Ahsan, Habib

Research: Dr. Ahsan's main research interest is in the area of molecular and genetic epidemiology of cancer. Specifically, he has been conducting research examining the impact of genetic variations, gene-environment and gene-gene interactions on cancer risk. Currently funded projects include population-based and family-based studies investigating these aspects in breast and skin cancers. Dr. Ahsan is also actively involved in methodological research in molecular and genetic epidemiology. He is introducing a newly-developed course on the research methods in molecular and genetic epidemiology which will be offered from the Division of Epidemiology of MSPH beginning Fall, 2001.

Fellow participation:

• A cohort study of health effects of arsenic exposure in Bangladesh. A prospective cohort study to examine the role of envrironmental arsenic exposure and its interactions with geneticsusceptibility in the development of skin and other cancers. Funded by NIH Superfund Program (P42ES10349-01).
• Estrogen-related genes and risk of breast cancer: an innovative approach. A family-based genetic epidemiologic study to examine the effects of estrogen-modulating genes and their interactions with hormonal and reproductive factors in breast cancer. Funded by the Department of Defense (BC-99-0500).
• Preparatory work for a genomewide SNP project in breast cancer. A pilot project to complete the prepratatory work and gather preliminary data for a large-scale proposal to investigate new candidate and modifier genes in breast cancer. Funded by the Avon Breast Cancer Research Program (CU-1470301).

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Endicott, Jean

Research: Genetic studies of unipolar and bipolar affective disorders. Study of the course of illness in patients with various subtypes of affective and psychotic disorders. Treatment and follow-up studies of women with premenstrual dysphoric disorder as well as studies of other correlates of varying degrees of premenstrual change in mood and behavior.

Fellow Participation: Fellows can design and conduct their own studies in consultation with senior staff. Data sets are available for fellows to use to address issues other than those of primary focus in the funded studies. Fellows can also participate in the development of different ways of characterizing the course of illness in probands and family members and use the data to generate hypotheses for later testing with new data sets which are being collected. The major skills that would be developed are those related to diagnostic assessment, particularly of subjects who are not already identified as patients, assessment of course of illness and an awareness of issues involved in genetic and follow-up studies when multiple sources of information must be used.

Erlenmeyer-Kimling, Nikki

Research: The Division of Developmental Behavioral Studies of the Department of Medical Genetics is engaged in studies pertaining to genetic aspects of schizophrenia These include:

(1) a longitudinal study of offspring of schizophrenic parents, who have a 10:1 relative risk for developing the illness compared with the general population. The study continues to test and clinically assess these offspring, who are now in mid-adulthood, as well as to analyze the extensive data base collected over 29 years of continuous follow-up.

(2) An ongoing study of nonpsychotic parents and adult siblings of schizophrenic probands is obtaining a variety of assessments of cognitive processing, memory and sensory gating in these relatives and the patient probands.

(3) Molecular genetic analyses aimed at the identification of schizophrenia-susceptibility genes are being carried out on multiplex pedigrees with schizophrenia from a study recently completed in Europe. Collection of further samples of pedigrees is planned.

Fellow Participation: Fellows will have the opportunity to participate in testing, structured diagnostic interviewing, or analysis of archived data, depending on their areas of interest and preparation. Projects include:

• Multiple projects available in connection with the New York High-Risk Project, a longitudinal, prospective study of children at risk for schizophrenia at risk for schizophrenia or affective disorders, with a 29-year database.
• Several subprojects and overall integration of a study of cognitive inhibition tasks in schizophrenic patients and their first-degree relatives.
• Subprojects in connection with pooling data or cognitive, neurological, social and psychological data from several longitudinal studies of children at risk for schizophrenia.
• Analysis of psychiatric-genetic data and, potentially, linkage data in a study of affected sib pairs and their relatives with schizophrenia or schizoaffective disorder.

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Durner, Martina

Fyer, Abby

Research: Dr. Fyer is Professor of Clinical Psychiatry at Columbia University College of Physicians and Surgeons and Co-Director of the Anxiety Disorders Clinic at New York State Psychiatric Institute. Dr. Fyer's main areas of research are genetics of different anxiety disorders, including panic disorder, social and specific phobia. Dr. Fyer has conducted numerous NIMH supported studies on familial and genetic aspects of anxiety disorders. She has published over 100 articles and authored a number of chapters on both genetics and treatment of anxiety disorders, as well as several widely used diagnostic instruments. She is currently involved in linkage and association studies of panic disorder, as well as several pilot studies to explore potential alternative phenotypes for molecular genetic studies of anxiety.

Fellow participation: Fellows will have the opportunity to participate in the studies at several levels appropriate to their area of scientific interest. These include:

• DNA Marker Linkage Studies of Panic Disorder and OCD.

• Response to 35% CO2 Inhalation in Panic Patients, Not Ill-Controls and First Degree Relatives

• Variability in Human Fear Conditioning

Hasin, Deborah

Research: Dr. Deborah Hasin is interested in predictors of the natural history of alcohol use disorders, and how this may differ in treated and untreated population. She is also interested in the effects of psychiatric comorbidity on the course of alcohol and drug use disorders. Dr. Hasin's group is involved in instrument development and testing for measurement of aspects of substance dependence and abuse, and for measurement of psychiatric comorbidity in heavy drinkers and drug users. Dr. Hasin's research also involves exploration of cultural and genetic influences on alcohol consumption and alcohol disorder symptoms in Israel.

Fellow participation: Dr. Deborah Hasin has field placements for fellows interested in the nosology and course of alcohol use disorders in general population samples, which contain family history information. The ongoing development of several research instruments would provide a good setting for fellows interested in instrumentation and the reliability and validity of measures of substance use and mental disorders. A small data set may be available for analysis of the relationship of ADH2 to various health behaviors in a sample of Israeli household residents.

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Knowles, Jim

Research: The primary research goal of the Knowles laboratory is to find genetic loci that have an etiologic role in the development of human disease in general, and psychiatric disease in specific. The laboratory is currently performing genome scans with polymorphic microsatellite DNA markers to look for genes for panic disorder, Alzheimer's disease, addictions to nicotine and opiates and OCD using high-throughput semi-automated genotyping methods. We are also investigating candidate genes for these disorders by assaying for DNA sequence variation in the relevant genes in multiplex pedigrees, haplotype relative risk triads and DNA libraries from the research populations at NYSPI. We have recently identified BMPR2 as the gene responsible for Familial Primary Pulmonary Hypertension, and are currently working to determine mutations in this gene cause the disorder. In the past, in collaboration with the laboratory of Dr. Conrad Gilliam, we identified a gene responsible for autosomal recessive retinitis pigmentosa.

Fellow Participation: Research fellows will initially be assigned a small laboratory project (i.e., investigation of a polymorphism in a candidate gene) to provide a training experience in the laboratory. Fellows will be supervised by Dr. Knowles and will be trained by existing personnel in the laboratory methods. Fellows who wish to continue working in the laboratory will then undertake larger projects that they may have helped design. Research fellows will also be expected to participate in weekly laboratory meetings where their work will undergo critical analysis and where they will develop their skills in the presentation of their results. When appropriate, fellows will write-up the results of their experiments for publication and presentation.

Lee, Joseph

Research: Dr. Lee's research effort concentrates in three areas: (1) genetics of Alzheimer's disease (AD) and memory, (2) genetics of aging, and (3) gene-environment interaction in complex traits. For the first area of research, our goal is to localize chromosomal regions that contain genes that influence AD among Caribbean Hispanics from New York and the Dominican Republic. In addition to AD, we have extended the phenotypes to quantitative traits in attempt to localize genes with small to modest effects. To this end, we are studying memory traits and their age-related decline as the phenotype. Because accumulation of amyloid-B in the brain is a hallmark phenotype associated AD and is associated with age-related memory decline, we are currently planing a feasibility study to examine amyloid-B as a risk factor phenotype. If found to be feasible, we will conduct a genome-wide search to localize contributing genes. For the second area of research, we are conducting a study on the genetics of aging using the Hispanic families recruited from northern Manhattan. We will explore the cognitive and functional components contributing to longevity and frailty, and will determine heritability of those components. The intent is to better understand the genetic factors that contribute to healthy aging. The first two areas of research are carried out in collaboration with Drs. Richard Mayeux and James Knowles. For the third area of research, we are conducting a study to assess gene-environmental interactions in complex traits with a goal of mapping genes that contribute to those traits. To this end, we proposed a family-based migrant study to take advantage of the Korean diaspora. Korean migrants are unique in that they are genetically similar because of the recent migration; yet, they are exposed to wide variation in cultural and environmental exposures. For this study, Koreans in the US, Kazakhstan, and Korea will be recruited. This study is carried out in collaboration with Drs. Joseph Terwilliger and Andrey Rzhetsky.

Fellow Participation: Genetics of memoryGenetics of agingGene-environment interaction in complex traits: the Korean Diaspora (when funded).

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Leibel, Rudy

Research: The Division of Molecular Genetics has about 25 scientists, students and technicians. Current research activities include efforts to identify genes (and relevant allelic variants) related to obesity and/or type 2 diabetes in rodents and humans. The lab has particular interest in the molecular physiology of the energy homeostasis and glucose/insulin metabolism. We use naturally occurring and en-induced mutations, and transgenic rodent models to identify candidate molecules. We vet these candidates in large numbers of human subjects using high throughput methods for detection of DNA sequence variation. The lab shares responsibility with the Columbia Genome Center for the creation and maintenance of the Columbia University microarray facility (CUMAP), and has personnel expert in the relevant molecular and information science. We have Genome Systems/Affymetrix microarray and readers and large, unique cDNA clone collections for mouse, human and yeast.

Fellow Participation:

• Molecular genetic analysis of the leptin axis in rodents and humans. This work includes organ-specific transgenic rescue of the leptin axis in mice.

• Regulation of gene expression in mouse adipose tissues.

• Molecular cloning of genes modifying susceptibility to type 2 diabetes in obese mice.

• Molecular genetics of beta cell neogenesis and replication using mouse strains with differential susceptibility to type 2 diabetes.

• Massive parallel gene expression in brain and other organs responsive to leptin.

• Molecular physiology and genetics of insulin resistance and type 2 diabetes in adolescents.

• Effects of experimental weight perturbation on energy homeostasis in human subjects and mice.

Malaspina, Dolores

Research: Projects examine the genetic and environmental antecedents to schizophrenia, as well as the inter-relationships of etiology, neurobiology and imaging, phenomenology and outcome in schizophrenia. Study populations are the patients from the inpatient schizophrenia research unit, members of birth cohorts, and schizophrenia and bipolar pedigree members.

Fellow Participation: Studies on the inpatient schizophrenia research unit, epidemiological studies in birth cohorts, and examining gene environment interaction in schizophrenia and bipolar pedigree members.

Mayeux, Richard

Research: Dr. Mayeux has led a multidisciplinary, population-based investigation of Alzheimer's disease, Parkinson's disease and stroke known as the Washington Heights-Inwood Community Aging Project. In 1992, Dr. Mayeux received the Leadership and Excellence in Alzheimer's Disease Award from the National Institute of Aging to continue his investigation of genetic and environmental interaction in the etiology and pathogenesis of Alzheimer's disease. He is one of the leading epidemiologists in the field of Alzheimer's Disease with a particular interest in minority health and aging. He was among the first to integrate molecular genetics and epidemiology in an attempt to identify biological markers of susceptibility to degenerative diseases of the aging nervous system such as Alzheimer's disease. In 1998, he began a study of Caribbean Hispanic families with Alzheimer's disease in order to identify new genes associated with this disorder.

Fellow Participation:

• The Epidemiology of Dementia in an Urban Community-This is a population-based study of risk factors for Alzheimer's disease and vascular dementia. Genetic, biological and clinical indicators of risk are being collected in 2500 elderly age 65 and older from three ethnic groups (African-American, Caribbean Hispanic and White).

• Alzheimer's Disease Research Center- This involves a variety of clinical studies including genetic research in early-onset and late-onset Alzheimer's disease, brain imaging and clinical trials.

• Genetic Epidemiology of Alzheimer's Disease in Hispanics. Principal Investigator- This is a family-based study of Alzheimer's disease among Hispanics from the Caribbean. A full-scale genome search is in progress along with continued data collection and ascertainment of families.

• Genetic Epidemiology of Aging in a Multiethnic Community. Principal Investigator-This study has just begun and will entail a study of familial aggregation of longevity and active and total life expectancy, identification of oldest living healthy siblings and eventually, a genome scan.

• Gender and Ethnic Differences in Mortality for Parkinson's Disease- This study involves the creation of a tri-state area registry for Parkinson's disease in order to investigate factors accounting for differences in mortality by gender and ethnic group. A related study is directed by Karen Marder, MD, MPH, who is collecting families with Parkinson's disease.

Ott, Jurg

Research: Dr. Ott is the head of a laboratory which focuses on mathematical and statistical methods for gene mapping, primarily for the genetic mapping of genes underlying human traits. Their work falls into two broad categories, 1) developing new and improving existing statistical methods, and 2) applying the resulting techniques to genetic data, generally collected by outside investigators. They mostly work with the following data types: Genetic linkage data (small or large families, observations are disease status and marker genotypes), association data (mostly case-control design, disease status and marker genotypes), and microarray data (expression levels).Currently, his area of primary interest is efficient localization of genes underlying so-called complex traits such as diabetes and psychiatric illnesses. We apply novel approaches, for example, scan statistics or the Ising model of physics. To handle the large numbers of marker loci in genomic screens, we developed resampling-based procedures of pre-selection. We also investigate the effects of errors on analysis and how errors can be made part of an analysis to mitigate some of their deleterious effects.

Fellow participation:

• Efficient methods for selecting markers for further analysis in case-control association studies.
• Joint analysis of genetic marker data in case-control association studies.
• Resampling and/or permutation methods for family data (such methods would be used to estimate empirical significance levels; they would be preferable over the simulation approaches in current use).
• Develop analysis methods for microarray expression data.
• Analyse data sets obtained from our collaborators.

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Rabinowitz, Dan

Research: Theory and application of statistics including statistical genetics and genetic epidemiology, familial aggregation, survival analysis, semi-parametrics, boundary crossing probabilities with statistical applications, computational methods, longitudinal data, case-control designs.

Fellow participation: A variety of topics, both methodological and computational, in statistical genetics and methods for genetic epidemiology including topics related to coping with incomplete genotype and/or phase information, topics related to familial aggregation, syndrome definition and heterogeneity, and topics related to linkage analysis with longitudinal traits.

Rzhetsky, Andrey

Research: Dr. Andrey Rzhetsky has expertise in Bioinformatics and has published more that thirty papers related to development of computational methods for biological applications. His major research interests are in computational analysis of regulatory and metabolic pathways and in phylogenetic analysis of protein and DNA sequences.

Fellow participation:

• Computational analysis of complex pathways
• Automated extraction of complex pathways from research literature
• Development of mathematical methods for prediction of complex pathways

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Terwilliger, Joe

Research: (See fellow participation below)

Fellow participation:

• Gene-Environment Interaction study in populations of the Korean Diaspora: In this project we study families of ethnic Koreans in South Korea, the USA, Russia, Kazakhstan, and adopted Koreans in Northern Europe and the USA. The goal is to study the relative contributions of genetic and environmental factors to numerous quantitative traits which are risk factors for common chronic and infectious diseases in these populations, and to identify the genes involved, and how their effect is impacted by the differing environmental and cultural conditions.
• Development of automated software systems for joint linkage and LD analysis: The methods described in the four papers by Göring and Terwilliger (2000) cover a wide range of statistical tests which are potentially powerful tools for general gene-mapping projects, and have been applied in numerous practical examples with my collaborators in Sweden and Finland. However, the techniques can be very cumbersome to apply by hand (the analysis in Kainulainen et al (1999) took me over 80 hours of human time). Therefore development of automated systems for directing the statistical analysis are needed. The preliminary versions of this software repeated the analysis of Kainulainen et al (1999) with one push of a button, but still took a weekend to do the calculations. Speeding up the programs, and making them user-friendly and widely available are a major part of my current research.
• Population simulation methods: As part of the 2000 Genetic Analysis Workshop, I simulated a large set of genes, as they evolved in a natural population over 200,000 generations from monomorphism, with various complications influencing population history and demographics, mutation and recombination hotspots, gene conversion, and so forth. The software is being expanded to include more sophisticated models of natural selection (potentially transient over time as environmental conditions necessarily change), and so forth, and it is being made more user-friendly, so that others can use this to test the impact of population parameters on their proposed LD analysis studies.
• Association analysis of pathways: A model for testing of several genetic loci acting in concert on a given phenotype has been incorporated in a preliminary analysis program. In this analysis, one simultaneously looks at association with numerous genes which are hypothesized to work together to produce some trait, such that variant genotypes of different loci in the pathway might be contributing simultaneously to the phenotypic outcome. Randomization tests to evaluate the statistical significance of these likelihood tests are used for inference. Development and generalization of this software is ongoing
• Data analysis and collaborations: Numerous outside collaborations are ongoing, in which I am helping plan and analyze genetic data for different groups, at Columbia, the Kansanterveyslaitos in Helsinki - Finland, Uppsala University and the Karolinska Institute in Sweden, University of Melbourne in Australia, and elsewhere.

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Warburton, Dorothy

Research: Dr. Dorothy Warburton is a cytogeneticist whose current primary interest is in the epidemiology of human chromosome abnormalities, particulalry as this relates to fetal loss. She has also been involved in gene discovery and gene mapping in humans and rodents. Currently work is focused on testing a hypothesis concerning the relationship between maternal age and trisomic conceptions, termed the "limited oocyte pool" hypothesis. Under this hypothesis, trisomy risk is related to the size of the remaining pool of oocytes, a variable correlated with biological aging. Age at menopause, ovarian follicle counts by ultrasound, X-chromosome aneuploidy and hormonal levels are all variables being analyzed in an epidemiological study conducted with colleague Jennie Kline in the Divison of Epidemiology. Further studies are planned to investigate highy skewed X-inactivation, a phenomenon linked to repetitive spontaneous abortion, as it relates to maternal aging and trisomy risk. Laboratory studies are also being carried out to investigate the early stages of human female meiosis by direct examination of fetal oocytes using FISH and immunochemical techniques.

Fellow participation:

• Analysis of trisomy recurrence risk: are there women at increased risk for trisomy in general, rather than for specific trisomies
• Studies of menopausal histories from women with spontaneous abortion of known karyotype
• Analysis of X-inactivation skewing in women with repetitive abortions, and abortions of known karyotype
• Microscopic analysis of human meiotic prophase in fetal oocytes: comparison of sites of recombination with genetic maps, and comparison of pairing timing and patterns among pairs of human chromosomes.

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Wickramaratne, Priya

Research: Dr. Wickramaratne's main research interests are the design and statistical analysis of epidemiologic studies- especially studies of familial aggregation of disease. She has had considerable experience working in the field of family studies of psychiatric disorders. She has published several articles dealing with both the methodology and substance of such studies. The focus of her current research is to evaluate existing epidemiologic approaches to the study of familial aggregation and (where appropriate) to develop improved approaches to the design and analyses of such studies.

Fellow participation:

• Investigate the magnitude of the bias in testing and estimating measures of familial aggregation in epidemiologic approaches, when single ascertainment does not hold.
  
• Develop methods of testing and estimating familial aggregation which allow for other realistic modes of ascertainment.