Genetic dissection of complex behaviors in mice and human; Functional genomics, Bipolar disorder, Autism
Genomics and complex trait analysis, Family-based studies of human disease, Bioinformatics.
Research in my laboratory involves identification of the genetic basis of behavioral and psychiatric disorders. To complement ongoing efforts in human psychiatric genetics, my laboratory embarked over the last several years on two main projects: a screen for novel behavioral mutations in the mouse, and the functional annotation of the mammalian genome using bioinformatics approaches. We are now less involved in studies of behavioral traits in the mouse and the main projects in the laboratory involve human genetic studies of neurodevelopmental and psychiatric disorders.
Genetics of Autism Spectrum Disorders:
In our genetic studies we take advantage of the Autism Genetics Resource Exchange (AGRE
), the largest publicly available collection of well-characterized families with multiple children with autism or associated disorders. To identify genes likely to contribute to ASD etiology, we used high-density genotype data from the AGRE collection and contrasted results to those obtained for healthy controls. Our results reveal tremendous complexity, i.e. a diverse mix of common and rare genetic variants, many of which act in pathways that form and maintain connections between neurons (Wang et al., 2009; Glessner et al., 2009; Bucan et al., 2009). In our recent studies of ASD, we collaborated with Dr. Robert Schultz at the on Center for Autism Research
(CAR). We combine whole genome sequence and exome SNP array analysis of subjects recruited and deep-phenotyped at CAR. These studies are focusing on the analysis of mutational load. Namely, instead of focusing on the role of a single gene, we investigate the role of a group of interacting genes; for example, genes known to have an essential role during development (Georgi et al., 2013), human disease genes among others. More work in a larger number of individuals will be required to determine which of the rare alleles, including copy number variants (CNVs), are indeed related to the ASDs and how they act to shape risk.
Genetics of Bipolar Disorder:
After many years of modeling behavioral phenotypes in the mouse, we are currently exploring the utility of established cell lines from patients with bipolar disorder. Recent studies have shown that, like the circadian pacemaker in the brain, cultured cells harbor self-sustaining and cell-autonomous circadian clocks that persist even during cell division. By monitoring circadian cycling of gene expression, we showed that the basic circadian machinery is not disrupted in fibroblasts of bipolar patients, although subtle inter-individual differences in the expression level of several core clock genes may lead to phenotypic differences (Yang et al., 2009).
Recently, we conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree (Georgi et al., 2014; Strauss et al., 2014). High-density SNP-array genotypes of 400 subjects were combined with whole genome sequence data for 30 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by a) resolving the phase in sequenced parent-child trios and b) by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified nominally significant linkage peaks. We report dozens of predicted deleterious genetic variants under each linkage peak, in addition to moderately frequent (in the Amish, but rare in 1000 Genomes) variants at the published bipolar and schizophrenia GWAS loci. In addition, we used high density SNP-array data to address the role of copy-number variation (CNV). Dissection of exonic and regulatory variants in genes identified additional credible candidate genes for functional studies and replication in population-based cohorts. The striking haplotype and locus heterogeneity we observed suggest that mechanistic studies on a large number of genes will be necessary to increase our knowledge about the etiology of bipolar illness and its relationship to other disorders. This project is a collaboration with Drs.Steven Paul
(Weill Cornell Medical College), David Craig
(TGen), Clinical for Special Children
and the Bipolar Sequencing Consortium
Kapfhamer D, Valledares O, Sun Y, Nolan P, Rux J, Arnold S, Veasey S, and Bucan, M: The role of Rab3A in regulation of rest/activity behavior and sleep. Nature Genetics 32: 290-5, 2002.
Yang, S., Van Dongen, H. P., Wang, K., Berrettini, W. and Bucan, M.: Assessment of circadian function in fibroblasts of patients with bipolar disorder. Mol Psychiatry 14(2): 143-55, 2009.
Wang, K., Li, M. and Bucan, M.: Pathway-Based Approaches for Analysis of Genomewide Association Studies. Am J Hum Genet 81(6), 2007.
Wang K, Li M, Hadley D, Liu R, Glessner J, Grant S, Hakonarson H, Bucan M: High-resolution copy number variation detection: application of an integrated hidden Markov Model on whole-genome SNP genotyping data. Genome Research 17: 1665-1674, 2007.
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., Imielinski, M., Frackelton, E. C., Reichert, J., Crawford, E. L., Munson, J., Sleiman, P. M., Chiavacci, R., Annaiah, K., Thomas, K., Hou, C., Glaberson, W., Flory, J., Otieno, F., Garris, M., Soorya, L., Klei, L., Piven, J., Meyer, K. J., Anagnostou, E., Sakurai, T., Game, R. M., Rudd, D. S., Zurawiecki, D., McDougle, C. J., Davis, L. K., Miller, J., Posey, D. J., Michaels, S., Kolevzon, A., Silverman, J. M., Bernier, R., Levy, S. E., Schultz, R. T., Dawson, G., Owley, T., McMahon, W. M., Wassink, T. H., Sweeney, J. A., Nurnberger, J. I., Coon, H., Sutcliffe, J. S., Minshew, N. J., Grant, S. F., Bucan, M., Cook, E. H., Buxbaum, J. D., Devlin, B., Schellenberg, G. D. and Hakonarson, H.: Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459(7246): 569-73, 2009.
Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J. T., Abrahams, B. S., Salyakina, D., Imielinski, M., Bradfield, J. P., Sleiman, P. M., Kim, C. E., Hou, C., Frackelton, E., Chiavacci, R., Takahashi, N., Sakurai, T., Rappaport, E., Lajonchere, C. M., Munson, J., Estes, A., Korvatska, O., Piven, J., Sonnenblick, L. I., Alvarez Retuerto, A. I., Herman, E. I., Dong, H., Hutman, T., Sigman, M., Ozonoff, S., Klin, A., Owley, T., Sweeney, J. A., Brune, C. W., Cantor, R. M., Bernier, R., Gilbert, J. R., Cuccaro, M. L., McMahon, W. M., Miller, J., State, M. W., Wassink, T. H., Coon, H., Levy, S. E., Schultz, R. T., Nurnberger, J. I., Haines, J. L., Sutcliffe, J. S., Cook, E. H., Minshew, N. J., Buxbaum, J. D., Dawson, G., Grant, S. F., Geschwind, D. H., Pericak-Vance, M. A., Schellenberg, G. D. and Hakonarson, H.: Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459(7246): 528-33, 2009.
Bucan, M., Abrahams, B. S., Wang, K., Glessner, J. T., Herman, E. I., Sonnenblick, L. I., Alvarez Retuerto, A. I., Imielinski, M., Hadley, D., Bradfield, J. P., Kim, C., Gidaya, N. B., Lindquist, I., Hutman, T., Sigman, M., Kustanovich, V., Lajonchere, C. M., Singleton, A., Kim, J., Wassink, T. H., McMahon, W. M., Owley, T., Sweeney, J. A., Coon, H., Nurnberger, J. I., Li, M., Cantor, R. M., Minshew, N. J., Sutcliffe, J. S., Cook, E. H., Dawson, G., Buxbaum, J. D., Grant, S. F., Schellenberg, G. D., Geschwind, D. H. and Hakonarson, H.: Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet 5(6): e1000536, 2009.
Liu, R., Hannenhalli, S. and Bucan, M.: Motifs and cis-regulatory modules mediating the expression of genes co-expressed in presynaptic neurons. Genome Biol 10(7): R72, 2009.
Bucan M, Eppig JT, Brown S: Mouse genomics programs and resources. Mammalian Genome 23 (9-10): 479-89, 2012.
Georgi, B., Wadhawan, S., Voight, B. and Bucan, M.: From Mouse to human: evolutionary genomics analysis of human orthologs of essential genes. PLOS Genetics Page: e1003484, 2013.
Georgi, B., Craig, D., Kember, R., Liu, W., Lindquist, I., Nasser, S., Egeland, J.A., Paul, S.M. and Bucan, M.: Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate. PLOS Genetics Page: e1004229, March 2014.
Strauss KA, Markx S, Georgi B, Paul SM, Jinks RN, Hoshi T, McDonald A, First MB, Liu W, Benkert AR, Heaps AD, Tian Y, Chakravarti A, Bucan M, Puffenberger EG: A population-based study of KCNH7p.Arg394His and bipolar spectrum disorder. Hum Mol Genet. 2014.
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Last updated: 08/14/2014
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