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656 results on '"Daniel, H Geschwind"'

1. Increased Striatal Presynaptic Dopamine in a Nonhuman Primate Model of Maternal Immune Activation: A Longitudinal Neurodevelopmental Positron Emission Tomography Study With Implications for Schizophrenia

Author

Jason Smucny, Roza M. Vlasova, Tyler A. Lesh, Douglas J. Rowland, Guobao Wang, Abhijit J. Chaudhari, Shuai Chen, Ana-Maria Iosif, Casey E. Hogrefe, Jeffrey L. Bennett, Cynthia M. Shumann, Judy A. Van de Water, Richard J. Maddock, Martin A. Styner, Daniel H. Geschwind, A. Kimberley McAllister, Melissa D. Bauman, and Cameron S. Carter

Subjects
Cognitive Neuroscience, Radiology, Nuclear Medicine and imaging, Neurology (clinical), Biological Psychiatry
Published
2023

2. Pathway-based Approach Reveals Differential Sensitivity to E2F1 Inhibition in Glioblastoma

Author

Alvaro G. Alvarado, Kaleab Tessema, Sree Deepthi Muthukrishnan, Mackenzie Sober, Riki Kawaguchi, Dan R. Laks, Aparna Bhaduri, Vivek Swarup, David A. Nathanson, Daniel H. Geschwind, Steven A. Goldman, and Harley I. Kornblum

Subjects
Article
Abstract

Analysis of tumor gene expression is an important approach for the classification and identification of therapeutic vulnerabilities. However, targeting glioblastoma (GBM) based on molecular subtyping has not yet translated into successful therapies. Here, we present an integrative approach based on molecular pathways to expose new potentially actionable targets. We used gene set enrichment analysis to conduct an unsupervised clustering analysis to condense the gene expression data from bulk patient samples and patient-derived gliomasphere lines into new gene signatures. We identified key targets that are predicted to be differentially activated between tumors and were functionally validated in a library of gliomasphere cultures. Resultant cluster-specific gene signatures associated not only with hallmarks of cell cycle and stemness gene expression, but also with cell type–specific markers and different cellular states of GBM. Several upstream regulators, such as PIK3R1 and EBF1 were differentially enriched in cells bearing stem cell like signatures and bear further investigation. We identified the transcription factor E2F1 as a key regulator of tumor cell proliferation and self-renewal in only a subset of gliomasphere cultures predicted to be E2F1 signaling dependent. Our in vivo work also validated the functional significance of E2F1 in tumor formation capacity in the predicted samples. E2F1 inhibition also differentially sensitized E2F1-dependent gliomasphere cultures to radiation treatment. Our findings indicate that this novel approach exploring cancer pathways highlights key therapeutic vulnerabilities for targeting GBM. Significance: Molecular classification of GBM has not yet resulted in the development of effective therapies. We have developed an integrative approach to identify molecular targets differentially utilized by individual tumors. This approach could lead to patient- and tumor-specific therapeutics.

Published
2022

3. A neural stem cell paradigm of pediatric hydrocephalus

Author

Phan Q Duy, Pasko Rakic, Seth L Alper, Stephanie M Robert, Adam J Kundishora, William E Butler, Christopher A Walsh, Nenad Sestan, Daniel H Geschwind, Sheng Chih Jin, and Kristopher T Kahle

Subjects
Cellular and Molecular Neuroscience, Cognitive Neuroscience
Abstract

Pediatric hydrocephalus, the leading reason for brain surgery in children, is characterized by enlargement of the cerebral ventricles classically attributed to cerebrospinal fluid (CSF) overaccumulation. Neurosurgical shunting to reduce CSF volume is the default treatment that intends to reinstate normal CSF homeostasis, yet neurodevelopmental disability often persists in hydrocephalic children despite optimal surgical management. Here, we discuss recent human genetic and animal model studies that are shifting the view of pediatric hydrocephalus from an impaired fluid plumbing model to a new paradigm of dysregulated neural stem cell (NSC) fate. NSCs are neuroprogenitor cells that comprise the germinal neuroepithelium lining the prenatal brain ventricles. We propose that heterogenous defects in the development of these cells converge to disrupt cerebrocortical morphogenesis, leading to abnormal brain–CSF biomechanical interactions that facilitate passive pooling of CSF and secondary ventricular distention. A significant subset of pediatric hydrocephalus may thus in fact be due to a developmental brain malformation leading to secondary enlargement of the ventricles rather than a primary defect of CSF circulation. If hydrocephalus is indeed a neuroradiographic presentation of an inborn brain defect, it suggests the need to focus on optimizing neurodevelopment, rather than CSF diversion, as the primary treatment strategy for these children.

Published
2022

12. Data from Pathway-based Approach Reveals Differential Sensitivity to E2F1 Inhibition in Glioblastoma

Author

Harley I. Kornblum, Steven A. Goldman, Daniel H. Geschwind, David A. Nathanson, Vivek Swarup, Aparna Bhaduri, Dan R. Laks, Riki Kawaguchi, Mackenzie Sober, Sree Deepthi Muthukrishnan, Kaleab Tessema, and Alvaro G. Alvarado

Abstract

Analysis of tumor gene expression is an important approach for the classification and identification of therapeutic vulnerabilities. However, targeting glioblastoma (GBM) based on molecular subtyping has not yet translated into successful therapies. Here, we present an integrative approach based on molecular pathways to expose new potentially actionable targets. We used gene set enrichment analysis to conduct an unsupervised clustering analysis to condense the gene expression data from bulk patient samples and patient-derived gliomasphere lines into new gene signatures. We identified key targets that are predicted to be differentially activated between tumors and were functionally validated in a library of gliomasphere cultures. Resultant cluster-specific gene signatures associated not only with hallmarks of cell cycle and stemness gene expression, but also with cell type–specific markers and different cellular states of GBM. Several upstream regulators, such as PIK3R1 and EBF1 were differentially enriched in cells bearing stem cell like signatures and bear further investigation. We identified the transcription factor E2F1 as a key regulator of tumor cell proliferation and self-renewal in only a subset of gliomasphere cultures predicted to be E2F1 signaling dependent. Our in vivo work also validated the functional significance of E2F1 in tumor formation capacity in the predicted samples. E2F1 inhibition also differentially sensitized E2F1-dependent gliomasphere cultures to radiation treatment. Our findings indicate that this novel approach exploring cancer pathways highlights key therapeutic vulnerabilities for targeting GBM.Significance:Molecular classification of GBM has not yet resulted in the development of effective therapies. We have developed an integrative approach to identify molecular targets differentially utilized by individual tumors. This approach could lead to patient- and tumor-specific therapeutics.

Published
2023

15. New insights into the genetic etiology of Alzheimer's disease and related dementias

Author

Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. A., Piñol-Ripoll, G., Pisanu, C., Polak, T., Popp, J., Posthuma, D., Priller, J., Puerta, R., Quenez, O., Quintela, I., Thomassen, J. Q., Rábano, A., Rainero, I., Rajabli, F., Ramakers, I., Real, L. M., Reinders, M. J. T., Reitz, C., Reyes-Dumeyer, D., Ridge, P., Riedel-Heller, S., Riederer, P., Roberto, N., Rodriguez-Rodriguez, E., Rongve, A., Allende, I. R., Rosende-Roca, M., Royo, J. L., Rubino, E., Rujescu, D., Sáez, M. E., Sakka, P., Saltvedt, I., Sanabria, Á., Sánchez-Arjona, M. B., Sanchez-Garcia, F., Juan, P. S., Sánchez-Valle, R., Sando, S. B., Sarnowski, C., Satizabal, C. L., Scamosci, M., Scarmeas, N., Scarpini, E., Scheltens, P., Scherbaum, N., Scherer, M., Schmid, M., Schneider, A., Schott, J. M., Selbæk, G., Seripa, D., Serrano, M., Sha, J., Shadrin, A. A., Skrobot, O., Slifer, S., Snijders, G. J. L., Soininen, H., Solfrizzi, V., Solomon, A., Song, Y. E., Sorbi, S., Sotolongo-Grau, O., Spalletta, G., Spottke, A., Squassina, A., Stordal, E., Tartan, J. P., Tárraga, L., Tesí, N., Thalamuthu, A., Thomas, T., Tosto, G., Traykov, L., Tremolizzo, L., Tybjærg-Hansen, A., Uitterlinden, A., Ullgren, A., Ulstein, I., Valero, S., Valladares, O., Broeckhoven, C. V., Vance, J., Vardarajan, B. N., van der Lugt, A., Dongen, J. V., van Rooij, J., van Swieten, J., Vandenberghe, R., Verhey, F., Vidal, J. -S., Vogelgsang, J., Vyhnalek, M., Wagner, M., Wallon, D., Wang, L. -S., Wang, R., Weinhold, L., Wiltfang, J., Windle, G., Woods, B., Yannakoulia, M., Zare, H., Zhao, Y., Zhang, X., Zhu, C., Zulaica, M., Laczo, J., Matoska, V., Serpente, M., Assogna, F., Piras, F., Ciullo, V., Shofany, J., Ferrarese, C., Andreoni, S., Sala, G., Zoia, C. P., Zompo, M. D., Benussi, A., Bastiani, P., Takalo, M., Natunen, T., Laatikainen, T., Tuomilehto, J., Antikainen, R., Strandberg, T., Lindström, J., Peltonen, M., Abraham, R., Al-Chalabi, A., Bass, N. J., Brayne, C., Brown, K. S., Collinge, J., Craig, D., Deloukas, P., Fox, N., Gerrish, A., Gill, M., Gwilliam, R., Harold, D., Hollingworth, P., Johnston, J. A., Jones, L., Lawlor, B., Livingston, G., Lovestone, S., Lupton, M., Lynch, A., Mann, D., Mcguinness, B., Mcquillin, A., O’Donovan, M. C., Owen, M. J., Passmore, P., Powell, J. F., Proitsi, P., Rossor, M., Shaw, C. E., Smith, A. D., Gurling, H., Todd, S., Mummery, C., Ryan, N., Lacidogna, G., Adarmes-Gómez, A., Mauleón, A., Pancho, A., Gailhajenet, A., Lafuente, A., Macias-García, D., Martín, E., Pelejà, E., Carrillo, F., Merlín, I. S., Garrote-Espina, L., Vargas, L., Carrion-Claro, M., Marín, M., Labrador, M., Buendia, M., Alonso, M. D., Guitart, M., Moreno, M., Ibarria, M., Periñán, M., Aguilera, N., Gómez-Garre, P., Cañabate, P., Escuela, R., Pineda-Sánchez, R., Vigo-Ortega, R., Jesús, S., Preckler, S., Rodrigo-Herrero, S., Diego, S., Vacca, A., Roveta, F., Salvadori, N., Chipi, E., Boecker, H., Laske, C., Perneczky, R., Anastasiou, C., Janowitz, D., Malik, R., Anastasiou, A., Parveen, K., López-García, S., Antonell, A., Mihova, K. Y., Belezhanska, D., Weber, H., Kochen, S., Solis, P., Medel, N., Lisso, J., Sevillano, Z., Politis, D. G., Cores, V., Cuesta, C., Ortiz, C., Bacha, J. I., Rios, M., Saenz, A., Abalos, M. S., Kohler, E., Palacio, D. L., Etchepareborda, I., Kohler, M., Novack, G., Prestia, F. A., Galeano, P., Castaño, E. M., Germani, S., Toso, C. R., Rojo, M., Ingino, C., Mangone, C., Rubinsztein, D. C., Teipel, S., Fievet, N., Deramerourt, V., Forsell, C., Thonberg, H., Bjerke, M., Roeck, E. D., Martínez-Larrad, M. T., Olivar, N., Cano, A., Macias, J., Maroñas, O., Nuñez-Llaves, R., Olivé, C., Adarmes-Gómez, A. D., Amer-Ferrer, G., Antequera, M., Burguera, J. A., Casajeros, M. J., Martinez de Pancorbo, M., Hevilla, S., Espinosa, M. A. L., Legaz, A., Manzanares, S., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, V., Martínez-Lage Álvarez, P., Iriarte, M. M., Periñán-Tocino, M. T., Real de Asúa, D., Rodrigo, S., Sastre, I., Vicente, M. P., Vivancos, L., Epelbaum, J., Hannequin, D., Campion, D., Deramecourt, V., Tzourio, C., Brice, A., Dubois, B., Williams, A., Thomas, C., Davies, C., Nash, W., Dowzell, K., Morales, A. C., Bernardo-Harrington, M., Turton, J., Lord, J., Brown, K., Vardy, E., Fisher, E., Warren, J. D., Ryan, N. S., Guerreiro, R., Uphill, J., Bass, N., Heun, R., Kölsch, H., Schürmann, B., Lacour, A., Herold, C., Powell, J., Patel, Y., Hodges, A., Becker, T., Warden, D., Wilcock, G., Clarke, R., Ben-Shlomo, Y., Hooper, N. M., Pickering-Brown, S., Sussams, R., Warner, N., Bayer, A., Heuser, I., Drichel, D., Klopp, N., Mayhaus, M., Riemenschneider, M., Pinchler, S., Feulner, T., Gu, W., van den Bussche, H., Hüll, M., Frölich, L., Wichmann, H. -E., Jöckel, K. -H., O’Donovan, M., Owen, M., Bahrami, S., Bosnes, I., Selnes, P., Bergh, S., Palotie, A., Daly, M., Jacob, H., Matakidou, A., Runz, H., John, S., Plenge, R., Mccarthy, M., Hunkapiller, J., Ehm, M., Waterworth, D., Fox, C., Malarstig, A., Klinger, K., Call, K., Behrens, T., Loerch, P., Mäkelä, T., Kaprio, J., Virolainen, P., Pulkki, K., Kilpi, T., Perola, M., Partanen, J., Pitkäranta, A., Kaarteenaho, R., Vainio, S., Turpeinen, M., Serpi, R., Laitinen, T., Mäkelä, J., Kosma, V. -M., Kujala, U., Tuovila, O., Hendolin, M., Pakkanen, R., Waring, J., Riley-Gillis, B., Liu, J., Biswas, S., Diogo, D., Marshall, C., Hu, X., Gossel, M., Graham, R., Cummings, B., Ripatti, S., Schleutker, J., Arvas, M., Carpén, O., Hinttala, R., Kettunen, J., Mannermaa, A., Laukkanen, J., Julkunen, V., Remes, A., Kälviäinen, R., Peltola, J., Tienari, P., Rinne, J., Ziemann, A., Esmaeeli, S., Smaoui, N., Lehtonen, A., Eaton, S., Lahdenperä, S., van Adelsberg, J., Michon, J., Kerchner, G., Bowers, N., Teng, E., Eicher, J., Mehta, V., Gormley, P., Linden, K., Whelan, C., Xu, F., Pulford, D., Färkkilä, M., Pikkarainen, S., Jussila, A., Blomster, T., Kiviniemi, M., Voutilainen, M., Georgantas, B., Heap, G., Rahimov, F., Usiskin, K., Lu, T., Oh, D., Kalpala, K., Miller, M., Mccarthy, L., Eklund, K., Palomäki, A., Isomäki, P., Pirilä, L., Kaipiainen-Seppänen, O., Huhtakangas, J., Lertratanakul, A., Hochfeld, M., Bing, N., Gordillo, J. E., Mars, N., Pelkonen, M., Kauppi, P., Kankaanranta, H., Harju, T., Close, D., Greenberg, S., Chen, H., Betts, J., Ghosh, S., Salomaa, V., Niiranen, T., Juonala, M., Metsärinne, K., Kähönen, M., Junttila, J., Laakso, M., Pihlajamäki, J., Sinisalo, J., Taskinen, M. -R., Tuomi, T., Challis, B., Peterson, A., Chu, A., Parkkinen, J., Muslin, A., Joensuu, H., Meretoja, T., Aaltonen, L., Mattson, J., Auranen, A., Karihtala, P., Kauppila, S., Auvinen, P., Elenius, K., Popovic, R., Schutzman, J., Loboda, A., Chhibber, A., Lehtonen, H., Mcdonough, S., Crohns, M., Kulkarni, D., Kaarniranta, K., Turunen, J. A., Ollila, T., Seitsonen, S., Uusitalo, H., Aaltonen, V., Uusitalo-Järvinen, H., Luodonpää, M., Hautala, N., Loomis, S., Strauss, E., Podgornaia, A., Hoffman, J., Tasanen, K., Huilaja, L., Hannula-Jouppi, K., Salmi, T., Peltonen, S., Koulu, L., Harvima, I., Wu, Y., Choy, D., Pussinen, P., Salminen, A., Salo, T., Rice, D., Nieminen, P., Palotie, U., Siponen, M., Suominen, L., Mäntylä, P., Gursoy, U., Anttonen, V., Sipilä, K., Davis, J. W., Quarless, D., Petrovski, S., Wigmore, E., Chen, C. -Y., Bronson, P., Tsai, E., Huang, Y., Maranville, J., Shaikho, E., Mohammed, E., Wadhawan, S., Kvikstad, E., Caliskan, M., Chang, D., Bhangale, T., Pendergrass, S., Holzinger, E., Chen, X., Hedman, Å., King, K. S., Wang, C., Xu, E., Auge, F., Chatelain, C., Rajpal, D., Liu, D., Xia, T. -H., Brauer, M., Kurki, M., Karjalainen, J., Havulinna, A., Jalanko, A., Palta, P., della Briotta Parolo, P., Zhou, W., Lemmelä, S., Rivas, M., Harju, J., Lehisto, A., Ganna, A., Llorens, V., Laivuori, H., Rüeger, S., Niemi, M. E., Tukiainen, T., Reeve, M. P., Heyne, H., Palin, K., Garcia-Tabuenca, J., Siirtola, H., Kiiskinen, T., Lee, J., Tsuo, K., Elliott, A., Kristiansson, K., Hyvärinen, K., Ritari, J., Koskinen, M., Pylkäs, K., Kalaoja, M., Karjalainen, M., Mantere, T., Kangasniemi, E., Heikkinen, S., Laakkonen, E., Sipeky, C., Heron, S., Karlsson, A., Jambulingam, D., Rathinakannan, V. S., Kajanne, R., Aavikko, M., Jiménez, M. G., della Briotta Parola, P., Kanai, M., Kaunisto, M., Kilpeläinen, E., Sipilä, T. P., Brein, G., Awaisa, G., Shcherban, A., Donner, K., Loukola, A., Laiho, P., Sistonen, T., Kaiharju, E., Laukkanen, M., Järvensivu, E., Lähteenmäki, S., Männikkö, L., Wong, R., Mattsson, H., Hiekkalinna, T., Paajanen, T., Pärn, K., Gracia-Tabuenca, J., Abner, E., Adams, P. M., Aguirre, A., Albert, M. S., Albin, R. L., Allen, M., Alvarez, L., Apostolova, L. G., Arnold, S. E., Asthana, S., Atwood, C. S., Ayres, G., Baldwin, C. T., Barber, R. C., Barnes, L. L., Beach, T. G., Becker, J. T., Beecham, G. W., Beekly, D., Benitez, B. A., Bennett, D., Bertelson, J., Margaret, F. E., Bird, T. D., Blacker, D., Boeve, B. F., Bowen, J. D., Boxer, A., Brewer, J., Burke, J. R., Burns, J. M., Buxbaum, J. D., Cairns, N. J., Cao, C., Carlson, C. S., Carlsson, C. M., Carney, R. M., Carrasquillo, M. M., Chasse, S., Chesselet, M. -F., Chesi, A., Chin, N. A., Chui, H. C., Craft, S., Crane, P. K., Cribbs, D. H., Crocco, E. A., Cruchaga, C., Cullum, M., Darby, E., Davis, B., De Jager, P. L., Decarli, C., Detoledo, J., Dick, M., Dickson, D. W., Dombroski, B. A., Doody, R. S., Duara, R., Ertekin-Taner, N., Evans, D. A., Fairchild, T. J., Fallon, K. B., Farlow, M. R., Farrell, J. J., Fernandez-Hernandez, V., Ferris, S., Frosch, M. P., Galasko, D. R., Gamboa, A., Gearing, M., Geschwind, D. H., Ghetti, B., Gilbert, J. R., Grabowski, T. J., Graff-Radford, N. R., Grant, S. F. A., Green, R. C., Growdon, J. H., Hakonarson, H., Hall, J., Hamilton, R. L., Harari, O., Harrell, L. E., Haut, J., Head, E., Henderson, V. W., Hernandez, M., Hohman, T., Honig, L. S., Huebinger, R. M., Huentelman, M. J., Hulette, C. M., Hyman, B. T., Hynan, L. S., Ibanez, L., Jarvik, G. P., Jayadev, S., Jin, L. -W., Johnson, K., Johnson, L., Kamboh, M. I., Karydas, A. M., Katz, M. J., Kaye, J. A., Keene, C. D., Khaleeq, A., Kim, R., Knebl, J., Kowall, N. W., Kramer, J. H., Laferla, F. M., Lah, J. J., Larson, E. B., Lee, E. B., Lerner, A., Leung, Y. Y., Leverenz, J. B., Levey, A. 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Aarsland, D, Garcia-Gonzalez, P, Abdelnour, C, Alarcón-Martín, E, Alcolea, D, Alegret, M, Alvarez, I, Álvarez, V, Armstrong, N, Tsolaki, A, Antúnez, C, Appollonio, I, Arcaro, M, Archetti, S, Pastor, A, Arosio, B, Athanasiu, L, Bailly, H, Banaj, N, Baquero, M, Barral, S, Beiser, A, Below, J, Benchek, P, Benussi, L, Berr, C, Besse, C, Bessi, V, Binetti, G, Bizarro, A, Blesa, R, Boada, M, Boerwinkle, E, Borroni, B, Boschi, S, Bossù, P, Bråthen, G, Bressler, J, Bresner, C, Brodaty, H, Brookes, K, Brusco, L, Buiza-Rueda, D, Bûrger, K, Burholt, V, Bush, W, Calero, M, Cantwell, L, Chene, G, Chung, J, Cuccaro, M, Carracedo, Á, Cecchetti, R, Cervera-Carles, L, Charbonnier, C, Chen, H, Chillotti, C, Ciccone, S, Claassen, J, Clark, C, Conti, E, Corma-Gómez, A, Costantini, E, Custodero, C, Daian, D, Dalmasso, M, Daniele, A, Dardiotis, E, Dartigues, J, de Deyn, P, de Paiva Lopes, K, de Witte, L, Debette, S, Deckert, J, Del Ser, T, Denning, N, Destefano, A, Dichgans, M, Diehl-Schmid, J, Diez-Fairen, M, Rossi, P, Djurovic, S, Duron, E, Düzel, E, Dufouil, C, Eiriksdottir, G, Engelborghs, S, Escott-Price, V, Espinosa, A, Ewers, M, Faber, K, Fabrizio, T, Nielsen, S, Fardo, D, Farotti, L, Fenoglio, C, Fernández-Fuertes, M, Ferrari, R, Ferreira, C, Ferri, E, Fin, B, Fischer, P, Fladby, T, Fließbach, K, Fongang, B, Fornage, M, Fortea, J, Foroud, T, Fostinelli, S, Fox, N, Franco-Macías, E, Bullido, M, Frank-García, A, Froelich, L, Fulton-Howard, B, Galimberti, D, García-Alberca, J, García-González, P, Garcia-Madrona, S, Garcia-Ribas, G, Ghidoni, R, Giegling, I, Giorgio, G, Goate, A, Goldhardt, O, Gomez-Fonseca, D, González-Pérez, A, Graff, C, Grande, G, Green, E, Grimmer, T, Grünblatt, E, Grunin, M, Gudnason, V, Guetta-Baranes, T, Haapasalo, A, Hadjigeorgiou, G, Haines, J, Hamilton-Nelson, K, Hampel, H, Hanon, O, Hardy, J, Hartmann, A, Hausner, L, Harwood, J, Heilmann-Heimbach, S, Helisalmi, S, Heneka, M, Hernández, I, Herrmann, M, Hoffmann, P, Holmes, C, Holstege, H, Vilas, R, Hulsman, 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Peters, O, Pijnenburg, Y, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, Tárraga, L, Tesí, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Broeckhoven, C, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael [0000-0001-5231-1714], Fabrizio, Tagliavini [0000-0003-1039-7315], Fladby, Tormod [0000-0002-9984-9797], Fornage, Myriam [0000-0003-0677-8158], Fox, Nick C [0000-0002-6660-657X], Bullido, María J [0000-0002-6477-1117], Froelich, Lutz [0000-0003-1494-0813], Galimberti, Daniela [0000-0002-9284-5953], García-Alberca, Jose Maria [0000-0003-2951-6644], Goate, Alison M [0000-0002-0576-2472], González-Pérez, Antonio [0000-0001-9771-5982], Green, Emma [0000-0002-8687-5590], Grünblatt, Edna [0000-0001-8505-7265], Gudnason, Vilmundur [0000-0001-5696-0084], Haapasalo, Annakaisa [0000-0003-0959-2957], Harwood, Janet [0000-0002-3225-0069], Heilmann-Heimbach, Stefanie [0000-0003-1057-465X], Herrmann, Martin J [0000-0001-9970-2122], Holstege, Henne [0000-0002-7688-3087], Biessels, Geert Jan [0000-0001-6862-2496], Jian, Xueqiu [0000-0002-0313-6494], Johansson, Charlotte [0000-0002-5351-1950], Jun, Gyungah R [0000-0002-3230-8697], Kastumata, Yuriko [0000-0002-0188-8094], Kehoe, Patrick G [0000-0002-7542-1139], Kornhuber, Johannes [0000-0002-8096-3987], Kosmidis, Mary H [0000-0001-8790-1220], Lage, Carmen [0000-0003-1703-121X], Launer, Lenore [0000-0002-3238-7612], Lee, Chien-Yueh [0000-0002-4304-974X], Lleó, Alberto [0000-0002-2568-5478], Lopez, Oscar [0000-0002-8546-8256], de Munain, Adolfo Lopez [0000-0002-9509-4032], Lunetta, Kathryn L [0000-0002-9268-810X], Ma, Yiyi [0000-0002-3609-8877], MacLeod, Catherine A [0000-0002-9314-7380], Marquié, Marta [0000-0002-0660-0950], Montes, Angel Martín [0000-0002-1694-786X], Mead, Simon [0000-0002-4326-1468], Medina, Miguel [0000-0002-7016-5340], Menéndez-González, Manuel [0000-0002-5218-0774], Mol, Merel [0000-0003-2533-2530], Morgan, Kevin [0000-0002-8217-2396], Nöthen, Markus M [0000-0002-8770-2464], Muchnik, Carolina [0000-0002-1542-3706], Nacmias, Benedetta [0000-0001-9338-9040], Nicolas, Gael [0000-0001-9391-7800], Nordestgaard, Børge G [0000-0002-1954-7220], Pasquier, Florence [0000-0001-9880-9788], Pastor, Pau [0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A [0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)

Subjects
tau Proteins/genetics, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Neurologi, MED/03 - GENETICA MEDICA, 45/43, Medizin, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], genetics [Alzheimer Disease], Genome-Wide Association Study, Humans, tau Proteins, Alzheimer Disease, Cognitive Dysfunction, VARIANTS, pathology [Alzheimer Disease], Tau Proteins, Settore BIO/13 - Biologia Applicata, Cognitive Dysfunction/psychology, 692/699/375/365/1283, IMPUTATION, article, 1184 Genetics, developmental biology, physiology, Biología y Biomedicina / Biología, AMYLOID-BETA, Settore MED/26 - NEUROLOGIA, Neurology, psychology [Cognitive Dysfunction], Medical Genetics, Human, Neuroscience(all), 631/208/205/2138, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, ddc:570, Genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Medicinsk genetik, MED/26 - NEUROLOGIA, Alzheimer Disease/genetics, neurology, tau Protein, NECROSIS-FACTOR-ALPHA, RISK LOCI, genetics [tau Proteins], PREDICTION MODELS, Human medicine, GENERATION, RESPONSES
Abstract

25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not

Published
2022

16. The UCLA ATLAS Community Health Initiative: Promoting precision health research in a diverse biobank

Author

Ruth Johnson, Yi Ding, Arjun Bhattacharya, Sergey Knyazev, Alec Chiu, Clara Lajonchere, Daniel H. Geschwind, and Bogdan Pasaniuc

Subjects
multi-ancestry, PheWAS, Human Genome, Global-Biobank Meta-analysis Initiative, Biochemistry, Genetics and Molecular Biology (miscellaneous), electronic health records, Mental Health, Good Health and Well Being, Networking and Information Technology R&D (NITRD), biobanks, Genetics, GWAS, Patient Safety, Generic health relevance, Aetiology, 2.6 Resources and infrastructure (aetiology), Biotechnology
Abstract

The UCLA ATLAS Community Health Initiative (ATLAS) has an initial target to recruit 150,000 participants from across the UCLA Health system with the goal of creating a genomic database to accelerate precision medicine efforts in California. This initiative includes a biobank embedded within the UCLA Health system that comprises de-identified genomic data linked to electronic health records (EHRs). The first freeze of data from September 2020 contains 27,987 genotyped samples imputed to 7.9 million SNPs across the genome and is linked with de-identified versions of the EHRs from UCLA Health. Here, we describe a centralized repository of the genotype data and provide tools and pipelines to perform genome- and phenome-wide association studies across a wide range of EHR-derived phenotypes and genetic ancestry groups. We demonstrate the utility of this resource through the analysis of 7 well-studied traits and recapitulate many previous genetic and phenotypic associations.

Published
2023

17. MicroRNA-eQTLs in the developing human neocortex link miR-4707-3p expression to brain size

Author

Michael J. Lafferty, Nil Aygün, Niyanta K. Patel, Oleh Krupa, Dan Liang, Justin M. Wolter, Daniel H. Geschwind, Luis de la Torre-Ubieta, and Jason L. Stein

Subjects
General Immunology and Microbiology, General Neuroscience, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

Expression quantitative trait loci (eQTL) data have proven important for linking non-coding loci to protein-coding genes. But eQTL studies rarely measure microRNAs (miRNAs), small non-coding RNAs known to play a role in human brain development and neurogenesis. Here, we performed small-RNA sequencing across 212 mid-gestation human neocortical tissue samples, measured 907 expressed miRNAs, discovering 111 of which were novel, and identified 85 local-miRNA-eQTLs. Colocalization of miRNA-eQTLs with GWAS summary statistics yielded one robust colocalization of miR-4707-3p expression with educational attainment and brain size phenotypes, where the miRNA expression increasing allele was associated with decreased brain size. Exogenous expression of miR-4707-3p in primary human neural progenitor cells decreased expression of predicted targets and increased cell proliferation, indicating miR-4707-3p modulates progenitor gene regulation and cell fate decisions. Integrating miRNA-eQTLs with existing GWAS yielded evidence of a miRNA that may influence human brain size and function via modulation of neocortical brain development.

Published
2023
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18. Defining the nature of human pluripotent stem cell-derived interneurons via single-cell analysis

Author

Andrew J. Lund, Istvan Mody, John Huang, Inma Cobos, William E. Lowry, Marcos Otero-Garcia, Justin Langerman, Ranmal A. Samarasinghe, Kathrin Plath, Damon Polioudakis, Shan Sabri, Xiaofei Wei, Bennett G. Novitch, Daniel H. Geschwind, and Thomas F. Allison

Subjects
Resource, Pluripotent Stem Cells, genetic structures, Interneuron, transcriptional factor programming, 1.1 Normal biological development and functioning, Clinical Sciences, single nuclei transcriptomics, Biology, Regenerative Medicine, Inhibitory postsynaptic potential, Biochemistry, Transcriptome, Neural Stem Cells, Single-cell analysis, Interneurons, human brain interneuron, Stem Cell Research - Nonembryonic - Human, Underpinning research, Genetics, medicine, Humans, Cellular Reprogramming Techniques, pluripotent stem cell, Stem Cell Research - Embryonic - Human, Induced pluripotent stem cell, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Induced Pluripotent Stem Cell - Human, musculoskeletal, neural, and ocular physiology, fungi, Neurosciences, Cell Differentiation, Cell Biology, Human brain, Stem Cell Research, Cortex (botany), medicine.anatomical_structure, nervous system, Neurological, neuronal specification, Biochemistry and Cell Biology, Single-Cell Analysis, Neuroscience, Transcription Factors, Developmental Biology
Abstract

Summary The specification of inhibitory neurons has been described for the mouse and human brain, and many studies have shown that pluripotent stem cells (PSCs) can be used to create interneurons in vitro. It is unclear whether in vitro methods to produce human interneurons generate all the subtypes found in brain, and how similar in vitro and in vivo interneurons are. We applied single-nuclei and single-cell transcriptomics to model interneuron development from human cortex and interneurons derived from PSCs. We provide a direct comparison of various in vitro interneuron derivation methods to determine the homogeneity achieved. We find that PSC-derived interneurons capture stages of development prior to mid-gestation, and represent a minority of potential subtypes found in brain. Comparison with those found in fetal or adult brain highlighted decreased expression of synapse-related genes. These analyses highlight the potential to tailor the method of generation to drive formation of particular subtypes., Highlights • Comparison of interneurons derived from human pluripotent cells by various methods • Single-cell analyses define heterogeneity of in vitro-derived interneurons • Direct comparison of in vitro- and in vivo-derived interneurons • Identification of transcriptional modules that developmentally define interneurons, Plath, Lowry and colleagues profile interneurons generated from human pluripotent stem cells by various methods to understand the heterogeneity and cellular state of interneuron cultures in vitro. Using single-cell analyses, the authors define the homogeneity and maturity achieved with each in vitro method. By directly comparing these interneurons with those born in the human brain, the authors highlight distinctions particularly in synaptic genes and transcription factor modules that distinguish in vitro- and in vivo-derived neurons.

Published
2021

20. Left-handedness, learning disability, autoimmune disease, and seizure history influence age at onset and phenotypical targeting of Alzheimer’s disease

Author

Zachary A. Miller, Rik Ossenkoppele, Neill R. Graff-Radford, Isabel E. Allen, Wendy Shwe, Lynne Rosenberg, Dustin J Olguin, Michael G. Erkkinen, P. Monroe Butler, Salvatore Spina, Jennifer S. Yokoyama, Rahul S. Desikan, Philip Scheltens, Wiesje van der Flier, Yolande Pijnenburg, Emma Wolters, Rosa Rademakers, Daniel H. Geschwind, Joel H. Kramer, Howard J. Rosen, Katherine P. Rankin, Lea T. Grinberg, William W. Seeley, Virginia Sturm, David C. Perry, Bruce L. Miller, Gil D. Rabinovici, and Maria Luisa Gorno-Tempini

Abstract

BackgroundRisk factors associated with sporadic non-amnestic and early-onset Alzheimer’s disease remain underexamined. We investigated a large, clinically heterogeneous Alzheimer’s disease cohort for frequencies of established Alzheimer’s disease risk factors (hypertension, hyperlipidemia, diabetes mellitus,APOE-ɛ4 frequency, and years of education), alongside a suite of novel factors with historical theoretical association (non-right-handedness, learning disability, seizures, and autoimmune disease).MethodsIn this case-control study, we screened the demographic and health histories of 750 consecutive early-onset and 750 late-onset Alzheimer’s disease patients from the University of California San Francisco Memory and Aging Center for the prevalence of conventional risk and novel Alzheimer’s disease factors and compared these results with 8,859 Alzheimer’s disease individuals from the National Alzheimer’s Coordinating Center, Amsterdam University Medical Center, Amsterdam, and Mayo Clinic, Jacksonville.ResultsEarly-onset Alzheimer’s disease was associated with significantly lower frequencies of established risk factors (hypertension, hyperlipidemia, diabetes mellitus, allpAPOE-ɛ4,p=0.03) and significantly higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, allpp=0.002, and autoimmune disease,p=0.007). Logistic regressions predicting EOAD vs. LOAD controlling for sex, education,APOE-ɛ4 status, typical, and novel risk factors, produced findings consistent with the above. Principal component analysis loaded novel factors into two components, non-right-handedness and learning disability versus seizure and autoimmune disease, and the combination of factors from both components resulted in an exponential decrease in age at onset from any single factor alone.APOE-ɛ4 provided no additional contribution to age at onset decreases within the non-amnestic Alzheimer’s disease cohort but shifted the age of onset 3 years earlier within amnestic presentations (p=0.013).ConclusionsWe identified non-right-handedness, learning disability, seizures, and autoimmune disease as novel factors that affect both the age at onset and phenotypical targeting of Alzheimer’s disease. Together these results support a new theoretical framework of neurodegenerative disease susceptibility and that through the collection of detailed developmental and health history, neurodegenerative disease risk in some may be highly predictable, offering new opportunities towards early detection, monitoring, therapeutic intervention, and ultimately disease prevention.

Published
2022

21. The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration

Author

Hannah Hafner, Lucas D Huffman, Xiao-Feng Zhao, Mitre Athaiya, Matthew C Finneran, Ashley L Kalinski, Rafi Kohen, Corey Flynn, Ryan Passino, Craig N Johnson, David Kohrman, Riki Kawaguchi, Lynda JS Yang, Jeffery L Twiss, Daniel H Geschwind, Gabriel Corfas, and Roman J Giger

Subjects
General Immunology and Microbiology, General Neuroscience, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

Upon trauma, the adult murine PNS displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1-day, 3-days, and 7-days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac in the injured nerve show high glycolytic flux compared to Mo/Mac in blood and dominate the early injury response. They subsequently give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood-nerve-barrier, proliferation of endoneurial and perineurial stromal cells, and accumulation of select serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1-/- mice, where Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand-receptor interactions. Our longitudinal analysis represents a new resource for nerve regeneration, reveals location specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/

Published
2022

22. Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Author

Masahiro Kanai, Roy Elzur, Wei Zhou, Mark J. Daly, Hilary K. Finucane, Kuan-Han H. Wu, Humaira Rasheed, Kristin Tsuo, Jibril B. Hirbo, Ying Wang, Arjun Bhattacharya, Huiling Zhao, Shinichi Namba, Ida Surakka, Brooke N. Wolford, Valeria Lo Faro, Esteban A. Lopera-Maya, Kristi Läll, Marie-Julie Favé, Juulia J. Partanen, Sinéad B. Chapman, Juha Karjalainen, Mitja Kurki, Mutaamba Maasha, Ben M. Brumpton, Sameer Chavan, Tzu-Ting Chen, Michelle Daya, Yi Ding, Yen-Chen A. Feng, Lindsay A. Guare, Christopher R. Gignoux, Sarah E. Graham, Whitney E. Hornsby, Nathan Ingold, Said I. Ismail, Ruth Johnson, Triin Laisk, Kuang Lin, Jun Lv, Iona Y. Millwood, Sonia Moreno-Grau, Kisung Nam, Priit Palta, Anita Pandit, Michael H. Preuss, Chadi Saad, Shefali Setia-Verma, Unnur Thorsteinsdottir, Jasmina Uzunovic, Anurag Verma, Matthew Zawistowski, Xue Zhong, Nahla Afifi, Kawthar M. Al-Dabhani, Asma Al Thani, Yuki Bradford, Archie Campbell, Kristy Crooks, Geertruida H. de Bock, Scott M. Damrauer, Nicholas J. Douville, Sarah Finer, Lars G. Fritsche, Eleni Fthenou, Gilberto Gonzalez-Arroyo, Christopher J. Griffiths, Yu Guo, Karen A. Hunt, Alexander Ioannidis, Nomdo M. Jansonius, Takahiro Konuma, Ming Ta Michael Lee, Arturo Lopez-Pineda, Yuta Matsuda, Riccardo E. Marioni, Babak Moatamed, Marco A. Nava-Aguilar, Kensuke Numakura, Snehal Patil, Nicholas Rafaels, Anne Richmond, Agustin Rojas-Muñoz, Jonathan A. Shortt, Peter Straub, Ran Tao, Brett Vanderwerff, Manvi Vernekar, Yogasudha Veturi, Kathleen C. Barnes, Marike Boezen, Zhengming Chen, Chia-Yen Chen, Judy Cho, George Davey Smith, Lude Franke, Eric R. Gamazon, Andrea Ganna, Tom R. Gaunt, Tian Ge, Hailiang Huang, Jennifer Huffman, Nicholas Katsanis, Jukka T. Koskela, Clara Lajonchere, Matthew H. Law, Liming Li, Cecilia M. Lindgren, Ruth J.F. Loos, Stuart MacGregor, Koichi Matsuda, Catherine M. Olsen, David J. Porteous, Jordan A. Shavit, Harold Snieder, Tomohiro Takano, Richard C. Trembath, Judith M. Vonk, David C. Whiteman, Stephen J. Wicks, Cisca Wijmenga, John Wright, Jie Zheng, Xiang Zhou, Philip Awadalla, Michael Boehnke, Carlos D. Bustamante, Nancy J. Cox, Segun Fatumo, Daniel H. Geschwind, Caroline Hayward, Kristian Hveem, Eimear E. Kenny, Seunggeun Lee, Yen-Feng Lin, Hamdi Mbarek, Reedik Mägi, Hilary C. Martin, Sarah E. Medland, Yukinori Okada, Aarno V. Palotie, Bogdan Pasaniuc, Daniel J. Rader, Marylyn D. Ritchie, Serena Sanna, Jordan W. Smoller, Kari Stefansson, David A. van Heel, Robin G. Walters, Sebastian Zöllner, null Biobank of the Americas, null Biobank Japan Project, null BioMe, null BioVU, null CanPath - Ontario Health Study, null China Kadoorie Biobank Collaborative Group, null Colorado Center for Personalized Medicine, null deCODE Genetics, null Estonian Biobank, FinnGen, null Generation Scotland, null Genes & Health Research Team, null LifeLines, null Mass General Brigham Biobank, null Michigan Genomics Initiative, null National Biobank of Korea, null Penn Medicine BioBank, null Qatar Biobank, null The Qskin Sun and Health Study, null Taiwan Biobank, null The Hunt Study, null Ucla Atlas Community Health Initiative, null Uganda Genome Resource, null Uk Biobank, Alicia R. Martin, Cristen J. Willer, Benjamin M. Neale, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Data Science Genetic Epidemiology Lab, Research Programs Unit, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and University of Helsinki

Subjects
biobank, meta-analysis, genome-wide association study, fine-mapping, Genetics, 1184 Genetics, developmental biology, physiology, GWAS, 3111 Biomedicine, heterogeneity, summary statistics, Biochemistry, Genetics and Molecular Biology (miscellaneous), linkage disequilibrium, miscalibration
Abstract

Funding Information: We acknowledge all the participants and researchers of the 23 biobanks that have contributed to the GBMI. Biobank-specific acknowledgments are included in the Data S3 . We thank H. Huang, A.R. Martin, B.M. Neale, Y. Okada, K. Tsuo, J.C. Ulirsch, Y. Wang, and all the members of Finucane and Daly labs for their helpful feedback. M.K. was supported by a Nakajima Foundation Fellowship and the Masason Foundation . H.K.F. was funded by NIH grant DP5 OD024582 . Publisher Copyright: © 2022 The Author(s) Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary statistics-based quality-control (QC) method, suspicious loci analysis of meta-analysis summary statistics (SLALOM), that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics. We validate SLALOM in simulations and the GWAS Catalog. Applying SLALOM to 14 meta-analyses from the Global Biobank Meta-analysis Initiative (GBMI), we find that 67% of loci show suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci are significantly depleted for having nonsynonymous variants as lead variant (2.7×; Fisher's exact p = 7.3 × 10−4). We find limited evidence of fine-mapping improvement in the GBMI meta-analyses compared with individual biobanks. We urge extreme caution when interpreting fine-mapping results from meta-analysis of heterogeneous cohorts.

Published
2022

23. Tuberous Sclerosis Complex is associated with a novel human tauopathy

Author

Ji-Hye L. Hwang, Olga S. Perloff, Stephanie E. Gaus, Camila Benitez, Carolina Alquezar, Celica Q. Cosme, Alissa L. Nana, Sarat C. Vatsavayai, Eliana M. Ramos, Daniel H. Geschwind, Bruce L. Miller, Aimee W. Kao, and William W. Seeley

Subjects
Adult, Aging, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Neurodegenerative, Alzheimer's Disease, Article, Pathology and Forensic Medicine, Neurofibrillary tangle, Cellular and Molecular Neuroscience, Rare Diseases, Tuberous Sclerosis, Clinical Research, Acquired Cognitive Impairment, Humans, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Related Dementias (ADRD), Epilepsy, Amyloid beta-Peptides, Neurology & Neurosurgery, Tumor Suppressor Proteins, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acetylation, TSC2, TSC1, Brain Disorders, Tauopathy, Frontotemporal Dementia (FTD), Tauopathies, Tuberous sclerosis complex, Mutation, Neurological, Dementia, Neurology (clinical), Tau
Abstract

Tuberous sclerosis complex (TSC) is a neurogenetic disorder leading to epilepsy, developmental delay, and neurobehavioral dysfunction. The syndrome is caused by pathogenic variants in TSC1 (coding for hamartin) or TSC2 (coding for tuberin). Recently, we reported a progressive frontotemporal dementia-like clinical syndrome in a patient with a mutation in TSC1, but the neuropathological changes seen in adults with TSC with or without dementia have yet to be systematically explored. Here, we examined neuropathological findings in adults with TSC (n = 11) aged 30-58years and compared them to age-matched patients with epilepsy unrelated to TSC (n = 9) and non-neurological controls (n = 10). In 3 of 11 subjects with TSC, we observed a neurofibrillary tangle-predominant "TSC tauopathy" not seen in epilepsy or non-neurological controls. This tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition. The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers. Tau acetylation (K274, K343) was prominent in both TSC1 and TSC2, whereas tau phosphorylation at a common phospho-epitope (S202) was observed only in TSC2. TSC tauopathy was observed in selected neocortical, limbic, subcortical, and brainstem sites and showed a 3-repeat greater than 4-repeat tau isoform pattern in both TSC1 and TSC2 mutation carriers, but no tangles were immunolabeled with MC1 or p62 antibodies. The findings suggest that individuals with TSC are at risk for a unique tauopathy in mid-life and that tauopathy pathogenesis may involve TSC1, TSC2, and related molecular pathways.

Published
2022

24. Rare Genetic Risk in Progressive Supranuclear Palsy

Author

Timothy Chang, Hui Wang, Wan‐Ping Lee, Urvashi Kumar, Yuk Yee Leung, Dennis W. Dickson, Clifton L. Dalgard, Li‐San Wang, Gerard D. Schellenberg, and Daniel H. Geschwind

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

25. Linear discriminant analysis of phenotypic data for classifying autism spectrum disorder by diagnosis and sex

Author

Zachary, Jacokes, Allison, Jack, Catherine A W, Sullivan, Elizabeth, Aylward, Susan Y, Bookheimer, Mirella, Dapretto, Raphael A, Bernier, Daniel H, Geschwind, Denis G, Sukhodolsky, James C, McPartland, Sara J, Webb, Carinna M, Torgerson, Jeffrey, Eilbott, Lauren, Kenworthy, Kevin A, Pelphrey, John D, Van Horn, and Julie, Wolf

Subjects
General Neuroscience
Abstract

Autism Spectrum Disorder (ASD) is a developmental condition characterized by social and communication differences. Recent research suggests ASD affects 1-in-44 children in the United States. ASD is diagnosed more commonly in males, though it is unclear whether this diagnostic disparity is a result of a biological predisposition or limitations in diagnostic tools, or both. One hypothesis centers on the ‘female protective effect,’ which is the theory that females are biologically more resistant to the autism phenotype than males. In this examination, phenotypic data were acquired and combined from four leading research institutions and subjected to multivariate linear discriminant analysis. A linear discriminant model was trained on the training set and then deployed on the test set to predict group membership. Multivariate analyses of variance were performed to confirm the significance of the overall analysis, and individual analyses of variance were performed to confirm the significance of each of the resulting linear discriminant axes. Two discriminant dimensions were identified between the groups: a dimension separating groups by the diagnosis of ASD (LD1: 87% of variance explained); and a dimension reflective of a diagnosis-by-sex interaction (LD2: 11% of variance explained). The strongest discriminant coefficients for the first discriminant axis divided the sample in domains with known differences between ASD and comparison groups, such as social difficulties and restricted repetitive behavior. The discriminant coefficients for the second discriminant axis reveal a more nuanced disparity between boys with ASD and girls with ASD, including executive functioning and high-order behavioral domains as the dominant discriminators. These results indicate that phenotypic differences between males and females with and without ASD are identifiable using parent report measures, which could be utilized to provide additional specificity to the diagnosis of ASD in female patients, potentially leading to more targeted clinical strategies and therapeutic interventions. The study helps to isolate a phenotypic basis for future empirical work on the female protective effect using neuroimaging, EEG, and genomic methodologies.

Published
2022

27. P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells

Author

Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Rachna Prasad, Yue Qin, Maverick Johnson, Qing Wang, Nathan VanderVeer-Harris, Amy Pham, Alvaro G. Alvarado, Michael C. Condro, Fuying Gao, Raymond Gau, Maria G. Castro, Pedro R. Lowenstein, Arjun Deb, Jason D. Hinman, Frank Pajonk, Terry C. Burns, Steven A. Goldman, Daniel H. Geschwind, and Harley I. Kornblum

Subjects
Multidisciplinary, Neurosciences, General Physics and Astronomy, Glioma, General Chemistry, Stem Cell Research, Chromatin, General Biochemistry, Genetics and Molecular Biology, Brain Disorders, Brain Cancer, Neoplasm Recurrence, Rare Diseases, Local, Neoplastic Stem Cells, Genetics, Humans, Stem Cell Research - Nonembryonic - Non-Human, Neoplasm Recurrence, Local, Histone Acetyltransferases, Cancer
Abstract

Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.

Published
2022

28. Single-nucleus expression analysis characterizes non-enhancing region of recurrent high-grade glioma

Author

Kunal S. Patel, Kaleab K. Tessema, Riki Kawaguchi, Alvaro G. Alvarado, Sree Deepthi Muthukrishnan, Akifumi Hagiwara, Vivek Swarup, Linda M. Liau, Anthony Wang, William Yong, Daniel H. Geschwind, Ichiro Nakano, Steven A. Goldman, Richard Everson, Benjamin M. Ellingson, and Harley I. Kornblum

Abstract

Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. We leveraged single-nucleus RNA-sequencing to compare prospectively identified biopsy specimens from CE and NE regions. Recurrent gliomas recapitulate the previously reported glioma cellular states of primary gliomas. Tumor cells in NE regions are enriched in oligodendrocyte progenitor cell-like and neural progenitor cell-like cellular states, while CE regions are enriched for astrocyte-like and mesenchymal-like states. These NE glioma cells have similar copy number alterations and proportions of proliferative and putative glioma stem cells relative to CE regions. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-neuron interactions. This comprehensive analysis illustrates differing tumor and non-tumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy.

Published
2022

29. Brain-trait-associated variants impact cell-type-specific gene regulation during neurogenesis

Author

Michael I. Love, Angela L. Elwell, Luis de la Torre-Ubieta, Dan Liang, Michael J. Lafferty, Daniel H. Geschwind, Kerry E. Cheek, Kenan P. Courtney, Jason L. Stein, Nil Aygün, Jessica T. Mory, Oleh Krupa, and Ellie Hadden-Ford

Subjects
Male, Chromosomal Proteins, Non-Histone, Neurogenesis, Primary Cell Culture, Quantitative Trait Loci, Neocortex, Genome-wide association study, Biology, Quantitative trait locus, Article, Fetus, Neural Stem Cells, Alzheimer Disease, Genetics, Humans, Genetic Predisposition to Disease, Alleles, Genetics (clinical), Neurons, Neuroticism, Regulation of gene expression, Genome, Human, Alternative splicing, Chromosome Mapping, Gene Expression Regulation, Developmental, Colocalization, Cell Differentiation, Parkinson Disease, Prognosis, Chromatin, Expression quantitative trait loci, Schizophrenia, Educational Status, Female, Transcriptome, Imputation (genetics), Genome-Wide Association Study
Abstract

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.

Published
2021

30. Three decades of ASD genetics: building a foundation for neurobiological understanding and treatment

Author

Daniel H. Geschwind and Katherine W Eyring

Subjects
Whole genome sequencing, Multifactorial Inheritance, Invited Review Article, Autism Spectrum Disorder, Systems biology, Context (language use), Genome-wide association study, General Medicine, Computational biology, Biology, medicine.disease, Autism spectrum disorder, Genetics, medicine, Humans, Autism, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Exome sequencing, Genome-Wide Association Study, Genetic association
Abstract

Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASDs) for which microarrays, whole exome sequencing and whole genome sequencing have yielded over a hundred causal loci. Genome-wide association studies in ASD have also been fruitful, identifying 5 genome-wide significant loci thus far and demonstrating a substantial role for polygenic inherited risk. Approaches rooted in systems biology and functional genomics have increasingly placed genes implicated by risk variants into biological context. Genetic risk affects a finite group of cell-types and biological processes, converging primarily on early stages of brain development (though, the expression of many risk genes persists through childhood). Coupled with advances in stem cell-based human in vitro model systems, these findings provide a basis for developing mechanistic models of disease pathophysiology.

Published
2021

31. The genetics of cortical organisation and development: A study of 2,347 neuroimaging phenotypes

Author

Varun Warrier, Eva-Maria Stauffer, Qin Qin Huang, Emilie M. Wigdor, Eric A.W. Slob, Jakob Seidlitz, Lisa Ronan, Sofie Valk, Travis T. Mallard, Andrew D. Grotzinger, Rafael Romero-Garcia, Simon Baron-Cohen, Daniel H. Geschwind, Madeline Lancaster, Graham K. Murray, Michael J. Gandal, Aaron Alexander-Bloch, Hyejung Won, Hilary C. Martin, Edward T. Bullmore, Richard A.I. Bethlehem, and Apollo - University of Cambridge Repository

Abstract

Our understanding of the genetic architecture of the human cerebral cortex is limited both in terms of the diversity of brain structural phenotypes and the anatomical granularity of their associations with genetic variants. Here, we conducted genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,843 individuals from the UK Biobank and the ABCD cohorts. These phenotypes include cortical thickness, surface area, grey matter volume, and measures of folding, neurite density, and water diffusion. We identified 4,349 experiment-wide significant loci associated with global and regional phenotypes. Multiple lines of analyses identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with surface area and volume specifically are associated with cephalic disorders. Finally, we identified complex inter-phenotype and inter-regional genetic relationships among the 13 phenotypes which reflect developmental differences among them. These analyses help refine the role of common genetic variants in human cortical development and organisation.One sentence summaryGWAS of 2,347 neuroimaging phenotypes shed light on the global and regional genetic organisation of the cortex, underlying cellular and developmental processes, and links to neurodevelopmental and cephalic disorders.

Published
2022

32. Functional regulatory variants implicate distinct transcriptional networks in dementia

Author

Yonatan A. Cooper, Noam Teyssier, Nina M. Dräger, Qiuyu Guo, Jessica E. Davis, Sydney M. Sattler, Zhongan Yang, Abdulsamie Patel, Sarah Wu, Sriram Kosuri, Giovanni Coppola, Martin Kampmann, and Daniel H. Geschwind

Subjects
Multidisciplinary, Alzheimer Disease, Genes, Reporter, Genetic Loci, Risk Factors, Untranslated Regions, Genetic Variation, Humans, Gene Regulatory Networks, Supranuclear Palsy, Progressive, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

Predicting the function of noncoding variation is a major challenge in modern genetics. In this study, we used massively parallel reporter assays to screen 5706 variants identified from genome-wide association studies for both Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP), identifying 320 functional regulatory variants (frVars) across 27 loci, including the complex 17q21.31 region. We identified and validated multiple risk loci using CRISPR interference or excision, including complement 4 ( C4A ) and APOC1 in AD and PLEKHM1 and KANSL1 in PSP. Functional variants disrupt transcription factor binding sites converging on enhancers with cell type–specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses suggest that noncoding genetic risk is driven by common genetic variants through their aggregate activity on specific transcriptional programs.

Published
2022

33. Multiplexed functional genomic assays to decipher the noncoding genome

Author

Yonatan A Cooper, Qiuyu Guo, and Daniel H Geschwind

Subjects
Genome, Genetics, Humans, General Medicine, Genomics, Molecular Biology, Genetics (clinical), Linkage Disequilibrium, Algorithms, Genome-Wide Association Study
Abstract

Linkage disequilibrium and the incomplete regulatory annotation of the noncoding genome complicates the identification of functional noncoding genetic variants and their causal association with disease. Current computational methods for variant prioritization have limited predictive value, necessitating the application of highly parallelized experimental assays to efficiently identify functional noncoding variation. Here, we summarize two distinct approaches, massively parallel reporter assays and CRISPR-based pooled screens and describe their flexible implementation to characterize human noncoding genetic variation at unprecedented scale. Each approach provides unique advantages and limitations, highlighting the importance of multimodal methodological integration. These multiplexed assays of variant effects are undoubtedly poised to play a key role in the experimental characterization of noncoding genetic risk, informing our understanding of the underlying mechanisms of disease-associated loci and the development of more robust predictive classification algorithms.

Published
2022

34. Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

Author

Michael I. Love, Justin M. Wolter, Marianna Yusupova, Oleh Krupa, Michael J. Lafferty, Angela L. Elwell, Dan Liang, Kenan P. Courtney, Melanie E. Garrett, Felix A Kyere, Jason L. Stein, Nil Aygün, Daniel H. Geschwind, Luis de la Torre-Ubieta, Kerry E. Cheek, Gregory E. Crawford, and Allison E. Ashley-Koch

Subjects
0301 basic medicine, Neurogenesis, Quantitative Trait Loci, Genome-wide association study, Quantitative trait locus, Biology, Genome, Article, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Genetic variation, Humans, Genetic Predisposition to Disease, Regulatory Elements, Transcriptional, Allele, Neurons, Genetics, Regulation of gene expression, Mental Disorders, General Neuroscience, Gene Expression Regulation, Developmental, Genetic Variation, Cell Differentiation, Chromatin, 030104 developmental biology, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract

Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, it remains poorly understood as to how these variants influence gene regulation. To model the functional impact of common genetic variation on the noncoding genome during human cortical development, we performed the assay for transposase accessible chromatin using sequencing (ATAC-seq) and analyzed chromatin accessibility quantitative trait loci (QTL) in cultured human neural progenitor cells and their differentiated neuronal progeny from 87 donors. We identified significant genetic effects on 988/1,839 neuron/progenitor regulatory elements, with highly cell-type and temporally specific effects. A subset (roughly 30%) of chromatin accessibility-QTL were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type-specific chromatin accessibility-QTL and brain-relevant genome-wide association data, we were able to fine-map and identify regulatory mechanisms underlying noncoding neuropsychiatric disorder risk loci.

Published
2021

35. A neurogenetic analysis of female autism

Author

Catherine Sullivan, Charles A. Nelson, Abha R. Gupta, Mirella Dapretto, Jeffrey Eilbott, Nadine Gaab, Allison Jack, Susan Y. Bookheimer, Raphael Bernier, Sara Jane Webb, Daniel H. Geschwind, Carinna M. Torgerson, Kevin A. Pelphrey, Zachary Jacokes, James C. McPartland, John D. Van Horn, and Elizabeth Aylward

Subjects
Male, Proband, medicine.medical_specialty, genetic structures, Adolescent, DNA Copy Number Variations, Genotype, Autism Spectrum Disorder, striatum, Neurogenetics, Neuroimaging, Audiology, behavioral disciplines and activities, mental disorders, medicine, Humans, genetics, Copy-number variation, Child, Sex Characteristics, medicine.diagnostic_test, AcademicSubjects/SCI01870, business.industry, social perception, Original Articles, medicine.disease, Magnetic Resonance Imaging, Corpus Striatum, Autism spectrum disorder, Cohort, functional MRI, Autism, AcademicSubjects/MED00310, Female, Neurology (clinical), Functional magnetic resonance imaging, business, Sex characteristics
Abstract

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8–17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts., Females are less frequently diagnosed with autism than males. Using functional brain imaging and genetic analyses, Jack et al. show that differences in the striatum, a part of the brain involved in attaching motivational value to stimuli in the environment, may contribute to autism risk in girls.

Published
2021

36. Emergent visual creativity in frontotemporal dementia is associated with dorsomedial visual cortex enhancement

Author

Adit Friedberg, Lorenzo Pasquini, Ryan Diggs, Erika A. Glaubitz, Lucia Lopez, Ignacio Illán-Gala, Leonardo Iaccarino, Renaud La Joie, Nidhi Mundada, Jesse Brown, Isabel Elaine Allen, Katherine P. Rankin, Luke W. Bonham, Jennifer S. Yokoyama, Eliana M. Ramos, Daniel H. Geschwind, Salvatore Spina, Lea T. Grinberg, Zachary A. Miller, Joel H. Kramer, Howard Rosen, Maria Luisa Gorno-Tempini, Gil Rabinovici, William W. Seeley, and Bruce L. Miller

Abstract

IMPORTANCEThe neurological substrates of visual creativity are unknown. We demonstrate the role of dorsomedial visual cortex in emergence of visual artistic creativity (VAC) in the setting of dementia. Our findings illuminate neural substrates of human creativity and suggest that hyperactivation of specific brain areas may manifest as enhanced cognitive or behavioral capacities.OBJECTIVETo determine the anatomical and physiological underpinnings of VAC in dementia.DESIGN, SETTING, AND PARTICIPANTSAs part of a prospective, longitudinal cohort study focused on frontotemporal dementia (FTD), 734 patients met research criteria for an FTD spectrum disorder between 2002 and 2019. Of these, seventeen showed emergence of visual artistic creativity (VAC-FTD). Two control groups (n = 51 each) were matched to VAC-FTD based on demographic and clinical parameters: (1) Not Visually Artistic FTD (NVA-FTD) and (2) Healthy Controls (HC).MAIN OUTCOMES AND MEASURESClinical, neuropsychological, genetic and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD to control groups.RESULTSEmergence of VAC occurred around the time of onset of symptoms, and was disproportionately seen in patients with temporal lobe predominant degeneration (n = 8/17). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in the patient-specific atrophy patterns in VAC-FTD (n = 17/17) and NVA-FTD (n = 45/51). Structural covariance analysis revealed that volume of this dorsal occipital region was strongly correlated, in VAC-FTD, but not in NVA-FTD or HC, with a volume in the primary motor cortex corresponding to the right hand representation. One patient, who underwent fluorodeoxyglucose positron emission tomography before and after VAC onset, showed increasing glucose metabolism in the dorsal occipital region over the interval when creativity emerged.CONCLUSIONS AND RELEVANCEFTD lesion-induced intensification of dorsal visual association cortex structure and function predisposes to emergence of VAC in certain environmental or genetic conditions. Paradoxical gains of function are early manifestations of neurodegenerative disease, and this study delineates a specific brain region associated with the emergence of VAC.

Published
2022

37. Distinct patterns of gene expression changes in the colon and striatum of young mice overexpressing alpha-synuclein support Parkinson Disease as a multi-system process

Author

Elizabeth Jane Videlock, Asa Hatami, Chunni Zhu, Riki Kawaguchi, Han Chen, Tasnin Khan, Swapna Joshi, Jill M. Hoffman, Ka Man Law, Carl Robert Rankin, Lin Chang, Nigel T. Maidment, Varghese John, Daniel H. Geschwind, and Charalabos Pothoulakis

Abstract

Background Parkinson Disease (PD) is increasingly being recognized as a disease of the gut-brain axis. Overexpression of human wild type α–synuclein under the neuron-specific Thy1 promoter (Thy1-haSyn) is a well-characterized mouse model of PD. In addition to a progressive motor phenotype, Thy1-haSyn mice have delayed colonic transit at three months of age mirroring prodromal constipation common in human PD. Identification of initial molecular changes in the gastrointestinal tract in PD could lead to early detection of PD and/or gut-targeted therapies to prevent motor symptoms in PD. Methods Colon and striatum gene expression profiling was performed in Thy1-haSyn and wild type (WT) mice aged 1 month and 3 months using 3′ RNA sequencing. Analysis of transcriptomic data included identification of differentially expressed genes, gene set enrichment analysis and weighted gene co-expression network analysis (WGCNA). WGCNA results were further analyzed by linear regression to identify modules most strongly associated with Thy1-haSyn in the colon and striatum, as well as in a combined multivariate model. Module annotation included enrichment for gene ontology terms, cell type signatures and risk genes. Results Differential gene expression in Thy1-haSyn vs WT was greater at one vs three months in both the colon and striatum. There was an opposite pattern of enrichment of mitochondrial genes related to PD (KEGG PD pathway) in striatum (enriched in WT) and colon (enriched in Thy1-haSyn). Colon Thy1-haSyn-associated WGCNA modules were enriched for PD risk genes and PD-relevant pathways including inflammation, autophagy, and oxidative stress. When combined with striatum modules, colon modules remained independent predictors of Thy1-haSyn genotype and increased the model fit (p = 0.048). Conclusions Overexpression of alpha synuclein acutely disrupts gene expression in the colon. While changes in colon gene expression are highly related to known PD-relevant mechanisms, they are distinct from brain changes and in some cases opposite in direction. These findings are in line with the emerging view of PD as a multi-system disease.

Published
2022

38. The Contributions of Rare Inherited and Polygenic Risk to ASD in Multiplex Families

Author

Timothy S Chang, Matilde Cirnigliaro, Stephanie A Arteaga, Laura Pérez-Cano, Elizabeth K Ruzzo, Aaron Gordon, Lucy Bicks, Jae-Yoon Jung, Jennifer K Lowe, Dennis P Wall, and Daniel H Geschwind

Abstract

Autism Spectrum Disorder (ASD) has a complex genetic architecture involving contributions from de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation, or its interaction with polygenic risk in ASD. Here, we performed whole genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having 2 or more affected children with ASD. Using this study design, we identify seven novel risk genes supported primarily by rare inherited variation, finding support for a total of 74 genes in our cohort and a total of 152 genes after combining with other studies. Probands demonstrated an increased burden of mutations in 2 or more known risk genes (KARGs) — in three families both probands inherited protein truncating variants in two KARGs. We also find that polygenic risk is over transmitted from unaffected parents to affected children with rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD polygenic risk over-transmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.

Published
2022

39. Long-term maturation of human cortical organoids matches key early postnatal transitions

Author

Steve Horvath, Aaron Gordon, Jimena Andersen, John R. Huguenard, Xinshu Xiao, Jin-Young Park, Christopher D. Makinson, Sergiu P. Pașca, Daniel H. Geschwind, Se-Jin Yoon, Stephen Tran, and Alfredo M. Valencia

Subjects
0301 basic medicine, General Neuroscience, Induced Pluripotent Stem Cells, Gene regulatory network, Cell Differentiation, Neurodegenerative Diseases, DNA Methylation, In Vitro Techniques, Biology, Article, Organoids, Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Directed differentiation, RNA editing, Gene expression, Histone deacetylase complex, Organoid, Humans, Gene Regulatory Networks, Epigenetics, Neuroscience, 030217 neurology & neurosurgery
Abstract

Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling.

Published
2021

40. Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts

Author

Ying Wang, Shinichi Namba, Esteban Lopera, Sini Kerminen, Kristin Tsuo, Kristi Läll, Masahiro Kanai, Wei Zhou, Kuan-Han Wu, Marie-Julie Favé, Laxmi Bhatta, Philip Awadalla, Ben Brumpton, Patrick Deelen, Kristian Hveem, Valeria Lo Faro, Reedik Mägi, Yoshinori Murakami, Serena Sanna, Jordan W. Smoller, Jasmina Uzunovic, Brooke N. Wolford, Cristen Willer, Eric R. Gamazon, Nancy J. Cox, Ida Surakka, Yukinori Okada, Alicia R. Martin, Jibril Hirbo, Kuan-Han H. Wu, Humaira Rasheed, Jibril B. Hirbo, Arjun Bhattacharya, Huiling Zhao, Esteban A. Lopera-Maya, Sinéad B. Chapman, Juha Karjalainen, Mitja Kurki, Maasha Mutaamba, Juulia J. Partanen, Ben M. Brumpton, Sameer Chavan, Tzu-Ting Chen, Michelle Daya, Yi Ding, Yen-Chen A. Feng, Christopher R. Gignoux, Sarah E. Graham, Whitney E. Hornsby, Nathan Ingold, Ruth Johnson, Triin Laisk, Kuang Lin, Jun Lv, Iona Y. Millwood, Priit Palta, Anita Pandit, Michael H. Preuss, Unnur Thorsteinsdottir, Matthew Zawistowski, Xue Zhong, Archie Campbell, Kristy Crooks, Geertruida H. de Bock, Nicholas J. Douville, Sarah Finer, Lars G. Fritsche, Christopher J. Griffiths, Yu Guo, Karen A. Hunt, Takahiro Konuma, Riccardo E. Marioni, Jansonius Nomdo, Snehal Patil, Nicholas Rafaels, Anne Richmond, Jonathan A. Shortt, Peter Straub, Ran Tao, Brett Vanderwerff, Kathleen C. Barnes, Marike Boezen, Zhengming Chen, Chia-Yen Chen, Judy Cho, George Davey Smith, Hilary K. Finucane, Lude Franke, Andrea Ganna, Tom R. Gaunt, Tian Ge, Hailiang Huang, Jennifer Huffman, Jukka T. Koskela, Clara Lajonchere, Matthew H. Law, Liming Li, Cecilia M. Lindgren, Ruth J.F. Loos, Stuart MacGregor, Koichi Matsuda, Catherine M. Olsen, David J. Porteous, Jordan A. Shavit, Harold Snieder, Richard C. Trembath, Judith M. Vonk, David Whiteman, Stephen J. Wicks, Cisca Wijmenga, John Wright, Jie Zheng, Xiang Zhou, Michael Boehnke, Daniel H. Geschwind, Caroline Hayward, Eimear E. Kenny, Yen-Feng Lin, Hilary C. Martin, Sarah E. Medland, Aarno V. Palotie, Bogdan Pasaniuc, Kari Stefansson, David A. van Heel, Robin G. Walters, Sebastian Zöllner, Cristen J. Willer, Mark J. Daly, and Benjamin M. Neale

Subjects
polygenic risk scores, Genetics, accuracy heterogeneity, Global-Biobank Meta-analysis Initiative, multi-ancestry genetic prediction, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.

Published
2023

41. Functional genomics links genetic origins to pathophysiology in neurodegenerative and neuropsychiatric disease

Author

Daniel H. Geschwind and Brie Wamsley

Subjects
Psychological intervention, Early detection, Context (language use), Neurodegenerative, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Genetics, 2.1 Biological and endogenous factors, Animals, Humans, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Aetiology, 030304 developmental biology, 0303 health sciences, Mental Disorders, Human Genome, Neurosciences, Neurodegenerative Diseases, Single Nucleotide, Genomics, Life stage, Genetic architecture, Brain Disorders, Mental Health, Gene Expression Regulation, Neurological, Functional genomics, Neuroscience, 030217 neurology & neurosurgery, Developmental Biology, Neuropsychiatric disease
Abstract

Neurodegenerative and neuropsychiatric disorders are pervasive and debilitating conditions characterized by diverse clinical syndromes and comorbidities, whose origins are as complex and heterogeneous as their associated phenotypes. Risk for these disorders involves substantial genetic liability, which has fueled large-scale genetic studies that have led to a flood of discoveries. In turn, these discoveries have exposed substantial gaps in our knowledge with regards to the complicated genetic architecture of each disorder and the substantial amount of genetic overlap among disorders, which implies some degree of shared pathophysiology underlying these clinically distinct, multifactorial disorders. Understanding the role of specific genetic variants will involve resolving the connections between molecular pathways, heterogeneous cell types, specific circuits and disease pathogenesis at the tissue and patient level. We consider the current known genetic basis of these disorders and highlight the utility of molecular systems approaches that establish the function of genetic variation in the context of specific neurobiological networks, cell-types, and life stages. Beyond expanding our knowledge of disease mechanisms, understanding these relationships provides promise for early detection and potential therapeutic interventions.

Published
2020

42. Brain volumetric deficits in MAPT mutation carriers: a multisite study

Author

Arthur W. Toga, Virginia E. Sturm, Walter A. Kukull, Leah K. Forsberg, Ging-Yuek Robin Hsiung, Ian R. A. Mackenzie, Howard Feldman, Howard J. Rosen, Neill R. Graff-Radford, Bruce L. Miller, Joel H. Kramer, Artfl, John C Van Swieten, Jersey Deng, Julie A. Fields, Adam L. Boxer, Sandra Weintraub, Bonnie Wong, Erik D. Roberson, Bradford C. Dickerson, Murray Grossman, Eliana Marisa Ramos, Maria I. Lapid, Stephanie A. Chu, Kejal Kantarci, Liwen Zhang, Ashley Vetor, Tatiana Foroud, William W. Seeley, Zbigniew K. Wszolek, John Kornak, Mario F. Mendez, Adam M. Staffaroni, Maria Carmela Tartaglia, Jamie Fong, Chiadi U. Onyike, Hilary W. Heuer, Irene Litvan, Nadine Tatton, Edward D. Huey, Lize C. Jiskoot, Danielle Brushaber, David J Irwin, Suzee E. Lee, Nupur Ghoshal, Janne M. Papma, Yvette Bordelon, Ralitza H. Gavrilova, Anna Karydas, Taru Flagan, David S. Knopman, Kelley Faber, Daniel H. Geschwind, Jennifer S. Yokoyama, Salvatore Spina, Rosa Rademakers, Bradley F. Boeve, Giovanni Coppola, Alexander Pantelyat, Daniel I. Kaufer, ARTFL/LEFFTDS Consortium, and Neurology

Subjects
Adult, Male, 0301 basic medicine, Heterozygote, Pathology, medicine.medical_specialty, Uncinate fasciculus, tau Proteins, Corpus callosum, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine, Humans, Dementia, Biology, Research Articles, Aged, Temporal cortex, business.industry, General Neuroscience, Parkinsonism, Brain, Middle Aged, medicine.disease, 030104 developmental biology, Frontotemporal Dementia, Mutation, Female, Human medicine, Neurology (clinical), business, Insula, 030217 neurology & neurosurgery, Research Article, Frontotemporal dementia
Abstract

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Published
2020

43. Microglia-organized scar-free spinal cord repair in neonatal mice

Author

Xuelian He, Bo Chen, Aboozar Monavarfeshani, Phillip G. Popovich, Anne Jacobi, Riki Kawaguchi, Daniel H. Geschwind, Junjie Zhu, Yu Zhang, Zhiyun Yang, Zhigang He, Yi Li, Songlin Zhou, Vivek Swarup, Q. Wang, Huyan Meng, and Zhongju Shi

Subjects
0301 basic medicine, Spinal Cord Regeneration, Pathology, medicine.medical_specialty, Cord, Article, Cicatrix, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Homeostasis, Protease Inhibitors, RNA-Seq, Axon, Spinal cord injury, Spinal Cord Injuries, Wound Healing, Multidisciplinary, Microglia, biology, business.industry, medicine.disease, Spinal cord, Axons, Fibronectins, Transplantation, Fibronectin, 030104 developmental biology, medicine.anatomical_structure, Animals, Newborn, Spinal Cord, nervous system, Crush injury, biology.protein, Single-Cell Analysis, business, 030217 neurology & neurosurgery
Abstract

Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons1–4. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal—but not adult—microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system. In neonatal mice, scar-free healing after spinal cord injury is organized by microglia, and transplantation of neonatal microglia or peptidase-inhibitor-treated adult microglia into adult mice after injury improves healing and axon regrowth.

Published
2020

45. Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect

Author

Daniel H. Geschwind, Mirella Dapretto, Jennifer K. Lowe, Kevin A. Pelphrey, Shulamite A. Green, Emily Fuster, Katherine E. Lawrence, Susan Y. Bookheimer, James C. McPartland, John D. Van Horn, Leanna M. Hernandez, Genevieve Patterson, Allison Jack, Nana J. Okada, Raphael Bernier, Jackson N Hoekstra, Namita T Padgaonkar, Jiwon Jung, Sara J Webb, Elizabeth Aylward, and Nadine Gaab

Subjects
Male, Imaging genetics, Autism Spectrum Disorder, Autism, Medical and Health Sciences, Developmental psychology, 2.1 Biological and endogenous factors, Genetic risk, Aetiology, Child, Pediatric, Brain Mapping, Functional connectivity, Brain, Serious Mental Illness, Magnetic Resonance Imaging, Genetic load, female protective effect, Mental Health, Autism spectrum disorder, Neurological, imaging genetics, Original Article, Female, social and economic factors, Psychology, polygenic risk, Adolescent, Intellectual and Developmental Disabilities (IDD), 1.1 Normal biological development and functioning, 2.3 Psychological, Underpinning research, mental disorders, Behavioral and Social Science, medicine, Genetics, Humans, Autistic Disorder, Neurology & Neurosurgery, Mechanism (biology), Prevention, functional connectivity, Psychology and Cognitive Sciences, Neurosciences, medicine.disease, Brain Disorders, GENDAAR Consortium, Polygenic risk score, Neurology (clinical)
Abstract

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8–17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Published
2022

46. The UCLA ATLAS Community Health Initiative: promoting precision health research in a diverse biobank

Author

Ruth Johnson, Yi Ding, Arjun Bhattacharya, Alec Chiu, Clara Lajonchere, Daniel H. Geschwind, and Bogdan Pasaniuc

Abstract

The UCLA ATLAS Community Health Initiative (ATLAS) has an initial target to recruit 150,000 participants from across the UCLA Health system, with the goal of creating a genomic database to accelerate precision medicine efforts in California. This initiative includes a biobank embedded within the UCLA Health system that comprises de-identified genomic data linked to electronic health records (EHR). The first freeze of data from September 2020 contains 27,987 genotyped samples imputed to 7.9 million SNPs across the genome and is linked with a de-identified EHR extract. This database enables the study of numerous clinically-related phenotypes within the same medical system. Here we describe a centralized repository of the genotype data and provide tools and pipelines to perform genome-wide and phenome-wide association studies across a wide range of EHR-derived phenotypes and genetic ancestry groups. We demonstrate the utility of this resource through the analysis of 7 well-studied traits and recapitulate many previous genetic and phenotypic associations.

Published
2022

47. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

Author

Tara E. Tracy, Jesus Madero-Pérez, Danielle L. Swaney, Timothy S. Chang, Michelle Moritz, Csaba Konrad, Michael E. Ward, Erica Stevenson, Ruth Hüttenhain, Grant Kauwe, Maria Mercedes, Lauren Sweetland-Martin, Xu Chen, Sue-Ann Mok, Man Ying Wong, Maria Telpoukhovskaia, Sang-Won Min, Chao Wang, Peter Dongmin Sohn, Jordie Martin, Yungui Zhou, Wenjie Luo, John Q. Trojanowski, Virginia M.Y. Lee, Shiaoching Gong, Giovanni Manfredi, Giovanni Coppola, Nevan J. Krogan, Daniel H. Geschwind, and Li Gan

Subjects
Proteomics, Aging, interactome, Neurodegenerative, Alzheimer's Disease, Severity of Illness Index, Medical and Health Sciences, protein-protein interaction, synapse, 2.1 Biological and endogenous factors, Protein Interaction Maps, Amino Acids, APEX, Aetiology, Alzheimer's Disease Related Dementias (ADRD), Neurons, Stem Cell Research - Induced Pluripotent Stem Cell - Human, neurodegeneration, Brain, Biological Sciences, Mitochondria, Frontotemporal Dementia (FTD), Tauopathies, Frontotemporal Dementia, Neurological, Disease Progression, Tau secretion, Subcellular Fractions, Protein Binding, Induced Pluripotent Stem Cells, tau Proteins, General Biochemistry, Genetics and Molecular Biology, Protein Domains, Alzheimer Disease, Acquired Cognitive Impairment, Humans, Biotinylation, Cell Nucleus, Stem Cell Research - Induced Pluripotent Stem Cell, affinity purification mass spectrometry, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Stem Cell Research, Brain Disorders, Synapses, Nerve Degeneration, Mutation, Mutant Proteins, Dementia, Tau, Energy Metabolism, Developmental Biology
Abstract

Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated inAD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau's role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.

Published
2022

48. Core Transcription Programs Controlling Injury-Induced Neurodegeneration of Retinal Ganglion Cells

Author

Feng Tian, Yuyan Cheng, Songlin Zhou, Qianbin Wang, Aboozar Monavarfeshani, Kun Gao, Weiqian Jiang, Riki Kawaguchi, Qing Wang, Mingjun Tang, Ryan Donahue, Huyan Meng, Anne Jacobi, Jiani Yin, Xinyi Cai, Shane Hegarty, Joanna Stanicka, Phillip Dmitriev, Daniel Taub, Clifford J. Woolf, Joshua R. Sanes, Daniel H. Geschwind, and Zhigang He

Subjects
sense organs, eye diseases
Abstract

SUMMARYNeurodegenerative diseases are characterized by neuronal death and regenerative failure. However, gene regulatory programs governing how initial neuronal injuries lead to neuronal death remain poorly understood. In adult mice, optic nerve crush (ONC) injury, which severs all axons of retinal ganglion cells (RGCs), results in massive death of axotomized RGCs and regenerative failure of survivors. We performed an in vivo CRISPR/Cas9-based genome-wide screen of 1893 transcription factors (TFs) to seek repressors of RGC survival and axon regeneration following ONC. In parallel, we profiled the epigenetic and transcriptional landscapes of injured RGCs by ATAC-seq and RNA-seq to identify critical injury responsive TFs and their targets. Remarkably, these independent analyses converged on a set of four ATF/CEBP transcription factors – ATF3, ATF4, C/EBPγ and CHOP (Ddit3) – as critical regulators of survival. Further studies indicate that these TFs contribute to two pro-death transcriptional programs: ATF3/CHOP preferentially regulate pathways activated by cytokines and innate immunity, whereas ATF4/C/EBPγ regulate pathways engaged by intrinsic neuronal stressors. Manipulation of these TFs also protects RGCs in an experimental model of glaucoma, a prevalent disease in which RGCs die. Together, our results reveal core transcription programs that transform an initial axonal insult into a degenerative result and suggest novel strategies for treating neurodegenerative diseases.

Published
2022

49. Case Report: Novel CSF1R Variant in a Patient With Behavioral Variant Frontotemporal Dementia Syndrome With Prodromal Repetitive Scratching Behavior

Author

Adit Friedberg, Eliana Marisa Ramos, Zhongan Yang, Luke W. Bonham, Jennifer S. Yokoyama, Peter A. Ljubenkov, Kyan Younes, Daniel H. Geschwind, and Bruce L. Miller

Subjects
Aging, Prevention, Clinical Sciences, Neurosciences, Neurodegenerative, frontotemporal dementia, repetitive behaviors, Brain Disorders, Rare Diseases, Neurology, Behavioral and Social Science, Neurological, Acquired Cognitive Impairment, Psychology, scratching, Dementia, Neurology (clinical), early symptoms, CSF1R-related leukoencephalopathy
Abstract

CSF1R-related leukoencephalopathy is an autosomal dominant neurodegenerative disease caused by mutations in the tyrosine kinase domain of the colony stimulating factor 1 receptor (CSF1R). Several studies have found that hematogenic stem cell transplantation is an effective disease modifying therapy however the literature regarding prodromal and early symptoms CSF1R-related leukoencephalopathy is limited. We describe a 63-year-old patient with 4 years of repetitive scratching and skin picking behavior followed by 10 years of progressive behavioral, cognitive, and motor decline in a pattern suggesting behavioral variant of frontotemporal dementia. Brain MRI demonstrated prominent frontal and parietal atrophy accompanied by underlying bilateral patchy white matter hyperintensities sparing the U fibers and cavum septum pellucidum. Whole-exome sequencing revealed a novel, predicted deleterious missense variant in a highly conserved amino acid in the tyrosine kinase domain of CSF1R (p.Gly872Arg). Given this evidence and the characteristic clinical and radiological findings this novel variant was classified as likely pathogenic according to the American College of Medical Genetics standard guidelines. Detailed description of the prodromal scratching and skin picking behavior and possible underlying mechanisms in this case furthers knowledge about early manifestations of CSF1R-related leukoencephalopathy with the hope that early detection and timely administration of disease modifying therapies becomes possible.

Published
2022

50. Sex Chromosome Aneuploidies are Underdiagnosed and Associated with Increased Risk of Mental Disorders

Author

Xabier Calle Sanchez, Simone Montalbano, Morteza Vaez, Morten Dybdahl Krebs, Jonas Bygbjerg-Grauholm, Preben B. Mortensen, Anders D. Børglum, David M. Hougaard, Merete Nordentoft, Daniel H. Geschwind, Alfonso Buil, Andrew J. Schork, Wesley K. Thompson, Armin Raznahan, Dorte Helenius, Thomas Werge, and Andrés Ingason

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published
2022

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