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4. Supercharging collaboration for bipolar research—Breakthrough discoveries for thriving with bipolar disorder (BD2).

Author

Altimus, C. M., Baxi, E. G., Frye, M. A., Nestler, E. J., Pham, D. L., and Burdick, K. E.

Subjects
BIPOLAR disorder, AFFECTIVE disorders, HEALTH care networks, GENETICS
Abstract

The article discusses the need for further research and understanding of bipolar disorder, a mood disorder that affects approximately 2% of the global population. The disorder is complex and heterogeneous, making it difficult to diagnose and treat effectively. The article introduces the BD2 initiative, which aims to address these challenges by increasing funding and collaboration in bipolar research. The initiative includes four interconnected programs focused on genetics, brain omics, hypothesis-driven discovery, and a learning health network. The goal is to accelerate the understanding of bipolar disorder and improve outcomes for individuals living with the illness. [Extracted from the article]

Published
2023
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5. The role of base excision repair in major depressive disorder and bipolar disorder

Author

Ceylan, Deniz (ORCID 0000-0002-1438-8240 & YÖK ID 137755), Kucuker, M.; Ozerdem, A.; Cabello-Arreola, A.; Ho, M. C.; Joseph, B.; Webb, L.; Croarkin, P.; Frye, M.; Veldic, M., School of Medicine, Ceylan, Deniz (ORCID 0000-0002-1438-8240 & YÖK ID 137755), Kucuker, M.; Ozerdem, A.; Cabello-Arreola, A.; Ho, M. C.; Joseph, B.; Webb, L.; Croarkin, P.; Frye, M.; Veldic, M., and School of Medicine

Abstract

NA

Published
2023

7. Magnetic Feshbach resonances between atoms in $^2$S and $^3$P$_0$ states: mechanisms and dependence on atomic properties

Author

Mukherjee, B., Frye, M. D., and Hutson, J. M.

Abstract

Magnetically tunable Feshbach resonances exist in ultracold collisions between atoms in 2 S and 3 P 0 states, such as an alkali-metal atom colliding with Yb or Sr in a clock state. We investigate the mechanisms of these resonances and identify the terms in the collision Hamiltonian responsible for them. They involve indirect coupling between the open and closed channels, via intermediate channels involving atoms in 3 P 1 states. The resonance widths are generally proportional to the square of the magnetic field and are strongly enhanced when the magnitude of the background scattering length is large. For any given pair of atoms, the scattering length can be tuned discretely by choosing different isotopes of the 3 P 0 atom. For each combination of an alkali-metal atom and either Yb or Sr, we consider the prospects of finding an isotopic combination that has both a large background scattering length and resonances at a high but experimentally accessible field. We conclude that 87 Rb + Yb , Cs + Yb , and 85 Rb + Sr are particularly promising combinations.

Published
2023
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8. Solar insolation in springtime influences age of onset of bipolar I disorder

Author

Bauer, M., Glenn, T., Alda, M., Aleksandrovich, M. A., Andreassen, O. A., Angelopoulos, E., Ardau, R., Ayhan, Y., Baethge, C., Bharathram, S. R., Bauer, R., Baune, B. T., Becerra‐Palars, C., Bellivier, F., Belmaker, R. H., Berk, M., Bersudsky, Y., Bicakci, Ş., Birabwa‐Oketcho, H., Bjella, T. D., Bossini, L., Cabrera, J., Cheung, E. Y. W., Del Zompo, M., Dodd, S., Donix, M., Etain, B., Fagiolini, A., Fountoulakis, K. N., Frye, M. A., Gonzalez‐Pinto, A., Gottlieb, J. F., Grof, P., Harima, H., Henry, C., Isometsä, E. T., Janno, S., Kapczinski, F., Kardell, M., Khaldi, S., Kliwicki, S., König, B., Kot, T. L., Krogh, R., Kunz, M., Lafer, B., Landén, M., Larsen, E. R., Lewitzka, U., Licht, R. W., Lopez‐Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez‐Cengotitabengoa, M., Melle, I., Meza‐Urzúa, F., Yee Ming, M., Monteith, S., Morken, G., Mosca, E., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nery, F. G., Nielsen, R. E., OʼDonovan, C., Omrani, A., Osher, Y., Østermark Sørensen, H., Ouali, U., Pica Ruiz, Y., Pilhatsch, M., Pinna, M., da Ponte, F. D. R., Quiroz, D., Ramesar, R., Rasgon, N., Reddy, M. S., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Scippa, Â. M., Severus, E., Simhandl, C., Stein, D. J., Strejilevich, S., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tagata, H., Tatebayashi, Y., Tondo, L., Torrent, C., Vaaler, A. E., Veeh, J., Vieta, E., Viswanath, B., Yoldi‐Negrete, M., Zetin, M., Zgueb, Y., and Whybrow, P. C.

Published
2017
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10. Clinical Correlates of Cardiac Conduction in Bipolar Disorder

Author

Prieto, M., primary, Carocca, A., additional, Fullerton, C., additional, Hidalgo, A., additional, Diaz, J., additional, San Martin, P., additional, Godoy, M., additional, Nuño, M., additional, De Leon, A., additional, Rodriguez, J., additional, Sanchez, R., additional, Batiz, F., additional, Castillo, A., additional, Cuellar-Barboza, A., additional, Biernacka, J., additional, and Frye, M., additional

Published
2022
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13. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Blokland, G.A., Grove, J, Chen, C.Y., Cotsapas, C., Tobet, S., Handa, R., Clair, D. St, Lencz, T., Mowry, B.J., Periyasamy, S., Cairns, M.J., Tooney, P.A., Wu, J.Q., Kelly, B., Kirov, G., Sullivan, P.F., Corvin, A., Riley, B.P., Esko, T., Milani, L., Jönsson, E.G., Palotie, A., Ehrenreich, H., Begemann, M., Steixner-Kumar, A., Sham, P.C., Iwata, N., Weinberger, D.R., Gejman, P.V., Sanders, A.R., Buxbaum, J.D., Rujescu, D., Giegling, I., Konte, B., Hartmann, A.M., Bramon, E., Murray, R.M., Pato, M.T., Lee, J., Melle, I., Molden, E., Ophoff, R.A., McQuillin, A., Bass, N.J., Adolfsson, R., Malhotra, A.K., Martin, N.G., Fullerton, J.M., Mitchell, P.B., Schofield, P.R., Forstner, A.J., Degenhardt, F., Schaupp, S., Comes, A.L., Kogevinas, M., Guzman-Parra, J., Reif, A., Streit, F., Sirignano, L., Cichon, S., Grigoroiu-Serbanescu, M., Hauser, J., Lissowska, J., Mayoral, F., Müller-Myhsok, B., Świątkowska, B., Schulze, T.G., Nöthen, M.M., Rietschel, M., Kelsoe, J., Leboyer, M., Jamain, S., Etain, B., Bellivier, F., Vincent, J.B., Alda, M., O'Donovan, C., Cervantes, P., Biernacka, J.M., Frye, M., McElroy, S.L., Scott, L.J., Stahl, E.A., Landén, M., Hamshere, M.L., Smeland, O.B., Djurovic, S., Vaaler, A.E., Andreassen, O.A., Baune, B.T., Air, T., Preisig, M., Uher, R., Levinson, D.F., Weissman, M.M., Potash, J.B., Shi, J., Knowles, J.A., Bralten, J.B., Perlis, R.H., Lucae, S., Blokland, G.A., Grove, J, Chen, C.Y., Cotsapas, C., Tobet, S., Handa, R., Clair, D. St, Lencz, T., Mowry, B.J., Periyasamy, S., Cairns, M.J., Tooney, P.A., Wu, J.Q., Kelly, B., Kirov, G., Sullivan, P.F., Corvin, A., Riley, B.P., Esko, T., Milani, L., Jönsson, E.G., Palotie, A., Ehrenreich, H., Begemann, M., Steixner-Kumar, A., Sham, P.C., Iwata, N., Weinberger, D.R., Gejman, P.V., Sanders, A.R., Buxbaum, J.D., Rujescu, D., Giegling, I., Konte, B., Hartmann, A.M., Bramon, E., Murray, R.M., Pato, M.T., Lee, J., Melle, I., Molden, E., Ophoff, R.A., McQuillin, A., Bass, N.J., Adolfsson, R., Malhotra, A.K., Martin, N.G., Fullerton, J.M., Mitchell, P.B., Schofield, P.R., Forstner, A.J., Degenhardt, F., Schaupp, S., Comes, A.L., Kogevinas, M., Guzman-Parra, J., Reif, A., Streit, F., Sirignano, L., Cichon, S., Grigoroiu-Serbanescu, M., Hauser, J., Lissowska, J., Mayoral, F., Müller-Myhsok, B., Świątkowska, B., Schulze, T.G., Nöthen, M.M., Rietschel, M., Kelsoe, J., Leboyer, M., Jamain, S., Etain, B., Bellivier, F., Vincent, J.B., Alda, M., O'Donovan, C., Cervantes, P., Biernacka, J.M., Frye, M., McElroy, S.L., Scott, L.J., Stahl, E.A., Landén, M., Hamshere, M.L., Smeland, O.B., Djurovic, S., Vaaler, A.E., Andreassen, O.A., Baune, B.T., Air, T., Preisig, M., Uher, R., Levinson, D.F., Weissman, M.M., Potash, J.B., Shi, J., Knowles, J.A., Bralten, J.B., Perlis, R.H., and Lucae, S.

Abstract

Item does not contain fulltext, BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and

Published
2022

14. Strategies and foundations for scientific discovery in longitudinal studies of bipolar disorder

Author

McInnis, MG, Andreassen, OA, Andreazza, AC, Alon, U, Berk, Michael, Brister, T, Burdick, KE, Cui, D, Frye, M, Leboyer, M, Mitchell, PB, Merikangas, K, Nierenberg, AA, Nurnberger, JI, Pham, D, Vieta, E, Yatham, LN, Young, AH, McInnis, MG, Andreassen, OA, Andreazza, AC, Alon, U, Berk, Michael, Brister, T, Burdick, KE, Cui, D, Frye, M, Leboyer, M, Mitchell, PB, Merikangas, K, Nierenberg, AA, Nurnberger, JI, Pham, D, Vieta, E, Yatham, LN, and Young, AH

Published
2022

15. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, Ruderfer, DM, Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, and Ruderfer, DM

Abstract

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Published
2022

17. Factory of the Year Prize - A Benchmarking

Author

Gallina, V, Viharos, Zsolt János, Nick, Gábor András, Frye, M, Kluth, A, and Szaller, Ádám

Subjects
QA75 Electronic computers. Computer science / számítástechnika, számítógéptudomány
Published
2022

32. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, N. Forstner, A.J. O’Connell, K.S. Coombes, B. Coleman, J.R.I. Qiao, Z. Als, T.D. Bigdeli, T.B. Børte, S. Bryois, J. Charney, A.W. Drange, O.K. Gandal, M.J. Hagenaars, S.P. Ikeda, M. Kamitaki, N. Kim, M. Krebs, K. Panagiotaropoulou, G. Schilder, B.M. Sloofman, L.G. Steinberg, S. Trubetskoy, V. Winsvold, B.S. Won, H.-H. Abramova, L. Adorjan, K. Agerbo, E. Al Eissa, M. Albani, D. Alliey-Rodriguez, N. Anjorin, A. Antilla, V. Antoniou, A. Awasthi, S. Baek, J.H. Bækvad-Hansen, M. Bass, N. Bauer, M. Beins, E.C. Bergen, S.E. Birner, A. Bøcker Pedersen, C. Bøen, E. Boks, M.P. Bosch, R. Brum, M. Brumpton, B.M. Brunkhorst-Kanaan, N. Budde, M. Bybjerg-Grauholm, J. Byerley, W. Cairns, M. Casas, M. Cervantes, P. Clarke, T.-K. Cruceanu, C. Cuellar-Barboza, A. Cunningham, J. Curtis, D. Czerski, P.M. Dale, A.M. Dalkner, N. David, F.S. Degenhardt, F. Djurovic, S. Dobbyn, A.L. Douzenis, A. Elvsåshagen, T. Escott-Price, V. Ferrier, I.N. Fiorentino, A. Foroud, T.M. Forty, L. Frank, J. Frei, O. Freimer, N.B. Frisén, L. Gade, K. Garnham, J. Gelernter, J. Giørtz Pedersen, M. Gizer, I.R. Gordon, S.D. Gordon-Smith, K. Greenwood, T.A. Grove, J. Guzman-Parra, J. Ha, K. Haraldsson, M. Hautzinger, M. Heilbronner, U. Hellgren, D. Herms, S. Hoffmann, P. Holmans, P.A. Huckins, L. Jamain, S. Johnson, J.S. Kalman, J.L. Kamatani, Y. Kennedy, J.L. Kittel-Schneider, S. Knowles, J.A. Kogevinas, M. Koromina, M. Kranz, T.M. Kranzler, H.R. Kubo, M. Kupka, R. Kushner, S.A. Lavebratt, C. Lawrence, J. Leber, M. Lee, H.-J. Lee, P.H. Levy, S.E. Lewis, C. Liao, C. Lucae, S. Lundberg, M. MacIntyre, D.J. Magnusson, S.H. Maier, W. Maihofer, A. Malaspina, D. Maratou, E. Martinsson, L. Mattheisen, M. McCarroll, S.A. McGregor, N.W. McGuffin, P. McKay, J.D. Medeiros, H. Medland, S.E. Millischer, V. Montgomery, G.W. Moran, J.L. Morris, D.W. Mühleisen, T.W. O’Brien, N. O’Donovan, C. Olde Loohuis, L.M. Oruc, L. Papiol, S. Pardiñas, A.F. Perry, A. Pfennig, A. Porichi, E. Potash, J.B. Quested, D. Raj, T. Rapaport, M.H. DePaulo, J.R. Regeer, E.J. Rice, J.P. Rivas, F. Rivera, M. Roth, J. Roussos, P. Ruderfer, D.M. Sánchez-Mora, C. Schulte, E.C. Senner, F. Sharp, S. Shilling, P.D. Sigurdsson, E. Sirignano, L. Slaney, C. Smeland, O.B. Smith, D.J. Sobell, J.L. Søholm Hansen, C. Soler Artigas, M. Spijker, A.T. Stein, D.J. Strauss, J.S. Świątkowska, B. Terao, C. Thorgeirsson, T.E. Toma, C. Tooney, P. Tsermpini, E.-E. Vawter, M.P. Vedder, H. Walters, J.T.R. Witt, S.H. Xi, S. Xu, W. Yang, J.M.K. Young, A.H. Young, H. Zandi, P.P. Zhou, H. Zillich, L. Adolfsson, R. Agartz, I. Alda, M. Alfredsson, L. Babadjanova, G. Backlund, L. Baune, B.T. Bellivier, F. Bengesser, S. Berrettini, W.H. Blackwood, D.H.R. Boehnke, M. Børglum, A.D. Breen, G. Carr, V.J. Catts, S. Corvin, A. Craddock, N. Dannlowski, U. Dikeos, D. Esko, T. Etain, B. Ferentinos, P. Frye, M. Fullerton, J.M. Gawlik, M. Gershon, E.S. Goes, F.S. Green, M.J. Grigoroiu-Serbanescu, M. Hauser, J. Henskens, F. Hillert, J. Hong, K.S. Hougaard, D.M. Hultman, C.M. Hveem, K. Iwata, N. Jablensky, A.V. Jones, I. Jones, L.A. Kahn, R.S. Kelsoe, J.R. Kirov, G. Landén, M. Leboyer, M. Lewis, C.M. Li, Q.S. Lissowska, J. Lochner, C. Loughland, C. Martin, N.G. Mathews, C.A. Mayoral, F. McElroy, S.L. McIntosh, A.M. McMahon, F.J. Melle, I. Michie, P. Milani, L. Mitchell, P.B. Morken, G. Mors, O. Mortensen, P.B. Mowry, B. Müller-Myhsok, B. Myers, R.M. Neale, B.M. Nievergelt, C.M. Nordentoft, M. Nöthen, M.M. O’Donovan, M.C. Oedegaard, K.J. Olsson, T. Owen, M.J. Paciga, S.A. Pantelis, C. Pato, C. Pato, M.T. Patrinos, G.P. Perlis, R.H. Posthuma, D. Ramos-Quiroga, J.A. Reif, A. Reininghaus, E.Z. Ribasés, M. Rietschel, M. Ripke, S. Rouleau, G.A. Saito, T. Schall, U. Schalling, M. Schofield, P.R. Schulze, T.G. Scott, L.J. Scott, R.J. Serretti, A. Shannon Weickert, C. Smoller, J.W. Stefansson, H. Stefansson, K. Stordal, E. Streit, F. Sullivan, P.F. Turecki, G. Vaaler, A.E. Vieta, E. Vincent, J.B. Waldman, I.D. Weickert, T.W. Werge, T. Wray, N.R. Zwart, J.-A. Biernacka, J.M. Nurnberger, J.I. Cichon, S. Edenberg, H.J. Stahl, E.A. McQuillin, A. Di Florio, A. Ophoff, R.A. Andreassen, O.A. HUNT All-In Psychiatry

Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Published
2021

33. Prediction of lithium response using genomic data

Author

Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, Alda, M, Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, and Alda, M

Abstract

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen’s kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

Published
2021

34. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JR, Qiao, Z, Als, TD, Bigdeli, TB, Borte, S, Bryois, J, Charney, AW, Drange, OK, Gandal, MJ, Hagenaars, SP, Ikeda, M, Kamitaki, N, Kim, M, Krebs, K, Panagiotaropoulou, G, Schilder, BM, Sloofman, LG, Steinberg, S, Trubetskoy, V, Winsvold, BS, Won, H-H, Abramova, L, Adorjan, K, Agerbo, E, Al Eissa, M, Albani, D, Alliey-Rodriguez, N, Anjorin, A, Antilla, V, Antoniou, A, Awasthi, S, Baek, JH, Baekvad-Hansen, M, Bass, N, Bauer, M, Beins, EC, Bergen, SE, Birner, A, Pedersen, CB, Boen, E, Boks, MP, Bosch, R, Brum, M, Brumpton, BM, Brunkhorst-Kanaan, N, Budde, M, Bybjerg-Grauholm, J, Byerley, W, Cairns, M, Casas, M, Cervantes, P, Clarke, T-K, Cruceanu, C, Cuellar-Barboza, A, Cunningham, J, Curtis, D, Czerski, PM, Dale, AM, Dalkner, N, David, FS, Degenhardt, F, Djurovic, S, Dobbyn, AL, Douzenis, A, Elvsashagen, T, Escott-Price, V, Ferrier, IN, Fiorentino, A, Foroud, TM, Forty, L, Frank, J, Frei, O, Freimer, NB, Frisen, L, Gade, K, Garnham, J, Gelernter, J, Pedersen, MG, Gizer, IR, Gordon, SD, Gordon-Smith, K, Greenwood, TA, Grove, J, Guzman-Parra, J, Ha, K, Haraldsson, M, Hautzinger, M, Heilbronner, U, Hellgren, D, Herms, S, Hoffmann, P, Holmans, PA, Huckins, L, Jamain, S, Johnson, JS, Kalman, JL, Kamatani, Y, Kennedy, JL, Kittel-Schneider, S, Knowles, JA, Kogevinas, M, Koromina, M, Kranz, TM, Kranzler, HR, Kubo, M, Kupka, R, Kushner, SA, Lavebratt, C, Lawrence, J, Leber, M, Lee, H-J, Lee, PH, Levy, SE, Lewis, C, Liao, C, Lucae, S, Lundberg, M, MacIntyre, DJ, Maier, W, Maihofer, A, Malaspina, D, Maratou, E, Martinsson, L, Mattheisen, M, McCarroll, SA, McGregor, NW, McGuffin, P, McKay, JD, Medeiros, H, Medland, SE, Millischer, V, Montgomery, GW, Moran, JL, Morris, DW, Muhleisen, TW, O'Brien, N, O'Donovan, C, Loohuis, LMO, Oruc, L, Papiol, S, Pardinas, AF, Perry, A, Pfennig, A, Porichi, E, Potash, JB, Quested, D, Raj, T, Rapaport, MH, DePaulo, JR, Regeer, EJ, Rice, JP, Rivas, F, Rivera, M, Roth, J, Roussos, P, Ruderfer, DM, Sanchez-Mora, C, Schulte, EC, Senner, F, Sharp, S, Shilling, PD, Sigurdsson, E, Sirignano, L, Slaney, C, Smeland, OB, Sobell, JL, Hansen, CS, Artigas, MS, Spijker, AT, Stein, DJ, Strauss, JS, Swiatkowska, B, Terao, C, Thorgeirsson, TE, Toma, C, Tooney, P, Tsermpini, E-E, Vawter, MP, Vedder, H, Walters, JTR, Witt, SH, Xi, S, Xu, W, Yang, JMK, Young, AH, Young, H, Zandi, PP, Zhou, H, Zillich, L, Adolfsson, R, Agartz, I, Alda, M, Alfredsson, L, Babadjanova, G, Backlund, L, Baune, BT, Bellivier, F, Bengesser, S, Berrettini, WH, Blackwood, DHR, Boehnke, M, Borglum, AD, Breen, G, Carr, VJ, Catts, S, Corvin, A, Craddock, N, Dannlowski, U, Dikeos, D, Esko, T, Etain, B, Ferentinos, P, Frye, M, Fullerton, JM, Gawlik, M, Gershon, ES, Goes, F, Green, MJ, Grigoroiu-Serbanescu, M, Hauser, J, Henskens, F, Hillert, J, Hong, KS, Hougaard, DM, Hultman, CM, Hveem, K, Iwata, N, Jablensky, A, Jones, I, Jones, LA, Kahn, RS, Kelsoe, JR, Kirov, G, Landen, M, Leboyer, M, Lewis, CM, Li, QS, Lissowska, J, Lochner, C, Loughland, C, Martin, NG, Mathews, CA, Mayoral, F, McElroy, SL, McIntosh, AM, McMahon, FJ, Melle, I, Michie, P, Milani, L, Mitchell, PB, Morken, G, Mors, O, Mortensen, PB, Mowry, B, Muller-Myhsok, B, Myers, RM, Neale, BM, Nievergelt, CM, Nordentoft, M, Nothen, MM, ODonovan, MC, Oedegaard, KJ, Olsson, T, Owen, MJ, Paciga, SA, Pantelis, C, Pato, C, Pato, MT, Patrinos, GP, Perlis, RH, Posthuma, D, Ramos-Quiroga, JA, Reif, A, Reininghaus, EZ, Ribases, M, Rietschel, M, Ripke, S, Rouleau, GA, Saito, T, Schall, U, Schalling, M, Schofield, PR, Schulze, TG, Scott, LJ, Scott, RJ, Serretti, A, Weickert, CS, Smoller, JW, Stefansson, H, Stefansson, K, Stordal, E, Streit, F, Sullivan, PF, Turecki, G, Vaaler, AE, Vieta, E, Vincent, JB, Waldman, ID, Weickert, TW, Werge, T, Wray, NR, Zwart, J, Biernacka, JM, Nurnberger, J, Cichon, S, Edenberg, HJ, Stahl, EA, McQuillin, A, Di Florio, A, Ophoff, RA, Andreassen, OA, Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JR, Qiao, Z, Als, TD, Bigdeli, TB, Borte, S, Bryois, J, Charney, AW, Drange, OK, Gandal, MJ, Hagenaars, SP, Ikeda, M, Kamitaki, N, Kim, M, Krebs, K, Panagiotaropoulou, G, Schilder, BM, Sloofman, LG, Steinberg, S, Trubetskoy, V, Winsvold, BS, Won, H-H, Abramova, L, Adorjan, K, Agerbo, E, Al Eissa, M, Albani, D, Alliey-Rodriguez, N, Anjorin, A, Antilla, V, Antoniou, A, Awasthi, S, Baek, JH, Baekvad-Hansen, M, Bass, N, Bauer, M, Beins, EC, Bergen, SE, Birner, A, Pedersen, CB, Boen, E, Boks, MP, Bosch, R, Brum, M, Brumpton, BM, Brunkhorst-Kanaan, N, Budde, M, Bybjerg-Grauholm, J, Byerley, W, Cairns, M, Casas, M, Cervantes, P, Clarke, T-K, Cruceanu, C, Cuellar-Barboza, A, Cunningham, J, Curtis, D, Czerski, PM, Dale, AM, Dalkner, N, David, FS, Degenhardt, F, Djurovic, S, Dobbyn, AL, Douzenis, A, Elvsashagen, T, Escott-Price, V, Ferrier, IN, Fiorentino, A, Foroud, TM, Forty, L, Frank, J, Frei, O, Freimer, NB, Frisen, L, Gade, K, Garnham, J, Gelernter, J, Pedersen, MG, Gizer, IR, Gordon, SD, Gordon-Smith, K, Greenwood, TA, Grove, J, Guzman-Parra, J, Ha, K, Haraldsson, M, Hautzinger, M, Heilbronner, U, Hellgren, D, Herms, S, Hoffmann, P, Holmans, PA, Huckins, L, Jamain, S, Johnson, JS, Kalman, JL, Kamatani, Y, Kennedy, JL, Kittel-Schneider, S, Knowles, JA, Kogevinas, M, Koromina, M, Kranz, TM, Kranzler, HR, Kubo, M, Kupka, R, Kushner, SA, Lavebratt, C, Lawrence, J, Leber, M, Lee, H-J, Lee, PH, Levy, SE, Lewis, C, Liao, C, Lucae, S, Lundberg, M, MacIntyre, DJ, Maier, W, Maihofer, A, Malaspina, D, Maratou, E, Martinsson, L, Mattheisen, M, McCarroll, SA, McGregor, NW, McGuffin, P, McKay, JD, Medeiros, H, Medland, SE, Millischer, V, Montgomery, GW, Moran, JL, Morris, DW, Muhleisen, TW, O'Brien, N, O'Donovan, C, Loohuis, LMO, Oruc, L, Papiol, S, Pardinas, AF, Perry, A, Pfennig, A, Porichi, E, Potash, JB, Quested, D, Raj, T, Rapaport, MH, DePaulo, JR, Regeer, EJ, Rice, JP, Rivas, F, Rivera, M, Roth, J, Roussos, P, Ruderfer, DM, Sanchez-Mora, C, Schulte, EC, Senner, F, Sharp, S, Shilling, PD, Sigurdsson, E, Sirignano, L, Slaney, C, Smeland, OB, Sobell, JL, Hansen, CS, Artigas, MS, Spijker, AT, Stein, DJ, Strauss, JS, Swiatkowska, B, Terao, C, Thorgeirsson, TE, Toma, C, Tooney, P, Tsermpini, E-E, Vawter, MP, Vedder, H, Walters, JTR, Witt, SH, Xi, S, Xu, W, Yang, JMK, Young, AH, Young, H, Zandi, PP, Zhou, H, Zillich, L, Adolfsson, R, Agartz, I, Alda, M, Alfredsson, L, Babadjanova, G, Backlund, L, Baune, BT, Bellivier, F, Bengesser, S, Berrettini, WH, Blackwood, DHR, Boehnke, M, Borglum, AD, Breen, G, Carr, VJ, Catts, S, Corvin, A, Craddock, N, Dannlowski, U, Dikeos, D, Esko, T, Etain, B, Ferentinos, P, Frye, M, Fullerton, JM, Gawlik, M, Gershon, ES, Goes, F, Green, MJ, Grigoroiu-Serbanescu, M, Hauser, J, Henskens, F, Hillert, J, Hong, KS, Hougaard, DM, Hultman, CM, Hveem, K, Iwata, N, Jablensky, A, Jones, I, Jones, LA, Kahn, RS, Kelsoe, JR, Kirov, G, Landen, M, Leboyer, M, Lewis, CM, Li, QS, Lissowska, J, Lochner, C, Loughland, C, Martin, NG, Mathews, CA, Mayoral, F, McElroy, SL, McIntosh, AM, McMahon, FJ, Melle, I, Michie, P, Milani, L, Mitchell, PB, Morken, G, Mors, O, Mortensen, PB, Mowry, B, Muller-Myhsok, B, Myers, RM, Neale, BM, Nievergelt, CM, Nordentoft, M, Nothen, MM, ODonovan, MC, Oedegaard, KJ, Olsson, T, Owen, MJ, Paciga, SA, Pantelis, C, Pato, C, Pato, MT, Patrinos, GP, Perlis, RH, Posthuma, D, Ramos-Quiroga, JA, Reif, A, Reininghaus, EZ, Ribases, M, Rietschel, M, Ripke, S, Rouleau, GA, Saito, T, Schall, U, Schalling, M, Schofield, PR, Schulze, TG, Scott, LJ, Scott, RJ, Serretti, A, Weickert, CS, Smoller, JW, Stefansson, H, Stefansson, K, Stordal, E, Streit, F, Sullivan, PF, Turecki, G, Vaaler, AE, Vieta, E, Vincent, JB, Waldman, ID, Weickert, TW, Werge, T, Wray, NR, Zwart, J, Biernacka, JM, Nurnberger, J, Cichon, S, Edenberg, HJ, Stahl, EA, McQuillin, A, Di Florio, A, Ophoff, RA, and Andreassen, OA

Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021

39. Positioning Europe for the EPITRANSCRIPTOMICS challenge

Author

Jantsch, M, Quattrone, A, O'Connell, M, Helm, M, Frye, M, Macias-Gonzales, M, Ohman, M, Ameres, S, Willems, L, Fuks, F, Oulas, A, Vanacova, S, Nielsen, H, Bousquet-Antonelli, C, Motorin, Y, Roignant, J, Balatsos, N, Dinnyes, A, Baranov, P, Kelly, V, Lamm, A, Rechavi, G, Pelizzola, M, Liepins, J, Kholodnyuk, I, Zammit, V, Ayers, D, Drablos, F, Dahl, J, Bujnicki, J, Jeronimo, C, Almeida, R, Neagu, M, Costache, M, Bankovic, J, Banovic, B, Kyselovic, J, Valor, L, Selbert, S, Pir, P, Demircan, T, Cowling, V, Schäfer, M, Rossmanith, W, Lafontaine, D, David, A, Carre, C, Lyko, F, Schaffrath, R, Schwartz, S, Verdel, A, Klungland, A, Purta, E, Timotijevic, G, Cardona, F, Davalos, A, Ballana, E, O Carroll, D, Ule, J, Fray, R, Jantsch MF, Quattrone A, O'Connell M, Helm M, Frye M, Macias-Gonzales M, Ohman M, Ameres S, Willems L, Fuks F, Oulas A, Vanacova S, Nielsen H, Bousquet-Antonelli C, Motorin Y, Roignant J, Balatsos N, Dinnyes A, Baranov P, Kelly V, Lamm A, Rechavi G, Pelizzola M, Liepins J, Kholodnyuk IH, Zammit V, Ayers D, Drablos F, Dahl JA, Bujnicki J, Jeronimo C, Almeida R, Neagu M, Costache M, Bankovic J, Banovic B, Kyselovic J, Valor LM, Selbert S, Pir P, Demircan T, Cowling V, Schäfer M, Rossmanith W, Lafontaine D, David A, Carre C, Lyko F, Schaffrath R, Schwartz S, Verdel A, Klungland A, Purta E, Timotijevic G, Cardona F, Davalos A, Ballana E, O Carroll D, Ule J, Fray R, Jantsch, M, Quattrone, A, O'Connell, M, Helm, M, Frye, M, Macias-Gonzales, M, Ohman, M, Ameres, S, Willems, L, Fuks, F, Oulas, A, Vanacova, S, Nielsen, H, Bousquet-Antonelli, C, Motorin, Y, Roignant, J, Balatsos, N, Dinnyes, A, Baranov, P, Kelly, V, Lamm, A, Rechavi, G, Pelizzola, M, Liepins, J, Kholodnyuk, I, Zammit, V, Ayers, D, Drablos, F, Dahl, J, Bujnicki, J, Jeronimo, C, Almeida, R, Neagu, M, Costache, M, Bankovic, J, Banovic, B, Kyselovic, J, Valor, L, Selbert, S, Pir, P, Demircan, T, Cowling, V, Schäfer, M, Rossmanith, W, Lafontaine, D, David, A, Carre, C, Lyko, F, Schaffrath, R, Schwartz, S, Verdel, A, Klungland, A, Purta, E, Timotijevic, G, Cardona, F, Davalos, A, Ballana, E, O Carroll, D, Ule, J, Fray, R, Jantsch MF, Quattrone A, O'Connell M, Helm M, Frye M, Macias-Gonzales M, Ohman M, Ameres S, Willems L, Fuks F, Oulas A, Vanacova S, Nielsen H, Bousquet-Antonelli C, Motorin Y, Roignant J, Balatsos N, Dinnyes A, Baranov P, Kelly V, Lamm A, Rechavi G, Pelizzola M, Liepins J, Kholodnyuk IH, Zammit V, Ayers D, Drablos F, Dahl JA, Bujnicki J, Jeronimo C, Almeida R, Neagu M, Costache M, Bankovic J, Banovic B, Kyselovic J, Valor LM, Selbert S, Pir P, Demircan T, Cowling V, Schäfer M, Rossmanith W, Lafontaine D, David A, Carre C, Lyko F, Schaffrath R, Schwartz S, Verdel A, Klungland A, Purta E, Timotijevic G, Cardona F, Davalos A, Ballana E, O Carroll D, Ule J, and Fray R

Abstract

The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20 years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the ~150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics.

Published
2018

40. EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity

Author

Frye, M. (Maike), Stritt, S. (Simon), Ortsärter, H. (Henrik), Hernandez Vasquez, M. (Magda), Kaakinen, M. (Mika), Vicente, A. (Andres), Wiseman, J. (John), Eklund, L. (Lauri), Martínez-Torrecuadrada, J. L. (Jorge L.), Vestweber, D. (Dietmar), Mäkinen, T. (Taija), Frye, M. (Maike), Stritt, S. (Simon), Ortsärter, H. (Henrik), Hernandez Vasquez, M. (Magda), Kaakinen, M. (Mika), Vicente, A. (Andres), Wiseman, J. (John), Eklund, L. (Lauri), Martínez-Torrecuadrada, J. L. (Jorge L.), Vestweber, D. (Dietmar), and Mäkinen, T. (Taija)

Abstract

Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function.

Published
2020

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