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Stanley Institute for Cognitive Genomics

The Stanley Institute for Cognitive Genomics is dedicated to genetics and neuroscience research that will enhance our understanding of schizophrenia, bipolar disorder, major depression and other cognitive disorders. The goal is to improve the diagnosis and treatment of these disorders.

Work at the Stanley Institute for Cognitive Genomics at CSHL is funded by gifts from Theodore and Vada Stanley and grants from the
National Institute of Mental Health.

About

Stanley InstituteSchizophrenia, bipolar disorder and major recurrent depression are cognitive disorders that create an enormous burden on patients, their families and our health care system.

Because vulnerability to these disorders tends to run in families, genetics is a factor; however the specific genetic components involved and how they impact symptoms or treatments of these disorders has yet to be fully worked out.  With recent advances in genomic technologies, CSHL is now poised to unravel the genetic complexity of cognitive disorders. Simultaneously, advanced technologies in neuroscience are allowing CSHL researchers to understand how the brain assembles neural circuits to control behaviors and cognitive processes like attention and decision-making. At the CSHL Stanley Institute for Cognitive Genomics, these two approaches – genetics and neuroscience – are integrated to form a dual-strategy aimed at improving the diagnosis and treatment of schizophrenia, bipolar disorder, depression and other cognitive disorders.

News
History

Researchers at CSHL began working on the genetics of cognitive disorders in 2005 following a generous gift from Ted and Vada Stanley. Under the leadership of James Watson, this effort grew substantially in 2007 with a gift from the Stanley’s to establish the Stanley Institute for Cognitive Genomics. At that time, new DNA sequencing technologies, called “Next Generation Sequencing” were being developed. CSHL Professor and sequencing pioneer W. Richard McCombie was one of the first to apply this technology to study the genetics of cognitive disorders putting the Stanley Institute on the map.

With the goal of improving diagnosis and the potential for personalized therapy, the Stanley Center began applying state-of-the-art genomics technologies to identify genetic variants contributing to schizophrenia, bipolar disorder and major depression. Together with collaborators in the U.S., Scotland, Ireland, Pakistan and Australia, CSHL focused first on sequencing the complete genomes or protein coding regions of the genomes of families that had many members suffering from mental illness. One of the key findings demonstrated an overlap among genes contributing to schizophrenia and autism. CSHL also showed a link between the genes involved in the modification of chromatin structure and schizophrenia.

In 2014, with continuing support from Ted and Vada Stanley, the Stanley Institute incorporated the efforts of CSHL neuroscientists focused on understanding how brain circuits assemble and function. Like the genetics group, neuroscientists are developing and applying new technologies, including sophisticated brain mapping technologies and novel behavioral paradigms for studying decision making, attention and other processes. Stanley Institute neuroscientists are now studying the function of genes that have been implicated in cognitive disorders.

Selected Publications

Roberts, N. J., Norris, A. L., Petersen, G. M., Bondy, M. L., Brand, R., Gallinger, S., Kurtz, R. C., Olson, S. H., Rustgi, A. K., Schwartz, A. G., Stoffel, E. M., Syngal, S., Zogopoulos, G., Ali, S. Z., Axilbund, J., Chaffee, K. G., Chen, Y. C., Cote, M. L., Childs, E. J., Douville, C., Goes, F. S., Herman, J. M., Iacobuzio-Donahue, C., Kramer, M., Makohon-Moore, A., McCombie, R. W., McMahon, K. W., Niknafs, N., Parla, J., Pirooznia, M., Potash, J. B., Rhim, A. D., Smith, A. L., Wang, Y., Wolfgang, C. L., Wood, L. D., Zandi, P. P., Goggins, M., Karchin, R., Eshleman, J. R., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Hruban, R. H. , Klein, A. P. (2016) Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov, 6(2) pp. 166-175.

Jiménez-Barrón, Laura T., O'Rawe, Jason A., Wu, Yiyang, Yoon, Margaret, Fang, Han, Iossifov, Ivan , Lyon, Gholson J. (2015) Genome-wide variant analysis of simplex autism families with an integrative clinical-bioinformatics pipeline. Molecular Case Studies, 1(1)

Guo, Y., Ding, X., Shen, Y., Lyon, G. J. , Wang, K. (2015) SeqMule: automated pipeline for analysis of human exome/genome sequencing data. Sci Rep, 5 pp. 14283.

Regan, Michael C., Romero-Hernandez, Annabel , Furukawa, Hiro (2015) A structural biology perspective on NMDA receptor pharmacology and function. Current Opinion in Structural Biology, 33 pp. 68-75.

Doerfel, Max , Lyon, Gholson J. (2015) The biological functions of Naa10 – from amino-terminal acetylation to human disease. Gene, 567(2) pp. 103-131.

Krishnan, K., Wang, B. S., Lu, J., Wang, L., Maffei, A., Cang, J. , Huang, Z. J. (2015) MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc Natl Acad Sci U S A, 112(34) pp. E4782-E4791.

Karakas, Erkan, Regan, Michael C. , Furukawa, Hiro (2015) Emerging structural insights into the function of ionotropic glutamate receptors. Trends in Biochemical Sciences, 40(6) pp. 328-337.

Lazarus, M. S., Krishnan, K. , Huang, Z. J. (2015) GAD67 Deficiency in Parvalbumin Interneurons Produces Deficits in Inhibitory Transmission and Network Disinhibition in Mouse Prefrontal Cortex. Cerebral Cortex, 25(5) pp. 1290-1296.

Delevich, K., Tucciarone, J., Huang, Z. J. , Li, B. (2015) The Mediodorsal Thalamus Drives Feedforward Inhibition in the Anterior Cingulate Cortex via Parvalbumin Interneurons. Journal of Neuroscience , 35(14) pp. 5743-53.

Hirschtritt, M. E., Lee, P. C., Pauls, D. L., Dion, Y., Grados, M. A., Illmann, C., King, R. A., Sandor, P., McMahon, W. M., Lyon, G. J., Cath, D. C., Kurlan, R., Robertson, M. M., Osiecki, L., Scharf, J. M. , Mathews, C. A. (2015) Lifetime Prevalence, Age of Risk, and Genetic Relationships of Comorbid Psychiatric Disorders in Tourette Syndrome. JAMA Psychiatry, 72(4) pp. 325.

Penzo, M. A., Robert, V., Tucciarone, J., De Bundel, D., Wang, M., Van Aelst, L., Darvas, M., Parada, L. F., Palmiter, R. D., He, M., Huang, Z. J. , Li, B. (2015) The paraventricular thalamus controls a central amygdala fear circuit. Nature, 519(7544) pp. 455-459.

Verleyen, W., Ballouz, S. , Gillis, J. (2015) Measuring the wisdom of the crowds in network-based gene function inference. Bioinformatics, 31(5) pp. 745-752.

Ballouz, S., Verleyen, W. , Gillis, J. (2015) Guidance for RNA-seq co-expression network construction and analysis: safety in numbers. Bioinformatics,

Perova, Z., Delevich, K. , Li, B. (2015) Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress. Journal of Neuroscience, 35(7) pp. 3201-3206.

Ahrens, S., Jaramillo, S., Yu, K., Ghosh, S., Hwang, G., Paik, R., Lai, C., He, M., Huang, Z. J. , Li, B. (2015) ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection. Nature Neuroscience, 18 pp. 104-111.

He, M., Person, T. N., Hebbring, S. J., Heinzen, E., Ye, Z., Schrodi, S. J., McPherson, E. W., Lin, S. M., Peissig, P. L., Brilliant, M. H., O'Rawe, J., Robison, R. J., Lyon, G. J. , Wang, K. (2015) SeqHBase: a big data toolset for family based sequencing data analysis. Journal of Medical Genetics, 52(4) pp. 282-288.

O'Rawe, J. A., Ferson, S. , Lyon, G. J. (2015) Accounting for uncertainty in DNA sequencing data. Trends Genet, 31(2) pp. 61-68.

Kim, Yongsoo, Venkataraju, Kannan Umadevi, Pradhan, Kith, Mende, Carolin, Taranda, Julian, Turaga, Srinivas C, Arganda-Carreras, Ignacio, Ng, Lydia, Hawrylycz, Michael J, Rockland, Kathleen S, Seung, H.  Sebastian , Osten, Pavel (2015) Mapping Social Behavior-Induced Brain Activation at Cellular Resolution in the Mouse. Cell Reports, 10(2) pp. 292-305.

O'Rawe, Jason, Wu, Yiyang, Rope, Alan, Jimenez Barron, Laura, Swensen, Jeffrey J., Fang, Han, Mittelman, David, Highnam, Gareth, Robison, Reid J., Yang, Edward, Wang, Kai , Lyon, Gholson (2015) A variant in TAF1 is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features. bioRxiv,

Myklebust, L. M., Van Damme, P., Stove, S. I., Dorfel, M. J., Abboud, A., Kalvik, T. V., Grauffel, C., Jonckheere, V., Wu, Y., Swensen, J., Kaasa, H., Liszczak, G., Marmorstein, R., Reuter, N., Lyon, G. J., Gevaert, K. , Arnesen, T. (2014) Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Human Molecular Genetics, 24(7) pp. 1956-1976.

Iossifov, I., O'Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., Smith, J. D., Paeper, B., Nickerson, D. A., Dea, J., Dong, S., Gonzalez, L. E., Mandell, J. D., Mane, S. M., Murtha, M. T., Sullivan, C. A., Walker, M. F., Waqar, Z., Wei, L., Willsey, A. J., Yamrom, B., Lee, Y. H., Grabowska, E., Dalkic, E., Wang, Z., Marks, S., Andrews, P., Leotta, A., Kendall, J., Hakker, I., Rosenbaum, J., Ma, B., Rodgers, L., Troge, J., Narzisi, G., Yoon, S., Schatz, M. C., Ye, K., McCombie, W. R., Shendure, J., Eichler, E. E., State, M. W. , Wigler, M. (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature, 515(7526) pp. 216-221.

Pirooznia, M., Kramer, M., Parla, J., Goes, F. S., Potash, J. B., McCombie, W. R. , Zandi, P. P. (2014) Validation and assessment of variant calling pipelines for next-generation sequencing. Human Genomics, 8

McCarthy, S. E., Gillis, J., Kramer, M., Lihm, J., Yoon, S., Berstein, Y., Mistry, M., Pavlidis, P., Solomon, R., Ghiban, E., Antoniou, E., Kelleher, E., O'Brien, C., Donohoe, G., Gill, M., Morris, D. W., McCombie, W. R. , Corvin, A. (2014) De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Molecular Psychiatry, 19(6) pp. 652-658.

Thomson, P. A., Parla, J. S., McRae, A. F., Kramer, M., Ramakrishnan, K., Yao, J., Soares, D. C., McCarthy, S., Morris, S. W., Cardone, L., Cass, S., Ghiban, E., Hennah, W., Evans, K. L., Rebolini, D., Millar, J. K., Harris, S. E., Starr, J. M., MacIntyre, D. J., McIntosh, A. M., Watson, J. D., Deary, I. J., Visscher, P. M., Blackwood, D. H., McCombie, W. R. , Porteous, D. J. (2014) 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: Analysis for association with psychiatric disorder and cognitive traits. Molecular Psychiatry, 19(6) pp. 668-675.

Karakas, E. , Furukawa, H. (2014) Crystal structure of a heterotetrameric NMDA receptor ion channel. Science, 344(6187) pp. 992-7.

Wang, M., Perova, Z., Arenkiel, B. R. , Li, B. (2014) Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress. Journal of Neuroscience, 34(22) pp. 7485-92.

Li, W., Wu, J., Kim, S. Y., Zhao, M., Hearn, S. A., Zhang, M. Q., Meistrich, M. L. , Mills, A. A. (2014) Chd5 orchestrates chromatin remodelling during sperm development. Nature Communications, 5 pp. 3812.

Penzo, M. A., Robert, V. , Li, B. (2014) Fear Conditioning Potentiates Synaptic Transmission onto Long-Range Projection Neurons in the Lateral Subdivision of Central Amygdala. Journal of Neuroscience, 34(7) pp. 2432-7.

Gillis, J., Ballouz, S. , Pavlidis, P. (2014) Bias tradeoffs in the creation and analysis of protein-protein interaction networks. Journal of Proteomics, 100 pp. 44-54.

Jespersen, A., Tajima, N., Fernandez-Cuervo, G., Garnier-Amblard, E. C. , Furukawa, H. (2014) Structural Insights into Competitive Antagonism in NMDA Receptors. Neuron, 81(2) pp. 366-78.

Yao, J., Zhang, K. X., Kramer, M., Pellegrini, M. , McCombie, W. R. (2014) FamAnn: an automated variant annotation pipeline to facilitate target discovery for family-based sequencing studies. Bioinformatics,

Fang, Han, Wu, Yiyang, Narzisi, G., O'Rawe, Jason, Jimenez Barron, Laura, Rosenbaum, J., Ronemus, M., Iossifov, I., Schatz, M. C. , Lyon, Gholson J. (2014) Reducing INDEL calling errors in whole genome and exome sequencing data. Genome Med, 6(10) pp. 89.

Paul, S., Kuo, A., Schalch, T., Vogel, H., Joshua-Tor, L., McCombie, W. R., Gozani, O., Hammell, M. , Mills, A. A. (2013) Chd5 Requires PHD-Mediated Histone 3 Binding for Tumor Suppression. Cell Reports, 3(1) pp. 92-102.

Mistry, M., Gillis, J. , Pavlidis, P. (2013) Genome-wide expression profiling of schizophrenia using a large combined cohort. Molecular Psychiatry, 18(2) pp. 215-225.

Ragan, T., Kadiri, L. R., Venkataraju, K. U., Bahlmann, K., Sutin, J., Taranda, J., Arganda-Carreras, I., Kim, Y., Seung, H. S. , Osten, P. (2012) Serial two-photon tomography for automated ex vivo mouse brain imaging. Nature Methods, 9(3) pp. 255-258.

Horev, G., Ellegood, J., Lerch, J. P., Son, Y. E., Muthuswamy, L., Vogel, H., Krieger, A. M., Buja, A., Henkelman, R. M., Wigler, M. H. , Mills, A. A. (2011) Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proceedings of the National Academy of Sciences of the United States of America, 108(41) pp. 17076-81.

Parla, J. S., Iossifov, I., Grabill, I., Spector, M. S., Kramer, M. , McCombie, W. R. (2011) A comparative analysis of exome capture. Genome Biology, 12(9) pp. R97.

Malhotra, D., McCarthy, S., Michaelson, J. J., Vacic, V., Burdick, K. E., Yoon, S., Cichon, S., Corvin, A., Gary, S., Gershon, E. S., Gill, M., Karayiorgou, M., Kelsoe, J. R., Krastoshevsky, O., Krause, V., Leibenluft, E., Levy, D. L., Makarov, V., Bhandari, A., Malhotra, A. K., McMahon, F. J., Nöthen, M. M., Potash, J. B., Rietschel, M., Schulze, T. G. , Sebat, J. (2011) High frequencies of de novo cnvs in bipolar disorder and schizophrenia. Neuron, 72(6) pp. 951-963.

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