T. Conrad Gilliam, Ph.D.


Research Description

My research focuses on the identification and characterization of heritable mutations that affect the nervous system. Research projects vary from genetic mapping of rare (Mendelian) disease mutations and characterization of their downstream consequences to the study of common heritable disorders using mouse models as well as genomic and bioinformatic approaches.

Study of rare genetic disorders has focused broadly on neurological disorders including the spinal muscular atrophies (motorneuron disease), different forms of epilepsy, and Wilson disease, a defect in copper transport that primarily affects the liver, but leads to neuropsychiatric symptoms when toxic levels of copper accumulate in the brain.

With new opportunities in genome science and bioinformatics, research has shifted toward the study of common heritable disorders including autism, bipolar disorder, anxiety disorders, schizophrenia, and Alzheimer’s disease. We use mouse models and disease-related ‘endophenotypes’ to inform the search for human disease genes. In the study of human anxiety disorders, we target an adaptive fear-related behavior - fear conditioning – that can be studied in humans and other model organisms.  We collaborate in these studies with Dr.Abraham Palmer (Human Genetics).  Similarly, in our study of schizophrenia we focus on bio-behavioral markers like working memory and executive functioning skills.  Our group and others have shown that heritable genetic variation in genes that alter dopamine metabolism at the synaptic nerve terminals affect performance on the specific cognitive tasks that are compromised in schizophrenia patients. In the study of autism, we have used gender and language-based endophenotypes as biomarkers to reduce the genetic complexity of the target phenotype. By focusing on genetically tractable disease sub-phenotypes, we hope to gain insight into the genetic architecture of complex human diseases.

Another approach we are pursuing is to shift the focus of gene mapping from individual gene mutations to the prediction of multi-gene patterns of inheritance. Genetic susceptibility to complex disorders arises from the fateful combination of heritable mutations distributed among multiple genes. Identification of these multigenic patterns of inheritance has proven elusive because the vast number of gene combinations that could lead to disease so dramatically exceeds the number of experimental observations possible in human studies. Assuming our genomes consist of ~ 25,000 genes, the number of possible combinations of 2, 3, and 10 genes increases exponentially from 109 to 1012 to 1030 respectively, in comparison to 103 to 104 observable ‘meiotic events’ in the largest human genetic studies. Thus, the ‘curse of dimensionality’ has thwarted progress in the study of common heritable disorders.

We are collaborating with experts in data-mining and network topology, systems biology, large-scale computing, and statistical genetics to develop new approaches to map the multi-gene determinants of common neuropsychiatric disorders. Our current approach uses technology developed by Rzhetsky and coworkers (Medicine and Human Genetics, beginning mid-2007) to first, extract molecular interaction networks from the electronic literature, and second, combine interaction data and genetic linkage data in a common probabilistic framework that allows us to survey disease-related inheritance across groups of interacting genes. By reducing possible gene-gene combinations to those documented in the literature or whole genome databases, we avoid the penalties of multiple-testing. We are collaborating to evaluate and benchmark the new approach, to develop models for the detection of gene-gene interactions, and ultimately, to use the new approach to identify multigenic patterns of inheritance that predict an individual’s susceptibility to major neuropsychiatric disorders.

Selected Publications

Rare Disease Studies: 

Gilliam TC, Brzustowicz LB, Castilla L, Lehner T, Penchaszadeh GK, Daniels RJ, Byth BC, Knowles J, Hislop JE, Shapira Y, Dubowitz V, Munsat TL, Ott J, and KE Davies (1990) Genetic homogeneity between acute and chronic forms of spinal muscular atrophy (SMA). 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.

S. Lutsenko, K Petrukhin, MJ Cooper, TC Gilliam, and J Kaplan. N-terminal domains of human Cu-transporting ATPases (the Wilson’s and Menkes disease proteins) bind Cu selectively in vivo and in vitro with stoichiometry of one Cu per metal-binding repeat. (1997). J. Biol Chem., 272 18939-18944.

Gavrilov DK, Shi X, Das K, Gilliam TC, and CH Wang. (1998). Differential SMN2 expression associated with SMA severity. Nature Genetics, 20; 230-231.

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.

Kalachikov S, Evgrafov O, Ross B, Winawer M,Barker-Cummings C, , Martinelli Boneschi F, Chang, C, Morozov P, Das K, Teplitskaya E, Yu A, Cayanis E, Penchazadeh G, Kottmann AH, Pedley TA, Hauser WA, Ottman R, and TC Gilliam (2002). Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features. Nature Genetics, 30, 335-341.

Huster, D, Finegold MJ, Morgan CT, Burkhead JL, Nixon R, Vanderwerf SM, Gilliam TC, and S. Lutsenko (2006). Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson Disease Gene) knockout mice. Am J Pathology. 168, 423-434.

Common Disease Studies: 

Gilliam TC, Freimer N, Kaufmann CA, Powchik P, Bassett A, Bengtsson O, and Wasmuth J. (1989). Deletion Mapping of DNA Markers to a Region of Chromosome 5 that Cosegregates with Schizophrenia. Genomics 5: 940-944.

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.

Aita VM, Liu J, Knowles JA, Terwilliger JD, Baltazar R, Grunn A, Yun O, Loth JE, Alexander JR, Lerer B, Endicott J, Wang Z, Penchazadeh GK, TC Gilliam, and M Baron. (1999). A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus. Am J Hum Genet. 64: 210-217.

Liu J, Juo SH, Holopainen P, Terwilliger JD, Tong X, Grunn A, Brito M, Mustalahti K, Green P, Gilliam TC, and J Partanen (2002). Genome wide linkage analysis of Finnish families with celiac disease supports the HLA DQ locus as the major genetic susceptibility factor. Am.J.Hum.Genet.70:51-59.

Yonan AL, Alarcón M, Cheng R, Magnusson PKE, Spence SJ, Grunn A, Palmer AA, Juo SH, Terwilliger JD, Liu J, Cantor RM, Geschwind DH, and TC Gilliam (2003). A Genomewide Screen of 345 Families for Autism Susceptibility Loci. Am. J. Hum Genet, 73, 886-977.

M Krauthammer, CA Kaufmann, TC Gilliam, and A Rzhetsky (2004). Molecular triangulation: Bridging linkage and molecular-network information for identifying candidate genes in Alzheimer’s disease. Proc. Nat. Acad, of Science (USA), 101; 15148-15153.

JL Stone, B Merriman, RM Cantor, AL Yonan, TC Gilliam, DH Geschwind, and SF Nelson (2004). Evidence for sex-specific risk alleles in autism spectrum disorder. Am J. Hum Genet 75: 2004.

GE Bruder, JG Keilp, H Xu, M Shikhman, E Schori, JM Gorman, and TC Gilliam (2005). Catechol-O-Methyltransfease (COMT) Genotypes and Working Memory: Associations with Differing Cognitive Operations. Biological Psychiatry, 58; 901-907.

Iossifov I, Zheng T, Baron M, Gilliam TC, and A Rzhetsky. Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network. Manuscript in Preparation.