T. Conrad Gilliam, Ph.D.

Key Words

  • Association Studies
  • Autism
  • Bipolar Disorder
  • Cardiovascular Disease
  • Celiac Disease
  • Epilepsy
  • Fear/Anxiety
  • Learning/ Memory
  • Linkage Studies
  • Neurobiology
  • Positional Cloning
  • Retinitis Pigmentosa
  • Schizophrenia
  • Wilson Disease


T. Conrad Gilliam, Ph.D.

One of the greatest challenges for the next generation of biomedical researchers will be to understand the genetic basis of common heritable illnesses. We are interested in a variety of approaches to identify gene variants that contribute to an individual’s predisposition to, or protection against, common heritable disorders. Much of our work focuses on neuropsychiatric disorders including schizophrenia, bipolar disorder, and autism, but extends to other multifactorial disorders such as celiac disease and cardiovascular disorders. Common themes throughout our studies include the use of genetically altered mice to inform genetic studies in humans and the use of whole genome gene expression and bioinformatics to elucidate pathogenetic pathways of disease.

Molecular genetics of fear and anxiety. A major weakness in the research methodology of modern psychiatry compared to neurology and other medical disciplines is the difficulty in developing good animal models. Since anxiety appears to be universal and evolutionarily conserved it is possible to model this behavior in experimental animals such as mice that are suitable for both physiological and genetic analysis. We are using a translational approach to study fear and anxiety through the study of fear conditioning in both mice and in humans. The study of fear conditioning offers two very significant advantages for molecular genetic analysis: the behavioral paradigms can be closely mimicked in human subjects, and the neurocircuits that underlie these behaviors are relatively well understood, and apparently highly conserved, in all vertebrates where they have been extensively studied. In the study of fear conditioning, therefore, we have an opportunity to integrate molecular biology and electrophysiology with information processing within a specific set of neural circuits. Through these studies, we hope to understand the molecular and physiological actions of specific genes related to fear in the context of the very neural circuits that subserve the fear learning and acquisition processes. These studies are prefaced upon pioneering studies from Dr. Eric Kandel’s laboratory in the Center for Neurobiology and Behavior at Columbia University. In collaboration with Dr. Kandel, we are studying genes whose over-expression or functional ablation in mice alters the animals’ response to fear conditioning, or modulates a fear-related behavior, will be tested for genetic variance related to fear conditioning, anxiety temperament, or anxiety disorder in humans. An essential feature of the study design is the translation of basic molecular biology in the mouse to human genetic analysis, and vice versa.

Working memory and schizophrenia. Schizophrenic patients consistently display impairment of working memory, a short term memory mechanism required for the execution of relatively simple everyday tasks. Working memory is used for the temporary storage and temporal integration of information; it permits us to perform appropriate behavioral tasks in response to environmental cues after the cues are removed. Continuing a conversation, driving a car, adding lists of numbers are examples of executive tasks that require an intact working memory. The prefrontal cortex (PFC) has been implicated in higher order cognitive functions as working memory by studies of both human and non-human primate lesions.

In collaboration with Dr. Kandel’s group, we are studying the molecular mechanism of working memory in the prefrontal cortex using a genetic approach. Genes that show specific expression in the prefrontal cortex will be isolated from the murine brain and their function with regard to working memory studied in transgenic mice. The promoters of the isolated genes will be used in order to study the function of candidate genes in the prefrontal cortex of transgenic mice. Whole genome gene expression and comparative genomic analyses will be used to piece together information about putative gene-gene interactions, co-regulation, and pathway information. Key genes identified by direct genetic manipulation and gene expression studies will form the basis for ‘candidate gene networks’. These genes will then be sequenced (coding and regulatory units) in control individuals who score at the top and bottom deciles for working memory tasks selected to mimic those used for the mouse studies. Next, the gene-variants will be evaluated in Schizophrenia patients who score poorly on working memory tasks.

Genetic study of autism. Autism is a highly heritable, profoundly debilitating disorder characterized by marked deficiencies in reciprocal communication and social interaction. Our lab works with a national organization, Cure Autism Now (CAN) to perform whole genome DNA marker analysis of 500 multiplex families with autism. This represents the largest study of its type in the world. A key component of this study is the collection of diverse phenotypic information from participating families. This information includes evaluation of language development, cognitive, biochemical, and behavioral assessments, and other assessments that appear to be co-inherited with autism. A major aim of these studies is to identify genetic linkage between DNA markers and ‘endophenotypes’ that are highly correlated with autism, but which may be determined by more easily detectable gene variants.

Genetic study of bipolar disorder. Bipolar affective disorder (BP), or manic depression, is a severe psychiatric disorder characterized by mania (BPI) or hypomania (BPII) alternating with periods of depression. BP is a major public health concern owing to lifetime prevalence of 0.5% to 1.5% and substantial morbidity and mortality. Briefly, our overall sample consists of 1,508 individuals (age 16 or over) in 57 extended pedigrees with high density of BP. We have for a number of years pursued evidence in our pedigrees for linkage to chromosome 21q.

Genetic study of celiac disease. Celiac disease (gluten-sensitive enteropathy) is a common multifactorial disorder resulting from intolerance to gluten, the major seed storage protein common to wheat, barley and rye. Part of an individual’s genetic susceptibility to celiac disease is due to inheritance of one or several HLA DQ alleles, however, the majority of genetic susceptibility arises from unknown gene variants. We are collaborating with clinical groups in Finland where we recently completed a whole genome DNA marker analysis of 60 families, each with at least two biopsy proven cases of celiac disease. . By a joint analysis of linkage and association, a LOD of 22 could be achieved for HLA DQ, assuming the penetrance of 0.6. Other hints of linkage throughout the genome are small, suggesting that other genetic factors may impart only small effects upon the disease. In collaboration with Dr. Wang (Functional Genomics), we are attempting to use whole genome gene expression to study the specific set of genes that are turned on or off in response to gluten induction in biopsy samples.

Genetic study of heart disease. In collaboration with Dr. Alfredo Morabia (Geneva, Switzerland), we are using genetic and genomic approaches to identify apolipoprotein E related pathway genes that contribute to cardiovascular disease. The study features prospective analysis of diet, exercise, and apoE status in over 5000 subjects studied over the course of several years.

Positional cloning of epilepsy genes. In collaborations with Drs. Ruth Ottman (Genetic Epidemiology; Columiba) and David Greenberg (CGC), we are using positional cloning strategies to systematically search genetically implicated segments of the genome for gene variants with major effect upon one of several manifestations of epilepsy.


Selected Publications

Brzustowicz LB., Lehner T, Castilla L, Penchaszadeh GK, Wilhelmsen K, Daniels R, Davies KE, Leppert M, Ziter F, Wood D, Dubowits V, Zerres K, Hausmanowa-Petrusewicz I, Ott J, Munsat T, and Gilliam TC (1990). Genetic mapping of chronic childhood-onset Spinal Muscular Atrophy to Chromosome 5q11.2-13.3. Nature 344: 540-541.

Gilliam TC, Brzustowicz LB, Castilla L, Lehner T, Penchaszadeh GK, Wilhelmsen K, Dubowitz V, Thomas N, Hislop J, Daniels R., Shapiro H, Munsat T, Ott J, and Davies K. (1990). Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 345: 823-825.

RE Tanzi, K Petrukhin, I Chernov, JL Pellequer, W. Wasco, B Ross, DM Romano, LM Brzustowicz, M Devoto, J Peppercorn, AI Bush, I Sternlieb, M Pirastu, JF Gusella, O Evgrafov, GK Penchaszadeh, B Honig, IS Edelman, MB Soares, IH Scheinberg, and TC Gilliam (1993). The Wilson disease gene is a copper transporting ATPase with homology to the Menkes Disease gene. Nature Genetics 5: 344-350.

Baron M, Freimer N, Risch N, Lerner B, Alexander JR, Straub R, Asokan S, Das K, Peterson A, Amos J, Endicott J, Ott J, and TC Gilliam. (1993) Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees. Nature Genetics 3: 49-55.

Banerjee P, Kleyn PW, Knowles JA, Lewis CA, Ross BM, Parano E, Kovats SG, Lee JL, Penchaszadeh GK, Ott J, Jacobson SG, and TC Gilliam. (1998). TULP1 mutation in two extended Dominican kindreds with autosomal recessive Retinitis pigmentosa. Nature Genetics, 18 177-179.

Larin D, Mekios C, Das K, Ross B, Yang A, and TC Gilliam. (1999). Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperon, HAH1p. J. Biol. Chem., 274: 28497-28504.

Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, Sharp J, Wheeler R, Kusumi K, Mole S, Liu W, Soares MB, Bonaldo MF, Hirasniemi Am de la Chapelle A, Gilliam TC, and AE Lehesjoki. (1999). The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nature Genetics, 23; 233-236.

TC Gilliam, E. Kandel, and T. Jessel. Genes and Behavior, in E Kandel, T Schwartz, T Jessel (2000). Principles of Neural Science 4th edition, McGraw-Hill, New York.

RE Straub, T Lehner, Y Luo, JE Loth, W Whao, L Sharpe, JR Alexander, K Das, R Simon, RR Fieve, B Lerer, J Endicott, J Ott, TC Gilliam, M Baron (1994). A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nature Genetics, 8, 291-296.

J Liu, DR Nyholt, E Parano, P Pavone, D Geschwind, C Lord, P Iversen, J Hoh, the AGRE Consortium, J Ott, and TC Gilliam. (2001). A Genome-wide Screen for Autism Susceptibility Loci. Am J Hum Genett 69:327-340.