously obtained pedigree sample.
Division of Developmental Behavioral Studies
The division, headed by Dr. L. Erlenmeyer-Kimling, continues its longitudinal, prospective study (now in year 30) 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 are strong predictors of adulthood schizophrenia-related psychoses in offspring of schizophrenic parents and may be indicators of the schizophrenia genotype. Ongoing work attempts to differentiate patterns of other childhood characteristics in children with these neurobehavioral deficits, comparing subjects who developed schizophrenia-related psychoses versus those who did not. Ratings of parental interviews (Dr. Paul Amminger) and videotaped interviews of the offspring (Dr. Salome Ott) suggest that specific childhood behaviors and negative symptoms may also predict later schizophrenia, whereas adolescent event-related brain potentials (Drs. David Friedman and Elizabeth Squires-Wheeler) may predict later negative symptoms.
Other work in the division continues (1) to examine a collection of European schizophrenia-pedigrees and to search for possible gene-linkages in collaboration with Dr. Knowles (Medical Genetics) and German colleagues; (2) to conduct collaborative analyses with pooled data from several inactive U.S. high-risk studies; and (3) to analyze sensory-gating data collected on schizophrenic patients, their first degree relatives, and normal controls.
Suicide in Schizophrenia
Dr. Jill Harkavy Friedman continues to investigate psychological, social, and biological factors related to suicidal behavior in schizophrenia.
Laboratory of Clinical Neurobiology
The research of the laboratory headed by Dr. Dolores Malaspina examines genetic and environmental factors and their interaction with respect to vulnerability to schizophrenia. Ongoing studies relate to psychophysiology, brain imaging, and phenomenology, as well as the pathophysiology of stress in schizophrenia and its association with neruoanatomy and cognitive deterioration. In a birth cohort study in Jerusalem, Dr. Malaspina has identified a significant effect of paternal age on risk of schizophrenia (accounting for up to a quarter of all schizophrenia cases) and has begun translational studies of the phenomena.
Huntington's Disease Research Group
Dr. Nancy Wexler's 20-year study in Venezuela of the world's largest Huntington's disease (HD) family (with a pedigree of over 16,000 individuals), which lead to the identification of the HD gene (at the tip of human chromosome 4), has also assisted in the mapping of other disease genes, including genes for familial Alzheimer's disease, kidney cancer, two kinds of neurofibromatosis, amyotrophic lateral sclerosis, dwarfism, and others. Identification of the HD gene has led to development of a presymptomatic test to determine, prior to onset of symptoms, which at-risk individuals actually carry the genes.
Molecular Neurobiology
Continuing efforts to identify psychosis-susceptibility genes, the laboratory, headed by Dr. Charles A. Kaufmann, has recently focused on novel statistical approaches, including scan statistics and neural networks, to compare genetically linked regions in schizophrenia and bipolar disorder. A statistically significant overlap in linked regions for these two psychotic disorders has been identified.
Dr. Niki Erlenmeyer-Kimling,
center, with Dr. Andrew Skodol
and Dr. Sharon Carpinello