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6. Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke

Author

Jaworek, T, Xu, H, Gaynor, BJ, Cole, JW, Rannikmae, K, Stanne, TM, Tomppo, L, Abedi, V, Amouyel, P, Armstrong, ND, Attia, J, Bell, S, Benavente, OR, Boncoraglio, GB, Butterworth, A, Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium, Carcel-Marquez, J, Chen, Z, Chong, M, Cruchaga, C, Cushman, M, Danesh, J, Debette, S, Duggan, DJ, Durda, JP, Engstrom, G, Enzinger, C, Faul, JD, Fecteau, NS, Fernandez-Cadenas, I, Gieger, C, Giese, A-K, Grewal, RP, Grittner, U, Havulinna, AS, Heitsch, L, Hochberg, MC, Holliday, E, Hu, J, Ilinca, A, INVENT Consortium, Irvin, MR, Jackson, RD, Jacob, MA, Janssen, RR, Jimenez-Conde, J, Johnson, JA, Kamatani, Y, Kardia, SL, Koido, M, Kubo, M, Lange, L, Lee, J-M, Lemmens, R, Levi, CR, Li, J, Li, L, Lin, K, Lopez, H, Luke, S, Maguire, J, McArdle, PF, McDonough, CW, Meschia, JF, Metso, T, Muller-Nurasyid, M, O'Connor, TD, O'Donnell, M, Peddareddygari, LR, Pera, J, Perry, JA, Peters, A, Putaala, J, Ray, D, Rexrode, K, Ribases, M, Rosand, J, Rothwell, PM, Rundek, T, Ryan, KA, Sacco, RL, Salomaa, V, Sanchez-Mora, C, Schmidt, R, Sharma, P, Slowik, A, Smith, JA, Smith, NL, Wassertheil-Smoller, S, Soederholm, M, Stine, OC, Strbian, D, Sudlow, CL, Tatlisumak, T, Terao, C, Thijs, V, Torres-Aguila, NP, Tregouet, D-A, Tuladhar, AM, Veldink, JH, Walters, RG, Weir, DR, Woo, D, Worrall, BB, Hong, CC, Ross, O, Zand, R, Leeuw, F-ED, Lindgren, AG, Pare, G, Anderson, CD, Markus, HS, Jern, C, Malik, R, Dichgans, M, Mitchell, BD, Kittner, SJ, and Early Onset Stroke Genetics Consortium of the International Stroke Genetics Consortium (ISGC)

Subjects
Neurology & Neurosurgery, 1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences
Abstract

BACKGROUND AND OBJECTIVES: Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke. METHODS: We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS. RESULTS: We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008). DISCUSSION: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

Published
2022

7. Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Author

Kittel-Schneider, S., Arteaga-Henriquez, G., Arias Vasquez, A., Asherson, P., Banaschewski, T., Brikell, I., Buitelaar, J.K., Cormand, B., Faraone, S.V, Freitag, C.M., Ginsberg, Y., Haavik, J., Hartman, Catharina A., Kuntsi, J., Larsson, H., Matura, S., McNeill, R.V., Ramos-Quiroga, J.A., Ribases, M., Romanos, M., Vainieri, I., Franke, B., Reif, A., Kittel-Schneider, S., Arteaga-Henriquez, G., Arias Vasquez, A., Asherson, P., Banaschewski, T., Brikell, I., Buitelaar, J.K., Cormand, B., Faraone, S.V, Freitag, C.M., Ginsberg, Y., Haavik, J., Hartman, Catharina A., Kuntsi, J., Larsson, H., Matura, S., McNeill, R.V., Ramos-Quiroga, J.A., Ribases, M., Romanos, M., Vainieri, I., Franke, B., and Reif, A.

Abstract

Item does not contain fulltext, Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co-occurrences are often unclear - are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.

Published
2022

8. 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

9. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, Gravel, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, and Gravel, S

Abstract

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

10. Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Author

Kittel-Schneider S, Arteaga-Henriquez G, Vasquez AA, Asherson P, Banaschewski T, Brikell I, Buitelaar J, Cormand B, Faraone SV, Freitag CM, Ginsberg Y, Haavik J, Hartman CA, Kuntsi J, Larsson H, Matura S, McNeill RV, Antoni Ramos-Quiroga J, Ribases M, Romanos M, Vainieri I, Franke B, and Reif A

Subjects
Epilepsy, Elimination disorders, Diabetes mellitus type II, Attention-deficit, hyperactivity disorder, Obesity, Somatic disorders, Non-mental disease, Asthma, Migraine
Abstract

Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co occurrences are often unclear are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.

Published
2022

11. 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

12. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication

Author

Arcos-Burgos, M, Jain, M, Acosta, M T, Shively, S, Stanescu, H, Wallis, D, Domené, S, Vélez, J I, Karkera, J D, Balog, J, Berg, K, Kleta, R, Gahl, W A, Roessler, E, Long, R, Lie, J, Pineda, D, Londoño, A C, Palacio, J D, Arbelaez, A, Lopera, F, Elia, J, Hakonarson, H, Johansson, S, Knappskog, P M, Haavik, J, Ribases, M, Cormand, B, Bayes, M, Casas, M, Ramos-Quiroga, J A, Hervas, A, Maher, B S, Faraone, S V, Seitz, C, Freitag, C M, Palmason, H, Meyer, J, Romanos, M, Walitza, S, Hemminger, U, Warnke, A, Romanos, J, Renner, T, Jacob, C, Lesch, K-P, Swanson, J, Vortmeyer, A, Bailey-Wilson, J E, Castellanos, F X, and Muenke, M

Published
2010
Full Text
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15. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Author

Demontis, D, Walters, R, Martin, J, Mattheisen, M, Als, T, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Baekvad-Hansen, M, Cerrato, F, Chambert, K, Churchhouse, C, Dumont, A, Eriksson, N, Gandal, M, Goldstein, J, Grasby, K, Grove, J, Gudmundsson, O, Hansen, C, Hauberg, M, Hollegaard, M, Howrigan, D, Huang, H, Maller, J, Martin, A, Martin, N, Moran, J, Pallesen, J, Palmer, D, Pedersen, C, Pedersen, M, Poterba, T, Poulsen, J, Ripke, S, Robinson, E, Satterstrom, F, Stefansson, H, Stevens, C, Turley, P, Walters, G, Won, H, Wright, M, Andreassen, O, Asherson, P, Burton, C, Boomsma, D, Cormand, B, Dalsgaard, S, Franke, B, Gelernter, J, Geschwind, D, Hakonarson, H, Haavik, J, Kranzler, H, Kuntsi, J, Langley, K, Lesch, K, Middeldorp, C, Reif, A, Rohde, L, Roussos, P, Schachar, R, Sklar, P, Sonuga-Barke, E, Sullivan, P, Thapar, A, Tung, J, Waldman, I, Medland, S, Stefansson, K, Nordentoft, M, Hougaard, D, Werge, T, Mors, O, Mortensen, P, Daly, M, Faraone, S, Borglum, A, Neale, B, Albayrak, O, Anney, R, Arranz, M, Banaschewski, T, Bau, C, Biederman, J, Buitelaar, J, Casas, M, Charach, A, Crosbie, J, Dempfle, A, Doyle, A, Ebstein, R, Elia, J, Freitag, C, Focker, M, Gill, M, Grevet, E, Hawi, Z, Hebebrand, J, Herpertz-Dahlmann, B, Hervas, A, Hinney, A, Hohmann, S, Holmans, P, Hutz, M, Ickowitz, A, Johansson, S, Kent, L, Kittel-Schneider, S, Lambregts-Rommelse, N, Lehmkuhl, G, Loo, S, McGough, J, Meyer, J, Mick, E, Middletion, F, Miranda, A, Mota, N, Mulas, F, Mulligan, A, Nelson, F, Nguyen, T, Oades, R, O'Donovan, M, Owen, M, Palmason, H, Ramos-Quiroga, J, Renner, T, Ribases, M, Rietschel, M, Rivero, O, Romanos, J, Romanos, M, Rothenberger, A, Royers, H, Sanchez-Mora, C, Scherag, A, Schimmelmann, B, Schafer, H, Sergeant, J, Sinzig, J, Smalley, S, Steinhausen, H, Thompson, M, Todorov, A, Vasquez, A, Walitza, S, Wang, Y, Warnke, A, Williams, N, Witt, S, Yang, L, Zayats, T, Zhang-James, Y, Smith, G, Davies, G, Ehli, E, Evans, D, Fedko, I, Greven, C, Groen-Blokhuis, M, Guxens, M, Hammerschlag, A, Hartman, C, Heinrich, J, Hottenga, J, Hudziak, J, Jugessur, A, Kemp, J, Krapohl, E, Murcia, M, Myhre, R, Nolte, I, Nyholt, D, Ormel, J, Ouwens, K, Pappa, I, Pennell, C, Plomin, R, Ring, S, Standl, M, Stergiakouli, E, St Pourcain, B, Stoltenberg, C, Sunyer, J, Thiering, E, Tiemeier, H, Tiesler, C, Timpson, N, Trzaskowski, M, van der Most, P, Vilor-Tejedor, N, Wang, C, Whitehouse, A, Zhao, H, Agee, M, Alipanahi, B, Auton, A, Bell, R, Bryc, K, Elson, S, Fontanillas, P, Furlotte, N, Hinds, D, Hromatka, B, Huber, K, Kleinman, A, Litterman, N, McIntyre, M, Mountain, J, Northover, C, Pitts, S, Sathirapongsasuti, J, Sazonova, O, Shelton, J, Shringarpure, S, Tian, C, Vacic, V, Wilson, C, ADHD Working Grp Psychiat Genomics, Early Lifecourse Genetic, 23andMe Res Team, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, Psychiatry, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), 23andme Research Team, University of St Andrews. Cellular Medicine Division, University of St Andrews. Institute of Behavioural and Neural Sciences, University of St Andrews. School of Medicine, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Neuropsychology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, Clinical Child and Family Studies, LEARN! - Child rearing, and APH - Methodology

Subjects
Netherlands Twin Register (NTR), Male, Trastorns per dèficit d'atenció amb hiperactivitat en els infants, LD SCORE REGRESSION, Medizin, Genome-wide association study, US CHILDREN, Genoma humà, Attention deficit disorder with hyperactivity in children, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, 2.1 Biological and endogenous factors, POLYGENIC RISK, Aetiology, Child, IDENTIFIES 11, SEXUAL-BEHAVIOR, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, Pediatric, 0303 health sciences, education.field_of_study, Genome, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Brain, 3rd-DAS, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, 3. Good health, Mental Health, Meta-analysis, Child, Preschool, Genetic Loci/genetics, Genome-Wide Association Study/methods, Trastorns per dèficit d'atenció amb hiperactivitat en els adults, Attention Deficit Disorder (ADD), Female, Attention Deficit Disorder with Hyperactivity/genetics, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, SDG 4 - Quality Education, Clinical psychology, Risk, Adolescent, DEFICIT HYPERACTIVITY DISORDER, Concordance, Population, PROVIDES INSIGHTS, QH426 Genetics, Biology, Quantitative trait locus, Brain/physiology, Polymorphism, Single Nucleotide, 23andMe Research Team, behavioral disciplines and activities, Gene Expression Regulation/genetics, Article, 150 000 MR Techniques in Brain Function, GENETIC ARCHITECTURE, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Clinical Research, Behavioral and Social Science, mental disorders, medicine, Genetics, Attention deficit hyperactivity disorder, Humans, Genetic Predisposition to Disease, Polymorphism, education, Preschool, QH426, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], ASSOCIATION METAANALYSIS, Prevention, Human Genome, Case-control study, MAJOR DEPRESSION, medicine.disease, Attention Deficit Hyperactivity Disorder (ADHD), Genetic architecture, Brain Disorders, ADHD Working Group of the Psychiatric Genomics Consortium, Gene Expression Regulation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, RC0321, Attention deficit disorder with hyperactivity in adults, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits. Postprint

Published
2019

16. Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells

Author

Sanchez-Mora, Cristina, Soler Artigas, Maria, Garcia-Martinez, Iris, Pagerols, Mireia, Rovira, Paula, Richarte, Vanesa, Franke, B., Arias-Vasquez, A., Ramos-Quiroga, J.A., Ribases, M., Sanchez-Mora, Cristina, Soler Artigas, Maria, Garcia-Martinez, Iris, Pagerols, Mireia, Rovira, Paula, Richarte, Vanesa, Franke, B., Arias-Vasquez, A., Ramos-Quiroga, J.A., and Ribases, M.

Abstract

Contains fulltext : 202022.pdf (publisher's version ) (Closed access)

Published
2019

17. Author correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia liability

Author

Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., Vink, J.M., Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., and Vink, J.M.

Abstract

Item does not contain fulltext, Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability", as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

Published
2019

18. [The gut-brain axis in attention deficit hyperactivity disorder: the role of the microbiota]

Author

Richarte V, Rosales K, Corrales M, Bellina M, Christian Fadeuilhe, Calvo E, Ibanez P, Sanchez-Mora C, Ribases M, and Ja, Ramos-Quiroga

Subjects
Adult, Male, Neuropeptides, Wechsler Scales, Brain, Feeding Behavior, Autonomic Nervous System, Hippocampus, Diet, Gastrointestinal Microbiome, Feces, Cross-Sectional Studies, Species Specificity, Attention Deficit Disorder with Hyperactivity, Interview, Psychological, Solitary Nucleus, Humans, Female, Genome, Bacterial
Abstract

Attention deficit hyperactivity disorder (ADHD) has a complex aetiology, mainly attributed to a number of susceptibility genes and environmental factors. Genetic association studies, however, have been inconsistent and have identified genetic variants with a moderate effect that explain a small proportion of the estimated inheritability of the disorder (10%). Recent studies suggest that the gut microbiota and diet play an important role in the development and symptoms of different mental disorders. Nevertheless, no clear evidence exists on the issue. This project proposes an alternative approach to identify mechanisms by which the intestinal microbial ecosystem and diet could contribute to the presence of ADHD.To identify biomarkers for ADHD by examining the gut microbiota.We conducted a cross-sectional study of adult patients with ADHD (n = 100) and control subjects (n = 100). Measures of ADHD evaluation and eating habits were performed in both groups. Samples of faecal material were obtained from which to extract bacterial DNA, then used to characterise the participants' gut microbiota. A meta-genomic association study was later performed to attempt to correlate the bacterial composition of the intestine with the clinical subtypes of the disorder.Comparing the gut microbiota profiles of subjects with ADHD and controls is expected to help account for the clinical heterogeneity of the disorder and identify new mechanisms involved in its development.El eje intestino-cerebro en el trastorno por deficit de atencion/hiperactividad: papel de la microbiota.Introduccion. El trastorno por deficit de atencion/hiperactividad (TDAH) presenta una etiologia compleja, atribuida principalmente a multiples genes de susceptibilidad y factores ambientales. No obstante, los estudios geneticos de asociacion han sido inconsistentes, identificando variantes geneticas de efecto moderado que explican una pequeña proporcion de la heredabilidad estimada del trastorno (10%). Recientes estudios sugieren que la microbiota intestinal y la dieta desempeñan un papel importante en el desarrollo y los sintomas de diferentes trastornos mentales. Sin embargo, en la actualidad no existe una claridad absoluta al respecto. El presente proyecto propone un abordaje alternativo para identificar mecanismos a traves de los cuales el ecosistema microbiano intestinal y la dieta podrian contribuir a la presencia del TDAH. Objetivo. Identificar biomarcadores para el TDAH a traves del estudio de la microbiota intestinal. Sujetos y metodos. Estudio transversal de pacientes adultos con TDAH (n = 100) y de individuos control (n = 100). En ambos grupos se tomaran medidas de evaluacion de TDAH y habitos alimentarios. Se obtendran muestras fecales para la extraccion del ADN bacteriano, que permitiran caracterizar la microbiota intestinal de los participantes, para posteriormente realizar un estudio de asociacion metagenomico e intentar correlacionar la composicion bacteriana intestinal con subtipos clinicos del trastorno. Resultados y conclusiones. Se espera que la comparacion de los perfiles de microbiota intestinal entre sujetos con TDAH y controles ayude a explicar la heterogeneidad clinica del trastorno e identificar nuevos mecanismos implicados en su desarrollo.

Published
2018

20. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia liability

Author

Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., Vink, J.M., Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., and Vink, J.M.

Abstract

Contains fulltext : 195179.pdf (publisher's version ) (Closed access), Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health–related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Published
2018

21. Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan

Author

Franke, B., Michelini, G., Asherson, P., Banaschewski, T., Bilbow, A., Buitelaar, J.K., Cormand, B., Faraone, S.V, Ginsberg, Y., Haavik, J., Kuntsi, J., Larsson, H., Lesch, K.P., Ramos-Quiroga, J.A., Rethelyi, J.M., Ribases, M., Reif, A., Franke, B., Michelini, G., Asherson, P., Banaschewski, T., Bilbow, A., Buitelaar, J.K., Cormand, B., Faraone, S.V, Ginsberg, Y., Haavik, J., Kuntsi, J., Larsson, H., Lesch, K.P., Ramos-Quiroga, J.A., Rethelyi, J.M., Ribases, M., and Reif, A.

Abstract

Contains fulltext : 196780pub.pdf (publisher's version ) (Open Access), Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.

Published
2018

22. Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: Genome-wide association study of both common and rare variants

Author

Yang, Li, Neale, Benjamin M., Liu, Lu, Lee, S. Hong, Wray, Naomi R., Ji, Ning, Li, Haimei, Qian, Qiujin, Wang, Dongliang, Li, Jun, Faraone, Stephen V., Wang, Yufeng, Doyle, Alysa, Reif, Andreas, Rothenberger, Aribert, Franke, Barbara, Sonuga-Barke, Edmund J.S., Steinhausen, Hans-Christoph, Buitelaar, Jan K, Kuntsi, Jonna, Biederman, Joseph, Lesch, Klaus Peter, Kent, Lindsey, Asherson, Philip, Oades, Robert D., Loo, Sandra K., Nelson, Stanley F., Smalley, Susan L., Banaschewski, Tobias, Vasquez, Alejandro Arias, Todorov, Alexandre, Charach, A., Miranda, Ana, Warnke, Andreas, Thapar, Anita, Cormand, B., Freitag, Christine, Mick, Eric, Mulas, Fernando, Middleton, Frank, Hakonarson, Hakon, Pálmason, Haukur, Schäfer, Helmut, Roeyers, Herbert, McGough, James J., Romanos, Jasmin, Crosbie, J., Meyer, Jobst, Ramos-Qiroga, J.A., Sergeant, Joseph A, Elia, Josephine, Langely, Kate, Nisenbaum, Laura, Romanos, Marcel, Daly, Mark, Ribases, M., Gill, Michael, O’Donovan, Michael, Owen, Michael, Casas, M., Bayes, M., Lambregts-Rommelse, Nanda, Williams, Nigel, Holmans, Peter, Anney, Richard J.L., Ebstein, Richard, Schachar, R., Medland, Sarah E., Ripke, Stephan, Walitza, Susanne, Nguyen, Thuy Trang, Renner, Tobias J., Hu, Xiaolan, Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: MHeNs School for Mental Health and Neuroscience, Yang, Li, Neale, Benjamin M, Liu, Lu, Lee, S Hong, Wray, Naomi R, Ji, Ning, Li, Haimei, Qian, Qiujin, Wang, Dongliang, Li, Jun, Faraone, Stephen V, Wang, Yufeng, and Psychiatric GWAS Consortium: ADHD Subgroup

Subjects
Male, Adolescent, DCN MP - Plasticity and memory, Medizin, SNP, Single-nucleotide polymorphism, Genome-wide association study, DCN PAC - Perception action and control, Biology, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Correlation, single nucleotide polymorphisms, Cellular and Molecular Neuroscience, Polymorphism (computer science), attention-deficit hyperactivity disorder, mental disorders, medicine, ddc:61, Humans, ADHD, GWAS, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Copy-number variation, Child, Genetics (clinical), Genetics & Heredity, Psychiatry, Genetics, neurodevelopment, pathway, Case-control study, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], medicine.disease, genetic architecture, Genetic architecture, Psychiatry and Mental health, polygenic disorders, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein-Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P=0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P=0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P=0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology. (c) 2013 Wiley Periodicals, Inc. Refereed/Peer-reviewed

Published
2013

23. SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder

Author

Merker, S., Reif, A., Ziegler, G.C., Weber, H., Mayer, U., Ehlis, A.C., Conzelmann, A., Johansson, S., Muller-Reible, C., Nanda, I., Haaf, T., Ullmann, R., Romanos, M., Fallgatter, A.J., Pauli, P., Strekalova, T., Jansch, C., Arias Vasquez, A., Haavik, J., Ribases, M., Ramos-Quiroga, J.A., Buitelaar, J.K., Franke, B., Lesch, K.P., Merker, S., Reif, A., Ziegler, G.C., Weber, H., Mayer, U., Ehlis, A.C., Conzelmann, A., Johansson, S., Muller-Reible, C., Nanda, I., Haaf, T., Ullmann, R., Romanos, M., Fallgatter, A.J., Pauli, P., Strekalova, T., Jansch, C., Arias Vasquez, A., Haavik, J., Ribases, M., Ramos-Quiroga, J.A., Buitelaar, J.K., Franke, B., and Lesch, K.P.

Abstract

Contains fulltext : 174505pub.pdf (publisher's version ) (Closed access), BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder with profound cognitive, behavioral, and psychosocial impairments with persistence across the life cycle. Our initial genome-wide screening approach for copy number variants (CNVs) in ADHD implicated a duplication of SLC2A3, encoding glucose transporter-3 (GLUT3). GLUT3 plays a critical role in cerebral glucose metabolism, providing energy for the activity of neurons, which, in turn, moderates the excitatory-inhibitory balance impacting both brain development and activity-dependent neural plasticity. We therefore aimed to provide additional genetic and functional evidence for GLUT3 dysfunction in ADHD. METHODS: Case-control association analyses of SLC2A3 single-nucleotide polymorphisms (SNPs) and CNVs were conducted in several European cohorts of patients with childhood and adult ADHD (SNP, n = 1,886 vs. 1,988; CNV, n = 1,692 vs. 1,721). These studies were complemented by SLC2A3 expression analyses in peripheral cells, functional EEG recordings during neurocognitive tasks, and ratings of food energy content. RESULTS: Meta-analysis of all cohorts detected an association of SNP rs12842 with ADHD. While CNV analysis detected a population-specific enrichment of SLC2A3 duplications only in German ADHD patients, the CNV + rs12842 haplotype influenced ADHD risk in both the German and Spanish cohorts. Duplication carriers displayed elevated SLC2A3 mRNA expression in peripheral blood cells and altered event-related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of ADHD, and an underestimation of energy units of high-caloric food. CONCLUSIONS: Taken together, our results indicate that both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to ADHD risk.

Published
2017

24. Lack of replication of previous autism spectrum disorder GWAS hits in European populations

Author

Torrico, B., Chiocchetti, A.G., Bacchelli, E., Trabetti, E., Hervas, A., Franke, B., Buitelaar, J.K., Rommelse, N.N.J., Yousaf, A., Duketis, E., Freitag, C.M., Caballero-Andaluz, R., Martinez-Mir, A., Scholl, F.G., Ribases, M., Battaglia, A., Malerba, G., Delorme, R., Benabou, M., Maestrini, E., Bourgeron, T., Cormand, B., Toma, C., Torrico, B., Chiocchetti, A.G., Bacchelli, E., Trabetti, E., Hervas, A., Franke, B., Buitelaar, J.K., Rommelse, N.N.J., Yousaf, A., Duketis, E., Freitag, C.M., Caballero-Andaluz, R., Martinez-Mir, A., Scholl, F.G., Ribases, M., Battaglia, A., Malerba, G., Delorme, R., Benabou, M., Maestrini, E., Bourgeron, T., Cormand, B., and Toma, C.

Abstract

Contains fulltext : 169730.pdf (publisher's version ) (Closed access), Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84-1.32) for rs10513025, 1.0002 (95% CI = 0.93-1.08) for rs4141463 and 1.01 (95% CI = 0.92-1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202-211. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Published
2017

25. Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder

Author

Brevik, E.J., Donkelaar, M.M.J. van, Weber, H., Sanchez-Mora, C., Jacob, C., Rivero, O., Kittel-Schneider, S., Garcia-Martinez, I., Aebi, M., Hulzen, K.J.E. van, Cormand, B., Ramos-Quiroga, J.A., Lesch, K.P., Reif, A., Ribases, M., Franke, B., Posserud, M.B., Johansson, S., Lundervold, A.J., Haavik, J., Zayats, T., Brevik, E.J., Donkelaar, M.M.J. van, Weber, H., Sanchez-Mora, C., Jacob, C., Rivero, O., Kittel-Schneider, S., Garcia-Martinez, I., Aebi, M., Hulzen, K.J.E. van, Cormand, B., Ramos-Quiroga, J.A., Lesch, K.P., Reif, A., Ribases, M., Franke, B., Posserud, M.B., Johansson, S., Lundervold, A.J., Haavik, J., and Zayats, T.

Abstract

Contains fulltext : 167832.pdf (publisher's version ) (Open Access), Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P < 5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. (c) 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Published
2016

26. Exome chip analyses in adult attention deficit hyperactivity disorder

Author

Zayats, T., Jacobsen, K.K., Kleppe, R., Jacob, C.P., Kittel-Schneider, S., Ribases, M., Ramos-Quiroga, J.A., Richarte, V., Casas, M., Mota, N.R., Grevet, E.H., Klein, M., Corominas, J., Bralten, J.B., Galesloot, T.E., Arias Vasquez, A., Herms, S., Forstner, A.J., Larsson, H., Breen, G., Asherson, P., Gross-Lesch, S., Lesch, K.P., Cichon, S., Gabrielsen, M.B., Holmen, O.L., Bau, C.H., Buitelaar, J.K., Kiemeney, L.A., Faraone, S.V, Cormand, B., Franke, B., Reif, A., Haavik, J., Johansson, S., Zayats, T., Jacobsen, K.K., Kleppe, R., Jacob, C.P., Kittel-Schneider, S., Ribases, M., Ramos-Quiroga, J.A., Richarte, V., Casas, M., Mota, N.R., Grevet, E.H., Klein, M., Corominas, J., Bralten, J.B., Galesloot, T.E., Arias Vasquez, A., Herms, S., Forstner, A.J., Larsson, H., Breen, G., Asherson, P., Gross-Lesch, S., Lesch, K.P., Cichon, S., Gabrielsen, M.B., Holmen, O.L., Bau, C.H., Buitelaar, J.K., Kiemeney, L.A., Faraone, S.V, Cormand, B., Franke, B., Reif, A., Haavik, J., and Johansson, S.

Abstract

Contains fulltext : 165997.pdf (publisher's version ) (Open Access), Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.

Published
2016

27. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., van Eijk, K. R., Isen, J. D., Loukola, A., Maciejewski, D. F., Mihailov, E., van der Most, P. J., Sanchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J. J., Abdellaoui, A., Bigdeli, T. B., Branje, S. J. T., Brown, S. A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S. D., Harris, J. M., Hartman, C. A., Henders, A. K., Heath, A. C., Hickie, I. B., Hickman, M., Hopfer, C. J., Hottenga, J. J., Huizink, A. C., Irons, D. E., Kahn, R. S., Korhonen, T., Kranzler, H. R., Krauter, K., van Lier, P. A. C., Lubke, G. H., Madden, P. A. F., Magi, R., McGue, M. K., Medland, S. E., Meeus, W. H. J., Miller, M. B., Montgomery, G. W., Nivard, M. G., Nolte, I. M., Oldehinkel, A. J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J. A., Richarte, V., Rose, R. J., Shin, J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, M. J., Koot, H. M., Paus, T., Hewitt, J. K., Ribases, M., Kaprio, J., Boks, M. P., Snieder, H., Spector, T., Munafo, M. R., Metspalu, A., Gelernter, J., Boomsma, D. I., Iacono, W. G., Martin, N. G., Gillespie, N. A., Derks, E. M., Vink, J. M., University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., van Eijk, K. R., Isen, J. D., Loukola, A., Maciejewski, D. F., Mihailov, E., van der Most, P. J., Sanchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J. J., Abdellaoui, A., Bigdeli, T. B., Branje, S. J. T., Brown, S. A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S. D., Harris, J. M., Hartman, C. A., Henders, A. K., Heath, A. C., Hickie, I. B., Hickman, M., Hopfer, C. J., Hottenga, J. J., Huizink, A. C., Irons, D. E., Kahn, R. S., Korhonen, T., Kranzler, H. R., Krauter, K., van Lier, P. A. C., Lubke, G. H., Madden, P. A. F., Magi, R., McGue, M. K., Medland, S. E., Meeus, W. H. J., Miller, M. B., Montgomery, G. W., Nivard, M. G., Nolte, I. M., Oldehinkel, A. J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J. A., Richarte, V., Rose, R. J., Shin, J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, M. J., Koot, H. M., Paus, T., Hewitt, J. K., Ribases, M., Kaprio, J., Boks, M. P., Snieder, H., Spector, T., Munafo, M. R., Metspalu, A., Gelernter, J., Boomsma, D. I., Iacono, W. G., Martin, N. G., Gillespie, N. A., Derks, E. M., and Vink, J. M.

Abstract

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N = 32 330) and four replication samples (N = 5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use.

Published
2016

28. Meta-analysis of the DRD5 VNTR in persistent ADHD

Author

Klein, M., Berger, S., Hoogman, M., Dammers, J.T., Makkinje, R.R., Heister, A., Galesloot, T.E., Kiemeney, L.A., Weber, H., Kittel-Schneider, S., Lesch, K.P., Reif, A., Ribases, M., Ramos-Quiroga, J.A., Cormand, B., Zayats, T., Hegvik, T.A., Jacobsen, K.K., Johansson, S., Haavik, J., Mota, N.R., Bau, C.H., Grevet, E.H., Doyle, A., Faraone, S.V, Arias-Vasquez, A., Franke, B., Klein, M., Berger, S., Hoogman, M., Dammers, J.T., Makkinje, R.R., Heister, A., Galesloot, T.E., Kiemeney, L.A., Weber, H., Kittel-Schneider, S., Lesch, K.P., Reif, A., Ribases, M., Ramos-Quiroga, J.A., Cormand, B., Zayats, T., Hegvik, T.A., Jacobsen, K.K., Johansson, S., Haavik, J., Mota, N.R., Bau, C.H., Grevet, E.H., Doyle, A., Faraone, S.V, Arias-Vasquez, A., and Franke, B.

Abstract

Contains fulltext : 167943pub.pdf (publisher's version ) (Closed access), Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. DRD5, the gene encoding the dopamine receptor D5, was recently confirmed as a candidate gene for ADHD in children through meta-analysis. In this study, we aimed at studying the association of the ADHD-associated variable number tandem repeat (VNTR) polymorphism upstream of DRD5 with adult ADHD. We compiled data from six sites of the International Multicentre persistent ADHD CollaboraTion (IMpACT) and reached N=6979 (3344 cases and 3635 healthy participants), the largest sample investigated so far. We tested the association of the common DRD5 alleles with categorically defined ADHD and with inattentive and hyperactive/impulsive symptom counts. Our findings provide evidence that none of the common DRD5 alleles are associated with ADHD risk or ADHD symptom counts in adults.

Published
2016

29. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

Author

Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., van Eijk, K. R., Isen, J. D., Loukola, A., Maciejewski, D. F., Mihailov, E., van der Most, P. J., Sanchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J. J., Abdellaoui, A., Bigdeli, T. B., Branje, S. J. T., Brown, S. A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S. D., Harris, J. M., Hartman, C. A., Henders, A. K., Heath, A. C., Hickie, I. B., Hickman, M., Hopfer, C. J., Hottenga, J. J., Huizink, A. C., Irons, D. E., Kahn, R. S., Korhonen, T., Kranzler, H. R., Krauter, K., van Lier, P. A. C., Lubke, G. H., Madden, P. A. F., Magi, R., McGue, M. K., Medland, S. E., Meeus, W. H. J., Miller, M. B., Montgomery, G. W., Nivard, M. G., Nolte, I. M., Oldehinkel, A. J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J. A., Richarte, V., Rose, R. J., Shin, J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, M. J., Koot, H. M., Paus, T., Hewitt, J. K., Ribases, M., Kaprio, J., Boks, M. P., Snieder, H., Spector, T., Munafo, M. R., Metspalu, A., Gelernter, J., Boomsma, D. I., Iacono, W. G., Martin, N. G., Gillespie, N. A., Derks, E. M., Vink, J. M., Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., van Eijk, K. R., Isen, J. D., Loukola, A., Maciejewski, D. F., Mihailov, E., van der Most, P. J., Sanchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J. J., Abdellaoui, A., Bigdeli, T. B., Branje, S. J. T., Brown, S. A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S. D., Harris, J. M., Hartman, C. A., Henders, A. K., Heath, A. C., Hickie, I. B., Hickman, M., Hopfer, C. J., Hottenga, J. J., Huizink, A. C., Irons, D. E., Kahn, R. S., Korhonen, T., Kranzler, H. R., Krauter, K., van Lier, P. A. C., Lubke, G. H., Madden, P. A. F., Magi, R., McGue, M. K., Medland, S. E., Meeus, W. H. J., Miller, M. B., Montgomery, G. W., Nivard, M. G., Nolte, I. M., Oldehinkel, A. J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J. A., Richarte, V., Rose, R. J., Shin, J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, M. J., Koot, H. M., Paus, T., Hewitt, J. K., Ribases, M., Kaprio, J., Boks, M. P., Snieder, H., Spector, T., Munafo, M. R., Metspalu, A., Gelernter, J., Boomsma, D. I., Iacono, W. G., Martin, N. G., Gillespie, N. A., Derks, E. M., and Vink, J. M.

Abstract

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Published
2016

30. Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

Author

Fernandez-Castillo, N., Cabana-Dominguez, J., Soriano, J., Sanchez-Mora, C., Roncero, C., Grau-López, L., Ros-Cucurull, E., Daigre, C., Donkelaar, M.M.J. van, Franke, B., Casas, M., Ribases, M., Cormand, B., Fernandez-Castillo, N., Cabana-Dominguez, J., Soriano, J., Sanchez-Mora, C., Roncero, C., Grau-López, L., Ros-Cucurull, E., Daigre, C., Donkelaar, M.M.J. van, Franke, B., Casas, M., Ribases, M., and Cormand, B.

Abstract

Contains fulltext : 152880.pdf (publisher's version ) (Open Access), Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 muM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 muM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence.

Published
2015

31. Case-Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder

Author

Sanchez-Mora, C., Ramos-Quiroga, J.A., Bosch, R., Corrales, M., Garcia-Martinez, I., Nogueira, M., Pagerols, M., Palomar, G., Richarte, V., Vidal, R., Arias Vasquez, A., Bustamante, M., Forns, J., Gross-Lesch, S., Guxens, M., Hinney, A., Hoogman, M., Jacob, C., Jacobsen, K.K., Kan, C.C., Kiemeney, B., Kittel-Schneider, S., Klein, M., Onnink, M., Rivero, O., Zayats, T., Buitelaar, J.K., Faraone, S.V., Franke, B., Haavik, J., Johansson, S., Lesch, K.P., Reif, A., Sunyer, J., Bayes, M., Casas, M., Cormand, B., Ribases, M., Sanchez-Mora, C., Ramos-Quiroga, J.A., Bosch, R., Corrales, M., Garcia-Martinez, I., Nogueira, M., Pagerols, M., Palomar, G., Richarte, V., Vidal, R., Arias Vasquez, A., Bustamante, M., Forns, J., Gross-Lesch, S., Guxens, M., Hinney, A., Hoogman, M., Jacob, C., Jacobsen, K.K., Kan, C.C., Kiemeney, B., Kittel-Schneider, S., Klein, M., Onnink, M., Rivero, O., Zayats, T., Buitelaar, J.K., Faraone, S.V., Franke, B., Haavik, J., Johansson, S., Lesch, K.P., Reif, A., Sunyer, J., Bayes, M., Casas, M., Cormand, B., and Ribases, M.

Abstract

Contains fulltext : 154715pub.pdf (publisher's version ) (Open Access), Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e-08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e-07) and in the joint analysis of both stages (P=9.7e-03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.

Published
2015

32. A combined population and family-based study of eight European populations demonstrates association between BDNF and eating disorders

Author

Ribases M, Gratacos M, Fernandez Aranda F, Cellini E, Nacmias B, Sorbi S, Di Bella D, Gorwood P, Kipman A, Mouren Simeoni MC, Hebebrand J, Hinney A, Remschmidt H, Karwautz A, Brecejl M, Gabrovsek M, Collier D, Treasure J, Estivill X., BELLODI , LAURA, Ribases, M, Gratacos, M, Fernandez Aranda, F, Cellini, E, Nacmias, B, Sorbi, S, Di Bella, D, Bellodi, Laura, Gorwood, P, Kipman, A, Mouren Simeoni, Mc, Hebebrand, J, Hinney, A, Remschmidt, H, Karwautz, A, Brecejl, M, Gabrovsek, M, Collier, D, Treasure, J, and Estivill, X.

Published
2003

33. Usefulness of analysis of cerebrospinal fluid for the diagnosis of neurotransmitters and pterin defects and glucose and folate transport deficiencies across blood brain barrier

Author

ORMAZABAL, A., GARCÍA CAZORLA, A., PÉREZ DUEÑAS, B., PINEDA, M., RUIZ, A., LÓPEZ LASO, E., GARCÍA SILVA, M., CARILHO, I., BARBOT, C., CORMAND, B., RIBASES, M., MOLLER, L., FERNÁNDEZ ALVAREZ, E., CAMPISTOL, J., and ARTUCH, R.

Abstract

Med Clin (Barc). 2006 Jun 17;127(3):81-5. [Usefulness of analysis of cerebrospinal fluid for the diagnosis of neurotransmitters and pterin defects and glucose and folate transport deficiencies across blood brain barrier] [Article in Spanish] Ormazabal A, García Cazorla A, Pérez Dueñas B, Pineda M, Ruiz A, López Laso E, García Silva M, Carilho I, Barbot C, Cormand B, Ribases M, Moller L, Fernández Alvarez E, Campistol J, Artuch R. Hospital Sant Joan de Déu, Esplugues, Barcelona, España. Abstract BACKGROUND AND OBJECTIVE: In the last few years, it has been described inborn errors of neurotransmitter and pterin metabolism and defects in folate and glucose transport across blood brain barrier. All these defects are classified as rare diseases and needs cerebrospinal fluid (CSF) sample analysis for diagnosis. Our aim was to evaluate the results of the application of a CSF analysis protocol in a pediatric population from Spain and Portugal presenting with neurological disorders of unknown origin. PATIENTS AND METHOD: We studied CSF samples from and 283 patients with neurological disorders of unknown origin and 127 controls. Neurotransmitters were analysed by HPLC with electrochemical detection, and pterins and 5-methyltetrahydrofolate were determined by HPLC with fluorescence detection. RESULTS: We diagnosed 3 patients with tyrosine hidroxylase deficiency, 2 with dopa responsive dystonia, 14 with GTP-ciclohydrolase deficiency, 2 with glucose transport deficiency and 43 with cerebral folate deficiency. CONCLUSIONS: This study allowed us to diagnose new patients, and more importantly, the establishment in all of them of a pharmacological or nutritional treatment. The most frequent defect found was CSF 5-methyltetrahydrofolate deficiency, which was present in different groups of patients. PMID: 16827996 [PubMed - indexed for MEDLINE]

Published
2006

34. DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders

Author

Reif, A., Nguyen, T.T., Weissflog, L., Jacob, C.P., Romanos, M., Renner, T.J., Buttenschon, H.N., Kittel-Schneider, S., Gessner, A., Weber, H., Neuner, M., Gross-Lesch, S., Zamzow, K., Kreiker, S., Walitza, S., Meyer, J., Freitag, C.M., Bosch, R., Casas, M., Gomez, N., Ribases, M., Bayes, M., Buitelaar, J.K., Kiemeney, L.A.L.M., Kooij, J.J., Kan, C.C., Hoogman, M., Johansson, S., Jacobsen, K.K., Knappskog, P.M., Fasmer, O.B., Asherson, P., Warnke, A., Grabe, H.J., Mahler, J., Teumer, A., Volzke, H., Mors, O.N., Schafer, H., Ramos-Quiroga, J.A., Cormand, B., Haavik, J., Franke, B., Lesch, K.P., Reif, A., Nguyen, T.T., Weissflog, L., Jacob, C.P., Romanos, M., Renner, T.J., Buttenschon, H.N., Kittel-Schneider, S., Gessner, A., Weber, H., Neuner, M., Gross-Lesch, S., Zamzow, K., Kreiker, S., Walitza, S., Meyer, J., Freitag, C.M., Bosch, R., Casas, M., Gomez, N., Ribases, M., Bayes, M., Buitelaar, J.K., Kiemeney, L.A.L.M., Kooij, J.J., Kan, C.C., Hoogman, M., Johansson, S., Jacobsen, K.K., Knappskog, P.M., Fasmer, O.B., Asherson, P., Warnke, A., Grabe, H.J., Mahler, J., Teumer, A., Volzke, H., Mors, O.N., Schafer, H., Ramos-Quiroga, J.A., Cormand, B., Haavik, J., Franke, B., and Lesch, K.P.

Abstract

Contains fulltext : 95784.pdf (publisher's version ) (Closed access), Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.

Published
2011

35. Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: a meta-analysis in four European populations

Author

Sanchez-Mora, C., Ribases, M., Casas, M., Bayes, M., Bosch, R., Fernandez-Castillo, N., Brunso, L., Jacobsen, K.K., Landaas, E.T., Lundervold, A.J., Gross-Lesch, S., Kreiker, S., Jacob, C.P., Lesch, K.P., Buitelaar, J.K., Hoogman, M., Kiemeney, L.A.L.M., Kooij, J.J., Mick, E., Asherson, P., Faraone, S.V., Franke, B., Reif, A., Johansson, S., Haavik, J., Ramos-Quiroga, J.A., Cormand, B., Sanchez-Mora, C., Ribases, M., Casas, M., Bayes, M., Bosch, R., Fernandez-Castillo, N., Brunso, L., Jacobsen, K.K., Landaas, E.T., Lundervold, A.J., Gross-Lesch, S., Kreiker, S., Jacob, C.P., Lesch, K.P., Buitelaar, J.K., Hoogman, M., Kiemeney, L.A.L.M., Kooij, J.J., Mick, E., Asherson, P., Faraone, S.V., Franke, B., Reif, A., Johansson, S., Haavik, J., Ramos-Quiroga, J.A., and Cormand, B.

Abstract

Contains fulltext : 97904.pdf (publisher's version ) (Closed access), Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4-8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiple-marker meta-analysis showed a nominal association (P = 0.02) of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R-6R haplotype (3'UTR VNTR-intron 8 VNTR) in the same dataset, we further tested for gene x gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene.

Published
2011

36. Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: A replication study

Author

Ribases, M., Ramos-Quiroga, J. A., Sanchez-Mora, C., Bosch, R., Richarte, V., Palomar, G., Gastaminza, X., Biesla, A., Muenke, Maximilian, Arcos-Burgos, Mauricio, Castellanos, Francisco Xavier, Ribases, M., Ramos-Quiroga, J. A., Sanchez-Mora, C., Bosch, R., Richarte, V., Palomar, G., Gastaminza, X., Biesla, A., Muenke, Maximilian, Arcos-Burgos, Mauricio, and Castellanos, Francisco Xavier

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable developmental disorder characterized by a persistent impairing pattern of inattention and/or hyperactivity-impulsivity. Using families from a genetic isolate, the Paisa population from Colombia, and five independent datasets from four different populations (United States, Germany, Norway and Spain), a highly consistent association was recently reported between ADHD and the latrophilin 3 (LPHN3) gene, a brain-specific member of the LPHN subfamily of G-protein-coupled receptors that is expressed in ADHD-related regions, such as amygdala, caudate nucleus, cerebellum and cerebral cortex. To replicate the association between LPHN3 and ADHD in adults, we undertook a case-control association study in 334 adult patients with ADHD and 334 controls with 43 single nucleotide polymorphisms (SNPs) covering the LPNH3 gene. Single- and multiple-marker analyses showed additional evidence of association between LPHN3 and combined type ADHD in adulthood [P = 0.0019; df = 1; odds ratio (OR) = 1.82 (1.25-2.70) and P = 5.1e-05; df = 1; OR = 2.25 (1.52-3.34), respectively]. These results further support the LPHN3 contribution to combined type ADHD, and specifically to the persistent form of the disorder, and point at this new neuronal pathway as a common susceptibility factor for ADHD throughout the lifespan.

Published
2011

37. An international multicenter association study of the serotonin transporter gene in persistent ADHD.

Author

Landaas, E.T., Johansson, S., Jacobsen, K.K., Ribases, M., Bosch, R., Sanchez-Mora, C., Jacob, C.P., Boreatti-Hummer, A., Kreiker, S., Lesch, K.P., Kiemeney, L.A.L.M., Kooij, J.J., Kan, C.C., Buitelaar, J.K., Faraone, S.V., Halmoy, A., Ramos-Quiroga, J.A., Cormand, B., Reif, A., Franke, B., Mick, E., Knappskog, P.M., Haavik, J., Landaas, E.T., Johansson, S., Jacobsen, K.K., Ribases, M., Bosch, R., Sanchez-Mora, C., Jacob, C.P., Boreatti-Hummer, A., Kreiker, S., Lesch, K.P., Kiemeney, L.A.L.M., Kooij, J.J., Kan, C.C., Buitelaar, J.K., Faraone, S.V., Halmoy, A., Ramos-Quiroga, J.A., Cormand, B., Reif, A., Franke, B., Mick, E., Knappskog, P.M., and Haavik, J.

Abstract

1 juli 2010, Contains fulltext : 88135.pdf (publisher's version ) (Closed access), Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5-HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta-analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5-HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta-analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67-1.09; P = 0.20]. For 5-HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta-analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00-1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5-HTTLPR and a role for rare variants cannot be excluded.

Published
2010

38. Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD.

Author

Franke, B., Arias Vasquez, A., Johansson, S., Hoogman, M., Romanos, J., Boreatti-Hummer, A., Heine, M., Jacob, C.P., Lesch, K.P., Casas, M., Ribases, M., Bosch, R., Sanchez-Mora, C., Gomez-Barros, N., Fernandez-Castillo, N., Bayes, M., Halmoy, A., Halleland, H., Landaas, E.T., Fasmer, O.B., Knappskog, P.M., Heister, J.G.A.M., Kiemeney, L.A.L.M., Kooij, J.J., Boonstra, A.M., Kan, C.C., Asherson, P., Faraone, S.V., Buitelaar, J.K., Haavik, J., Cormand, B., Ramos-Quiroga, J.A., Reif, A., Franke, B., Arias Vasquez, A., Johansson, S., Hoogman, M., Romanos, J., Boreatti-Hummer, A., Heine, M., Jacob, C.P., Lesch, K.P., Casas, M., Ribases, M., Bosch, R., Sanchez-Mora, C., Gomez-Barros, N., Fernandez-Castillo, N., Bayes, M., Halmoy, A., Halleland, H., Landaas, E.T., Fasmer, O.B., Knappskog, P.M., Heister, J.G.A.M., Kiemeney, L.A.L.M., Kooij, J.J., Boonstra, A.M., Kan, C.C., Asherson, P., Faraone, S.V., Buitelaar, J.K., Haavik, J., Cormand, B., Ramos-Quiroga, J.A., and Reif, A.

Abstract

01 februari 2010, Contains fulltext : 89288.pdf (publisher's version ) (Closed access), Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4-5% in children and 1-4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3'-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3'-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Published
2010

39. Meta-analysis of brain-derived neurotrophic factor p.Val66Met in adult ADHD in four European populations.

Author

Sanchez-Mora, C., Ribases, M., Ramos-Quiroga, J.A., Casas, M., Bosch, R., Boreatti-Hummer, A., Heine, M., Jacob, C.P., Lesch, K.P., Fasmer, O.B., Knappskog, P.M., Kooij, J.J., Kan, C.C., Buitelaar, J.K., Mick, E., Asherson, P., Faraone, S.V., Franke, B., Johansson, S., Haavik, J., Reif, A., Bayes, M., Cormand, B., Sanchez-Mora, C., Ribases, M., Ramos-Quiroga, J.A., Casas, M., Bosch, R., Boreatti-Hummer, A., Heine, M., Jacob, C.P., Lesch, K.P., Fasmer, O.B., Knappskog, P.M., Kooij, J.J., Kan, C.C., Buitelaar, J.K., Mick, E., Asherson, P., Faraone, S.V., Franke, B., Johansson, S., Haavik, J., Reif, A., Bayes, M., and Cormand, B.

Abstract

Contains fulltext : 87687.pdf (publisher's version ) (Closed access), Attention-deficit hyperactivity disorder (ADHD) is a multifactorial, neurodevelopmental disorder that often persists into adolescence and adulthood and is characterized by inattention, hyperactivity and impulsiveness. Before the advent of the first genome-wide association studies in ADHD, genetic research had mainly focused on candidate genes related to the dopaminergic and serotoninergic systems, although several other genes had also been assessed. Pharmacological data, analysis of animal models and association studies suggest that Brain-Derived Neurotrophic Factor (BDNF) is also a strong candidate gene for ADHD. Several polymorphisms in BDNF have been reported and studied in psychiatric disorders but the most frequent is the p.Val66Met (rs6265G > A) single nucleotide polymorphism (SNP), with functional effects on the intracellular trafficking and secretion of the protein. To deal with the inconsistency raised among different case-control and family-based association studies regarding the p.Val66Met contribution to ADHD, we performed a meta-analysis of published as well as unpublished data from four different centers that are part of the International Multicentre Persistent ADHD CollaboraTion (IMpACT). A total of 1,445 adulthood ADHD patients and 2,247 sex-matched controls were available for the study. No association between the p.Val66Met polymorphism and ADHD was found in any of the four populations or in the pooled sample. The meta-analysis also showed that the overall gene effect for ADHD was not statistically significant when gender or comorbidity with mood disorders were considered. Despite the potential role of BDNF in ADHD, our data do not support the involvement of p.Val66Met in the pathogenesis of this neuropsychiatric disorder.

Published
2010

40. Common variants in the TPH1 and TPH2 regions are not associated with persistent ADHD in a combined sample of 1,636 adult cases and 1,923 controls from four European populations.

Author

Johansson, S., Halmoy, A., Mavroconstanti, T., Jacobsen, K.K., Landaas, E.T., Reif, A., Jacob, C., Boreatti-Hummer, A., Kreiker, S., Lesch, K.P., Kan, C.C., Kooij, J.J., Kiemeney, L.A.L.M., Buitelaar, J.K., Franke, B., Ribases, M., Bosch, R., Bayes, M., Casas, M., Ramos-Quiroga, J.A., Cormand, B., Knappskog, P., Haavik, J., Johansson, S., Halmoy, A., Mavroconstanti, T., Jacobsen, K.K., Landaas, E.T., Reif, A., Jacob, C., Boreatti-Hummer, A., Kreiker, S., Lesch, K.P., Kan, C.C., Kooij, J.J., Kiemeney, L.A.L.M., Buitelaar, J.K., Franke, B., Ribases, M., Bosch, R., Bayes, M., Casas, M., Ramos-Quiroga, J.A., Cormand, B., Knappskog, P., and Haavik, J.

Abstract

1 juli 2010, Contains fulltext : 89467.pdf (publisher's version ) (Closed access), The tryptophan hydroxylase 1 and 2 (TPH1 and TPH2) genes encode the rate-limiting enzymes in the serotonin biosynthesis. Genetic variants in both genes have been implicated in several psychiatric disorders. For attention-deficit/hyperactivity disorder (ADHD) in children, the results are conflicting, and little is known about their role in adult ADHD patients. We therefore first genotype-tagged all common variants within both genes in a Norwegian sample of 451 patients with a diagnosis of adult ADHD and 584 controls. Six of the single nucleotide polymorphisms (SNPs) were subsequently genotyped in three additional independent European Caucasian samples of adult ADHD cases and controls from the International Multicenter persistent ADHD Collaboration (IMpACT). None of the SNPs reached formal study-wide significance in the total meta-analysis sample of 1,636 cases and 1,923 controls, despite having a power of >80% to detect a variant conferring an OR = 1.25 at P = 0.001 level. Only the TPH1 SNP rs17794760 showed nominal significance [OR = 0.84 (0.71-1.00), P = 0.05]. In conclusion, in the single largest ADHD genetic study of TPH1 and TPH2 variants presented to date (n = 3,559 individuals), we did not find consistent evidence for a substantial effect of common genetic variants on persistent ADHD.

Published
2010

41. Gene-environment interaction in anorexia nervosa

Author

Karwautz, A.F.K., primary, Wagner, G., additional, Waldherr, K., additional, Fernandez-Aranda, F., additional, Krug, I., additional, Ribases, M., additional, Holliday, J., additional, Collier, D.A., additional, and Treasure, J.L., additional

Published
2008
Full Text
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42. Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Author

Mercader, J.M., primary, Saus, E., additional, Agüera, Z., additional, Bayés, M., additional, Claudette, B., additional, Carreras, A., additional, de Cid, R., additional, Dierssen, M., additional, Fernández-Aranda, F., additional, Forcano, L., additional, Gorwood, P., additional, Hebebrand, J., additional, Hinney, A., additional, Puig, A., additional, Ribases, M., additional, Gratacòs, M., additional, and Estivill, X., additional

Published
2008
Full Text
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45. Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa

Author

Gabrovsek, M., primary, Brecelj-Anderluh, M., additional, Bellodi, L., additional, Cellini, E., additional, Di Bella, D., additional, Estivill, X., additional, Fernandez-Aranda, F., additional, Freeman, B., additional, Geller, F., additional, Gratacos, M., additional, Haigh, R., additional, Hebebrand, J., additional, Hinney, A., additional, Holliday, J., additional, Hu, X., additional, Karwautz, A., additional, Nacmias, B., additional, Ribases, M., additional, Remschmidt, H., additional, Komel, R., additional, Sorbi, S., additional, Tomori, M., additional, Treasure, J., additional, Wagner, G., additional, Zhao, J., additional, and Collier, D.A., additional

Published
2003
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47. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium

Author

Stringer, S, Minică, C C, Verweij, K J H, Mbarek, H, Bernard, M, Derringer, J, van Eijk, K R, Isen, J D, Loukola, A, Maciejewski, D F, Mihailov, E, van der Most, P J, Sánchez-Mora, C, Roos, L, Sherva, R, Walters, R, Ware, J J, Abdellaoui, A, Bigdeli, T B, Branje, S J T, Brown, S A, Bruinenberg, M, Casas, M, Esko, T, Garcia-Martinez, I, Gordon, S D, Harris, J M, Hartman, C A, Henders, A K, Heath, A C, Hickie, I B, Hickman, M, Hopfer, C J, Hottenga, J J, Huizink, A C, Irons, D E, Kahn, R S, Korhonen, T, Kranzler, H R, Krauter, K, van Lier, P A C, Lubke, G H, Madden, P A F, Mägi, R, McGue, M K, Medland, S E, Meeus, W H J, Miller, M B, Montgomery, G W, Nivard, M G, Nolte, I M, Oldehinkel, A J, Pausova, Z, Qaiser, B, Quaye, L, Ramos-Quiroga, J A, Richarte, V, Rose, R J, Shin, J, Stallings, M C, Stiby, A I, Wall, T L, Wright, M J, Koot, H M, Paus, T, Hewitt, J K, Ribasés, M, Kaprio, J, Boks, M P, Snieder, H, Spector, T, Munafò, M R, Metspalu, A, Gelernter, J, Boomsma, D I, Iacono, W G, Martin, N G, Gillespie, N A, Derks, E M, and Vink, J M

Abstract

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Published
2016
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48. The 5-HT[sub2A] --1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres.

Author

Gorwood, P., Ades, J., Bellodi, L., Cellini, E., Collier, D.A., Di Bella, D., Di Bernardo, M., Estivill, X., Fernandez-Aranda, F., Gratacos, M., Hebebrand, J., Hinney, A., Hu, X., Karwautz, A., Kipman, A., Mouren-Simeoni, M.-C., Nacmias, B., Ribases, M., and Remschmidt, H.

Subjects
GENETIC polymorphisms, ANOREXIA nervosa, EATING disorders
Abstract

Several case-control association studies have raised the possibility that the A allele of a -1438 G/A polymorphism in the type 2A serotonin receptor (HTR2A) gene may be a risk factor for anorexia nervosa. However the absence of linkage and the existence of negative association studies raise the possibility of false positive findings, resulting from population stratification or lack of statistical power. To address this controversy we recruited a sample of 316 patients with anorexia nervosa from six European centres, and utilised a family-based transmission disequilibrium (TDT) approach to analyse the HTR2A-1438 G/A polymorphism. Age at onset and minimal BMI were also taken into consideration in order to detect clinical heterogeneity or a quantitative trait effect. The TDT approach showed that the A allele was transmitted 133 times and not transmitted 148 times (McNemar X² = 0.29, df = 1, P = 0.59). Also, the haplotypebased haplotype relative risk method showed no evidence for association of the A allele, in samples from each centre (X² < 2.15, df = 1, P > 0.14) and in the total sample (X² = 0.55, df = 1; P = 0.46). Furthermore, we found no evidence for heterogeneity of the A allele frequency between samples (X² = 2.54, df = 4, P = 0.64), either according to minimal-BMI (F1/242 = 2.14, P = 0.45) or age at onset (F1/224 = 2.39; P = 0.12). QTL-TDT analyses also showed no direct role of the A allele on these traits. We thus found no evidence for a significant role of the 5-HT[sub 2A] gene in anorexia nervosa. Previous results may have been exposed to stratification bias (which we controlled by the TDT method) and/or the risk of type 1 error (from which we were less exposed because of the sample size). [ABSTRACT FROM AUTHOR]

Published
2002

50. Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa<FNR HREF="fn1"></FNR><FN ID="fn1">EC Framework V ‘Factors in Healthy Eating’ consortium coordinated by Janet Treasure and David Collier.</FN>

Author

Gabrovsek, M., Brecelj-Anderluh, M., Bellodi, L., Cellini, E., Bella, D. Di, Estivill, X., Fernandez-Aranda, F., Freeman, B., Geller, F., Gratacos, M., Haigh, R., Hebebrand, J., Hinney, A., Holliday, J., Hu, X., Karwautz, A., Nacmias, B., Ribases, M., Remschmidt, H., Komel, R., Sorbi, S., Tomori, M., Treasure, J., Wagner, G., Zhao, J., and Collier, D.A.

Abstract

The high activity Val158 (H) allele of the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio-based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case-control study in an European population from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (χ2 = 0, ns). Allele-wise case-control analysis using separate samples simply combined from the centers was also not significant, with the frequencies of the H allele 50% in cases and same in controls. Stratified analysis of data from all centers gave an odds ratio of 0.98 (Cornfield 95% confidence limits 0.78–1.24). Analysis by genotype was likewise not significant (overall χ2 = 0.42). Because we were not able to support the primary hypothesis that Val158Met is a risk factor for AN, we did not perform secondary analysis of minimum body mass index (mBMI), age at onset or illness subtype (restricting or binge purging anorexia). Overall we found no support for the hypothesis that the Val158 allele of COMT gene is associated with AN in our combined European sample. © 2003 Wiley-Liss, Inc.

Published
2004
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