Stanford School of Medicine, 1977, MD

Research Interests

  • Psychiatric Genetics
  • Genetic Epidemiology
  • Schizophrenia
  • Twin Studies
  • Nosology of Psychiatric Disorders
  • Genetics of Psychiatric and Drug Abuse Disorders

Research Description

The major focus of my research is in the genetics of psychiatric and substance abuse disorders. Two major methodologies are used in this research. The first involves large population based twin samples. In these twins, we address the aggregate role of genetic and environmental factors. We seek to understand how these factors interact and correlate, and how, through development, the vulnerability to psychiatric illness and drug abuse is expressed. I have focused my work with twin samples from Virginia – in particular the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders – but also worked with twin samples from Norway, Sweden and Holland. My work has focused on a wide range of disorders including major depression, anxiety disorders, eating disorders, externalizing behaviors, alcoholism, and drug abuse. I have worked a lot toward understanding the genetic and environmental sources of comorbidity of psychiatric and substance use disorders. My work has recently focused on developmental models, models examining the structure of genetic and environmental risk factors for DSM disorders examined at the criteria level and the sources of cross-generational transmission of risk to drug abuse and criminality. I have a new grant that will contribute to the understanding of the causes major depressive disorder, the commonest psychiatric disorder and a leading cause of disability throughout the world. This research will improve our ability to diagnose depression from electronic health records, generate insights into the genetic architecture of depression, separating out specific from non-specific genetic risk factors, and will identify, from the analysis of exome sequencing data, genes that are involved in the etiology of the disorder. The research will provide new insights into disease, and well enable the development of more effective therapy.

The second major research strategy that I work with is molecular genetics. I am closely involved in molecular genetics studies of schizophrenia, alcoholism, major depression and nicotine dependence. We have used the strategies of linkage analysis, candidate gene association analysis, but most of the current focus now is on genome wide association and sequence data. I have recently been especially interested in polygene models as applied to GWAS data. I am the PI on an NIHM funded project that involves analysis of the CONVERGE study of major depression. We interviewed 12,000 cases with recurrent depression in China and controls and have low-pass sequence on all subjects. I am also PI on the VCU Alcohol Research Center that focused on gene networks that impact on response to alcohol across multiple invertebrate and vertebrate species including man. I am PI on a grant collecting a large sample of severely ill cases with Alcohol Use Disorder from the US which, together with other parallel efforts, will identify key risk genes for this disorder which can, in turn, improve our understanding of its biological causes and open up new therapeutic opportunities. Another project will collect samples from 10,000 South Korean women with recurrent major depressive disorder and 10,000 matched controls. All subjects will be genotyped and the location of genetic risk factors identified in a genome-wide association analysis. The cohort will also provide detailed information about the likely environmental causes of depression, and when combined with a similarly deeply phenotyped cohort from China, will form a uniquely powerful resource for the discovery of genes involved in recurrent major depressive disorder. In addition to this I am working on a project that seeks to clarify the etiology of key internalizing psychiatric disorders and closely associated functional medical disorders by applying a range of methods from epidemiology, genetic epidemiology and molecular genetics to the large informative population-based cohort in the Netherlands called Lifelines. We will attempt to understand the origins of the comorbidity between these disorders and how genes and environment contribute to their development. To meet these goals, we will apply advanced statistical methods to a unique set of epidemiological and molecular genetic resources. Finally, I have a large grant which will be collecting clinical information and DNA on 27,500 cases with bipolar disorder and 16,000 controls in the following sites in Taiwan, South Korea, Singapore, India, and Pakistan. Studying BP genetics in Asia is important to the world and the U.S., as Asia constitutes 57% of the world population, and many underrepresented groups in the U.S., such as Native Americans and Hispanics, descend in part from early Asian populations. The six countries in A-BIG-NET cover 40% of the Asian populations. This project will generate a BP-I genetic resource of 20,900 case and 7,200 controls with rich phenotypic information and genetic data from a novel technology combining low-pass whole genome (1xWGS) and deep exome sequencing (55xWES).

I have an active ongoing interest in psychiatric nosology. I have been heavily involved in the developments of DSM-III-R and DSM-IV and chaired the Scientific Review Committee for DSM-5. I am vice-chair for the APA steering committee to revise DSM-5. Finally, I have a developed interest in the interface between Psychiatry and Philosophy with several paper-writing projects on-going.


Selected Publications

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