Virginia Institute for Psychiatric and Behavioral Genetics


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Virginia Institute for Psychiatric and Behavioral Genetics

  1. 1. Virginia Institute for Psychiatric and Behavioral Genetics Annual Report July 2004-June 2005
  2. 2. Kenneth S. Kendler, M.D., Co-Director (804) 828-8590
  3. 3. Table of Contents Executive Summary 2 About VCU 3 Introduction 4 Facilities 5 VIPBG Faculty and Staff 7 Major Areas of Research 10 Major Accomplishments 13 VIPBG Publications 15 Active Research Grants 19 Budget Breakdown 24 Research Initiatives for 2005-2006 25 Lindon J. Eaves, Ph.D., Co-Director Michael C. Neale, Ph.D., Associate Director (804) 828-8155 (804) 828-3369 Virginia Institute for Psychiatric and Behavioral Genetics Virginia Commonwealth University 800 E. Leigh Street, P.O. Box 980126 Richmond, VA 23298-0126 (804) 828-5360
  4. 4. From the Directors Psychiatric disorders are among the most frequent, distressing and poor- ly understood human disorders. Schizophrenia, autism, depression, anti-social behavior, ADHD, substance abuse, alcoholism: the list is long and the conse- quences often devastating. The VIPBG was founded eight years ago in the conviction that the com- plexities of human behavior and its disorders would yield better to a community of minds than a loose collection of scattered individualists. Forty years ago, one person could know all there was to know about Genetics. The same solitary geneticist might count hairs on fruit-flies one day and draw the chromosomes of an onion the next. These days, it helps to have company. No longer is it possible Lindon J. Eaves for any one individual - despite his or her level of brilliance or industry - to have Director command of all that is needed to conduct cutting edge work in psychiatric or behavioral genetics. New insights still arise from data collected more than a decade ago. VIPBG molecular geneticists and statisticians continue to analyze samples of DNA collect- ed almost 20 years ago in a study of schizophrenia. Grants from NIH continue to support analysis of data from large longitudinal studies of adult and juvenile twins that began in the mid 80's and are only now reaching their completion. Modern genetics poses new mathematical and computational challenges. Institute faculty have obtained grants to develop new statistical approaches to diagnosis and the daunting task of finding genes that affect behavior buried in the haystack of the human genome. Old data continue to inspire new studies. A study of the children of twins Kenneth S. Kendler involves more than 2,000 families. A new study of the roles of genetic and envi- Director ronmental influences in infant twins is just beginning in collaboration with the University of Puerto Rico. International collaboration continues with scholars in the U.S., The Netherlands, Norway, Sweden, United Kingdom and Australia. Some of us are collaborating in twin studies of brain structure and function, others in studies of gene expression, still others in aging. We are obtaining DNA samples in preparation for a large scale molecular-genetic study of the interaction between genetic and environmental influences in risk to psychiatric and substance use dis- orders. New methods of classifying and measuring liability to psychiatric and substance abuse disorders are being developed. The future of Psychiatric Genetics requires new minds to grasp opportunities that are scarcely imag- inable today. Recruitment of more pre- and post-doctoral students has led to remodeling of space to accommodate them. We are proud that our NIMH pre- and post-doctoral training grant was renewed at a time when funds were hard to obtain. In addition to teaching formal graduate courses at VCU, VIPBG faculty contribute to a series of international workshops in statistical genetics that have graduated more than 1000 alumni over the last 15 years. This spring, many of us worked on a text published by the APPI that tries to bring the principles of Psychiatric Genetics to a wider audience of students and clinicians. Forty years ago, the burning question was simply "Do genes affect behav- ior?" Today's questions are more complicated and include: "Which genes affect behavior?" "How do genetics and environmental risk factors inter-relate?" and Michael C. Neale "How do genes act over time and through development to alter the chances of ill- Associate Director ness." Tomorrow's questions will be yet more complex. We are planning to be there to help answer them. 2
  5. 5. About Virginia Commonwealth University Virginia Commonwealth University is an urban, public institution enrolling more than 28,500 undergraduate, graduate and first professional students on two campuses in Richmond, Virginia. The Monroe Park Campus is situated in the heart of Richmond’s Fan District, a large residential neighborhood of Victorian townhouses. The MCV Campus, which houses VCU’s prestigious health sciences programs and the VCU Medical Center, is located two miles east of the Monroe Park Campus in historic Court End, near the city’s government and financial cen- ters. More than 1,650 full-time faculty and 950 adjunct faculty comprise the university’s teaching force. The total workforce of the university — faculty, physicians, nurses, and admin- istrative and support staff — is more than 15,000. VCU attracts more than $140 million in spon- sored research funding, placing it among the top research institutions in the country. Research strengths at VCU include the basic and health sciences, business, behavioral sciences, public affairs, and the humanities. Among VCU’s many national rankings are 20 graduate pro- grams in the top tier of the U.S. News and World Report review. For more informa- tion: The biomedical research strengths of VCU have played a lead role in launch- ing the Virginia Biotechnology Research Park, a public-private partnership of the university, surrounding localities, the state and the business community. VCU is comprised of the schools of Allied Health Professions, the Arts, Business, Dentistry, Education, Engineering, Medicine, Nursing, Pharmacy and Social Work, and the College of Humanities and Sciences, which includes the L. Douglas Wilder school of Government and Public Affairs and the schools of Mass Communications and World Studies. The academic units offer the following degree pro- grams: 54 baccalaureate, 62 master’s, 24 doctoral, and first professional degrees in dentistry, medicine and pharmacy. The governance system of the university is headed by the Board of Visitors, a 16-member body appointed by the governor of Virginia. This group has the legal authority and responsibil- ity for Virginia Commonwealth University as established by legislation passed by the General Assembly of Virginia. The president is selected by and responsible to the Board of Visitors, which determines major policies for the university. The University Council, made up of 75 members including faculty, students, administra- tors and four subcommittees — the Executive Committee, the Committee on Student Affairs, the Committee on Academic Affairs and the Committee on Faculty Affairs — meets monthly September to May to review proposals for new policies and programs, as well as changes in existing policies and programs. 3
  6. 6. Introduction About the Institute Created in 1996, VIPBG is directed jointly by Dr. Lindon Eaves, Distinguished Professor of Human Genetics, and Dr. Kenneth Kendler, Rachel Brown Banks Distinguished Professor of Psychiatry, who have collaborated for over 20 years. Faculty of VIPBG have their primary appointments in either the Departments of Psychiatry or Human Genetics. Researchers within the Institute provide expertise and sup- port to numerous VCU departments and pro- grams (e.g. Psychology, Pharmacology, The Massey Cancer Center) and have established col- laborative arrangements with other universities, federal agencies and industrial partners, (e.g., Institute of Psychiatry, London; Oxford University; Harvard University; Duke University; Glaxo Smith Kline). Many of these partnerships are with renowned scholars in leading institu- tions in the US and around the world. The faculty at VIPBG have a longstanding record in training productive research scientists in the areas of genetic epidemiology, and psychiatric and behavioral genetics. Two faculty currently hold research career awards, both funded through NIMH. A total of 15 faculty hold 27 federally funded grants, most of them through NIMH, NIDA, NIAAA and NINDS with 23 grants funded by other agencies. VIPBG unites expertise in molecular genetics, mathematical genetics, alcohol, nicotine and other substance abuse disorders, genetics of complex traits, psychiatry, clinical psychology, epidemiology, data analysis, software develop- ment and dissemination, establishment and maintenance of large population-based twin registries, ascertainment of large samples of high-density families appropriate for linkage analysis, and the study of minority populations. 4
  7. 7. Facilities Located in Virginia's Biotechnology Research Park adjacent to VCU's medical campus, VIPBG occupies 16,200 square feet of customized contiguous office space on the first floor of Biotech One. The space includes offices for faculty and staff, a state-of-the-art molecular genet- ics laboratory, fire-resistant facilities for data storage, a conference room (capacity 15-20 peo- ple) with a library, and a computer room. Faculty are supported by research assistants and secretarial, fiscal, and computer staff, most of whom are supported from external grants. Molecular Genetics Laboratory Drs. Riley and Chen direct the Molecular Genetics Laboratory in the Department of Psychiatry, which totals over 2800 square feet. It has 14 desk/lab bench stations and 45 linear feet of bench space - the capacity for 16 lab staff. In addition to that, our lab has a dedicated com- puter room, a dedicated bacterial/tissue culture room and a reagent preparation and storage room. Equipment includes a stand-alone computer network, a Beckman Coulter SNPStream 12/48 multiplex SNP genotyping platform, a SpectruMedix 9610 96-capillary automated laser flu- orescent sequencer, four Tetrad PCR machines, one LJL fluorescent plate reader (serving as both FP-TDI SNP genotyping system and fluorimeter for DNA quantitation), one iCycler real time PCR machine, one pyrosequencer and all small equipment necessary to our program of work (hybridization ovens, centrifuges, hoods, incubators, shakers, etc.). Future equipment and plat- form additions are planned. The lab currently has a dedicated computer room equipped with a Novell server, which provides data transfer and back up services for all lab staff. Pentium- equipped personal computers and two Unix servers are available for lab staff to plan and design experiments, and to analyze data. For CPU-intensive data analysis and networking tasks, VIPBG's computing facilities are available. Computing Facilities VIPBG computing resources comprise desktop and laptop PCs running Windows XP or Linux, which are connected via switched ethernet to the local cluster of servers, to VCU research computing, and to the Internet. The local cluster features 64-bit Unix systems, with up to 2Gb RAM and 70Gb RAID disk space, and a Linux Beowulf cluster that incorporates a 250Gb RAID disk, 1Tb Network Attached Storage and 15 AMD Opteron dual-processor nodes each with 2Gb RAM and 36Gb disk space. These high-speed workstations provide powerful CPU and networking performance for computer-intensive applications common in genetic studies. FORTRAN and C compilers, SAS, Splus, R, Mx, and various linkage & association software packages including Genehunter and Merlin are installed. Most faculty and students access these machines with X-windows software running on a local Pentium PC's. A separate linux server supplies standard word processing and office software and provides PC backup and printing services via central HP and Xerox laser printers. VCU's central research computing facilities include two SGI Origin 2000 multiprocessor sys- tems, a 52-node Linux beowulf cluster, and a Sun 420R 4 processor system, and these are supported by approximately 20 Gb RAM and two terabytes of disk storage. 5
  8. 8. Bioinformatics Lab In the Bioinformatics Lab, we are working interactively on the study of gene struc- tures of schizophrenia susceptibility genes (e.g. DTNBP1), on the design and establish- ment of a comprehensive bioinformatics system to efficiently manage various types of data, and on the development of computational tools for lab experimental support (e.g. PCR primer design, selection of candidate genes or genetic markers). For more informa- tion, go to Versatile Software for Biomedical Genetic Applications The Structural Equation Modeling Package Mx, created by Dr. Michael Neale, is a comprehensive user-friendly resource with a powerful graphical user interface for the sta- tistical analysis of genetically informative data that is being used worldwide. Population-Based Twin Registries VCU scientists spearheaded the creation of the Mid-Atlantic Twin Registry (MATR) through merging of the Virginia, North Carolina and South Carolina Twin Registries. The MATR is directed and maintained by VIPBG personnel and currently has enrolled more than 51,000 individual twins, making it one of the largest population- based resources for genetic research in the world. The MATR currently is providing research participants for seven projects and later this year will expand its efforts to sup- port recruitment for and operation of three additional projects. All MATR operations and affiliated studies are governed by the MATR's suite of more than 80 standard operating procedures, which ensures consistent approach to all research subjects and protection of their rights and privacy. High-Density Family Collections Successful linkage studies in complex illnesses such as psychiatric and substance use disorders require large samples of families with multiple affected members. VIPBG houses the world's largest collection of high density schizophrenia families, and growing samples of families with epilepsy, alcoholism, nicotine-dependence and attention-deficit hyperactivity disorder (ADHD). 6
  9. 9. VIPBG Faculty and Staff Faculty Jill Opalesky, M.S. Assistant Professor Xiangning “Sam” Chen, Ph.D. Assistant Professor of Human Genetics and Psychiatry, Co-director of Molecular Genetics Lab Carol A. Prescott, Ph.D. Associate Professor of Psychiatry Linda A. Corey, Ph.D. Professor of Human Genetics Brien P. Riley, Ph.D. Assistant Professor of Human Genetics and Psychiatry, Co-director of Molecular Genetics Lab Lindon J. Eaves, Ph.D. Distinguished Professor of Human Genetics and Professor of Psychiatry, Co-director Judy L. Silberg, Ph.D. of VIPBG Associate Professor of Human Genetics Debra L. Foley, Ph.D. Edwin van den Oord, Ph.D. Assistant Professor of Human Genetics Associate Professor of Psychiatry John M. (Jack) Hettema, M.D., Ph.D. Zhongming Zhao, Ph.D. Assistant Professor of Psychiatry Assistant Professor of Psychiatry and the Center for the Study of Biological Complexity Kristen C. Jacobson, Ph.D. Assistant Professor of Psychiatry Research Associates Steven Aggen, Ph.D. Kenneth S. Kendler, Ph.D. Department of Psychiatry Rachel Brown Banks Distinguished Professor of Psychiatry, Professor of Human Genetics, Co- director of VIPBG Charles Gardner, Ph.D. Department of Psychiatry Hermine H. Maes, Ph.D. Assistant Professor of Human Genetics Po-Hsiu Kuo, Ph.D. Department of Psychiatry Donna R. Miles, Ph.D. Assistant Professor of Human Genetics John Myers, M.S. Department of Psychiatry Michael C. Neale, Ph.D. Professor of Psychiatry and Human Genetics Jaime Robles, Ph.D. Departments of Psychiatry and Human Genetics 7
  10. 10. Thomas Kubarych, Ph.D. Vladimir Vladimirov, M.D., Ph.D. Department of Psychiatry Department of Psychiatry Timothy York, Ph.D. Postdoctoral Fellows Departments of Psychiatry and Human Genetics Charles Anderson, Ph.D. Department of Psychiatry Lan Zhang, M.D., Ph.D. Department of Psychiatry Paul Andrews, Ph.D. Department of Psychiatry Graduate Students Jessica Baker Jozsef Bukszar, Ph.D. Department of Psychology Department of Psychiatry Elizabeth Prom Nathan Gillespie, Ph.D. Department of Integrative Life Sciences Department of Psychiatry James Eric Schmitt Robin Page Goin-Kochel, Ph.D. Department of Human Genetics Department of Psychiatry Kelly Tracy Cizhong Jiang, Ph.D. Department of Human Genetics Dept. of Psychiatry Molecular Genetics Lab Gursharan Kalsi, Ph.D. Department of Psychiatry Seon-Sook An, Ph.D. Lab Specialist Joseph McClay, Ph.D. Departments of Psychiatry and Human Genetics Shaon Hossain Lab Specialist Daekwan Seo, Ph.D. Department of Psychiatry Robert Ribble Lab Specialist Dawn Thiselton, Ph.D. Department of Psychiatry Jennifer Vittum Lab Specialist Cristina Vargas-Irwin, Ph.D. Department of Psychiatry Xu Wang Lab Specialist 8
  11. 11. Brandon Wormley Karen Beebe Lab Specialist Research Assistant Deborah Bratton Psychiatry Staff Administrative Office Specialist Karen Brown-Davis Fiscal Technician Terry Crosby Research Specialist Frank Butera, M.A. Research Specialist Eric Doersch Programmer/ Network Administrator Stacey Garnett Financial Services Manager Melissa Hayes Adminstrative Office Specialist Lisa Halberstadt, M.S. Research Specialist Sandy Lee-Muzik Research Specialist Barabara L.S. Herrmann Admin Office Specialist Terry Martin, M.S. Research Specialist Rebecca Ortiz Administrative Assistant Anne Taylor-Morris Research Specialist Indrani Ray Info Tech Specialist Gwen Reilly Research Specialist Cheryl Smith Administrative Office Specialist Patricia Solari Research Assistant Helen Wang Systems Analyst Elizabeth Thomas MATR Project Coordinator Human Genetics Staff Carol Williams Cindy Beck Info Tech Specialist MATR Applications Analyst Susan Williams, M.S. Research Specialist 9
  12. 12. Major Areas of Research VIPBG's multidisciplinary research is organized around two mutually reinforcing principal themes: the development of methods for the analysis of genetic and environmental risk to complex traits (statistical genetics and genetic epidemiology) and the gathering of empiri- cal data that permit the analysis of the causes of medically relevant normal behavioral variation and biomedical conditions with behavioral components (molecular, substance abuse, psychiatric and behavioral genetics). Currently, VIPBG is supported by research grants totaling over $25 million from federal and private sources, including 25 R01's, two K awards and a T32 National Research Scholarship Award. More than 500 papers in leading journals have been authored or co- authored by VIPBG faculty. In a recent survey of high-impact research in psychiatry, VCU was ranked second among federally funded U.S. universities ( Three VIPBG researchers are ranked among the top 20 highly cited in psychiatry worldwide. Listed here are the major areas of research that make up VIPBG’s core responsibilities. More specific grant descriptions can be found beginning on page 19. Schizophrenia VIPBG is currently working on a number of projects concerning schizophrenia. One of the major projects is funded by the National Institutes of Mental Health. Principal Investigators are Drs. Kenneth Kendler and Brien Riley. The study focuses on the characterization and understanding of the dysbindin gene, the first widely replicated susceptibility gene for schizophrenia, found in our laboratory three years ago. A second major project in schizophrenia, funded by the National Institute for Research on Schizophrenia and Depression (NARSAD), is being conducted by Dr. Xiangning Chen. His team is working to characterize and find the susceptibility locus for schizophrenia under the 5q linkage peak. Nicotine Dependence One of the major projects at VIPBG concerning nicotine dependence is titled “Genetic Etiology of Tobacco Initiation and Nicotine Dependence” and is funded by the Tobacco Settlement Foundation from the Commonwealth of Virginia. It is being conducted in collaboration with Drs. Xiangning Chen and Kenneth Kendler. A strategy is being used for testing candidate genes using a modified case control sample to be able to test specifically for genes predisposing to initiation and genes predisposing to nicotine dependence conditional upon initiation. 10
  13. 13. Major Depression Dr. Judy Silberg conducts two of VIPBG’s studies on depression. She received a NARSAD award for studying the influence of genetic (in particular the serotonin transporter gene, 5HT) and environmen- tal factors in the development of young adult depression. The title of the project is “Genetic and envi- ronmental pathways to young adult depression.” Dr. Silberg also heads the NIMH funded study, "Parental effects on depression and disruptive behavior in children of twins.” Dr. Kenneth Kendler is currently conducting additional research and collaboration with Nancy Pedersen of the Karolinska Institute examining depression in the largest interview-based twin sample yet studied of over ten thousand twin-pairs. They are examining gender differences, age of onset effects, and the inter-relationship between risk for depression and risk for cardiovascular disease. Substance Use and Abuse/Dependence The “Irish Affected Sib Pair Study of Alcohol Dependence” study, led by Dr. Carol Prescott, is a major project of VIPBG’s, where the goals are to study the genetic epidemiology of alcoholism and alcohol- related behaviors, susceptibility genes for alcohol dependence, and the genetic basis of individual dif- ferences in personality and cognition. To conduct this project, a team of experts has been assembled in clinical assessment, statistical genetics and molecular genetics. Dr. Kenneth Kendler is involved in the analyses of existing data from a comprehensive program of research looking at the genetics of substance use and abuse/dependence. In development since 1983, this research program is supported by a number of major twin studies. Dr. Michael Neale’s recently funded project, “Psychometric and genetic assessments of substance use,” develops, tests, and applies methods to investigate the assessment and classification of sub- stance use and abuse patterns, including genetic item response theory models and genetic latent class models. Collaborators on this project include Drs. Dorret Boomsma and Jacqueline Vink at Free University of Amsterdam, Dr. Brian Flaherty at University of Washington, Seattle, and Dr. Gitta Lubke at University of Notre Dame. Development of Analytic Techniques Dr. Edwin van den Oord and his group of researchers have focused on the study and development of techniques for the analysis of large scale genetic data with an application to psychiatric and behav- ioral phenotypes. Examples of specific areas are data mining and knowledge discovery, control of false discoveries, phenotype refinement and psychometrics, and the statistical modeling of the inter- play of genes and environment. Specific applications include schizophrenia, depression, and respira- tory diseases. 11
  14. 14. Assessment of Psychopathology The project, “Psychopathology: Models, Measurement, and Classification,” headed by Dr. Michael Neale, develops and applies an array of methods to examine the empirical basis for the DSM noso- logical system and will develop more efficient methods of analysis of the available data. Existing methods applied to these data include latent class analysis, item response theory, multiple rater models and modern regression methods. Extensions of these methods have been developed and applied, particularly multiple rater models for longitudinal data, multivariate contingent causal models for ordinal data, and structured versions of latent class and item response models that are suitable for the analysis of data collected from families or other clustered groups. The long term goals of the project are to improve the efficiency of measurement, nosology, and knowledge of the etiology of common psychiatric disorders and their comorbidity. Child and Adolescent Development A number of studies headed by Drs. Lindon Eaves and Judy Silberg look at the development of children and adolescents. In one of their studies, the analysis of the interplay of genes and envi- ronment and ageing is conducted. The “Children of Twins” study, just recently initiated, unravels the causal effects of parent treat- ment on offspring behavior from secondary genetic association between parents and children. Drs. Silberg and Eaves hope to find out whether the genes or environment influence the associa- tion between aspects of the home environment such as marital conflict, maternal smoking in pregnancy or parents psychopathology and children disorders such as depression and anti-social behavior. Research Training “Research Training: Psychiatric and Statistical Genetics” is a program headed by Dr. Michael Neale to support multi-disciplinary training in Psychiatric and Behavioral Genetics. Training usually consists of 4-5 years in duration for predoctoral and 2-3 years for postdoctoral students. Applicants are accepted from a broad array of disciplines, including medicine, psychiatry, psychology, biostatistics, neuro- science, molecular genetics and biology. Drs. Hermine Maes, Lindon Eaves, and Timothy York are co-investigators on the research training pro- gram, “Pre- & Post-doctoral Training Program in Cancer Control.” The overarching aim of this program is to provide high quality training in cancer control and generate a group of young scientists with unique research skills. Training occurs in the Massey Cancer Center and Virginia Commonwealth University including research in quality care/health services, cancer prevention interventions and dis- parity issues, genetic influences using large twin and family databases, and cancer-related pain and quality of life. 12
  15. 15. Major Accomplishments A number of great accomplishments we are proud to announce have occurred in the past year at VIPBG. Below is a list of some of those. If you are interested in acquiring more information on any of the following, please contact the researcher named at the end of each. Research Funding 1. The project, "Axis I and Axis II Psychiatry Disorders in Norwegian Twins" has been fund- ed by NIMH. This is a collaborative project with colleagues in Norway to conduct both pre- liminary and extensive analyses of the first interview-based assessed sample of twins for a complete set of Axis I and Axis II psychiatric disorders. (Dr. Kenneth Kendler) 2. The National Institute for Child Health and Development (NICH) ia awarding VIPBG $1.5M for a study of infant twins in Puerto Rico. The title of the grant is "Gene environment interplay in infant development” and represents a collaborative effort between VCU (Drs. Eaves and Silberg), Drs. Glorisa Canino and Vivian Febo at the University of Puerto Rico, and Dr. Helen Egger, a child psychiatrist at Duke University. The collaboration between UPR and VCU was originally established by VCU's president, Eugene Trani in 1999. (Dr. Judy Silberg) 3. VIPBG has received the four year renewal of the NIDA grant entitled "Twin Family Study of Drug Use, Abuse and Dependence." This project is funded for three years of extensive data analysis on this retrospective developmental study of detailed genetic and environmen- tal risk factors for substance use, abuse and dependence. (Dr. Kenneth Kendler) Research Accomplishments 1. Association signals have been observed with schizophrenia in two candidate genes, AKT1 and TRAR4. (Drs. Dawn Thiselton, Vladimir Vladimirov, and Brien Riley) 2. An additional area of research at VIPBG, currently unfunded, is in the philosophical and conceptual issues within psychiatry in general and psychiatric genetics more specifically. Dr. Kenneth Kendler has been writing a series of review papers trying to summarize and articulate the deeper conceptual issues in the field. (Dr. Kenneth Kendler) 3. A new cross-platform application was created called Iga972 for optimizing two-stage linkage disequalibrium studies. (Drs. Jaime Robles and Edwin van den Oord) 13
  16. 16. 4. Three small affective neuroscience pilots are in the works: One is being conducted with Dr. Scott Vrana looking at modulation of acoustic startle, as well as, response of facial musculature, pulse, and galvanic skin response to a series of affectively charges slides. The second project is being conducted in collaboration with Dr. Danny Pine and involves higher-tech computer-based assessments of a variety of affectively related constructs. The third is a project being conducted in collaboration with Dr. Paul Ekman which involves the analysis of facial response, emotional stimuli in separated identical and fra- ternal twin-pairs collected through the famous Minnesota Twin-Registry. (Dr. Kenneth Kendler) 5. A genome scan of 511 sibling pairs to identify susceptibility genes for alcohol depend- ence has been completed. (Dr. Carol Prescott) 6. Multivariate analyses have identified shared genetic risk between major depression, a range of anxiety disorders, and trait neuroticism. (Dr. Jack Hettema) 7. Publication in the American Journal of Psychiatry, a review article entitled "Toward a Philosophical Foundation of Psychiatry." This is the first comprehensive philosophical analysis of critical conceptual issues in the field of psychiatry published in a major psy- chiatric journal in the last decade. (Dr. Kenneth Kendler) 8. Analyses of symptoms of depression indicate that while assessment is good for those at high risk, it is poor for most of the general population. (Dr. Steven Aggen) 14
  17. 17. VIPBG Publications from July 2004 to June 2005 Aggen SH, Neale MC, Kendler KS. (2005) DSM Chen X, Dunham C, Kendler S, Wang X, O'Neill criteria for major depression: evaluating symptom FA, Walsh D, Kendler KS. (2004) Regulator of G- patterns using latent-trait item response models. protein signaling 4 (RGS4) gene is associated with Psychol Med 35(4):475-87 schizophrenia in Irish high density families. Am J Med Genet B Neuropsychiatr Genet 129(1):23-6. Agrawal A, Neale MC, Jacobson KC, Prescott CA, Kendler KS. (2005) Illicit drug use and Coventry WL, Gillespie NA, Heath AC, Martin NG. abuse/dependence: modeling of two-stage variables (2004) Perceived social support in a large communi- using the CCC approach. Addict Behav 30(5): 1043- ty sample--age and sex differences. Soc Psychiatry 8. Psychiatr Epidemiol 39(8):625-36. Agrawal A, Neale MC, Prescott CA, Kendler Crider A, Kremen WS, Xian H, Jacobson KC, KS. (2004) A twin study of early cannabis use and Waterman B, Eisen SA, Tsuang MT, Lyons MJ. subsequent use and abuse/dependence of other illic- (2004) Stability, consistency, and heritability of it drugs. Psychol Med 34(7): 1227-37. electrodermal response lability in middle-aged male twins. Psychophysiology 41(4):501-9. Agrawal A, Prescott CA, Kendler KS. (2004) Forms of cannabis and cocaine: a twin study. Am J Dawood, K., Kirk, K. M., Bailey, J. M., Andrews, P. Med Genet B Neuropsychiatr Genet 129(1):125-8. W., & Martin, N. G. (2005) Genetic and environ- mental influences on the frequency of orgasm Bartels M, van den Oord EJ, Hudziak JJ, Rietveld in women. Twin Research and Human Genetics 8: MJ, van Beijsterveldt CE, Boomsma DI. (2004) 27-33. Genetic and environmental mechanisms underlying stability and change in problem behaviors at ages 3, Eaves L, Silberg J, Foley D, Bulik C, Maes H, 7, 10, and 12. Dev Psychol 40(5):852-67. Erkanli A, Angold A, Costello EJ, Worthman C (2004) Genetic and environmental influences on the Breslau J, Kendler KS, Su M, Gaxiola-Aguilar S, relative timing of pubertal change. Twin Research Kessler RC. (2005) Lifetime risk and persistence of 7:471-81 psychiatric disorders across ethnic groups in the United States. Psychol Med 35(3):317-27. Eaves LJ, Silberg JL. (2005) Parent-child feed- back predicts sibling contrast: using twin studies to Caspi A, Moffitt TE, Cannon M, McClay J, Murray test theories of parent-offspring interaction in infant R, Harrington H, Taylor A, Arseneault L, Williams behavior. Twin Res Hum Genet 8(1):1-4. B, Braithwaite A, Poulton R, Craig IW. (2005) Moderation of the effect of adolescent-onset Fanous AH, Kendler KS. (2005) Genetic hetero- cannabis use on adult psychosis by a functional geneity, modifier genes, and quantitative pheno- polymorphism in the catechol-O-methyltransferase types in psychiatric illness: searching for a frame- gene: longitudinal evidence of a gene X environment work. Mol Psychiatry 10(1):6-13. interaction. Biol Psychiatry 57(10):1117-27. Foley DL, Rutter M, Angold A, Pickles A, Maes Chen X, Wang X, O'Neill AF, Walsh D, Kendler HM, Silberg JL, Eaves LJ. (2005) Making sense KS. (2004) Variants in the catechol-o-methyltrans- of informant disagreement for overanxious disorder. ferase (COMT) gene are associated with schizophre- J Anxiety Disord 19(2):193-210. nia in Irish high-density families. Mol Psychiatry 9(10):962-7. Foley DL, Pickles A, Maes HM, Silberg JL, Eaves LJ. (2004) Course and short-term outcomes Chen X, Wu B, Kendler KS. (2004) Association of separation anxiety disorder in a community sam- study of the Epac gene and tobacco smoking and ple of twins. J Am Acad Child Adolesc Psychiatry nicotine dependence. Am J Med Genet B 43(9):1107-14. Neuropsychiatr Genet 129(1):116-9. 15
  18. 18. Foley DL, Eaves LJ, Wormley B, Silberg JL, Kendler KS, Gardner CO, Jacobson KC, Maes HH, Kuhn J, Riley B. (2004) Childhood Neale MC, Prescott CA (2005) Genetic and envi- adversity, monoamine oxidase a genotype, and risk ronmental influences in illicit drug use and tobacco for conduct disorder. Arch Gen Psychiatry use across birth cohorts. Psychological Medicine 61(7):738-44. 35:1-8. Geithner CA, Thomis MA, Vanden Eynde B, Maes Kendler KS, Myers J, Prescott CA. (2005) Sex HH, Loos RJ, Peeters M, Claessens AL, Vlietinck R, differences in the relationship between social sup- Malina RM, Beunen GP. (2004) Growth in peak aer- port and risk for major depression: a longitudinal obic power during adolescence. Med Sci Sports study of opposite-sex twin pairs. Am J Psychiatry Exerc 36(9):1616-24. 162(2):250-6. Gillespie NA, Whitfield JB, Williams B, Heath AC, Kendler KS. (2005) Psychiatric genetics: a Martin NG. (2005) The relationship between stress- methodologic critique. Am J Psychiatry 162(1):3-11. ful life events, the serotonin transporter (5-HTTL- PR) genotype and major depression. Psychol Med Kendler KS, Kuhn JW, Prescott CA. (2004) 35(1):101-11. Childhood sexual abuse, stressful life events and risk for major depression in women. Psychol Med Gillespie NA, Evans DE, Wright MM, Martin NG. 34(8):1475-82. (2004) Genetic simplex modeling of Eysenck's dimensions of personality in a sample of young Australian twins. Twin Res 7(6):637-48. Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. (2005) The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry 62(2):182-9. Goin-Kochel, R.P. & Myers, B.J. (2005) Parental report of early autistic symptoms: Differences in ages of detection and frequencies of characteristics among three autism-spectrum disorders. Journal on Developmental Disabilities 11(2): 21-39. Haller DL, Miles DR, & Cropsey KL. (2004) Kendler KS, Aggen SH, Prescott CA, Smoking stage of change is associated with retention Jacobson KC, Neale MC. (2004) Level of family in a smoke-free residential drug treatment program dysfunction and genetic influences on smoking in for women. Addictive Behaviors 29: 1265-1270. women. Psychol Med 34(7):1263-9. Hettema JM, Prescott CA, Kendler KS. (2004) Kendler KS. (2004) Schizophrenia genetics and Genetic and environmental sources of covariation dysbindin: a corner turned? Am J Psychiatry between generalized anxiety disorder and neuroti- 161(9):1533-6. cism. Am J Psychiatry 161(9):1581-7. Kerns RT, Ravindranathan A, Hassan S, Cage MP, Kendler KS, Kuhn JW, Vittum J, Prescott York T, Sikela JM, Miles MF. (2005) Ethanol CA, Riley B. (2005) The interaction of stressful life responsive brain region expression networks: impli- events and a serotonin transporter polymorphism in cations for behavioral responses to acute ethanol in the prediction of episodes of major depression: a DBA/2J versus C57BL/6J mice. Journal of replication. Arch Gen Psychiatry62(5):529-35. Neuroscience 25(9):225-2266. Kendler KS. (2005) Toward a philosophical struc- Khan AA, Jacobson KC, Gardner CO, Prescott ture for psychiatry. Am J Psychiatry 162(3):433-40. CA, Kendler KS. (2005) Personality and comor- bidity of common psychiatric disorders. Br J Psychiatry 186:190-6. 16
  19. 19. Kjeldsen MJ, Corey LA, Solaas MH, Friis ML, Mowry BJ, Holmans PA, Pulver AE, Gejman PV, Harris JR, Kyvik KO, Christensen K, Pellock JM. Riley B, Williams NM, Laurent C, Schwab SG, (2005) Genetic factors in seizures: a population- Wildenauer DB, Bauche S, Owen MJ, Wormley B, based study of 47,626 US, Norwegian and Danish Sanders AR, Nestadt G, Liang KY, Duan J, Ribble twin pairs. Twin Res Hum Genet 8(2):138-47. R, Norton N, Soubigou S, Maier W, Ewen-White KR, DeMarchi N, Carpenter B, Walsh D, Williams Kooij, J. J. S., Buitenlaar, J. K., Van den Oord, E. H, Jay M, Albus M, Nertney DA, Papadimitriou G, J. C. G., Furer, J. W., Rijnders, C. A. Th., & O'Neill A, O'Donovan MC, Deleuze JF, Lerer FB, Hodiamont, P. P. G. (2005) Internal and external Dikeos D, Kendler KS, Mallet J, Silverman JM, validity of Attention-Deficit/Hyperactivity Disorder Crowe RR, Levinson DF. (2004) Multicenter linkage in a population-based sample of adults. study of schizophrenia loci on chromosome 22q. Psychological Medicine 35:817-827. Mol Psychiatry 9(8):784-95. Kubarych, TS, Aggen, SH, Hettema, JM, Nakken KO, Solaas MH, Kjeldsen MJ, Friis ML, Kendler, KS and Neale, MC (2005) Pellock JM, Corey LA. (2005) Which seizure-pre- Endorsement Frequencies and Factor Structure of cipitating factors do patients with epilepsy most fre- DSM-III-R and DSM-IV Generalized Anxiety quently report? Epilepsy Behav 6(1):85-9. Disorder Symptoms in Women: Implications for future research, classification, treatment and comor- Neale BM, Sullivan PF, Kendler KS. (2005) A bidity. International Journal of Methods in genome scan of neuroticism in nicotine dependent Psychiatric Research 14(2): 69-81. smokers. Am J Med Genet B Neuropsychiatr Genet 5;132(1):65-9. Maes HH, Sullivan PF, Bulik CM, Neale MC, Prescott CA, Eaves LJ, Kendler KS. (2004) A Perry BL, Miles DR, Burruss K, & Svikis DS. twin study of genetic and environmental influences (2004) Premenstrual symptomatology and alcohol n tobacco initiation, regular tobacco use and nico- consumption in college women. Journal of Studies tine dependence. Psychol Med 34(7):1251-61. on Alcohol 65(4), 464-8. Mazzeo SE, Slof RM, Tozzi F, Kendler KS, Bulik Prescott CA, Sullivan PF, Myers JM, Patterson CM. (2004) Characteristics of men with persistent DG, Devitt M, Halberstadt LJ, Walsh D, Kendler thinness. Obes Res 12(9):1367-9. KS. (2005) The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and valida- Mehta PD, Neale MC, Flay BR. (2004) Squeezing tion of diagnosis by interview and family history. interval change from ordinal panel data: latent Alcohol Clin Exp Res 29(3):417-29. growth curves with ordinal outcomes. Psychol Methods 9(3):301-33. Prescott CA, Caldwell CB, Carey G, Vogler GP, Trumbetta SL, Gottesman II. (2005) The Messias E, Kirkpatrick B, Bromet E, Ross D, Washington University Twin Study of alcoholism. Buchanan RW, Carpenter WT Jr, Tek C, Kendler Am J Med Genet B Neuropsychiatr Genet KS, Walsh D, Dollfus S. (2004) Summer birth and 134(1):48-55. deficit schizophrenia: a pooled analysis from 6 countries. Arch Gen Psychiatry 61(10):985-9. Robles JR, van den Oord EJ. (2004) lga972: a cross-platform application for optimizing LD studies Min HK, Moxley G, Neale MC, Schwartz LB. using a genetic algorithm. Bioinformatics (2004) Effect of sex and haplotype on plasma 20(17):3244-5. tryptase levels in healthy adults. J Allergy Clin Immunol 114(1):48-51. Schmitt JE, Prescott CA, Gardner CO, Neale MC, Kendler KS. (2005) The differential heritabil- Mogass M, York TP, Li L, Rujirabanjerd S, Shiang ity of regular tobacco use based on method of R. (2004) Genomewide analysis of gene expression administration. Twin Res Hum Genet 8(1):60-2. associated with Tcof1 in mouse neuroblastoma. Biochemical and Biophysical Research Seddon JM, Cote J, Page WF, Aggen SH, Neale Communications 325(1): 124-32. MC. (2005) The US twin study of age-related macu- lar degeneration: relative roles of genetic and envi- ronmental influences. Arch Ophthalmol 123(3):321-7. 17
  20. 20. Silberg, JL, Eaves, LJ. (2004) Analysing the con- Whitfield JB, Zhu G, Madden PA, Neale MC, Heath tributions of genes and parent-child interaction to AC, Martin NG. (2004) The genetics of alcohol childhood behavioural and emotional problems: a intake and of alcohol dependence. Alcohol Clin Exp model for the children of twins. Psychol Med Res 28(8):1153-60. 34(2):347-56. Yang S, Liu Y, Lin AA, Cavalli-Sforza LL, Zhao Z, Sullivan PF, Walsh D, O'Neill FA, Kendler KS. Su B. (2005) Adaptive evolution of MRGX2, a (2004) Evaluation of genetic substructure in the human sensory neuron specific gene involved in Irish Study of High-Density Schizophrenia Families. nociception. Gene 352:30-35 Psychiatr Genet 14(4):187-9. York TP, Miles MF, Kendler KS, Jackson-Cook C, Taneja PR, Pandya A, Foley DL, Nicely LV, Arnos Bowman ML, Eaves LJ. (2005) Epistatic and envi- KS. (2004) Attitudes of deaf individuals towards ronmental control of genome-wide gene expression. genetic testing. Am J Med Genet A 130(1):17-21. Twin Res Hum Genet 8(1):5-15. Thiselton DL, Webb BT, Neale BM, Ribble Zhang F, Zhao Z (2004) The influence of neigh- RC, O'Neill FA, Walsh D, Riley BP, Kendler KS. boring-nucleotide composition on single nucleotide (2004) No evidence for linkage or association of polymorphisms (SNPs) in the mouse genome and its neuregulin-1 (NRG1) with disease in the Irish study comparison with human SNPs. Genomics of high-density schizophrenia families (ISHDSF). 84:785-795 Mol Psychiatry 9(8):777-83. Zhang F, Zhao Z (2005) SNPNB: analyzing neigh- Thomis MA, Huygens W, Heuninckx S, Chagnon M, boring-nucleotide biases on single nucleotide poly- Maes HH, Claessens AL, Vlietinck R, Bouchard C, morphisms (SNPs). Bioinformatics 21:2517-2519. Beunen GP. (2004) Exploration of myostatin poly- morphisms and the angiotensin-converting enzyme insertion/deletion genotype in responses of human muscle to strength training. Eur J Appl Physiol 92(3):267-74. Tozzi F, Aggen SH, Neale BM, Anderson CB, Mazzeo SE, Neale MC, Bulik CM. (2004) The structure of perfectionism: a twin study. Behav Genet 34(5):483-94 van den Oord EJ. (2005) Controlling false discov- eries in candidate gene studies. Mol Psychiatry 10(3):230-1. Van den Oord, E. J. C. G. (2005).Testing for nor- mality by estimating johnson-curve population dis- tributions in MULTILOG. Applied Psychological Measurement 29:26-44. Van den Oord, E. J. C. G. (2005) Concordance rates. In B.Everitt & D. Howell (Eds.), (pp. 359). Chichester: Wiley. Van den Oord, E. J. C. G. (2005) Population stratification. In B.Everitt & D. Howell (Eds.),. Chichester: Wiley. 18
  21. 21. Active Research Grants 1. AD Williams 5. Bank of America Candidate Genes in Anxiety Disorders Parental Effects on Childhood Behavior in PI: Jack Hettema the Offspring of Twins (Hazel Thorpe Carmen The main purpose of this grant is to collect pilot and George Gay Carmen Trust Research) data for case-control genetic association analyses of PI: Judy Silberg candidate genes for anxiety disorders using patients This is a five-year study to analyze the non-genetic from the VCU psychiatry clinic. contributions of family background to risk to child- hood and adolescent depression and conduct dis- 2. AD Williams turbance. The unique power of the design lies in the Candidate Gene Studies of Anorexia Nervosa use of 2320 adult MZ and DZ twins with their PI: Brien Riley spouses and children ascertained from approxi- This project aims to initiate a pilot study of four mately 100,000 adults twins that will be ascer- genes with plausible biological hypotheses and posi- tained through the Mid-Atlantic Twin Registry. tional evidence from linkage studies for involvement in AN. This project will bring together the expertise 6. GlaxoSmithKline of two researchers who have not previously collabo- The Genetic Epidemiology of Psychiatric rated to develop VCU's first study of the molecular and Respiratory Phenotypes genetics of eating disorders. PI: Edwin van den Oord The aim of this project is to analyze complex large 3. AD Williams scale genetic epidemiological data with novel statis- Behavioral and Genetic Markers of Drug tical methods to produce new phenotype and genet- Addiction in an Adolescent Murine Model ic understanding of psychiatric and respiratory PI: Edwin van den Oord phenotypes. The progression towards addictive behavior has been described as involving the transition through 7. MCC several stages, beginning with the initial contact Identification of biomarkers for tobacco with the drug, followed by its regular use, which, in use: Normal variation and the control of turn, may finally result in substance dependence, or gene expression in MZ and DZ twins addiction. This project’s aim is to develop new high- PI: Tim York throughput phenotype measures of the addiction This project is designed to characterize genetic and proves plus risk factors such as impulsivity and like environmental sources of individual variation in those to genetic variation. gene expression profiles and evaluate the role of gene expression in mediating the impact of known 4. AD Williams risk factors for cancer, tobacco use, alcohol use, and Neighboring-Nucleotide Effects on Single obesity. Nucleotide Polymorphisms in the Mouse Genome 8. NARSAD PI: Zhongming Zhao Exploring the use of haplotype maps to In this project, the aim is to perform an initial detect susceptibility to schizophrenia analysis of the sequence context of SNPs in the PI: Edwin van den Oord mouse genome, to compare that to what is found in In this pilot study, the aim consists of a small hap- the human genome, and to further establish an effi- lotype map-based search to detect susceptibility cient system for the emerging data. It will be the genes for schizophrenia. first investigation of the SNP neighboring sequence context in the mouse genome. 19
  22. 22. 9. NARSAD 13. NARSAD Using Biological haplotypes to identify A Bioinformatics Approach to Studying susceptible genes for schizophrenia Schizophrenia Susceptibility Genes PI: Xiangning Chen PI: Zhongming Zhao In this project, the aim is in a new approach to iden- In this project, the aim is in a bioinformatics tify susceptible haplotypes for schizophrenia for the approach to first investigate the structures of candi- 5q22-31 linkage peak implicated in the genome scan date genes for schizophrenia and reveal the evolu- study of the Irish high density schizophrenia fami- tionary and functional changes. lies. The plan is to establish chromosome 5 specific hybrid haploid cell lines for a few families of the 14. NARSAD Irish subjects who were linked to the chromosome African Haplotype Studies of Schizophrenia linkage peak. Genotyping these individual chromo- Candidate Genes somes would enable us to obtain biological haplo- PI: Brien Riley types for these subjects. This project’s goal is to genotype sufficient single genetic markers in samples of 23 South African 10. NARSAD Bantu multiply-affected families (44 cases, N=129) Understanding Influences on Comorbidity and 113 Ethiopian Gurage cases plus parents and between ASB and MDD population controls (N=300) to identify haplotype PI: Kristen Jacobson block structure and assess evidence for association The main purpose of this project is to provide two of these genes with schizophrenia. We will follow up years of salary support for Dr. Jacobson during her positive evidence with sequencing to identify liabili- first few years as an Assistant Professor at the ty alleles or further genotyping as appropriate. Virginia Institute for Psychiatric and Behavioral Genetics in the Department of Psychiatry at the 15. NARSAD Medical College of Virginia of Virginia Investigation into a Candidate Susceptibility Commonwealth University (MCV/VCU). The objec- Locus for Schizophrenia on Xp11.23: a tive of this funding is use a genetically informative Microdeletion Segregating with X-linked design to examine the relationship between depres- Retinitis Pigmentosa in a Small Family sive symptoms and antisocial behavior. PI: Dawn Thiselton This project investigates the potential role of genes 11. NARSAD in schizophrenia, by 1) assessing a larger sample of Genetic Heterogeneity of Major Depression: familial cases and control individuals for deletions A Twin Study of Comorbidity overlapping this interval by STS screening of affect- PI: Carol Prescott ed males 2) conducting association analyses This project’s purpose is to fund the analysis of data between polymorphic variants in the deleted genes from the Virginia Adult Twin Study of Psychiatric (other than RP2) and disease 3) fully characterizing and Substance Use Disorders (VATSPSUD), a longi- the deleted genes as to genomic organization and tudinal study of more than 9000 twins and their transcriptional expression, to pave the way for parents. The goal of this project is to clarify the future studies into their function in the healthy and mechanisms underlying the comorbidity between schizophrenic brain. major depression (MD) and substance use disorders (SUD), including alcoholism, nicotine dependence, 16. NCI 93423 R25 and abuse of illicit substances (cannabis, cocaine, Pre- & Post-doctoral Training Program in stimulants, sedatives, opiates, and hallucinogens). Cancer Control Co-PI: Hermine Maes 12. NARSAD The overarching aim of this grant is to provide high Genetic and environmental pathways to quality training in cancer control and generate a young adult depression group of young scientists with unique research PI: Judy Silberg skills. We provide pre-doctoral training in the areas This grant is a study of young adult depression with of human genetics, biostatistics and psychology and a focus on the interaction of the 5HT (the serotonin pre- and post-doctoral training in a multidiscipli- transporter gene) with life events in predicting nary environment in behavioral science, behavioral depressive disorders in young adults. genetics and genetic epidemiology, health services research and palliative care. 20
  23. 23. 17. NIA 18384 R01 21. NIDA 14041 K12 A Longitudinal Twin Study of Cognition and Building Research Careers in Women's Aging Health PI subc: Lindon Eaves Scholars: Donna Miles, Kristen Jacobson The goal of this project is to conduct a longitudinal To increase the number of researchers, Virginia study to investigate ways in which genes and envi- Commonwealth University (VCU) has established an ronmental factors contribute to cognitive and adap- Interdisciplinary Women's Health Research (IWHR) tive aging, and how the relative influence of genes scholars program. The program will be based on a and environmental factors may change over time. strong research foundation in five areas relevant to We study the now middle-aged subjects from the women's health: substance abuse, psychiatric genet- Vietnam Era Twin Registry who we have been ics, reproductive health, cancer, and diseases associ- studying for the past 12 years. ated with aging. 18. NIAAA 11408 R01 22. NIDA 018673 R01 Irish Affected Sib Pair Study of Alcohol Psychometric and Genetic Assessments of Dependence Substance Use PI: Carol Prescott PI: Michael Neale The goal of this project is to detect the genomic This project aims to develop a series of novel location of susceptibility loci (SL) for alcoholism. approaches to phenotyping drug use and abuse. The Identifying the location of these genes is the first general scheme is to develop statistical models from step toward understanding their mechanism of theory, implement them in user friendly software, action and developing more effective treatments. To and examine their statistical properties. conduct this project, we have assembled a team of experts in clinical assessment, statistical genetics 23. NIMH 41953 R01 and molecular genetics. The Genetic Epidemiology of Schizophrenia in Ireland 19. NICHD 1R01HD049685-01 PI: Kenneth Kendler Gene environment interplay in infant In this third and final submission of this competitive development renewal, the goal is to critically extend the Irish PI: Judy Silberg Study of High-Density Schizohprenia Families This study’s aim is to extend the collaborative (ISHDSF) by collecting 500 proband-parent triads Puerto Rican Infant Twin Study ("PRINTS") for for family-based association studies. We have select- characterizing the interplay of genes and the family ed triads with a positive family history of psychosis environment in the development of behavioral prob- to reduce the rate of "phenocopies,” interview par- lems and psychopathology in preschool children. ents for their personal and family history of schizo- phrenia and schizophrenia spectrum illness so as to 20. NIDA 011287 R01 weight transmissions on the basis of the probability A Twin-Family Study of Drug Use, Abuse, that they contain a susceptibility allele and sample and Dependence all living and available relatives with schizophrenia PI: Kenneth Kendler or chronic schizoaffective disorder so as to weight, This competitive renewal is for 4 years of support in those triad-families, those that are more likely to for a series of detailed analyses of a unique twin be segregating a susceptibility allele in a given chro- data set, collection of which is now nearing comple- mosomal region. tion. We articulate 4 primary aims: 1. The Development of PSUD. 2. Contextual Factors 3. 24. NIMH 45712 R01 Heterogeneity 4. Sequella - Given an initial episode Familial Psychiatric Disorder & Attention in of PSU, we will explore what predicts further use Schizophrenia and the development of PSUD. Given the develop- PI subc: Kenneth Kendler ment of PSUD, we will clarify the factors that pre- This project’s goal is to replicate and extend impor- dict subsequent adult outcomes. tant findings from the first phase of this project indicating that there is a significantly increased familial aggregation of schizophrenia, schizophrenia spectrum personality disorders, and certain neu- rocognitive impairments in families of probands with childhood-onset schizophrenia compared to families of community control and adult-onset schizophrenia probands. 21
  24. 24. 25. NIMH 49492 R01 30. NIMH 65320 R01 The Epidemiology of Mood, Anxiety and Candidate Genes in Models of Adolescent Alcohol Disorders Health PI: Kenneth Kendler PI: Edwin van den Oord This project is a competitive renewal of a large- The overall aim of this project is to facilitate the scale, population based, longitudinal study of integration of measured genotypes in etiological female-female, male-male and male-female twin models of behavioral traits and psychiatric disor- pairs ascertained through the birth-certificate-based ders. Virginia Twin Registry. This grant supports further data analysis focused on understanding sex differ- 31. NIMH 65322 R01 ences in risk for mood disorders. Psychopathology: Models, Measurement and Classification 26. NIMH 49716 R01 PI: Michael Neale The Transmission of Vulnerability Factors This project’s aim is to develop and apply an array for Schizophrenia of methods to examine the empirical basis for the PI subc: Kenneth Kendler DSM nosological system and will develop more effi- This project is designed to test key hypotheses cient methods of analysis of the available data. regarding the transmission of measurable nonsymp- tomatic characteristics of individuals that reflect 32. NIMH 66277 K08 their predisposition to schizophrenia. Genetics of Fear and Anxiety Disorders PI: Jack Hettema 27. NIMH 60324 R01 This K08 Mentored Clinical Scientist Development The Genetic Epidemiology of Juvenile Award provides advanced research training in the Anxiety Disorders genetics of fear and anxiety disorders for Dr. John PI: Debra Foley M. Hettema, M.D., Ph.D. Specific research objec- The goal of this project is to analyze longitudinal tives examine self-report measures in anxiety disor- data already collected at personal interview with a ders, their relationship with personality traits like large population-based sample of juvenile twins and neuroticism, factors underlying comorbidity their parents to develop a detailed understanding of amongst the anxiety disorders and with depressive the developmental genetic epidemiology of the more disorders, and the relationship between experimen- common juvenile anxiety disorders (separation anxi- tal measures such as fear conditioning and self- ety, overanxious disorder, phobias). report fears. Dr. Hettema will also pilot an MRI study in identical twin pairs concordant and discor- 28. NIMH 068881 R01 dant for anxiety disorders. Multicenter Genetic Studies of Schizophrenia 33. NIMH 068484 K01 PI: Brien Riley Genetics of Vulnerability to Antisocial This is a revised four-year competing project for col- Behavior laborative linkage and association studies of schizo- PI: Kristen Jacobson phrenia in a multicenter sample of 860 informative This project is to fund Kristen Jacobson to gain pedigrees under a narrow diagnostic model. training and experience in the measurement and analysis of neuropsychological traits that may be 29. NIMH 62368 R01 related to vulnerability to antisocial behavior. The Parental Effects on Depression and candidate then applies this knowledge and experi- Disruptive Behavior in Children of Twins ence to the pilot data collection of neuropsychologi- PI: Judy Silberg cal traits and antisocial behavior from a sample of This is a study proposed to analyze the non-genetic 25 adult, male-male sibling pairs, under the guid- contributions of family background to risk to child- ance of Scott Vrana, Ph.D., a co-sponsor of the hood and adolescent depression and conduct distur- application at Virginia Commonwealth University. bance. 22
  25. 25. 34. NIMH 068521 R01 39. VTSF 8520012 Developmental Genetic Epidemiology of Virginia Youth Tobacco Project: Psychopathology Longitudinal Twin Study: Transitions to PI: Lindon Eaves Substance Abuse This five-year data analysis project is to yield a com- Co-PI: Donna Miles prehensive understanding of the developmental A component of the Virginia Commonwealth Youth interplay between genetic and social factors in the Tobacco Project, the purpose of this study is to trajectory of mood and behavioral disorders from address basic etiological questions regarding the early adolescence into young adulthood. transition from tobacco use to nicotine dependence and to examine the role of genetic and environmen- 35. NIMH 068643 R01 tal factors that contribute to the progression of Axis I & Axis II Psychiatric Disorders in tobacco use into nicotine dependence between ado- Norwegian Twins lescence and young adulthood. PI: Kenneth Kendler The goal of this study is to conduct detailed analysis 40. VTSF 8520012 of a population-based study of young adult twins in Virginia Youth Tobacco Project: Candidate Norway assessed using personal interviews for the Genes for Nicotine Dependence in Humans lifetime history of both major axis I psychiatric and PI: Kenneth S. Kendler, Sam Chen substance use disorders and all axis II disorders. The aim of the study is to identify and characterize the individual genes that determine vulnerability to 36. Pfizer nicotine dependence (ND) in humans. Discovery of Gender Differences in the Development of the specific genetic variants in humans which influ- MDD and Anxiety Disorders ence liability to ND has important implications for PI: Jack Hettema the reduction of the disease burden imposed by The present study proposes to examine the risk fac- tobacco use. tors for major depression and anxiety disorders and attempt to understand what predicts their high 41. VTSF comorbidity and increased prevalence in women. Genetic Etiology of Tobacco Initiation and Multivariate regression, discrete-time survival Nicotine Dependence analysis, and structural equation modeling will be PI: Kenneth Kendler utilized to understand the multistage process of the This project aims to clarify the role of genetic, family development of comorbidity between depression environmental, and individual-specific environmen- and anxiety. tal risk factors in the etiology of tobacco initiation and the progression to nicotine dependence. We aim 37. Thomas F. and Kate Miller Jeffress Memorial Trust to use molecular tools to identify individual genes Analysis of Genetic Variation in Human CpG that influence vulnerability to tobacco initiation and Islands the progression to nicotine dependence. PI: Zhongming Zhao This study aims to investigate the distribution and patterns of single nucleotide polymorphisms in CpG islands or in promoter-associated CpG islands in the human genome. 38. VA Linkage Disequilibrium Mapping of Susceptibility Genes for Schizophrenia PI: Brien Riley One of the goals of this study is to genotype microsatellite markers in the Irish Study of High Density Schizophrenia Families (ISHDSF) more densely in the region corresponding to the 95% con- fidence interval (CI) for linkage on chromosome 20p. 23
  26. 26. Research Initiatives for 2005-6 1. Initiation of the Clinical Outcome Study of Autism Genetics This study has been in the planning stages for several years. With key collaborators at several other centers and institutions, as well as some potential funding from a private foundation, we plan to begin site and sample recruitment during 2005- 2006. (Dr. Brien Riley) 2. Candidate-gene genetic association studies Using multivariate anxiety-depression phenotype with subjects selected for very high or very low genetic loading. (Dr. Jack Hettema) 3. Brain Imaging Brain imaging of twins concordant or dis- cordant for anxiety disorders. (Dr. Jack Hettema) 4. SIBS4 project The "SIBS4" project in collaboration with Drs. Mike Neale, Leena Peltonin and Jouko Lonnqvist. This is an ambitious study in the planning phases to try to assess a broad array of psychiatric, psy- chological, metabolic, and cardiovascular risk factors in a large sample of large sib- ships including parents, ascertained using population-based registries in Finland.(Dr. Kenneth Kendler) 5. Study of Genotype Environment Interactions In collaboration with Drs. Lindon Eaves, Kenneth Kendler and others, we are plan- ning a research initiative to do a large scale study of genotype environment interac- tions using our well characterized population-based twin registries. This project will begin by obtaining high quality DNA from blood samples and analyzed using a vari- ety of sophisticated methods including quite high quality environmental measures to try to clarify the interrelationship of specified genetic and environmental risk fac- tors in the etiology of psychiatric and substance use disorders. 25
  27. 27. Virginia Institute for Psychiatric and Behavioral Genetics Virginia Commonwealth University 800 E. Leigh Street, P.O. Box 980126 Richmond, VA 23298-0126 (804) 828-5360 Virginia Commonwealth University is an equal opportunity, affirmative action university providing access to education and employment without regard to age, race, color, national origin, gender, religion, sexual orientation, veteran’s status, political affiliation or disability.