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3. Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder, and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, 'basket' trial

Author

Arteaga-Henríquez, G., Ramos-Sayalero, C., Ibañez-Jimenez, P., Rosales-Ortiz, S.K., Kilencz, T., Schiweck, C., Schnorr, I., Siegl, A., Arias Vasquez, A., Bitter, I., Fadeuilhe, C., Ferrer, M., Lavebratt, C., Matura, S., Reif, A., Réthelyi, J.M., Richarte, V., Rommelse, N.N.J., Ramos-Quiroga, J.A., Arteaga-Henríquez, G., Ramos-Sayalero, C., Ibañez-Jimenez, P., Rosales-Ortiz, S.K., Kilencz, T., Schiweck, C., Schnorr, I., Siegl, A., Arias Vasquez, A., Bitter, I., Fadeuilhe, C., Ferrer, M., Lavebratt, C., Matura, S., Reif, A., Réthelyi, J.M., Richarte, V., Rommelse, N.N.J., and Ramos-Quiroga, J.A.

Abstract

Contains fulltext : 307165.pdf (Publisher’s version ) (Open Access), Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved), at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic showed a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3, 15 juni 2024

Published
2024

4. 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, CC, Verweij, KJH, Mbarek, H, Bernard, M, Derringer, J, van Eijk, KR, Isen, JD, Loukola, A, Maciejewski, DF, Mihailov, E, van der Most, PJ, Sánchez-Mora, C, Roos, L, Sherva, R, Walters, R, Ware, JJ, Abdellaoui, A, Bigdeli, TB, Branje, SJT, Brown, SA, Bruinenberg, M, Casas, M, Esko, T, Garcia-Martinez, I, Gordon, SD, Harris, JM, Hartman, CA, Henders, AK, Heath, AC, Hickie, IB, Hickman, M, Hopfer, CJ, Hottenga, JJ, Huizink, AC, Irons, DE, Kahn, RS, Korhonen, T, Kranzler, HR, Krauter, K, van Lier, PAC, Lubke, GH, Madden, PAF, Mägi, R, McGue, MK, Medland, SE, Meeus, WHJ, Miller, MB, Montgomery, GW, Nivard, MG, Nolte, IM, Oldehinkel, AJ, Pausova, Z, Qaiser, B, Quaye, L, Ramos-Quiroga, JA, Richarte, V, Rose, RJ, Shin, J, Stallings, MC, Stiby, AI, Wall, TL, Wright, MJ, Koot, HM, Paus, T, Hewitt, JK, Ribasés, M, Kaprio, J, Boks, MP, Snieder, H, Spector, T, Munafò, MR, Metspalu, A, Gelernter, J, Boomsma, DI, Iacono, WG, Martin, NG, Gillespie, NA, Derks, EM, and Vink, JM

Subjects
Humans, Marijuana Abuse, Carrier Proteins, Potassium Channels, Cell Adhesion Molecules, Membrane Proteins, Marijuana Smoking, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Young Adult, CD56 Antigen, Potassium Channels, Sodium-Activated, and over, Sodium-Activated, Antigens, CD56, Genetics, Tobacco, Substance Abuse, Human Genome, Drug Abuse, Brain Disorders, Pediatric Research Initiative, Tobacco Smoke and Health, Prevention, Biotechnology, Clinical Research, 2.1 Biological and endogenous factors, Mental Health, Psychology, Clinical Sciences, Public Health and Health Services
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

Published
2016

9. Transcriptomic risk scores for attention deficit/hyperactivity disorder

Author

Cabana-Domínguez, J., primary, Tejedor, N. Llonga, additional, Arribas, L., additional, Alemany, S., additional, Vilar-Ribó, L., additional, Carabí, P., additional, Demontis, D., additional, Christian, F., additional, Montse, C., additional, Richarte, V., additional, Børglum, A., additional, Ramos-Quiroga, J.A., additional, Artigas, M. Soler, additional, and Ribasés, M., additional

Published
2023
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12. 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

14. Eye Vergence Responses During an Attention Task in Adults With ADHD and Clinical Controls

Author

Jiménez EC, Avella-Garcia C, Kustow J, Cubbin S, Corrales M, Richarte V, Esposito FL, Morata I, Perera A, Varela P, Cañete J, Faraone SV, Super H, and Ramos-Quiroga JA

Subjects
diagnosis, genetic structures, binocular, mental disorders, biomarker, eye vergence, ADHD, behavioral disciplines and activities, adults
Abstract

Objective: ADHD patients show poor oculomotor control and recent studies show that attention-related eye vergence is weak in ADHD children. We aimed to assess vergence as a potential diagnostic biomarker for ADHD in adults. Method: We assessed the modulation in the angle of vergence while performing an attention task (N = 144), comparing the results for adults previously diagnosed with ADHD (N = 108) with age-matched clinical controls (N = 36). Results: Significant differences in eye vergence response modulation between clinical controls and ADHD patients were documented. Diagnostic test accuracy was 79%. Conclusion: In combination with an attention task, eye vergence responses could be used as an objective marker to support the clinical diagnosis of adult ADHD.

Published
2021

15. Correction to: Attention-deficit/hyperactivity disorder and lifetime cannabis use: Genetic overlap and causality

Author

Soler Artigas, M., Sánchez-Mora, C., Rovira, P., Richarte, V., Garcia-Martinez, I., Pagerols, M., Demontis, D., Stringer, S., Vink, J.M., Borglum, A.D., Neale, B.M., Franke, B., Faraone, S.V., Casas, M., Ramos-Quiroga, J.A., Ribasés, M., Soler Artigas, M., Sánchez-Mora, C., Rovira, P., Richarte, V., Garcia-Martinez, I., Pagerols, M., Demontis, D., Stringer, S., Vink, J.M., Borglum, A.D., Neale, B.M., Franke, B., Faraone, S.V., Casas, M., Ramos-Quiroga, J.A., and Ribasés, M.

Abstract

Item does not contain fulltext

Published
2021

16. Gut microbiota signature in treatment-naïve attention-deficit/hyperactivity disorder

Author

Richarte, V., Sánchez-Mora, C., Corrales, M., Fadeuilhe, C., Vilar-Ribó, L., Arribas, L., Garcia, E., Rosales-Ortiz, S.K., Arias-Vasquez, A., Soler-Artigas, M., Ribasés, M., Ramos-Quiroga, J.A., Richarte, V., Sánchez-Mora, C., Corrales, M., Fadeuilhe, C., Vilar-Ribó, L., Arribas, L., Garcia, E., Rosales-Ortiz, S.K., Arias-Vasquez, A., Soler-Artigas, M., Ribasés, M., and Ramos-Quiroga, J.A.

Abstract

Contains fulltext : 237833.pdf (Publisher’s version ) (Open Access), Compelling evidence supports alterations in gut microbial diversity, bacterial composition, and/or relative abundance of several bacterial taxa in attention-deficit/hyperactivity disorder (ADHD). However, findings for ADHD are inconsistent among studies, and specific gut microbiome signatures for the disorder remain unknown. Given that previous studies have mainly focused on the pediatric form of the disorder and involved small sample sizes, we conducted the largest study to date to compare the gastrointestinal microbiome composition in 100 medication-naïve adults with ADHD and 100 sex-matched healthy controls. We found evidence that ADHD subjects have differences in the relative abundance of several microbial taxa. At the family level, our data support a lower relative abundance of Gracilibacteraceae and higher levels of Selenomonadaceae and Veillonellaceae in adults with ADHD. In addition, the ADHD group showed higher levels of Dialister and Megamonas and lower abundance of Anaerotaenia and Gracilibacter at the genus level. All four selected genera explained 15% of the variance of ADHD, and this microbial signature achieved an overall sensitivity of 74% and a specificity of 71% for distinguishing between ADHD patients and healthy controls. We also tested whether the selected genera correlate with age, body mass index (BMI), or scores of the ADHD rating scale but found no evidence of correlation between genera relative abundance and any of the selected traits. These results are in line with recent studies supporting gut microbiome alterations in neurodevelopment disorders, but further studies are needed to elucidate the role of the gut microbiota on the ADHD across the lifespan and its contribution to the persistence of the disorder from childhood to adulthood.

Published
2021

17. Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders

Author

Patel, Y, Parker, N, Shin, J, Howard, D, French, L, Thomopoulos, SI, Pozzi, E, Abe, Y, Abe, C, Anticevic, A, Alda, M, Aleman, A, Alloza, C, Alonso-Lana, S, Ameis, SH, Anagnostou, E, McIntosh, AA, Arango, C, Arnold, PD, Asherson, P, Assogna, F, Auzias, G, Ayesa-Arriola, R, Bakker, G, Banaj, N, Banaschewski, T, Bandeira, CE, Baranov, A, Bargallo, N, Bau, CHD, Baumeister, S, Baune, BT, Bellgrove, MA, Benedetti, F, Bertolino, A, Boedhoe, PSW, Boks, M, Bollettini, I, del Mar Bonnin, C, Borgers, T, Borgwardt, S, Brandeis, D, Brennan, BP, Bruggemann, JM, Bulow, R, Busatto, GF, Calderoni, S, Calhoun, VD, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carr, VJ, Cascella, N, Cercignani, M, Chaim-Avancini, TM, Christakou, A, Coghill, D, Conzelmann, A, Crespo-Facorro, B, Cubillo, AI, Cullen, KR, Cupertino, RB, Daly, E, Dannlowski, U, Davey, CG, Denys, D, Deruelle, C, Di Giorgio, A, Dickie, EW, Dima, D, Dohm, K, Ehrlich, S, Ely, BA, Erwin-Grabner, T, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Fatjo-Vilas, M, Fedor, JM, Fitzgerald, KD, Ford, JM, Frodl, T, Fu, CHY, Fullerton, JM, Gabel, MC, Glahn, DC, Roberts, G, Gogberashvili, T, Goikolea, JM, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Green, MJ, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Guerrero-Pedraza, A, Gur, RE, Gur, RC, Haar, S, Haarman, BCM, Haavik, J, Hahn, T, Hajek, T, Harrison, BJ, Harrison, NA, Hartman, CA, Whalley, HC, Heslenfeld, DJ, Hibar, DP, Hilland, E, Hirano, Y, Ho, TC, Hoekstra, PJ, Hoekstra, L, Hohmann, S, Hong, LE, Hoschl, C, Hovik, MF, Howells, FM, Nenadic, I, Jalbrzikowski, M, James, AC, Janssen, J, Jaspers-Fayer, F, Xu, J, Jonassen, R, Karkashadze, G, King, JA, Kircher, T, Kirschner, M, Koch, K, Kochunov, P, Kohls, G, Konrad, K, Kramer, B, Krug, A, Kuntsi, J, Kwon, JS, Landen, M, Landro, NI, Lazaro, L, Lebedeva, IS, Leehr, EJ, Lera-Miguel, S, Lesch, K-P, Lochner, C, Louza, MR, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Malpas, CB, Portella, MJ, Marsh, R, Martyn, FM, Mataix-Cols, D, Mathalon, DH, McCarthy, H, McDonald, C, McPhilemy, G, Meinert, S, Menchon, JM, Minuzzi, L, Mitchell, PB, Moreno, C, Morgado, P, Muratori, F, Murphy, CM, Murphy, D, Mwangi, B, Nabulsi, L, Nakagawa, A, Nakamae, T, Namazova, L, Narayanaswamy, J, Jahanshad, N, Nguyen, DD, Nicolau, R, O'Gorman Tuura, RL, O'Hearn, K, Oosterlaan, J, Opel, N, Ophoff, RA, Oranje, B, Garcia de la Foz, VO, Overs, BJ, Paloyelis, Y, Pantelis, C, Parellada, M, Pauli, P, Pico-Perez, M, Picon, FA, Piras, F, Plessen, KJ, Pomarol-Clotet, E, Preda, A, Puig, O, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Rauer, L, Reddy, J, Redlich, R, Reif, A, Reneman, L, Repple, J, Retico, A, Richarte, V, Richter, A, Rosa, PGP, Rubia, KK, Hashimoto, R, Sacchet, MD, Salvador, R, Santonja, J, Sarink, K, Sarro, S, Satterthwaite, TD, Sawa, A, Schall, U, Schofield, PR, Schrantee, A, Seitz, J, Serpa, MH, Setien-Suero, E, Shaw, P, Shook, D, Silk, TJ, Sim, K, Simon, S, Simpson, HB, Singh, A, Skoch, A, Skokauskas, N, Soares, JC, Soreni, N, Soriano-Mas, C, Spalletta, G, Spaniel, F, Lawrie, SM, Stern, ER, Stewart, SE, Takayanagi, Y, Temmingh, HS, Tolin, DF, Tomecek, D, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, van Amelsvoort, T, van der Wee, NJA, van der Werff, SJA, van Haren, NEM, van Wingen, GA, Vance, A, Vazquez-Bourgon, J, Vecchio, D, Venkatasubramanian, G, Vieta, E, Vilarroya, O, Vives-Gilabert, Y, Voineskos, AN, Volzke, H, von Polier, GG, Walton, E, Weickert, TW, Weickert, CS, Weideman, AS, Wittfeld, K, Wolf, DH, Wu, M-J, Yang, TT, Yang, K, Yoncheva, Y, Yun, J-Y, Cheng, Y, Zanetti, MV, Ziegler, GC, Franke, B, Hoogman, M, Buitelaar, JK, van Rooij, D, Andreassen, OA, Ching, CRK, Veltman, DJ, Schmaal, L, Stein, DJ, van den Heuvel, OA, Turner, JA, van Erp, TGM, Pausova, Z, Thompson, PM, Paus, T, Patel, Y, Parker, N, Shin, J, Howard, D, French, L, Thomopoulos, SI, Pozzi, E, Abe, Y, Abe, C, Anticevic, A, Alda, M, Aleman, A, Alloza, C, Alonso-Lana, S, Ameis, SH, Anagnostou, E, McIntosh, AA, Arango, C, Arnold, PD, Asherson, P, Assogna, F, Auzias, G, Ayesa-Arriola, R, Bakker, G, Banaj, N, Banaschewski, T, Bandeira, CE, Baranov, A, Bargallo, N, Bau, CHD, Baumeister, S, Baune, BT, Bellgrove, MA, Benedetti, F, Bertolino, A, Boedhoe, PSW, Boks, M, Bollettini, I, del Mar Bonnin, C, Borgers, T, Borgwardt, S, Brandeis, D, Brennan, BP, Bruggemann, JM, Bulow, R, Busatto, GF, Calderoni, S, Calhoun, VD, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carr, VJ, Cascella, N, Cercignani, M, Chaim-Avancini, TM, Christakou, A, Coghill, D, Conzelmann, A, Crespo-Facorro, B, Cubillo, AI, Cullen, KR, Cupertino, RB, Daly, E, Dannlowski, U, Davey, CG, Denys, D, Deruelle, C, Di Giorgio, A, Dickie, EW, Dima, D, Dohm, K, Ehrlich, S, Ely, BA, Erwin-Grabner, T, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Fatjo-Vilas, M, Fedor, JM, Fitzgerald, KD, Ford, JM, Frodl, T, Fu, CHY, Fullerton, JM, Gabel, MC, Glahn, DC, Roberts, G, Gogberashvili, T, Goikolea, JM, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Green, MJ, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Guerrero-Pedraza, A, Gur, RE, Gur, RC, Haar, S, Haarman, BCM, Haavik, J, Hahn, T, Hajek, T, Harrison, BJ, Harrison, NA, Hartman, CA, Whalley, HC, Heslenfeld, DJ, Hibar, DP, Hilland, E, Hirano, Y, Ho, TC, Hoekstra, PJ, Hoekstra, L, Hohmann, S, Hong, LE, Hoschl, C, Hovik, MF, Howells, FM, Nenadic, I, Jalbrzikowski, M, James, AC, Janssen, J, Jaspers-Fayer, F, Xu, J, Jonassen, R, Karkashadze, G, King, JA, Kircher, T, Kirschner, M, Koch, K, Kochunov, P, Kohls, G, Konrad, K, Kramer, B, Krug, A, Kuntsi, J, Kwon, JS, Landen, M, Landro, NI, Lazaro, L, Lebedeva, IS, Leehr, EJ, Lera-Miguel, S, Lesch, K-P, Lochner, C, Louza, MR, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Malpas, CB, Portella, MJ, Marsh, R, Martyn, FM, Mataix-Cols, D, Mathalon, DH, McCarthy, H, McDonald, C, McPhilemy, G, Meinert, S, Menchon, JM, Minuzzi, L, Mitchell, PB, Moreno, C, Morgado, P, Muratori, F, Murphy, CM, Murphy, D, Mwangi, B, Nabulsi, L, Nakagawa, A, Nakamae, T, Namazova, L, Narayanaswamy, J, Jahanshad, N, Nguyen, DD, Nicolau, R, O'Gorman Tuura, RL, O'Hearn, K, Oosterlaan, J, Opel, N, Ophoff, RA, Oranje, B, Garcia de la Foz, VO, Overs, BJ, Paloyelis, Y, Pantelis, C, Parellada, M, Pauli, P, Pico-Perez, M, Picon, FA, Piras, F, Plessen, KJ, Pomarol-Clotet, E, Preda, A, Puig, O, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Rauer, L, Reddy, J, Redlich, R, Reif, A, Reneman, L, Repple, J, Retico, A, Richarte, V, Richter, A, Rosa, PGP, Rubia, KK, Hashimoto, R, Sacchet, MD, Salvador, R, Santonja, J, Sarink, K, Sarro, S, Satterthwaite, TD, Sawa, A, Schall, U, Schofield, PR, Schrantee, A, Seitz, J, Serpa, MH, Setien-Suero, E, Shaw, P, Shook, D, Silk, TJ, Sim, K, Simon, S, Simpson, HB, Singh, A, Skoch, A, Skokauskas, N, Soares, JC, Soreni, N, Soriano-Mas, C, Spalletta, G, Spaniel, F, Lawrie, SM, Stern, ER, Stewart, SE, Takayanagi, Y, Temmingh, HS, Tolin, DF, Tomecek, D, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, van Amelsvoort, T, van der Wee, NJA, van der Werff, SJA, van Haren, NEM, van Wingen, GA, Vance, A, Vazquez-Bourgon, J, Vecchio, D, Venkatasubramanian, G, Vieta, E, Vilarroya, O, Vives-Gilabert, Y, Voineskos, AN, Volzke, H, von Polier, GG, Walton, E, Weickert, TW, Weickert, CS, Weideman, AS, Wittfeld, K, Wolf, DH, Wu, M-J, Yang, TT, Yang, K, Yoncheva, Y, Yun, J-Y, Cheng, Y, Zanetti, MV, Ziegler, GC, Franke, B, Hoogman, M, Buitelaar, JK, van Rooij, D, Andreassen, OA, Ching, CRK, Veltman, DJ, Schmaal, L, Stein, DJ, van den Heuvel, OA, Turner, JA, van Erp, TGM, Pausova, Z, Thompson, PM, and Paus, T

Abstract

IMPORTANCE: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. MAIN OUTCOMES AND MEASURES: Interregional profiles of group difference in cortical thickness between cases and controls. RESULTS: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene

Published
2021

18. Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders

Author

Patel, Y., Parker, N., Shin, J., Howard, D., French, L., Thomopoulos, S.I., Pozzi, E., Abe, Y., Abé, C., Anticevic, A., Alda, M., Aleman, A., Alloza, C., Alonso-Lana, S., Ameis, S.H., Anagnostou, E., McIntosh, A.A., Arango, C., Arnold, P.D., Asherson, P., Assogna, F., Auzias, G., Ayesa-Arriola, R., Bakker, G., Banaj, N., Banaschewski, T., Bandeira, C.E., Baranov, A., Bargalló, N., Bau, C.H.D., Baumeister, S., Baune, B.T., Bellgrove, M.A., Benedetti, F., Bertolino, A., Boedhoe, P.S.W., Boks, M., Bollettini, I., Del Mar Bonnin, C., Borgers, T., Borgwardt, S., Brandeis, D., Brennan, B.P., Bruggemann, J.M., Bülow, R., Busatto, G.F., Calderoni, S., Calhoun, V.D., Calvo, R., Canales-Rodríguez, E.J., Cannon, D.M., Carr, V.J., Cascella, N., Cercignani, M., Chaim-Avancini, T.M., Christakou, A., Coghill, D., Conzelmann, A., Crespo-Facorro, B., Cubillo, A.I., Cullen, K.R., Cupertino, R.B., Daly, E., Dannlowski, U., Davey, C.G., Denys, D., Deruelle, C., Di Giorgio, A., Dickie, E.W., Dima, D., Dohm, K., Ehrlich, S., Ely, B.A., Erwin-Grabner, T., Ethofer, T., Fair, D.A., Fallgatter, A.J., Faraone, S.V., Fatjó-Vilas, M., Fedor, J.M., Fitzgerald, K.D., Ford, J.M., Frodl, T., Fu, C.H.Y., Fullerton, J.M., Gabel, M.C., Glahn, D.C., Roberts, G., Gogberashvili, T., Goikolea, J.M., Gotlib, I.H., Goya-Maldonado, R., Grabe, H.J., Green, M.J., Grevet, E.H., Groenewold, N.A., Grotegerd, D., Gruber, O., Gruner, P., Guerrero-Pedraza, A., Gur, R.E., Gur, R.C., Haar, S., Haarman, B.C.M., Haavik, J., Hahn, T., Hajek, T., Harrison, B.J., Harrison, N.A., Hartman, C.A., Whalley, H.C., Heslenfeld, D.J., Hibar, D.P., Hilland, E., Hirano, Y., Ho, T.C., Hoekstra, P.J., Hoekstra, L., Hohmann, S., Hong, L.E., Höschl, C., Høvik, M.F., Howells, F.M., Nenadic, I., Jalbrzikowski, M., James, A.C., Janssen, J., Jaspers-Fayer, F., Xu, J., Jonassen, R., Karkashadze, G., King, J.A., Kircher, T., Kirschner, M., Koch, K., Kochunov, P., Kohls, G., Konrad, K., Krämer, B., Krug, A., Kuntsi, J., Kwon, J.S., Landén, M., Landrø, N.I., Lazaro, L., Lebedeva, I.S., Leehr, E.J., Lera-Miguel, S., Lesch, K.-P., Lochner, C., Louza, M.R., Luna, B., Lundervold, A.J., Macmaster, F.P., Maglanoc, L.A., Malpas, C.B., Portella, M.J., Marsh, R., Martyn, F.M., Mataix-Cols, D., Mathalon, D.H., McCarthy, H., McDonald, C., McPhilemy, G., Meinert, S., Menchón, J.M., Minuzzi, L., Mitchell, P.B., Moreno, C., Morgado, P., Muratori, F., Murphy, C.M., Murphy, D., Mwangi, B., Nabulsi, L., Nakagawa, A., Nakamae, T., Namazova, L., Narayanaswamy, J., Jahanshad, N., Nguyen, D.D., Nicolau, R., O'Gorman Tuura, R.L., O'Hearn, K., Oosterlaan, J., Opel, N., Ophoff, R.A., Oranje, B., García De La Foz, V.O., Overs, B.J., Paloyelis, Y., Pantelis, C., Parellada, M., Pauli, P., Picó-Pérez, M., Picon, F.A., Piras, F., Plessen, K.J., Pomarol-Clotet, E., Preda, A., Puig, O., Quidé, Y., Radua, J., Ramos-Quiroga, J.A., Rasser, P.E., Rauer, L., Reddy, J., Redlich, R., Reif, A., Reneman, L., Repple, J., Retico, A., Richarte, V., Richter, A., Rosa, P.G.P., Rubia, K.K., Hashimoto, R., Sacchet, M.D., Salvador, R., Santonja, J., Sarink, K., Sarró, S., Satterthwaite, T.D., Sawa, A., Schall, U., Schofield, P.R., Schrantee, A., Seitz, J., Serpa, M.H., Setién-Suero, E., Shaw, P., Shook, D., Silk, T.J., Sim, K., Simon, S., Simpson, H.B., Singh, A., Skoch, A., Skokauskas, N., Soares, J.C., Soreni, N., Soriano-Mas, C., Spalletta, G., Spaniel, F., Lawrie, S.M., Stern, E.R., Stewart, S.E., Takayanagi, Y., Temmingh, H.S., Tolin, D.F., Tomecek, D., Tordesillas-Gutiérrez, D., Tosetti, M., Uhlmann, A., Van Amelsvoort, T., Van Der Wee, N.J.A., Van Der Werff, S.J.A., Van Haren, N.E.M., Van Wingen, G.A., Vance, A., Vázquez-Bourgon, J., Vecchio, D., Venkatasubramanian, G., Vieta, E., Vilarroya, O., Vives-Gilabert, Y., Voineskos, A.N., Völzke, H., Von Polier, G.G., Walton, E., Weickert, T.W., Weickert, C.S., Weideman, A.S., Wittfeld, K., Wolf, D.H., Wu, M.-J., Yang, T.T., Yang, K., Yoncheva, Y., Yun, J.-Y., Cheng, Y., Zanetti, M.V., Ziegler, G.C., Franke, B., Hoogman, M., Buitelaar, J.K., Van Rooij, D., Andreassen, O.A., Ching, C.R.K., Veltman, D.J., Schmaal, L., Stein, D.J., Van Den Heuvel, O.A., Turner, J.A., Van Erp, T.G.M., Pausova, Z., Thompson, P.M., Paus, T., Patel, Y., Parker, N., Shin, J., Howard, D., French, L., Thomopoulos, S.I., Pozzi, E., Abe, Y., Abé, C., Anticevic, A., Alda, M., Aleman, A., Alloza, C., Alonso-Lana, S., Ameis, S.H., Anagnostou, E., McIntosh, A.A., Arango, C., Arnold, P.D., Asherson, P., Assogna, F., Auzias, G., Ayesa-Arriola, R., Bakker, G., Banaj, N., Banaschewski, T., Bandeira, C.E., Baranov, A., Bargalló, N., Bau, C.H.D., Baumeister, S., Baune, B.T., Bellgrove, M.A., Benedetti, F., Bertolino, A., Boedhoe, P.S.W., Boks, M., Bollettini, I., Del Mar Bonnin, C., Borgers, T., Borgwardt, S., Brandeis, D., Brennan, B.P., Bruggemann, J.M., Bülow, R., Busatto, G.F., Calderoni, S., Calhoun, V.D., Calvo, R., Canales-Rodríguez, E.J., Cannon, D.M., Carr, V.J., Cascella, N., Cercignani, M., Chaim-Avancini, T.M., Christakou, A., Coghill, D., Conzelmann, A., Crespo-Facorro, B., Cubillo, A.I., Cullen, K.R., Cupertino, R.B., Daly, E., Dannlowski, U., Davey, C.G., Denys, D., Deruelle, C., Di Giorgio, A., Dickie, E.W., Dima, D., Dohm, K., Ehrlich, S., Ely, B.A., Erwin-Grabner, T., Ethofer, T., Fair, D.A., Fallgatter, A.J., Faraone, S.V., Fatjó-Vilas, M., Fedor, J.M., Fitzgerald, K.D., Ford, J.M., Frodl, T., Fu, C.H.Y., Fullerton, J.M., Gabel, M.C., Glahn, D.C., Roberts, G., Gogberashvili, T., Goikolea, J.M., Gotlib, I.H., Goya-Maldonado, R., Grabe, H.J., Green, M.J., Grevet, E.H., Groenewold, N.A., Grotegerd, D., Gruber, O., Gruner, P., Guerrero-Pedraza, A., Gur, R.E., Gur, R.C., Haar, S., Haarman, B.C.M., Haavik, J., Hahn, T., Hajek, T., Harrison, B.J., Harrison, N.A., Hartman, C.A., Whalley, H.C., Heslenfeld, D.J., Hibar, D.P., Hilland, E., Hirano, Y., Ho, T.C., Hoekstra, P.J., Hoekstra, L., Hohmann, S., Hong, L.E., Höschl, C., Høvik, M.F., Howells, F.M., Nenadic, I., Jalbrzikowski, M., James, A.C., Janssen, J., Jaspers-Fayer, F., Xu, J., Jonassen, R., Karkashadze, G., King, J.A., Kircher, T., Kirschner, M., Koch, K., Kochunov, P., Kohls, G., Konrad, K., Krämer, B., Krug, A., Kuntsi, J., Kwon, J.S., Landén, M., Landrø, N.I., Lazaro, L., Lebedeva, I.S., Leehr, E.J., Lera-Miguel, S., Lesch, K.-P., Lochner, C., Louza, M.R., Luna, B., Lundervold, A.J., Macmaster, F.P., Maglanoc, L.A., Malpas, C.B., Portella, M.J., Marsh, R., Martyn, F.M., Mataix-Cols, D., Mathalon, D.H., McCarthy, H., McDonald, C., McPhilemy, G., Meinert, S., Menchón, J.M., Minuzzi, L., Mitchell, P.B., Moreno, C., Morgado, P., Muratori, F., Murphy, C.M., Murphy, D., Mwangi, B., Nabulsi, L., Nakagawa, A., Nakamae, T., Namazova, L., Narayanaswamy, J., Jahanshad, N., Nguyen, D.D., Nicolau, R., O'Gorman Tuura, R.L., O'Hearn, K., Oosterlaan, J., Opel, N., Ophoff, R.A., Oranje, B., García De La Foz, V.O., Overs, B.J., Paloyelis, Y., Pantelis, C., Parellada, M., Pauli, P., Picó-Pérez, M., Picon, F.A., Piras, F., Plessen, K.J., Pomarol-Clotet, E., Preda, A., Puig, O., Quidé, Y., Radua, J., Ramos-Quiroga, J.A., Rasser, P.E., Rauer, L., Reddy, J., Redlich, R., Reif, A., Reneman, L., Repple, J., Retico, A., Richarte, V., Richter, A., Rosa, P.G.P., Rubia, K.K., Hashimoto, R., Sacchet, M.D., Salvador, R., Santonja, J., Sarink, K., Sarró, S., Satterthwaite, T.D., Sawa, A., Schall, U., Schofield, P.R., Schrantee, A., Seitz, J., Serpa, M.H., Setién-Suero, E., Shaw, P., Shook, D., Silk, T.J., Sim, K., Simon, S., Simpson, H.B., Singh, A., Skoch, A., Skokauskas, N., Soares, J.C., Soreni, N., Soriano-Mas, C., Spalletta, G., Spaniel, F., Lawrie, S.M., Stern, E.R., Stewart, S.E., Takayanagi, Y., Temmingh, H.S., Tolin, D.F., Tomecek, D., Tordesillas-Gutiérrez, D., Tosetti, M., Uhlmann, A., Van Amelsvoort, T., Van Der Wee, N.J.A., Van Der Werff, S.J.A., Van Haren, N.E.M., Van Wingen, G.A., Vance, A., Vázquez-Bourgon, J., Vecchio, D., Venkatasubramanian, G., Vieta, E., Vilarroya, O., Vives-Gilabert, Y., Voineskos, A.N., Völzke, H., Von Polier, G.G., Walton, E., Weickert, T.W., Weickert, C.S., Weideman, A.S., Wittfeld, K., Wolf, D.H., Wu, M.-J., Yang, T.T., Yang, K., Yoncheva, Y., Yun, J.-Y., Cheng, Y., Zanetti, M.V., Ziegler, G.C., Franke, B., Hoogman, M., Buitelaar, J.K., Van Rooij, D., Andreassen, O.A., Ching, C.R.K., Veltman, D.J., Schmaal, L., Stein, D.J., Van Den Heuvel, O.A., Turner, J.A., Van Erp, T.G.M., Pausova, Z., Thompson, P.M., and Paus, T.

Abstract

Importance Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. Objective To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. Design, Setting, and Participants Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. Main Outcomes and Measures Interregional profiles of group difference in cortical thickness between cases and controls. Results A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (exce

Published
2021
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19. Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Author

Rovira P, Demontis D, Sánchez-Mora C, Zayats T, Klein M, Mota NR, Weber H, Garcia-Martínez I, Pagerols M, Vilar L, Arribas L, Richarte V, Corrales M, Fadeuilhe C, Bosch R, Martin GE, Almos P, Doyle AE, Grevet EH, Grimm O, Halmøy A, Hoogman M, Hutz M, Jacob CP, Kittel-Schneider S, Knappskog PM, Lundervold AJ, Rivero O, Rovaris DL, Salatino-Oliveira A, da Silva BS, Svirin E, Sprooten E, Strekalova T, ADHD Working Group of the Psychiatric Genomics Consortium, 23andMe Research team, Arias-Vasquez A, Sonuga-Barke EJS, Asherson P, Bau CHD, Buitelaar JK, Cormand B, Faraone SV, Haavik J, Johansson SE, Kuntsi J, Larsson H, Lesch KP, Reif A, Rohde LA, Casas M, Børglum AD, Franke B, Ramos-Quiroga JA, Artigas MS, and Ribasés M

Subjects
mental disorders, behavioral disciplines and activities
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Published
2020

20. Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Author

Rovira, P., Demontis, D., Sánchez-Mora, C., Zayats, T., Klein, M., Mota, N., Weber, H., Garcia-Martínez, I., Pagerols, M., Vilar-Ribó, L., Arribas, L., Richarte, V., Corrales, M., Fadeuilhe, C., Bosch, Rosa, Martin, G.E., Almos, P., Doyle, A.E., Grevet, E.H., Grimm, O., Halmøy, A., Hoogman, M., Hutz, M., Jacob, C.P., Kittel-Schneider, S., Knappskog, P.M., Lundervold, A.J., Rivero, O., Rovaris, D.L., Salatino-Oliveira, A., Silva, B.S. da, Svirin, E., Sprooten, E., Strekalova, T., Arias-Vasquez, A., Sonuga-Barke, E.J., Asherson, P., Bau, C.H.D., Buitelaar, J.K., Cormand, B., Faraone, S.V, Haavik, J., Johansson, S.E., Kuntsi, J., Larsson, H., Lesch, K.P., Reif, A., Rohde, L.A., Casas, M., Børglum, A.D., Franke, B., Ramos-Quiroga, J.A., Artigas, M. Soler, Ribasés, M., Rovira, P., Demontis, D., Sánchez-Mora, C., Zayats, T., Klein, M., Mota, N., Weber, H., Garcia-Martínez, I., Pagerols, M., Vilar-Ribó, L., Arribas, L., Richarte, V., Corrales, M., Fadeuilhe, C., Bosch, Rosa, Martin, G.E., Almos, P., Doyle, A.E., Grevet, E.H., Grimm, O., Halmøy, A., Hoogman, M., Hutz, M., Jacob, C.P., Kittel-Schneider, S., Knappskog, P.M., Lundervold, A.J., Rivero, O., Rovaris, D.L., Salatino-Oliveira, A., Silva, B.S. da, Svirin, E., Sprooten, E., Strekalova, T., Arias-Vasquez, A., Sonuga-Barke, E.J., Asherson, P., Bau, C.H.D., Buitelaar, J.K., Cormand, B., Faraone, S.V, Haavik, J., Johansson, S.E., Kuntsi, J., Larsson, H., Lesch, K.P., Reif, A., Rohde, L.A., Casas, M., Børglum, A.D., Franke, B., Ramos-Quiroga, J.A., Artigas, M. Soler, and Ribasés, M.

Abstract

Contains fulltext : 225384.pdf (Publisher’s version ) (Open Access), Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Published
2020

21. Attention-deficit/hyperactivity disorder and lifetime cannabis use: Genetic overlap and causality

Author

Soler Artigas, M., Sánchez-Mora, C., Rovira, P., Richarte, V., Garcia-Martinez, I., Pagerols, M., Demontis, D., Stringer, S., Vink, J.M., Borglum, A.D., Neale, B.M., Franke, B., Faraone, S.V., Casas, M., Ramos-Quiroga, J.A., Ribasés, M., Soler Artigas, M., Sánchez-Mora, C., Rovira, P., Richarte, V., Garcia-Martinez, I., Pagerols, M., Demontis, D., Stringer, S., Vink, J.M., Borglum, A.D., Neale, B.M., Franke, B., Faraone, S.V., Casas, M., Ramos-Quiroga, J.A., and Ribasés, M.

Abstract

Contains fulltext : 219447.pdf (Publisher’s version ) (Closed access), Attention-deficit/hyperactivity disorder (ADHD) is a severely impairing neurodevelopmental disorder with a prevalence of 5% in children and adolescents and of 2.5% in adults. Comorbid conditions in ADHD play a key role in symptom progression, disorder course and outcome. ADHD is associated with a significantly increased risk for substance use, abuse and dependence. ADHD and cannabis use are partly determined by genetic factors; the heritability of ADHD is estimated at 70-80% and of cannabis use initiation at 40-48%. In this study, we used summary statistics from the largest available meta-analyses of genome-wide association studies (GWAS) of ADHD (n = 53,293) and lifetime cannabis use (n = 32,330) to gain insights into the genetic overlap and causal relationship of these two traits. We estimated their genetic correlation to be r2 = 0.29 (P = 1.63 x 10-5) and identified four new genome-wide significant loci in a cross-trait analysis: two in a single variant association analysis (rs145108385, P = 3.30 x 10-8 and rs4259397, P = 4.52 x 10-8) and two in a gene-based association analysis (WDPCP, P = 9.67 x 10-7 and ZNF251, P = 1.62 x 10-6). Using a two-sample Mendelian randomization approach we found support that ADHD is causal for lifetime cannabis use, with an odds ratio of 7.9 for cannabis use in individuals with ADHD in comparison to individuals without ADHD (95% CI (3.72, 15.51), P = 5.88 x 10-5). These results substantiate the temporal relationship between ADHD and future cannabis use and reinforce the need to consider substance misuse in the context of ADHD in clinical interventions.

Published
2020

23. Updated European Consensus Statement on diagnosis and treatment of adult ADHD

Author

Kooij, J. J. S. Bijlenga, D. Salerno, L. Jaeschke, R. and Bitter, I Balazs, J. Thome, J. Dom, G. Kasper, S. and Nunes Filipe, C. Stes, S. Mohr, P. Leppamaki, S. Casas, M. Bobes, J. Mccarthy, J. M. Richarte, V Philipsen, A. Kjems Pehlivanidis, A. Niemela, A. Styr, B. Semerci, B. and Bolea-Alamanac, B. Edvinsson, D. Baeyens, D. Wynchank, D. Sobanski, E. Philipsen, A. McNicholas, F. Caci, H. and Mihailescu, I Manor, I Dobrescu, I Saito, T. Krause, J. Fayyad, J. Ramos-Quiroga, J. A. Foeken, K. Rad, F. and Adamou, M. Ohlmeier, M. Fitzgerald, M. Gill, M. and Lensing, M. Mukaddes, N. Motavalli Brudkiewicz, P. and Gustafsson, P. Tani, P. Oswald, P. Carpentier, P. J. De Rossi, P. Delorme, R. Simoska, S. Markovska Pallanti, S. and Young, S. Bejerot, S. Lehtonen, T. Kustow, J. and Mueller-Sedgwick, U. Hirvikoski, T. Pironti, V Ginsberg, Y. and Felegyhazy, Z. Garcia-Portilla, M. P. Asherson, P.

Subjects
mental disorders, behavioral disciplines and activities
Abstract

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD. (c) 2018 The Author(s). Published by Elsevier Masson SAS.

Published
2019

24. Updated European Consensus Statement on diagnosis and treatment of adult ADHD

Author

Kooij, J. J. S., Bijlenga, D., Salerno, L., Jaeschke, R., Bitter, I, Balazs, J., Thome, J., Dom, G., Kasper, S., Nunes Filipe, C., Stes, S., Mohr, P., Leppamaki, S., Casas, M., Bobes, J., Mccarthy, J. M., Richarte, V, Philipsen, A. Kjems, Pehlivanidis, A., Niemela, A., Styr, B., Semerci, B., Bolea-Alamanac, B., Edvinsson, Dan, Baeyens, D., Wynchank, D., Sobanski, E., Philipsen, A., McNicholas, F., Caci, H., Mihailescu, I, Manor, I, Dobrescu, I, Saito, T., Krause, J., Fayyad, J., Ramos-Quiroga, J. A., Foeken, K., Rad, F., Adamou, M., Ohlmeier, M., Fitzgerald, M., Gill, M., Lensing, M., Mukaddes, N. Motavalli, Brudkiewicz, P., Gustafsson, P., Tani, P., Oswald, P., Carpentier, P. J., De Rossi, P., Delorme, R., Simoska, S. Markovska, Pallanti, S., Young, S., Bejerot, S., Lehtonen, T., Kustow, J., Mueller-Sedgwick, U., Hirvikoski, T., Pironti, V, Ginsberg, Y., Felegyhazy, Z., Garcia-Portilla, M. P., Asherson, P., Kooij, J. J. S., Bijlenga, D., Salerno, L., Jaeschke, R., Bitter, I, Balazs, J., Thome, J., Dom, G., Kasper, S., Nunes Filipe, C., Stes, S., Mohr, P., Leppamaki, S., Casas, M., Bobes, J., Mccarthy, J. M., Richarte, V, Philipsen, A. Kjems, Pehlivanidis, A., Niemela, A., Styr, B., Semerci, B., Bolea-Alamanac, B., Edvinsson, Dan, Baeyens, D., Wynchank, D., Sobanski, E., Philipsen, A., McNicholas, F., Caci, H., Mihailescu, I, Manor, I, Dobrescu, I, Saito, T., Krause, J., Fayyad, J., Ramos-Quiroga, J. A., Foeken, K., Rad, F., Adamou, M., Ohlmeier, M., Fitzgerald, M., Gill, M., Lensing, M., Mukaddes, N. Motavalli, Brudkiewicz, P., Gustafsson, P., Tani, P., Oswald, P., Carpentier, P. J., De Rossi, P., Delorme, R., Simoska, S. Markovska, Pallanti, S., Young, S., Bejerot, S., Lehtonen, T., Kustow, J., Mueller-Sedgwick, U., Hirvikoski, T., Pironti, V, Ginsberg, Y., Felegyhazy, Z., Garcia-Portilla, M. P., and Asherson, P.

Abstract

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD.

Published
2019
Full Text
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25. [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

26. Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder

Author

Pagerols M, Richarte V, Sánchez-Mora C, Rovira P, Soler Artigas M, Garcia-Martínez I, Calvo-Sánchez E, Corrales M, da Silva BS, Mota NR, Victor MM, Rohde LA, Grevet EH, Bau CHD, Cormand B, Casas M, Ramos-Quiroga JA, and Ribasés M

Subjects
mental disorders
Abstract

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies.

Published
2018

27. Genome-Wide Association meta-analysis of age at first cannabis use

Author

Minica, C.C., Verweij, K.J.H., Most, P.J. van der, Mbarek, H., Bernard, M., Eijk, K.R. van, Lind, P.A., Liu, M.Z., Maciejewski, D.F., Palviainen, T., Sánchez-Mora, C., Sherva, R., Taylor, M., Walters, R.K., Abdellaoui, A., Bigdeli, T.B., Branje, S.J.T., Brown, S.A., Casas, M., Corley, R.P., Smith, G.D., Davies, G.E., Ehli, E.A., Farrer, L.A., Fedko, I.O., Garcia-Martinez, I., Gordon, S.D., Hartman, C.A., Heath, A.C., Hickie, I.B., Hickman, M., Hopfer, C.J., Hottenga, J.J., Kahn, R.S., Kaprio, J., Korhonen, T., Kranzler, H.R., Krauter, K., Lier, P.A.C. van, Madden, P.A.F., Medland, S.E., Neale, M.C., Meeus, W.H.J., Montgomery, G.W., Nolte, I.M., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Richarte, V., Rose, R.J., Shin, J., Stallings, M.C., Wall, T.L., Ware, J.J., Wright, M.J., Zhao, H., Koot, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Loukola, A., Boks, M.P.M., Snieder, H., Munafò, M.R., Gelernter, J., Boomsma, D.I., Martin, N.G., Gillespie, N.A., Vink, J.M., Derks, E.M., Minica, C.C., Verweij, K.J.H., Most, P.J. van der, Mbarek, H., Bernard, M., Eijk, K.R. van, Lind, P.A., Liu, M.Z., Maciejewski, D.F., Palviainen, T., Sánchez-Mora, C., Sherva, R., Taylor, M., Walters, R.K., Abdellaoui, A., Bigdeli, T.B., Branje, S.J.T., Brown, S.A., Casas, M., Corley, R.P., Smith, G.D., Davies, G.E., Ehli, E.A., Farrer, L.A., Fedko, I.O., Garcia-Martinez, I., Gordon, S.D., Hartman, C.A., Heath, A.C., Hickie, I.B., Hickman, M., Hopfer, C.J., Hottenga, J.J., Kahn, R.S., Kaprio, J., Korhonen, T., Kranzler, H.R., Krauter, K., Lier, P.A.C. van, Madden, P.A.F., Medland, S.E., Neale, M.C., Meeus, W.H.J., Montgomery, G.W., Nolte, I.M., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Richarte, V., Rose, R.J., Shin, J., Stallings, M.C., Wall, T.L., Ware, J.J., Wright, M.J., Zhao, H., Koot, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Loukola, A., Boks, M.P.M., Snieder, H., Munafò, M.R., Gelernter, J., Boomsma, D.I., Martin, N.G., Gillespie, N.A., Vink, J.M., and Derks, E.M.

Abstract

Contains fulltext : 195854.pdf (publisher's version ) (Closed access), Background and aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identify associations with genetic variants. Methods: A twin-based heritability analysis using 8,055 twins from three cohorts was performed. We then carried-out a genome wide survival meta-analysis of age at first cannabis use in a discovery sample of 24,953 individuals from nine European, North American, and Australian cohorts, and a replication sample of 3,735 individuals. Results: The twin-based heritability for age at first cannabis use was 38% (95% confidence interval [CI] 19-60%). Shared and unique environmental factors explained 39% (95% CI 20-56%) and 22% (95% CI 16-29%). The genome wide survival meta-analysis identified five SNPs on chromosome 16 within the Calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high LD (r2>0.8) with the strongest association at the intronic variant rs1574587 (P=4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P=1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been previously associated with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. Conclusion: Age at cannabis initiation appears to be moderately heritable in Western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

Published
2018

28. Gene-wide Association Study Reveals RNF122 Ubiquitin Ligase as a Novel Susceptibility Gene for Attention Deficit Hyperactivity Disorder

Author

Garcia-Martínez I, Sánchez-Mora C, Soler Artigas M, Rovira P, Pagerols M, Corrales M, Calvo-Sánchez E, Richarte V, Bustamante M, Sunyer J, Cormand B, Casas M, Ramos-Quiroga JA, and Ribasés M

Subjects
mental disorders
Abstract

Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood-onset neurodevelopmental condition characterized by pervasive impairment of attention, hyperactivity, and/or impulsivity that can persist into adulthood. The aetiology of ADHD is complex and multifactorial and, despite the wealth of evidence for its high heritability, genetic studies have provided modest evidence for the involvement of specific genes and have failed to identify consistent and replicable results. Due to the lack of robust findings, we performed gene-wide and pathway enrichment analyses using pre-existing GWAS data from 607 persistent ADHD subjects and 584 controls, produced by our group. Subsequently, expression profiles of genes surpassing a follow-up threshold of P-value < 1e-03 in the gene-wide analyses were tested in peripheral blood mononucleated cells (PBMCs) of 45 medication-naive adults with ADHD and 39 healthy unrelated controls. We found preliminary evidence for genetic association between RNF122 and ADHD and for its overexpression in adults with ADHD. RNF122 encodes for an E3 ubiquitin ligase involved in the proteasome-mediated processing, trafficking, and degradation of proteins that acts as an essential mediator of the substrate specificity of ubiquitin ligation. Thus, our findings support previous data that place the ubiquitin-proteasome system as a promising candidate for its involvement in the aetiology of ADHD.

Published
2017

29. Are patients with bipolar disorder and comorbid attention-deficit hyperactivity disorder more neurocognitively impaired?

Author

Torres I, Sole B, Corrales M, Jiménez E, Rotger S, Serra-Pla JF, Forcada I, Richarte V, Ester Mora, Jacas C, Gómez N, Mur M, Colom F, Vieta E, Casas M, Martinez-Aran A, Goikolea JM, and Ramos-Quiroga JA

Subjects
bipolar disorder, comorbidity and neurocognition, attention-deficit hyperactivity disorder, mental disorders, behavioral disciplines and activities
Abstract

OBJECTIVE: Research on neurocognitive impairment in adult patients with comorbid bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) is very scarce. This study assessed the neurocognitive profile of a comorbid group (BD+ADHD) compared with that of pure BD (pBD) group, pure ADHD (pADHD) group and healthy controls (HCs). METHODS: This was a three-site study comprising 229 subjects: 70 patients with pBD, 23 with BD+ADHD, 50 with pADHD, and 86 HCs. All patients with BD had been euthymic for at least 6 months. Neuropsychological performance was assessed using a comprehensive neurocognitive battery. RESULTS: Our results showed that all the clinical groups had poorer performance than the HCs in all the neurocognitive domains except for executive functions. No significant differences were observed between the pBD and BD+ADHD groups in any of the cognitive domains, with these two groups showing greater impairment than the pADHD group in executive functions and visual memory. CONCLUSIONS: Our results, although preliminary, suggest that the BD+ADHD group showed the same neurocognitive profile as pBD patients, most likely reflecting the same neurobiological basis. On the other hand, the pADHD group showed a more selective moderate impairment in attention.

Published
2017

30. Updated European Consensus Statement on diagnosis and treatment of adult ADHD

Author

Kooij, J.J.S., primary, Bijlenga, D., additional, Salerno, L., additional, Jaeschke, R., additional, Bitter, I., additional, Balázs, J., additional, Thome, J., additional, Dom, G., additional, Kasper, S., additional, Nunes Filipe, C., additional, Stes, S., additional, Mohr, P., additional, Leppämäki, S., additional, Casas, M., additional, Bobes, J., additional, Mccarthy, J.M., additional, Richarte, V., additional, Kjems Philipsen, A., additional, Pehlivanidis, A., additional, Niemela, A., additional, Styr, B., additional, Semerci, B., additional, Bolea-Alamanac, B., additional, Edvinsson, D., additional, Baeyens, D., additional, Wynchank, D., additional, Sobanski, E., additional, Philipsen, A., additional, McNicholas, F., additional, Caci, H., additional, Mihailescu, I., additional, Manor, I., additional, Dobrescu, I., additional, Saito, T., additional, Krause, J., additional, Fayyad, J., additional, Ramos-Quiroga, J.A., additional, Foeken, K., additional, Rad, F., additional, Adamou, M., additional, Ohlmeier, M., additional, Fitzgerald, M., additional, Gill, M., additional, Lensing, M., additional, Motavalli Mukaddes, N., additional, Brudkiewicz, P., additional, Gustafsson, P., additional, Tani, P., additional, Oswald, P., additional, Carpentier, P.J., additional, De Rossi, P., additional, Delorme, R., additional, Markovska Simoska, S., additional, Pallanti, S., additional, Young, S., additional, Bejerot, S., additional, Lehtonen, T., additional, Kustow, J., additional, Müller-Sedgwick, U., additional, Hirvikoski, T., additional, Pironti, V., additional, Ginsberg, Y., additional, Félegyházy, Z., additional, Garcia-Portilla, M.P., additional, and Asherson, P., additional

Published
2018
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31. 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, Hamdi, Bernard, M., Derringer, Jaime, van Eijk, K. R., Isen, J. D., Loukola, Anu, Maciejewski, D. F., Mihailov, E., van der Most, Peter J., Sánchez-Mora, C., Roos, L., Sherva, R., Walters, R.G., Ware, James S., Abdellaoui, A., Bigdeli, T. B., Branje, S. J.T., Brown, A.S., Bruinenberg, M., Casas, M., Esko, Tonu, Garcia-Martinez, I., Gordon, Scott D., Harris, Juliette M, Hartman, Catharine A, Henders, Anjali K., Heath, Andrew C., Hickie, Ian B., Hickman, M., Hopfer, C. J., Hottenga, J.J., Huizink, A.C., Irons, D. E., Kahn, R. S., Korhonen, T.K., Kranzler, H. R., Krauter, K., van Lier, P.A.C., Lubke, G.H., Madden, Pamela A. F., Mägi, Reedik, McGue, M. K., Medland, Sarah E., Meeus, W.H.J., Miller, Michael B., Montgomery, Grant W., Nivard, Michel G, Nolte, Ilja M., Oldehinkel, Albertine J., Pausova, Zdenka, Qaiser, B., Quaye, Lydia, Ramos-Quiroga, J. A., Richarte, V., Rose, R.J., Shin, J.J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, Margaret J., Koot, H.M., Paus, T., Hewitt, J. K., Ribasés, M., Kaprio, Jaakko, Boks, M. P., Snieder, H., Spector, T.D., Munafò, M. R., Metspalu, A., Gelernter, J., Boomsma, Dorret I., Iacono, William G, Martin, Nicholas G., Gillespie, N. A., Derks, Eske M., and Vink, J. M.

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, Research Support, N.I.H., Extramural, Journal Article, Biological Psychiatry, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
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

Published
2016

32. Dopamine receptor DRD4 gene and stressful life events in persistent attention deficit hyperactivity disorder

Author

Sánchez-Mora C, Richarte V, Garcia-Martínez I, Pagerols M, Corrales M, Bosch R, Vidal R, Viladevall L, Casas M, Cormand B, Ramos-Quiroga JA, and Ribasés M

Subjects
ADHD, Attention deficit hyperactivity disorder, DRD4, GxE interaction, Stressful life events, mental disorders
Abstract

We performed a case-control association study in persistent ADHD considering eight candidate genes (DRD4, DAT1/SLC6A3, COMT, ADRA2A, CES1, CYP2D6, LPHN3, and OPRM1) and found additional evidence for the involvement of the Dup 120bp and VNTR 48bp functional variants within the dopamine receptor DRD4 gene in the etiology of adult ADHD. We subsequently investigated the interaction of stressful life events with these two DRD4 polymorphisms, and the impact of such events on the severity of ADHD symptomatology. The gene-by-environment analysis revealed an independent effect of stressful experiences on the severity of persistent ADHD, and a gene-by-environment interaction on the inattentive dimension of the disorder, where non carriers of the Dup 120bp (L) - VNTR 48bp (7R) haplotype were more sensitive to environmental adversity than carriers. These results are in agreement with previous works reporting a relationship between DRD4 and the effect of adverse experiences, which may explain the discordant findings in previous genetic studies and strengthen the importance of gene-by-environment interactions on the severity of ADHD. © 2015 Wiley Periodicals, Inc.

Published
2015

33. New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder

Author

Silvia Alemany, Ribasés M, Vilor-Tejedor N, Bustamante M, Sánchez-Mora C, Bosch R, Richarte V, Cormand B, Casas M, Ja, Ramos-Quiroga, and Sunyer J

Subjects
Attention-deficit/hyperactivity disorder, Conners Continuous Performance Test, GWAS, SORCS2, adults
Abstract

Attention deficit is one of the core symptoms of the attention-deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit-reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT-II) were assessed in 479 unmedicated adult ADHD individuals. A Genome-Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome-wide significance (P < 5E-08), 27 loci showed suggestive evidence of association with the CPT outcomes (P < E-05). The most relevant associated SNP was located in the SORCS2 gene (P = 3.65E-07), previously associated with bipolar disorder (BP), Alzheimer disease (AD), and brain structure in elderly individuals. We detected other genes suggested to be involved in synaptic plasticity, cognitive function, neurological and neuropsychiatric disorders, and smoking behavior such as NUAK1, FGF20, NETO1, BTBD9, DLG2, TOP3B, and CHRNB4. Also, several of the pathways nominally associated with the CPT outcomes are relevant for ADHD such as the ubiquitin proteasome, neurodegenerative disorders, axon guidance, and AD amyloid secretase pathways. To our knowledge, this is the first GWAS and pathway analysis of attention function in patients with persistent ADHD. Overall, our findings reinforce the conceptualization of attention function as a potential endophenotype for studying the molecular basis of adult ADHD. © 2015 Wiley Periodicals, Inc.

Published
2015

34. Updated European Consensus Statement on diagnosis and treatment of adult ADHD.

Author

Kooij, J.J.S., Bijlenga, D., Salerno, L., Jaeschke, R., Bitter, I., Balázs, J., Thome, J., Dom, G., Kasper, S., Nunes Filipe, C., Stes, S., Mohr, P., Leppämäki, S., Casas, M., Bobes, J., Mccarthy, J.M., Richarte, V., Kjems Philipsen, A., Pehlivanidis, A., and Niemela, A.

Subjects
NEUROBIOLOGY, ADULTS, OLD age, ATTENTION-deficit disorder in adults, DIAGNOSIS, TREATMENT of attention-deficit hyperactivity disorder
Abstract

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD. [ABSTRACT FROM AUTHOR]

Published
2019
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35. Exome chip analyses in adult attention deficit hyperactivity disorder

Author

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

Abstract

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 (MAF⩾1%), 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
Full Text
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36. 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.L., Eijk, K.R. van, Isen, J.D., Loukola, A., Maciejewski, D.F., Mihailov, E., Most, P.J. van der, 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., Lier, P.A.C. van, 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, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Kaprio, J., Boks, M.P.M., 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., Vink, J.M., Stringer, S., Minica, C.C., Verweij, K.J.H., Mbarek, H., Bernard, M., Derringer, J.L., Eijk, K.R. van, Isen, J.D., Loukola, A., Maciejewski, D.F., Mihailov, E., Most, P.J. van der, 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., Lier, P.A.C. van, 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, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Kaprio, J., Boks, M.P.M., 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

Contains fulltext : 156357.pdf (publisher's version ) (Open Access), 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=32330) 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

37. 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

38. 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

39. 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

Adolescent development: Characteristics and determinants, Afd culturele antropologie, Leerstoel Branje, Leerstoel Meeus, Sub Biomol.Mass Spectrometry & Proteom., Sub High energy Astrophysics begr 1/1/15, 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, Dominique 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, Vink, J M, Adolescent development: Characteristics and determinants, Afd culturele antropologie, Leerstoel Branje, Leerstoel Meeus, Sub Biomol.Mass Spectrometry & Proteom., Sub High energy Astrophysics begr 1/1/15, 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, Dominique 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

Published
2016

40. 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

Neurogenetica, Brain, Onderzoeksgroep 2, Stringer, S., Minică, C. C., Verweij, K. J.H., Mbarek, Hamdi, Bernard, M., Derringer, Jaime, van Eijk, K. R., Isen, J. D., Loukola, Anu, Maciejewski, D. F., Mihailov, E., van der Most, Peter J., Sánchez-Mora, C., Roos, L., Sherva, R., Walters, R.G., Ware, James S., Abdellaoui, A., Bigdeli, T. B., Branje, S. J.T., Brown, A.S., Bruinenberg, M., Casas, M., Esko, Tonu, Garcia-Martinez, I., Gordon, Scott D., Harris, Juliette M, Hartman, Catharine A, Henders, Anjali K., Heath, Andrew C., Hickie, Ian B., Hickman, M., Hopfer, C. J., Hottenga, J.J., Huizink, A.C., Irons, D. E., Kahn, R. S., Korhonen, T.K., Kranzler, H. R., Krauter, K., van Lier, P.A.C., Lubke, G.H., Madden, Pamela A. F., Mägi, Reedik, McGue, M. K., Medland, Sarah E., Meeus, W.H.J., Miller, Michael B., Montgomery, Grant W., Nivard, Michel G, Nolte, Ilja M., Oldehinkel, Albertine J., Pausova, Zdenka, Qaiser, B., Quaye, Lydia, Ramos-Quiroga, J. A., Richarte, V., Rose, R.J., Shin, J.J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, Margaret J., Koot, H.M., Paus, T., Hewitt, J. K., Ribasés, M., Kaprio, Jaakko, Boks, M. P., Snieder, H., Spector, T.D., Munafò, M. R., Metspalu, A., Gelernter, J., Boomsma, Dorret I., Iacono, William G, Martin, Nicholas G., Gillespie, N. A., Derks, Eske M., Vink, J. M., Neurogenetica, Brain, Onderzoeksgroep 2, Stringer, S., Minică, C. C., Verweij, K. J.H., Mbarek, Hamdi, Bernard, M., Derringer, Jaime, van Eijk, K. R., Isen, J. D., Loukola, Anu, Maciejewski, D. F., Mihailov, E., van der Most, Peter J., Sánchez-Mora, C., Roos, L., Sherva, R., Walters, R.G., Ware, James S., Abdellaoui, A., Bigdeli, T. B., Branje, S. J.T., Brown, A.S., Bruinenberg, M., Casas, M., Esko, Tonu, Garcia-Martinez, I., Gordon, Scott D., Harris, Juliette M, Hartman, Catharine A, Henders, Anjali K., Heath, Andrew C., Hickie, Ian B., Hickman, M., Hopfer, C. J., Hottenga, J.J., Huizink, A.C., Irons, D. E., Kahn, R. S., Korhonen, T.K., Kranzler, H. R., Krauter, K., van Lier, P.A.C., Lubke, G.H., Madden, Pamela A. F., Mägi, Reedik, McGue, M. K., Medland, Sarah E., Meeus, W.H.J., Miller, Michael B., Montgomery, Grant W., Nivard, Michel G, Nolte, Ilja M., Oldehinkel, Albertine J., Pausova, Zdenka, Qaiser, B., Quaye, Lydia, Ramos-Quiroga, J. A., Richarte, V., Rose, R.J., Shin, J.J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, Margaret J., Koot, H.M., Paus, T., Hewitt, J. K., Ribasés, M., Kaprio, Jaakko, Boks, M. P., Snieder, H., Spector, T.D., Munafò, M. R., Metspalu, A., Gelernter, J., Boomsma, Dorret I., Iacono, William G, Martin, Nicholas G., Gillespie, N. A., Derks, Eske M., and Vink, J. M.

Published
2016

41. Exome chip analyses in adult attention deficit hyperactivity disorder

Author

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

Published
2016
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45. 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

46. Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study

Author

Ribasés, M., primary, Ramos-Quiroga, J. A., additional, Sánchez-Mora, C., additional, Bosch, R., additional, Richarte, V., additional, Palomar, G., additional, Gastaminza, X., additional, Bielsa, A., additional, Arcos-Burgos, M., additional, Muenke, M., additional, Castellanos, F. X., additional, Cormand, B., additional, Bayés, M., additional, and Casas, M., additional

Published
2010
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47. Vafidemstat reduces aggressiveness in three different psychiatric disorders. final data from the reimagine trial.

Author

Bullock, R., Ferrer, M., Gutierrez, S., Richarte, V., Gisbert, L., Lara, B., Valverde, M., Ropacki, M., Xaus, J., Ramos-Quiroga, J. A., and Buesa, C.

Subjects
MENTAL illness, AUTISM spectrum disorders, ATTENTION-deficit hyperactivity disorder, BORDERLINE personality disorder, CHIEF executive officers
Abstract

Introduction: The influence of epigenetic mechanisms on psychiatric conditions has been proposed, but little molecular and pharmacological evidence is available. Vafidemstat is a brain-penetrant small molecule that inhibits LSD1 and modifies transcription in the brain through epigenetic effects. In preclinical models, vafidemstat reverts aggressive behaviour and corrects the abnormal response to stress of immediate early genes in the prefrontal cortex. Objectives: To investigate vafidemstat as a treatment for aggression in autistic spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD). Methods: REIMAGINE is a Phase IIa open-label trial that includes three psychiatric cohorts. 30 subjects (X ADHD, X ASD, X BPD) have been recruited based on significant or persistent agitation or aggression that was disruptive to patient's daily living. Patients received 1.2 mg of vafidemstat for eight weeks. Results: Preliminary positive results in partial cohorts have been previously released, showing the efficacy of vafidemstat in reducing aggressiveness in the three indications, assessedwith theClinicalGlobal Impression (CGI) and Neuropsychiatric inventory (NPI) agitationaggression (NPI-A/A) scales. Overall patient functioning has been assessed using the total NPI in addition to disease-specific scales. Here, the final data of the complete patient population will be presented, showing analysis and cohort comparisons not previously published. Conclusions: REIMAGINE supports vafidemstat as an emerging therapeutic option to treat aggression, as well as non-aggression features of psychiatric diseases with high unmet medical need where current treatments do not exist or have unfavourable side effects, including sedation or weight gain. Disclosure: Roger Bullock, Sonia Gutierrez, Michael Ropacki and Jordi Xaus are employees of Oryzon Genomics SA. Carlos buesa is Chief Executive Officer and stakeholder of Oryzon Genomics SA. REIMAGINE clinical trial has been sponsored by Oryzon Genomics SA. [ABSTRACT FROM AUTHOR]

Published
2020

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