T. Conrad Gilliam, Ph.D.
M.I.N.D. Institute Distinguished Lecturer Series: November 9, 2005
T. Conrad Gilliam, Ph.D., is professor and chair of Human Genetics at the University of Chicago. Dr. Gilliam has led international studies to map disease loci for all three forms of spinal muscular atrophy and an X-liked form of parkinsonism and to identify and characterize disease genes for Wilson disease, two forms of epilepsy, and retinitis pigmentosa. He currently investigates the genetic basis of common heritable disorders including: schizophrenia, autism, anxiety disorder, bipolar disorder, Alzheimer’s disease and cardiovascular disease. Dr. Gilliam received his undergraduate and graduate degrees in biochemistry from Clemson University and the University of Missouri. He did his post-doctoral training at the University of London and Harvard University mapping the genetic loci for cystic fibrosis and Huntington’s disease. In 1987 he was recruited to Columbia University where he was professor of genetics and development and director of the Columbia Genome Center until 2004.
Our research is generally focused upon identification of genetic determinants of common genetic disorders, with a particular emphasis on neurological and psychiatric genetic disease, including: schizophrenia, autism, anxiety disorder, bipolar disorder, Alzheimer’s disease and cardiovascular disease. We are interested in novel genomic and bioinformatic approaches to realize this goal, and when possible, we use mouse models to inform the search for human disease genes. In the study of human anxiety disorders, for example, we study a well-characterized fear-related phenotype, fear conditioning, in both humans and in mice. Short term selective breeding paradigms are used to generate phenotypic extremes for fear conditioning, to map quantitative trait loci, and to explore alterations in gene expression related to fear-conditioning. Trait-related genes identified from such studies are then genotyped in a random human population scored for attributes of fear conditioning to identify human trait alleles, which, in turn are genotyped in families segregating several different anxiety disorders. In all our studies the common goal is to (1) harness the vast stores of information embedded in the DNA sequence of scores of organisms including the human, (2) use animal models to inform the human studies, (3) explore heritable “endophenotypes” to focus and simplify the search for disease-related genetic determinants, and (4) integrate these various approaches in a standardized and systematic way to optimize the search for genetic determinants of common genetic disorders.
Genomic Approaches to Mapping Autism Spectrum Disorder Susceptibility Loci (4 pm)
One of the major challenges to biomedical research in the 21st century is to devise strategies to identify the multigenic transmission patterns that correlate with common heritable disorders. Modern gene mapping studies are remarkably efficient for tracking the single-gene mutations responsible for most rare, Mendelian disorders, but inept for tracking the multigene inheritance patterns that predispose individuals to the type common heritable disorders that constitute the bulk of today’s public health burden. It appears that single gene surveys of disease-related genetic variation are limited to the detection of weak genotype:phenotype correlations when the phenotype is a disease classification and the underlying genotype is multifactorial. We are exploring experimental and computational genomic strategies to predict biologically meaningful interactions between key autism candidate genes with the hope that a systematic survey of allelic variation across predicted “candidate gene networks” will lead to improved genotype:phenotype correlation, and insight into the genetic basis of autism spectrum disorder.
Genetic Mapping of Autism Spectrum Disorder Susceptibility Loci (6 pm)
Family and twin studies indicate that for a majority of individuals diagnosed with autism and related spectrum disorders (ASD), a significant genetic predisposition to disease results from the cumulative effects of heritable genetic variants affecting multiple genes. Similar to most complex genetic disorders, identification of disease-predisposing genetic variation has been fraught with difficulty, and the main genetic clues to disease etiology result from the characterization of disease-causing mutations in a small minority of cases. Results from an ongoing collaborative gene mapping study of the Autism Genetic Resource Exchange (AGRE) study sample will be discussed in the context of other genetic studies, and with a view to the future prospects of identifying genetic determinants of common heritable disorders like autism.