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1. Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease

Author

Huang, Yong, Wang, Minghui, Ni, Haofei, Zhang, Jinglong, Li, Aiqun, Hu, Bin, Junqueira Alves, Chrystian, Wahane, Shalaka, Rios de Anda, Mitzy, Ho, Lap, Li, Yuhuan, Kang, Sangjo, Neff, Ryan, Kostic, Ana, Buxbaum, Joseph D., Crary, John F., Brennand, Kristen J., Zhang, Bin, Zou, Hongyan, and Friedel, Roland H.

Published
2024
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2. The functional and evolutionary impacts of human-specific deletions in conserved elements

Author

Xue, James R, Mackay-Smith, Ava, Mouri, Kousuke, Garcia, Meilin Fernandez, Dong, Michael X, Akers, Jared F, Noble, Mark, Li, Xue, Lindblad-Toh, Kerstin, Karlsson, Elinor K, Noonan, James P, Capellini, Terence D, Brennand, Kristen J, Tewhey, Ryan, Sabeti, Pardis C, Reilly, Steven K, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Genereux, Diane P, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Keough, Kathleen C, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Lind, Abigail, Marinescu, Voichita D, Marques-Bonet, Tomas, Mason, Victor C, Meadows, Jennifer RS, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Ryder, Oliver A, Schäffer, Daniel E, Serres, Aitor, Shapiro, Beth, Smit, Arian FA, Springer, Mark, Srinivasan, Chaitanya, and Steiner, Cynthia

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Neurosciences, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Neurological, Humans, Conserved Sequence, Evolution, Molecular, Genome, Genomics, RNA-Binding Proteins, Sequence Deletion, Brain, Gene Expression Regulation, Developmental, Zoonomia Consortium†, General Science & Technology
Abstract

Conserved genomic sequences disrupted in humans may underlie uniquely human phenotypic traits. We identified and characterized 10,032 human-specific conserved deletions (hCONDELs). These short (average 2.56 base pairs) deletions are enriched for human brain functions across genetic, epigenomic, and transcriptomic datasets. Using massively parallel reporter assays in six cell types, we discovered 800 hCONDELs conferring significant differences in regulatory activity, half of which enhance rather than disrupt regulatory function. We highlight several hCONDELs with putative human-specific effects on brain development, including HDAC5, CPEB4, and PPP2CA. Reverting an hCONDEL to the ancestral sequence alters the expression of LOXL2 and developmental genes involved in myelination and synaptic function. Our data provide a rich resource to investigate the evolutionary mechanisms driving new traits in humans and other species.

Published
2023

4. Common Alleles: Next Steps in the Study of Common Variants

Author

Won, Hyejung, primary, Wray, Naomi R., additional, Binder, Elisabeth B., additional, Brennand, Kristen J., additional, Franke, Barbara, additional, Gandal, Michael J., additional, Stevens, Beth, additional, Südhof, Thomas, additional, and Ziller, Michael J., additional

Published
2023
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8. Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies

Author

Mishra, Himanshu K, Ying, Noelle M, Luis, Angelica, Wei, Heather, Nguyen, Metta, Nakhla, Timothy, Vandenburgh, Sara, Alda, Martin, Berrettini, Wade H, Brennand, Kristen J, Calabrese, Joseph R, Coryell, William H, Frye, Mark A, Gage, Fred H, Gershon, Elliot S, McInnis, Melvin G, Nievergelt, Caroline M, Nurnberger, John I, Shilling, Paul D, Oedegaard, Ketil J, Zandi, Peter P, Kelsoe, John R, Welsh, David K, and McCarthy, Michael J

Subjects
Depression, Sleep Research, Bipolar Disorder, Mental Health, Serious Mental Illness, Neurosciences, Brain Disorders, Mental health, Circadian Rhythm, Humans, Lithium, Lithium Compounds, Neurons, Pharmacogenomics of Bipolar Disorder Study, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Published
2021

9. Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

Author

Webb, Bryn D, Evans, Anthony, Naidich, Thomas P, Bird, Lynne M, Parikh, Sumit, Garcia, Meilin Fernandez, Henderson, Lindsay B, Millan, Francisca, Si, Yue, Brennand, Kristen J, Hung, Peter, Rucker, Janet C, Wheeler, Patricia G, and Schadt, Eric E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Brain Disorders, Rare Diseases, Neurosciences, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, Neurological, Adult, Ataxia, Child, Child, Preschool, Female, Haploinsufficiency, Humans, Magnetic Resonance Imaging, Male, Muscle Hypotonia, Mutation, Missense, Retrospective Studies, Syndrome, Transcription Factor Brn-3A, Tremor, United States, Exome Sequencing, Young Adult, ataxia, intention tremor, paroxysmal tonic upgaze, POU4F1, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.

Published
2021

10. Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder

Author

Mishra, Himanshu K., Wei, Heather, Rohr, Kayla E., Ko, Insu, Nievergelt, Caroline M., Maihofer, Adam X., Shilling, Paul D., Alda, Martin, Berrettini, Wade H., Brennand, Kristen J., Calabrese, Joseph R., Coryell, William H., Frye, Mark, Gage, Fred, Gershon, Elliot, McInnis, Melvin G., Nurnberger, John, Oedegaard, Ketil J., Zandi, Peter P., Kelsoe, John R., and McCarthy, Michael J.

Published
2023
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11. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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12. Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

Author

Seah, Carina, Breen, Michael S., Rusielewicz, Tom, Bader, Heather N., Xu, Changxin, Hunter, Christopher J., McCarthy, Barry, Deans, P. J. Michael, Chattopadhyay, Mitali, Goldberg, Jordan, Desarnaud, Frank, Makotkine, Iouri, Flory, Janine D., Bierer, Linda M., Staniskyte, Migle, Noggle, Scott A., Huckins, Laura M., Paull, Daniel, Brennand, Kristen J., and Yehuda, Rachel

Published
2022
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14. The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease

Author

Bendl, Jaroslav, Hauberg, Mads E., Girdhar, Kiran, Im, Eunju, Vicari, James M., Rahman, Samir, Fernando, Michael B., Townsley, Kayla G., Dong, Pengfei, Misir, Ruth, Kleopoulos, Steven P., Reach, Sarah M., Apontes, Pasha, Zeng, Biao, Zhang, Wen, Voloudakis, Georgios, Brennand, Kristen J., Nixon, Ralph A., Haroutunian, Vahram, Hoffman, Gabriel E., Fullard, John F., and Roussos, Panos

Published
2022
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15. Convergent coexpression of autism-associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies

Author

Liao, Calwing, Moyses-Oliveira, Mariana, De Esch, Celine E.F., Bhavsar, Riya, Nuttle, Xander, Li, Aiqun, Yu, Alex, Burt, Nicholas D., Erdin, Serkan, Fu, Jack M., Wang, Minghui, Morley, Theodore, Han, Lide, Dion, Patrick A., Rouleau, Guy A., Zhang, Bin, Brennand, Kristen J., Talkowski, Michael E., and Ruderfer, Douglas M.

Published
2023
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17. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder

Author

McCarthy, Michael J, Wei, Heather, Nievergelt, Caroline M, Stautland, Andrea, Maihofer, Adam X, Welsh, David K, Shilling, Paul, Alda, Martin, Alliey-Rodriguez, Ney, Anand, Amit, Andreasson, Ole A, Balaraman, Yokesh, Berrettini, Wade H, Bertram, Holli, Brennand, Kristen J, Calabrese, Joseph R, Calkin, Cynthia V, Claasen, Ana, Conroy, Clara, Coryell, William H, Craig, David W, D’Arcangelo, Nicole, Demodena, Anna, Djurovic, Srdjan, Feeder, Scott, Fisher, Carrie, Frazier, Nicole, Frye, Mark A, Gage, Fred H, Gao, Keming, Garnham, Julie, Gershon, Elliot S, Glazer, Kara, Goes, Fernando, Goto, Toyomi, Harrington, Gloria, Jakobsen, Petter, Kamali, Masoud, Karberg, Elizabeth, Kelly, Marisa, Leckband, Susan G, Lohoff, Falk, McInnis, Melvin G, Mondimore, Francis, Morken, Gunnar, Nurnberger, John I, Obral, Sarah, Oedegaard, Ketil J, Ortiz, Abigail, Ritchey, Megan, Ryan, Kelly, Schinagle, Martha, Schoeyen, Helle, Schwebel, Candice, Shaw, Martha, Shekhtman, Tatyana, Slaney, Claire, Stapp, Emma, Szelinger, Szabolcs, Tarwater, Bruce, Zandi, Peter P, and Kelsoe, John R

Subjects
Bipolar Disorder, Depression, Sleep Research, Serious Mental Illness, Brain Disorders, Clinical Research, Mental Health, Mental health, Adult, Animals, Antimanic Agents, Cells, Cultured, Circadian Rhythm, Fibroblasts, Genotyping Techniques, Humans, Inositol 1, 4, 5-Trisphosphate Receptors, Lithium Compounds, Luminescent Measurements, Mice, NIH 3T3 Cells, Period Circadian Proteins, Polymorphism, Single Nucleotide, Prospective Studies, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Published
2019

18. Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels

Author

Nudell, Victoria, Wei, Heather, Nievergelt, Caroline, Maihofer, Adam X, Shilling, Paul, Alda, Martin, Berrettini, Wade H, Brennand, Kristen J, Calabrese, Joseph R, Coryell, William H, Covault, Jonathan M, Frye, Mark A, Gage, Fred, Gershon, Elliot, McInnis, Melvin G, Nurnberger, John I, Oedegaard, Ketil J, Shekhtman, Tatyana, Zandi, Peter P, Kelsoe, John R, and McCarthy, Michael J

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Bipolar Disorder, Sleep Research, Brain Disorders, Bipolar disorder, Calcium channel, Circadian rhythm, Gene expression
Abstract

Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is involved in -circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs. Using Per2-luc, a bioluminescent reporter, we verified that cells entrain to temperature rhythms in vitro. Under constant temperature conditions, the LTCC antagonist verapamil shortened the circadian period, and the RYR antagonist dantrolene lengthened the period. However, neither drug affected temperature entrainment. Fibroblasts from BD patients and controls also entrained to temperature. In cells from BD patients, the rhythm amplitude was lower under entrained, but not constant, conditions. Temperature entrainment was otherwise similar between BD and control cells. However, the CACNA1C genotype among BD cells predicted the degree to which cells entrained. We conclude that assessment of rhythms under entrained conditions reveals additional rhythm abnormalities in BD that are not observable under constant temperature conditions.

Published
2019

20. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk

Author

Rajarajan, Prashanth, Borrman, Tyler, Liao, Will, Schrode, Nadine, Flaherty, Erin, Casiño, Charlize, Powell, Samuel, Yashaswini, Chittampalli, LaMarca, Elizabeth A, Kassim, Bibi, Javidfar, Behnam, Espeso-Gil, Sergio, Li, Aiqun, Won, Hyejung, Geschwind, Daniel H, Ho, Seok-Man, MacDonald, Matthew, Hoffman, Gabriel E, Roussos, Panos, Zhang, Bin, Hahn, Chang-Gyu, Weng, Zhiping, Brennand, Kristen J, and Akbarian, Schahram

Subjects
Human Genome, Prevention, Brain Disorders, Neurosciences, Schizophrenia, Stem Cell Research, Genetics, Mental Health, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Neurological, Mental health, Brain, Cells, Cultured, Chromatin, Chromatin Assembly and Disassembly, Chromosomes, Human, Connectome, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Male, Neural Stem Cells, Neurogenesis, Neuroglia, Neurons, Nucleic Acid Conformation, Protein Interaction Maps, Proteomics, Risk, Transcription, Genetic, Transcriptome, General Science & Technology
Abstract

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type-specific disease risk vulnerabilities in spatial genome organization.

Published
2018

21. A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility

Author

Voloudakis, Georgios, Vicari, James M., Venkatesh, Sanan, Hoffman, Gabriel E., Dobrindt, Kristina, Zhang, Wen, Beckmann, Noam D., Higgins, Christina A., Argyriou, Stathis, Jiang, Shan, Hoagland, Daisy, Gao, Lina, Corvelo, André, Cho, Kelly, Lee, Kyung Min, Bian, Jiantao, Lee, Jennifer S., Iyengar, Sudha K., Luoh, Shiuh-Wen, Akbarian, Schahram, Striker, Robert, Assimes, Themistocles L., Schadt, Eric E., Lynch, Julie A., Merad, Miriam, tenOever, Benjamin R., Charney, Alexander W., Brennand, Kristen J., Fullard, John F., and Roussos, Panos

Published
2022
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22. Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome

Author

Fulton, Sasha L., Wenderski, Wendy, Lepack, Ashley E., Eagle, Andrew L., Fanutza, Tomas, Bastle, Ryan M., Ramakrishnan, Aarthi, Hays, Emma C., Neal, Arianna, Bendl, Jaroslav, Farrelly, Lorna A., Al-Kachak, Amni, Lyu, Yang, Cetin, Bulent, Chan, Jennifer C., Tran, Tina N., Neve, Rachael L., Roper, Randall J., Brennand, Kristen J., Roussos, Panos, Schimenti, John C., Friedman, Allyson K., Shen, Li, Blitzer, Robert D., Robison, Alfred J., Crabtree, Gerald R., and Maze, Ian

Published
2022
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25. The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample

Author

Oedegaard, Ketil J, Alda, Martin, Anand, Anit, Andreassen, Ole A, Balaraman, Yokesh, Berrettini, Wade H, Bhattacharjee, Abesh, Brennand, Kristen J, Burdick, Katherine E, Calabrese, Joseph R, Calkin, Cynthia V, Claasen, Ana, Coryell, William H, Craig, David, DeModena, Anna, Frye, Mark, Gage, Fred H, Gao, Keming, Garnham, Julie, Gershon, Elliot, Jakobsen, Petter, Leckband, Susan G, McCarthy, Michael J, McInnis, Melvin G, Maihofer, Adam X, Mertens, Jerome, Morken, Gunnar, Nievergelt, Caroline M, Nurnberger, John, Pham, Son, Schoeyen, Helle, Shekhtman, Tatyana, Shilling, Paul D, Szelinger, Szabolcs, Tarwater, Bruce, Yao, Jun, Zandi, Peter P, and Kelsoe, John R

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Health Sciences, Brain Disorders, Human Genome, Genetics, Depression, Mental Health, Clinical Research, Prevention, Behavioral and Social Science, Detection, screening and diagnosis, Evaluation of treatments and therapeutic interventions, 4.2 Evaluation of markers and technologies, 6.1 Pharmaceuticals, Mental health, Aged, Antidepressive Agents, Bipolar Disorder, Diagnostic and Statistical Manual of Mental Disorders, Female, Follow-Up Studies, Genome-Wide Association Study, Humans, Lithium Compounds, Male, Middle Aged, Pharmacogenetics, Prospective Studies, Retrospective Studies, Secondary Prevention, Valproic Acid, Bipolar disorder, Lithium, Mood stabilizer, GWAS, Prospective trial, Personalized medicine, Precision medicine, Clinical Sciences, Public Health and Health Services, Psychology, Psychiatry, Clinical sciences, Epidemiology, Clinical and health psychology
Abstract

BackgroundBipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response.Methods/designThis study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response.DiscussionLithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost.Trial registrationClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.

Published
2016

28. Multi-omic profiling of the developing human cerebral cortex at the single-cell level

Author

Zhu, Kaiyi, primary, Bendl, Jaroslav, additional, Rahman, Samir, additional, Vicari, James M., additional, Coleman, Claire, additional, Clarence, Tereza, additional, Latouche, Ovaun, additional, Tsankova, Nadejda M., additional, Li, Aiqun, additional, Brennand, Kristen J., additional, Lee, Donghoon, additional, Yuan, Guo-Cheng, additional, Fullard, John F., additional, and Roussos, Panos, additional

Published
2023
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29. Lineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome

Author

Rahman, Samir, primary, Dong, Pengfei, additional, Apontes, Pasha, additional, Fernando, Michael B, additional, Kosoy, Roman, additional, Townsley, Kayla G, additional, Girdhar, Kiran, additional, Bendl, Jaroslav, additional, Shao, Zhiping, additional, Misir, Ruth, additional, Tsankova, Nadia, additional, Kleopoulos, Steven P, additional, Brennand, Kristen J, additional, Fullard, John F, additional, and Roussos, Panos, additional

Published
2023
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33. Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders

Author

Brennand, Kristen J, Marchetto, M Carol, Benvenisty, Nissim, Brüstle, Oliver, Ebert, Allison, Belmonte, Juan Carlos Izpisua, Kaykas, Ajamete, Lancaster, Madeline A, Livesey, Frederick J, McConnell, Michael J, McKay, Ronald D, Morrow, Eric M, Muotri, Alysson R, Panchision, David M, Rubin, Lee L, Sawa, Akira, Soldner, Frank, Song, Hongjun, Studer, Lorenz, Temple, Sally, Vaccarino, Flora M, Wu, Jun, Vanderhaeghen, Pierre, Gage, Fred H, and Jaenisch, Rudolf

Subjects
Biochemistry and Cell Biology, Biological Sciences, Brain Disorders, Bioengineering, Neurosciences, Clinical Research, Stem Cell Research, Neurological, Brain, Brain Diseases, Drug Discovery, Humans, Induced Pluripotent Stem Cells, Mosaicism, Neurogenesis, Precision Medicine, Clinical Sciences, Biochemistry and cell biology
Abstract

As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.

Published
2015

34. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder

Author

Mertens, Jerome, Wang, Qiu-Wen, Kim, Yongsung, Yu, Diana X, Pham, Son, Yang, Bo, Zheng, Yi, Diffenderfer, Kenneth E, Zhang, Jian, Soltani, Sheila, Eames, Tameji, Schafer, Simon T, Boyer, Leah, Marchetto, Maria C, Nurnberger, John I, Calabrese, Joseph R, Oedegaard, Ketil J, McCarthy, Michael J, Zandi, Peter P, Alda, Martin, Nievergelt, Caroline M, Mi, Shuangli, Brennand, Kristen J, Kelsoe, John R, Gage, Fred H, and Yao, Jun

Subjects
Stem Cell Research - Induced Pluripotent Stem Cell, Bipolar Disorder, Serious Mental Illness, Regenerative Medicine, Neurosciences, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Mental Health, Stem Cell Research, Brain Disorders, Mental health, Action Potentials, Antipsychotic Agents, Calcium Signaling, Dentate Gyrus, Endophenotypes, Humans, Induced Pluripotent Stem Cells, Lithium Compounds, Male, Mitochondria, Neurons, Patch-Clamp Techniques, Pharmacogenomics of Bipolar Disorder Study, General Science & Technology
Abstract

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Published
2015

36. List of contributors

Author

Abdolmaleky, Hamid Mostafavi, primary, Akbarian, Schahram, additional, Ambrosini, Alexander, additional, Avramopoulos, Dimitrios, additional, Bendersky, Cari J., additional, Bendl, Jaroslav, additional, Bérubé, Nathalie G., additional, Bhat, Unis Ahmad, additional, Borreggine, Kristin, additional, Braun, Patricia R., additional, Brennand, Kristen J., additional, Castro, Amanda, additional, Chakravarty, Sumana, additional, Chang, Connie, additional, Cohen, Sophie, additional, Coppedè, Fabio, additional, Dahrendorff, Jan, additional, Dunn, Jeffrey T., additional, Eberwine, James H., additional, Elia, Josephine, additional, Fang, Gang, additional, Fels, Samuel, additional, Fernando, Michael B., additional, Franklin, Tamara Brook, additional, Fries, Gabriel R., additional, Frizzola, Meg, additional, Fullard, John F., additional, Ganguly, Sebanti, additional, Gapp, Katharina, additional, Garcia, Meilin Fernandez, additional, Gatta, Eleonora, additional, Grayson, Dennis R., additional, Gropman, Andrea L., additional, Guidotti, Alessandro, additional, Gupta, Praveer, additional, Hakonarson, Hakon, additional, Hunter, Richard G., additional, Imamura, Takuya, additional, Izaki, Yumiko, additional, Jakub, Taryn, additional, Keung, Crystal, additional, Kramer, Jamie M., additional, Kumar, Arvind, additional, Kundakovic, Marija, additional, Labonté, Benoit, additional, LaMarca, Elizabeth A., additional, Lee, Richard S., additional, Lima, Camila N.C., additional, Lutz, Pierre-Eric, additional, Matt, Stephanie M., additional, Milian, Allison A., additional, Miyashiro, Kevin Y., additional, Murgatroyd, Chris, additional, Nakashima, Kinichi, additional, Paul, Bidisha, additional, Peedicayil, Jacob, additional, Pinjari, Omar F., additional, Poddar, Karuna, additional, Potash, James B., additional, Powell, Samuel K., additional, Quesnel, Katerine, additional, Rayfield, Jessica, additional, Reddy, R. Gajendra, additional, Richter, Troy A., additional, Roth, Eric D., additional, Roth, Tania L., additional, Roussos, Panos, additional, Ruzicka, W. Brad, additional, Salarda, Erika M., additional, Santhosh, Samuel, additional, Saudagar, Vikram, additional, Stoccoro, Andrea, additional, Syed, Shariful A., additional, Thiagalingam, Sam, additional, Tollefsbol, Trygve O., additional, Turecki, Gustavo, additional, Uddin, Monica, additional, Uesaka, Masahiro, additional, Walker, Deena, additional, Yamamoto, Naoki, additional, Yost, Oliver, additional, and Zannas, Anthony S., additional

Published
2021
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39. Neuronal impact of patient-specific aberrant NRXN1α splicing

Author

Flaherty, Erin, Zhu, Shijia, Barretto, Natalie, Cheng, Esther, Deans, P. J. Michael, Fernando, Michael B., Schrode, Nadine, Francoeur, Nancy, Antoine, Alesia, Alganem, Khaled, Halpern, Madeline, Deikus, Gintaras, Shah, Hardik, Fitzgerald, Megan, Ladran, Ian, Gochman, Peter, Rapoport, Judith, Tsankova, Nadejda M., McCullumsmith, Robert, Hoffman, Gabriel E., Sebra, Robert, Fang, Gang, and Brennand, Kristen J.

Published
2019
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40. Synergistic effects of common schizophrenia risk variants

Author

Schrode, Nadine, Ho, Seok-Man, Yamamuro, Kazuhiko, Dobbyn, Amanda, Huckins, Laura, Matos, Marliette R., Cheng, Esther, Deans, P. J. Michael, Flaherty, Erin, Barretto, Natalie, Topol, Aaron, Alganem, Khaled, Abadali, Sonya, Gregory, James, Hoelzli, Emily, Phatnani, Hemali, Singh, Vineeta, Girish, Deeptha, Aronow, Bruce, Mccullumsmith, Robert, Hoffman, Gabriel E., Stahl, Eli A., Morishita, Hirofumi, Sklar, Pamela, and Brennand, Kristen J.

Published
2019
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41. Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons

Author

Hook, Vivian, Brennand, Kristen J, Kim, Yongsung, Toneff, Thomas, Funkelstein, Lydiane, Lee, Kelly C, Ziegler, Michael, and Gage, Fred H

Subjects
Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research, Mental Health, Schizophrenia, Brain Disorders, Neurosciences, Serious Mental Illness, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mental health, Adult, Case-Control Studies, Catecholamines, Cells, Cultured, Dynorphins, Enkephalins, Exocytosis, Female, Humans, Induced Pluripotent Stem Cells, Infant, Newborn, Male, Neural Stem Cells, Neurons, Biochemistry and Cell Biology, Clinical Sciences
Abstract

This study investigated human-induced pluripotent stem cell (hiPSC) -derived neurons for their ability to secrete neurotransmitters in an activity-dependent manner, the fundamental property required for chemical neurotransmission. Cultured hiPSC neurons showed KCl stimulation of activity-dependent secretion of catecholamines--dopamine (DA), norepinephrine (NE), and epinephrine (Epi)--and the peptide neurotransmitters dynorphin and enkephlain. hiPSC neurons express the biosynthetic enzymes for catecholamines and neuropeptides. Because altered neurotransmission contributes to schizophrenia (SZ), we compared SZ to control cultures of hiPSC neurons and found that SZ cases showed elevated levels of secreted DA, NE, and Epi. Consistent with increased catecholamines, the SZ neuronal cultures showed a higher percentage of tyrosine hydroxylase (TH)-positive neurons, the first enzymatic step for catecholamine biosynthesis. These findings show that hiPSC neurons possess the fundamental property of activity-dependent neurotransmitter secretion and can be advantageously utilized to examine regulation of neurotransmitter release related to brain disorders.

Published
2014

43. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Maury, Eduardo A., primary, Sherman, Maxwell A., additional, Genovese, Giulio, additional, Gilgenast, Thomas G., additional, Kamath, Tushar, additional, Burris, S.J., additional, Rajarajan, Prashanth, additional, Flaherty, Erin, additional, Akbarian, Schahram, additional, Chess, Andrew, additional, McCarroll, Steven A., additional, Loh, Po-Ru, additional, Phillips-Cremins, Jennifer E., additional, Brennand, Kristen J., additional, Macosko, Evan Z., additional, Walters, James T.R., additional, O’Donovan, Michael, additional, Sullivan, Patrick, additional, Sebat, Jonathan, additional, Lee, Eunjung A., additional, Walsh, Christopher A., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Thiruvahindrapuram, Bhooma, additional, Wang, Zhouzhi, additional, Scherer, Stephen W., additional, Howrigan, Daniel P, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Farh, Kai-How, additional, Fromer, Menachem, additional, Goldstein, Jacqueline I., additional, Huang, Hailiang, additional, Lee, Phil, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Belliveau, Richard A., additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Chambert, Kimberley D., additional, O'Dushlaine, Colm, additional, Scolnick, Edward M., additional, Smoller, Jordan W., additional, Moran, Jennifer L., additional, Palotie, Aarno, additional, Petryshen, Tracey L., additional, Wu, Wenting, additional, Greer, Douglas S., additional, Antaki, Danny, additional, Shetty, Aniket, additional, Gujral, Madhusudan, additional, Brandler, William M., additional, Malhotra, Dheeraj, additional, Fuentes Fajarado, Karin V., additional, Maile, Michelle S., additional, Holmans, Peter A., additional, Carrera, Noa, additional, Craddock, Nick, additional, Escott-Price, Valentina, additional, Georgieva, Lyudmila, additional, Hamshere, Marian L., additional, Kavanagh, David, additional, Legge, Sophie E., additional, Pocklington, Andrew J., additional, Richards, Alexander L., additional, Ruderfer, Douglas M., additional, Williams, Nigel M., additional, Kirov, George, additional, Owen, Michael J., additional, Pinto, Dalila, additional, Cai, Guiqing, additional, Davis, Kenneth L., additional, Drapeau, Elodie, additional, Friedman, Joseph I, additional, Haroutunian, Vahram, additional, Parkhomenko, Elena, additional, Reichenberg, Abraham, additional, Silverman, Jeremy M., additional, Buxbaum, Joseph D., additional, Domenici, Enrico, additional, Agartz, Ingrid, additional, Djurovic, Srdjan, additional, Mattingsdal, Morten, additional, Melle, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Söderman, Erik, additional, Albus, Margot, additional, Alexander, Madeline, additional, Laurent, Claudine, additional, Levinson, Douglas F., additional, Amin, Farooq, additional, Atkins, Joshua, additional, Cairns, Murray J., additional, Scott, Rodney J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Bacanu, Silviu A., additional, Bigdeli, Tim B., additional, Reimers, Mark A., additional, Webb, Bradley T., additional, Wolen, Aaron R., additional, Wormley, Brandon K., additional, Kendler, Kenneth S., additional, Riley, Brien P., additional, Kähler, Anna K., additional, Magnusson, Patrik K.E., additional, Hultman, Christina M., additional, Bertalan, Marcelo, additional, Hansen, Thomas, additional, Olsen, Line, additional, Rasmussen, Henrik B., additional, Werge, Thomas, additional, Mattheisen, Manuel, additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Roffman, Joshua L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Kahn, René S, additional, Strengman, Eric, additional, Ophoff, Roel A., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Michie, Patricia T., additional, Pantelis, Christos, additional, Schall, Ulrich, additional, Jablensky, Assen V., additional, Kelly, Brian J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Cheng, Wei, additional, Cloninger, C. Robert, additional, Svrakic, Dragan M, additional, Cohen, David, additional, Cormican, Paul, additional, Donohoe, Gary, additional, Morris, Derek W., additional, Corvin, Aiden, additional, Gill, Michael, additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Farrell, Martilias S., additional, Giusti-Rodríguez, Paola, additional, Kim, Yunjung, additional, Szatkiewicz, Jin P., additional, Williams, Stephanie, additional, Curtis, David, additional, Pimm, Jonathan, additional, Gurling, Hugh, additional, McQuillin, Andrew, additional, Davidson, Michael, additional, Weiser, Mark, additional, Degenhardt, Franziska, additional, Forstner, Andreas J., additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Cichon, Sven, additional, Nöthen, Markus M., additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, McCarley, Robert W., additional, Levy, Deborah L., additional, Mesholam-Gately, Raquelle I., additional, Seidman, Larry J., additional, Dikeos, Dimitris, additional, Papadimitriou, George N., additional, Dinan, Timothy, additional, Duan, Jubao, additional, Sanders, Alan R., additional, Gejman, Pablo V., additional, Gershon, Elliot S., additional, Dudbridge, Frank, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Salomaa, Veikko, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Knowles, James A., additional, Pato, Michele T., additional, Pato, Carlos N., additional, Frank, Josef, additional, Meier, Sandra, additional, Schulze, Thomas G., additional, Strohmaier, Jana, additional, Witt, Stephanie H., additional, Rietschel, Marcella, additional, Franke, Lude, additional, Karjalainen, Juha, additional, Freedman, Robert, additional, Olincy, Ann, additional, Freimer, Nelson B., additional, Purcell, Shaun M., additional, Roussos, Panos, additional, Stahl, Eli A., additional, Sklar, Pamela, additional, Giegling, Ina, additional, Hartmann, Annette M., additional, Konte, Bettina, additional, Rujescu, Dan, additional, Godard, Stephanie, additional, Hirschhorn, Joel N., additional, Pers, Tune H., additional, Price, Alkes, additional, Esko, Tõnu, additional, Gratten, Jacob, additional, Lee, S. Hong, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Mowry, Bryan J., additional, de Haan, Lieuwe, additional, Meijer, Carin J., additional, Hansen, Mark, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Joa, Inge, additional, Kalaydjieva, Luba, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Zai, Clement C., additional, Knight, Jo, additional, Lerer, Bernard, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Stroup, T. Scott, additional, Lönnqvist, Jouko, additional, Suvisaari, Jaana, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Blackwood, Douglas H.R., additional, Metspalu, Andres, additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Collier, David A., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Powell, John, additional, Myin-Germeys, Inez, additional, Van Os, Jim, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Pulver, Ann E., additional, Nicodemus, Kristin K., additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, Adolfsson, Rolf, additional, O'Callaghan, Eadbhard, additional, Oh, Sang-Yun, additional, O'Neill, F. Anthony, additional, Paunio, Tiina, additional, Pietiläinen, Olli, additional, Perkins, Diana O., additional, Quested, Digby, additional, Savitz, Adam, additional, Li, Qingqin S., additional, Schwab, Sibylle G., additional, Shi, Jianxin, additional, Spencer, Chris C.A., additional, Thirumalai, Srinivas, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wildenauer, Dieter B., additional, Bramon, Elvira, additional, Darvasi, Ariel, additional, Posthuma, Danielle, additional, St. Clair, David, additional, Shanta, Omar, additional, Klein, Marieke, additional, Park, Peter J., additional, Weinberger, Daniel, additional, Moran, John V., additional, Gage, Fred H., additional, Vaccarino, Flora M., additional, Gleeson, Joseph, additional, Mathern, Gary, additional, Courchesne, Eric, additional, Roy, Subhojit, additional, Bizzotto, Sara, additional, Coulter, Michael, additional, Dias, Caroline, additional, D'Gama, Alissa, additional, Ganz, Javier, additional, Hill, Robert, additional, Huang, August Yue, additional, Khoshkhoo, Sattar, additional, Kim, Sonia, additional, Lodato, Michael, additional, Miller, Michael, additional, Borges-Monroy, Rebeca, additional, Rodin, Rachel, additional, Zhou, Zinan, additional, Bohrson, Craig, additional, Chu, Chong, additional, Cortes-Ciriano, Isidro, additional, Dou, Yanmei, additional, Galor, Alon, additional, Gulhan, Doga, additional, Kwon, Minseok, additional, Luquette, Joe, additional, Viswanadham, Vinay, additional, Jones, Attila, additional, Rosenbluh, Chaggai, additional, Cho, Sean, additional, Langmead, Ben, additional, Thorpe, Jeremy, additional, Erwin, Jennifer, additional, Jaffe, Andrew, additional, McConnell, Michael, additional, Narurkar, Rujuta, additional, Paquola, Apua, additional, Shin, Jooheon, additional, Straub, Richard, additional, Abyzov, Alexej, additional, Bae, Taejeong, additional, Jang, Yeongjun, additional, Wang, Yifan, additional, Gage, Fred, additional, Linker, Sara, additional, Reed, Patrick, additional, Wang, Meiyan, additional, Urban, Alexander, additional, Zhou, Bo, additional, Zhu, Xiaowei, additional, Pattni, Reenal, additional, Amero, Aitor Serres, additional, Juan, David, additional, Lobon, Irene, additional, Marques-Bonet, Tomas, additional, Moruno, Manuel Solis, additional, Perez, Raquel Garcia, additional, Povolotskaya, Inna, additional, Soriano, Eduardo, additional, Averbuj, Dan, additional, Ball, Laurel, additional, Breuss, Martin, additional, Yang, Xiaoxu, additional, Chung, Changuk, additional, Emery, Sarah B., additional, Flasch, Diane A., additional, Kidd, Jeffrey M., additional, Kopera, Huira C., additional, Kwan, Kenneth Y., additional, Mills, Ryan E., additional, Moldovan, John B., additional, Sun, Chen, additional, Zhao, Xuefang, additional, Zhou, Weichen, additional, Frisbie, Trenton J., additional, Cherskov, Adriana, additional, Fasching, Liana, additional, Jourdon, Alexandre, additional, Pochareddy, Sirisha, additional, Scuderi, Soraya, additional, and Sestan, Nenad, additional

Published
2023
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44. R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription

Author

LaMarca, Elizabeth A., primary, Saito, Atsushi, additional, Plaza-Jennings, Amara, additional, Hellmich, Allyse, additional, Fernando, Michael B., additional, Javidfar, Behnam, additional, Espeso-Gil, Sergio, additional, Estill, Molly, additional, Liao, Will, additional, Townsley, Kayla, additional, Florio, Anna, additional, Ethridge, James E., additional, Do, Catherine, additional, Tycko, Benjamin, additional, Shen, Li, additional, Kamiya, Atsushi, additional, Tsankova, Nadejda M., additional, Brennand, Kristen J., additional, and Akbarian, Schahram, additional

Published
2023
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45. Aligning Stem Cell Models and Postmortem Studies to Query Striatal Neurodevelopment in Schizophrenia.

Author

Brennand, Kristen J.

Subjects
*STEM cells, *AUTOPSY, *POSTMORTEM changes, *AMISULPRIDE, *NEURAL development, *MEDIUM spiny neurons, *INDUCED pluripotent stem cells, *DOPAMINE
Abstract

This article explores the use of stem cell models and postmortem studies to investigate the neurodevelopment of the striatum in schizophrenia. Stem cell-derived neurons have been found to exhibit similar cellular characteristics to those observed in postmortem analyses. The authors of this study developed a method to directly compare stem cell-derived neurons with postmortem brain tissue from the same individuals, focusing on the striatum. They found that the stem cell-derived neurons exhibited schizophrenia-associated signatures similar to those seen in adult brain tissue, suggesting an accelerated developmental trajectory in schizophrenia. The study also contributes to the ongoing debate about the accuracy of postmortem human neurons as representations of disease processes in the living brain. [Extracted from the article]

Published
2024
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48. Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Author

Stern, Shani, Zhang, Lei, Wang, Meiyan, Wright, Rebecca, Rosh, Idan, Hussein, Yara, Stern, Tchelet, Choudhary, Ashwani, Tripathi, Utkarsh, Reed, Patrick, Sadis, Hagit, Nayak, Ritu, Shemen, Aviram, Agarwal, Karishma, Cordeiro, Diogo, Peles, David, Hang, Yuqing, Mendes, Ana P. D., Baul, Tithi D., Roth, Julien G., Coorapati, Shashank, Boks, Marco P., McCombie, W. Richard, Hulshoff Pol, Hilleke, Brennand, Kristen J., Réthelyi, János M., Kahn, René S., Marchetto, Maria C., and Gage, Fred H.

Abstract

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

Published
2024
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50. The functional and evolutionary impacts of human-specific deletions in conserved elements

Author

Xue, James R., Mackay-Smith, Ava, Mouri, Kousuke, Garcia, Meilin Fernandez, Dong, Michael X., Akers, Jared F., Noble, Mark, Li, Xue, Lindblad-Toh, Kerstin, Karlsson, Elinor K., Noonan, James P., Capellini, Terence D., Brennand, Kristen J., Tewhey, Ryan, Sabeti, Pardis C., and Reilly, Steven K.

Subjects
Article
Abstract

INTRODUCTION: Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits. RATIONALE: Sequencing advancements have identified millions of genetic changes between chimpanzee and human genomes; however, the functional impacts of the ~1 to 5% difference between our species is largely unknown. hCONDELs are one class of these predominantly noncoding sequence changes. Although large hCONDELs (>1 kb) have been previously identified, the vast majority of all hCONDELs (95.7%) are small (

Published
2023

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