66 results on '"Mota, NR"'
Search Results
2. The link between cognition and somatic conditions related to insulin resistance in the UK Biobank study cohort: a systematic review
- Author
-
Universitat Rovira i Virgili, Fanelli G; Mota NR; Salas-Salvadó J; Bulló M; Fernandez-Aranda F; Camacho-Barcia L; Testa G; Jiménez-Murcia S; Bertaina-Anglade V; Franke B; Poelmans G; van Gils V; Jansen WJ; Vos SJB; Wimberley T; Dalsgaard S; Barta C; Serretti A; Fabbri C; Bralten J, Universitat Rovira i Virgili, and Fanelli G; Mota NR; Salas-Salvadó J; Bulló M; Fernandez-Aranda F; Camacho-Barcia L; Testa G; Jiménez-Murcia S; Bertaina-Anglade V; Franke B; Poelmans G; van Gils V; Jansen WJ; Vos SJB; Wimberley T; Dalsgaard S; Barta C; Serretti A; Fabbri C; Bralten J
- Abstract
Clinical and genomic studies have shown an overlap between neuropsychiatric disorders and insulin resistance (IR)-related somatic conditions, including obesity, type 2 diabetes, and cardiovascular diseases. Impaired cognition is often observed among neuropsychiatric disorders, where multiple cognitive domains may be affected. In this review, we aimed to summarise previous evidence on the relationship between IR-related diseases/traits and cognitive performance in the large UK Biobank study cohort. Electronic searches were conducted on PubMed, Scopus, and Web of Science until April 2022. Eighteen articles met the inclusion criteria and were qualitatively reviewed. Overall, there is substantial evidence for an association between IR-related cardio-metabolic diseases/traits and worse performance on various cognitive domains, which is largely independent of possible confoundings. The most consistent findings referred to IR-related associations with poorer verbal and numerical reasoning ability, as well as slower processing speed. The observed associations might be mediated by alterations in immune-inflammation, brain integrity/connectivity, and/or comorbid somatic or psychiatric diseases/traits. Our findings provide impetus for further research into the underlying neurobiology and possible new therapeutic targets.
- Published
- 2022
3. 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
4. The genetic architecture of the human cerebral cortex
- Author
-
Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, Medland, SE, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, and Medland, SE
- Abstract
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
- Published
- 2020
5. 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
6. Genetic underpinnings of sociability in the UK Biobank
- Author
-
Bralten, J, primary, Klemann, CJHM, additional, Mota, NR, additional, De Witte, W, additional, Arango, C, additional, Fabbri, C, additional, Kas, MJ, additional, van der Wee, N, additional, Penninx, BWJH, additional, Serretti, A, additional, Franke, B, additional, and Poelmans, G, additional
- Published
- 2019
- Full Text
- View/download PDF
7. Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study.
- Author
-
Wimberley T, Brikell I, Astrup A, Larsen JT, Petersen LV, Albiñana C, Vilhjálmsson BJ, Bulik CM, Chang Z, Fanelli G, Bralten J, Mota NR, Salas-Salvadó J, Fernandez-Aranda F, Bulló M, Franke B, Børglum A, Mortensen PB, Horsdal HT, and Dalsgaard S
- Abstract
Background: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM., Methods: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 ( n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders., Results: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa., Conclusions: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.
- Published
- 2024
- Full Text
- View/download PDF
8. Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions.
- Author
-
Fanelli G, Franke B, Fabbri C, Werme J, Erdogan I, De Witte W, Poelmans G, Ruisch IH, Reus LM, van Gils V, Jansen WJ, Vos SJB, Alam KA, Martinez A, Haavik J, Wimberley T, Dalsgaard S, Fóthi Á, Barta C, Fernandez-Aranda F, Jimenez-Murcia S, Berkel S, Matura S, Salas-Salvadó J, Arenella M, Serretti A, Mota NR, and Bralten J
- Abstract
The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|r
g |=0.21-1, pFDR <0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1 , that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain., Competing Interests: Declarations of interest AS is or has been a consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier and Taliaz. BF discloses having received educational speaking fees and travel support from Medice. CF was a speaker for Janssen. GP is director/chief scientific officer and WDW as well as IHR are employees of Drug Target ID, Ltd., but their activities at this company do not constitute competing interests with regard to this paper. JH has received lecture honoraria as part of continuing medical education programs sponsored by Shire, Takeda, Medice, and Biocodex. JSS reported receiving research support through his institution from the Patrimonio Comunal Olivarero, Almond Board of California and Pistachio Growers of California; he is serving on the board of and receiving grant support through his institution from the International Nut and Dried Foundation, Instituto Danone Spain and Institute Danone International. FFA and SJM have been consultants/speakers for NovoNordisk. All other authors report no biomedical financial interests or potential conflicts of interest.- Published
- 2024
- Full Text
- View/download PDF
9. Multi-polygenic scores in psychiatry: From disorder specific to transdiagnostic perspectives.
- Author
-
Shi Y, Sprooten E, Mulders P, Vrijsen J, Bralten J, Demontis D, Børglum AD, Walters GB, Stefansson K, van Eijndhoven P, Tendolkar I, Franke B, and Mota NR
- Subjects
- Humans, Psychopathology, Anxiety Disorders, Multifactorial Inheritance genetics, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity genetics, Substance-Related Disorders, Psychiatry
- Abstract
The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R
2 = 0.041, p = 5e-4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)- Published
- 2024
- Full Text
- View/download PDF
10. Autism spectrum disorder and brain volume link through a set of mTOR-related genes.
- Author
-
Arenella M, Mota NR, Teunissen MWA, Brunner HG, and Bralten J
- Subjects
- Humans, Brain, TOR Serine-Threonine Kinases genetics, Genetic Predisposition to Disease, Autism Spectrum Disorder genetics, Intellectual Disability
- Abstract
Background: Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD., Methods: We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA., Results: Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81)., Conclusions: This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)
- Published
- 2023
- Full Text
- View/download PDF
11. Evaluation of patients treated by telemedicine in the beginning of the COVID-19 pandemic in São Paulo, Brazil: A non-randomized clinical trial preliminary study.
- Author
-
Chechter M, Dutra da Silva GM, E Costa RAP, Miklos TG, Antonio da Silva N, Lorber G, Vasconcellos Mota NR, Dos Santos Cortada AP, de Nazare Lima da Cruz L, de Melo PMP, de Souza BC, Emmerich FG, de Andrade Zanotto PM, and Aaron Scheinberg M
- Abstract
We performed a pilot open-label, non-randomized controlled clinical trial in a clinic in São Paulo, Brazil in the beginning of the COVID-19 pandemic. "This medical pilot project was carried out during the pandemic of a new and unknown agent. It was necessary to find a new and safe therapeutic approach for pathogens with high potential for severity and contamination. The repositioning of safe and accessible pre-existing and approved medications and the telemedicine approach improved treated covid patients' symptoms and reduced the risk of disease transmission. The emergency application of a new medical technology was the major limitation of the study. This innovative care model is a low-cost safe strategy, and we understand that applicability can be expanded to other regions in emergency situations." The 187 patients of the study (mean age of 37.6 ± 15,6 years) were divided into four groups: (1) asymptomatic, (2) mild symptoms, (3) moderate symptoms and (4) severe symptoms and were followed up for five days. A drug intervention was performed in group 3 and the patients of Group 4 were oriented to seek hospital care. Of all the patients, 23.0% were asymptomatic, 29.4% reported mild symptoms, 43.9% moderate symptoms and 3.7% severe symptoms. Three patients were hospitalized and discharged after recovery. Our results indicate that the use of telemedicine with diagnosis and drug treatment is a safe and effective strategy to reduce overload of health services and the exposure of healthcare providers and the population. The patients that initiated the treatment in the early stages of the disease presented satisfactory clinical response, reducing the need of face-to-face consultations and hospitalizations. The patients who followed the protocol treatment for COVID-19 with hydroxychloroquine and azithromycin for five days presented statistically significant improvement of clinical symptoms when compared to moderate patients who opted for not following the protocol (p < 0.05) and to all no treatment patients (p < 0.001)., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)
- Published
- 2023
- Full Text
- View/download PDF
12. Genetic liability to major psychiatric disorders contributes to multi-faceted quality of life outcomes in children and adults.
- Author
-
Shi Y, Franke B, Mota NR, and Sprooten E
- Abstract
Importance: Psychiatric disorders can have an immense impact on socioeconomic, physical, and social-psychological facets of life. Psychiatric disorders are also highly heritable. Under a liability threshold model, an important question arises as to what extent genetic liability for psychiatric disorders relates to, and possibly impacts on, different aspects of quality of life in the general population., Objective: To characterize the link between psychiatric genetic liability and diverse aspects of quality of life in childhood and adulthood., Design Setting and Participants: We used data from two multi-site, population-based cohorts, i.e. preadolescent children in the USA enrolled at age 9-10 years from the Adolescent Brain Cognitive Development (ABCD) study (N=4,645) and white British adults between age 40-69 years from the UK Biobank (UKB) study (N=377,664). Due to the current limitations of our genetic methods, only data from unrelated individuals of European descent could be included., Main Outcomes and Measures: To derive robust measures capturing multiple domains of quality of life in each of the cohorts, we integrated an array of measurements of academic, economic, and physical status, as well as social well-being, in a second-level three-factor confirmatory factor analysis. The genetic liabilities to seven major psychiatric disorders were quantified by a set of polygenic scores (PGSs) derived from the largest genome-wide association studies to date, independent of the target cohorts, of major depressive disorder (MDD, N=142k-173k), anxiety disorders (ANX, N=22k-144k), attention-deficit/hyperactivity disorder (ADHD, N=226k), autism spectrum disorder (ASD, N=55k), schizophrenia (SCZ, N=130k), bipolar disorder (BIP, N=353k-414k), and cannabis use disorder (CUD, N=384k). Using general linear models we assessed associations between PGSs and the estimated latent factors, controlling for age, sex, site, genotyping batch, plate, and genetic ancestry., Results: In each cohort, three latent factors indexing distinct but correlated quality of life domains, (1) educational performance and cognition (Edu, in ABCD) / social economic status (SES, in UKB), (2) physical health (Hea), (3) adverse social experience (Adv, in ABCD) / social well-being (Soc, in UKB), were estimated with excellent model fit indices. In addition, a general factor was derived that captured the covariances between the three latent factors (QoL). In the ABCD cohort, ADHD-PGS was significantly associated with Edu (β = -0.13, t = -8.29, p = 1.53e-16), Adv (β = -0.09, t = -5.79, p = 7.81e-09), and general QoL (β = -0.14, t = -8.74, p = 3.37e-18) factors. In the UKB cohort, all examined disorder PGSs were significantly associated with the general QoL latent factor and at least one first-order subdomain, with ADHD-PGS (β = -0.06 ~ -0.10, t = -29.1 ~ -52.5, p < 5.91e-186) and MDD-PGS (β = -0.04 ~ -0.07, t = -23.8 ~ -36.3, p < 3.63e-125) showing the largest effects., Conclusions and Relevance: The present study reveals an inverse relationship between psychiatric genetic liabilities and multiple quality of life metrics, with ADHD-associated genetic risk being the main contributor in both children and adults, and MDD additionally showing effects in adults. All effect sizes observed were small, as expected. Understanding potential real-world outcomes of quantitative measures of disorder-related genetic risks in the general population can provide a scientific foundation for societal intervention and policy-making processes, with profound implications for promoting a flourishing society.
- Published
- 2023
- Full Text
- View/download PDF
13. The link between cognition and somatic conditions related to insulin resistance in the UK Biobank study cohort: a systematic review.
- Author
-
Fanelli G, Mota NR, Salas-Salvadó J, Bulló M, Fernandez-Aranda F, Camacho-Barcia L, Testa G, Jiménez-Murcia S, Bertaina-Anglade V, Franke B, Poelmans G, van Gils V, Jansen WJ, Vos SJB, Wimberley T, Dalsgaard S, Barta C, Serretti A, Fabbri C, and Bralten J
- Subjects
- Humans, Biological Specimen Banks, Cognition, United Kingdom epidemiology, Insulin Resistance, Diabetes Mellitus, Type 2
- Abstract
Clinical and genomic studies have shown an overlap between neuropsychiatric disorders and insulin resistance (IR)-related somatic conditions, including obesity, type 2 diabetes, and cardiovascular diseases. Impaired cognition is often observed among neuropsychiatric disorders, where multiple cognitive domains may be affected. In this review, we aimed to summarise previous evidence on the relationship between IR-related diseases/traits and cognitive performance in the large UK Biobank study cohort. Electronic searches were conducted on PubMed, Scopus, and Web of Science until April 2022. Eighteen articles met the inclusion criteria and were qualitatively reviewed. Overall, there is substantial evidence for an association between IR-related cardio-metabolic diseases/traits and worse performance on various cognitive domains, which is largely independent of possible confoundings. The most consistent findings referred to IR-related associations with poorer verbal and numerical reasoning ability, as well as slower processing speed. The observed associations might be mediated by alterations in immune-inflammation, brain integrity/connectivity, and/or comorbid somatic or psychiatric diseases/traits. Our findings provide impetus for further research into the underlying neurobiology and possible new therapeutic targets., Competing Interests: Declarations of interest AS is or has been consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier. BF discloses having received educational speaking fees from Medice GmbH. CF was a speaker for Janssen. GP is director of Drug Target ID (DTID), Ltd. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
14. Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.
- Author
-
Tielbeek JJ, Uffelmann E, Williams BS, Colodro-Conde L, Gagnon É, Mallard TT, Levitt BE, Jansen PR, Johansson A, Sallis HM, Pistis G, Saunders GRB, Allegrini AG, Rimfeld K, Konte B, Klein M, Hartmann AM, Salvatore JE, Nolte IM, Demontis D, Malmberg ALK, Burt SA, Savage JE, Sugden K, Poulton R, Harris KM, Vrieze S, McGue M, Iacono WG, Mota NR, Mill J, Viana JF, Mitchell BL, Morosoli JJ, Andlauer TFM, Ouellet-Morin I, Tremblay RE, Côté SM, Gouin JP, Brendgen MR, Dionne G, Vitaro F, Lupton MK, Martin NG, Castelao E, Räikkönen K, Eriksson JG, Lahti J, Hartman CA, Oldehinkel AJ, Snieder H, Liu H, Preisig M, Whipp A, Vuoksimaa E, Lu Y, Jern P, Rujescu D, Giegling I, Palviainen T, Kaprio J, Harden KP, Munafò MR, Morneau-Vaillancourt G, Plomin R, Viding E, Boutwell BB, Aliev F, Dick DM, Popma A, Faraone SV, Børglum AD, Medland SE, Franke B, Boivin M, Pingault JB, Glennon JC, Barnes JC, Fisher SE, Moffitt TE, Caspi A, Polderman TJC, and Posthuma D
- Subjects
- Animals, Mice, Genome-Wide Association Study, Aggression psychology, Multifactorial Inheritance genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Antisocial Personality Disorder genetics, Conduct Disorder genetics, Conduct Disorder psychology
- Abstract
Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10
-10 ). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
- Full Text
- View/download PDF
15. Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.
- Author
-
O'Leary A, Fernàndez-Castillo N, Gan G, Yang Y, Yotova AY, Kranz TM, Grünewald L, Freudenberg F, Antón-Galindo E, Cabana-Domínguez J, Harneit A, Schweiger JI, Schwarz K, Ma R, Chen J, Schwarz E, Rietschel M, Tost H, Meyer-Lindenberg A, Pané-Farré CA, Kircher T, Hamm AO, Burguera D, Mota NR, Franke B, Schweiger S, Winter J, Heinz A, Erk S, Romanczuk-Seiferth N, Walter H, Ströhle A, Fehm L, Fydrich T, Lueken U, Weber H, Lang T, Gerlach AL, Nöthen MM, Alpers GW, Arolt V, Witt S, Richter J, Straube B, Cormand B, Slattery DA, and Reif A
- Subjects
- Animals, Mice, Humans, Genome-Wide Association Study, Mice, Knockout, RNA Splicing Factors genetics, Autism Spectrum Disorder genetics, Depressive Disorder, Major genetics, Mental Disorders genetics
- Abstract
Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
16. ADHD co-morbidities: A review of implication of gene × environment effects with dopamine-related genes.
- Author
-
Kanarik M, Grimm O, Mota NR, Reif A, and Harro J
- Subjects
- Adult, Comorbidity, Dopamine genetics, Dopamine Plasma Membrane Transport Proteins genetics, Genetic Predisposition to Disease genetics, Humans, Morbidity, Attention Deficit Disorder with Hyperactivity epidemiology, Attention Deficit Disorder with Hyperactivity genetics, Receptors, Dopamine D4 genetics
- Abstract
ADHD is a major burden in adulthood, where co-morbid conditions such as depression, substance use disorder and obesity often dominate the clinical picture. ADHD has substantial shared heritability with other mental disorders, contributing to comorbidity. However, environmental risk factors exist but their interaction with genetic makeup, especially in relation to comorbid disorders, remains elusive. This review for the first time summarizes present knowledge on gene x environment (GxE) interactions regarding the dopamine system. Hitherto, mainly candidate (GxE) studies were performed, focusing on the genes DRD4, DAT1 and MAOA. Some evidence suggest that the variable number tandem repeats in DRD4 and MAOA may mediate GxE interactions in ADHD generally, and comorbid conditions specifically. Nevertheless, even for these genes, common variants are bound to suggest risk only in the context of gender and specific environments. For other polymorphisms, evidence is contradictory and less convincing. Particularly lacking are longitudinal studies testing the interaction of well-defined environmental factors with polygenic risk scores reflecting the dopamine system in its entirety., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
17. Evidence From Imaging Resilience Genetics for a Protective Mechanism Against Schizophrenia in the Ventral Visual Pathway.
- Author
-
Hettwer MD, Lancaster TM, Raspor E, Hahn PK, Mota NR, Singer W, Reif A, Linden DEJ, and Bittner RA
- Subjects
- Brain metabolism, Humans, Magnetic Resonance Imaging, Multifactorial Inheritance, Visual Pathways diagnostic imaging, Visual Pathways pathology, Schizophrenia diagnostic imaging, Schizophrenia genetics, Schizophrenia metabolism
- Abstract
Introduction: Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits., Method: Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33 224 healthy subjects (UK Biobank)., Finding: We observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r = 0.35; P = .0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG., Conclusion: Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and nonsocial visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept, and schizophrenia resilience models., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
18. Multivariate Genetic Structure of Externalizing Behavior and Structural Brain Development in a Longitudinal Adolescent Twin Sample.
- Author
-
Teeuw J, Klein M, Mota NR, Brouwer RM, van 't Ent D, Al-Hassaan Z, Franke B, Boomsma DI, and Hulshoff Pol HE
- Subjects
- Adolescent, Brain diagnostic imaging, Child, Genetic Structures, Humans, Magnetic Resonance Imaging, Twins genetics, White Matter diagnostic imaging
- Abstract
Externalizing behavior in its more extreme form is often considered a problem to the individual, their families, teachers, and society as a whole. Several brain structures have been linked to externalizing behavior and such associations may arise if the (co)development of externalizing behavior and brain structures share the same genetic and/or environmental factor(s). We assessed externalizing behavior with the Child Behavior Checklist and Youth Self Report, and the brain volumes and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]) with magnetic resonance imaging in the BrainSCALE cohort, which consisted of twins and their older siblings from 112 families measured longitudinally at ages 10, 13, and 18 years for the twins. Genetic covariance modeling based on the classical twin design, extended to also include siblings of twins, showed that genes influence externalizing behavior and changes therein ( h
2 up to 88%). More pronounced externalizing behavior was associated with higher FA (observed correlation rph up to +0.20) and lower MD ( rph up to -0.20), with sizeable genetic correlations (FA ra up to +0.42; MD ra up to -0.33). The cortical gray matter (CGM; rph up to -0.20) and cerebral white matter (CWM; rph up to +0.20) volume were phenotypically but not genetically associated with externalizing behavior. These results suggest a potential mediating role for global brain structures in the display of externalizing behavior during adolescence that are both partially explained by the influence of the same genetic factor.- Published
- 2022
- Full Text
- View/download PDF
19. Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders.
- Author
-
Fanelli G, Franke B, De Witte W, Ruisch IH, Haavik J, van Gils V, Jansen WJ, Vos SJB, Lind L, Buitelaar JK, Banaschewski T, Dalsgaard S, Serretti A, Mota NR, Poelmans G, and Bralten J
- Subjects
- Brain, Genome-Wide Association Study, Humans, Insulin, Attention Deficit Disorder with Hyperactivity psychology, Autism Spectrum Disorder psychology, Depressive Disorder, Major genetics, Diabetes Mellitus, Type 2 genetics
- Abstract
The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain "insulinopathies" were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (r
g = -0.315, p = 3.9 × 10-8 ), OCD and obesity (rg = -0.379, p = 3.4 × 10-5 ), and OCD and T2DM (rg = -0.172, p = 3 × 10-4 ). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 × 10-4 ). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 × 10-4 ). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
20. Insights into attention-deficit/hyperactivity disorder from recent genetic studies.
- Author
-
Brikell I, Burton C, Mota NR, and Martin J
- Subjects
- Humans, Molecular Biology, Phenotype, Risk Factors, Attention Deficit Disorder with Hyperactivity epidemiology, Attention Deficit Disorder with Hyperactivity genetics, Genome-Wide Association Study, Multifactorial Inheritance genetics
- Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder (NDD). In this narrative review, we summarize recent advances in quantitative and molecular genetic research from the past 5-10 years. Combined with large-scale international collaboration, these advances have resulted in fast-paced progress in understanding the etiology of ADHD and how genetic risk factors map on to clinical heterogeneity. Studies are converging on a number of key insights. First, ADHD is a highly polygenic NDD with a complex genetic architecture encompassing risk variants across the spectrum of allelic frequencies, which are implicated in neurobiological processes. Second, genetic studies strongly suggest that ADHD diagnosis shares a large proportion of genetic risks with continuously distributed traits of ADHD in the population, with shared genetic risks also seen across development and sex. Third, ADHD genetic risks are shared with those implicated in many other neurodevelopmental, psychiatric and somatic phenotypes. As sample sizes and the diversity of genetic studies continue to increase through international collaborative efforts, we anticipate further success with gene discovery, characterization of how the ADHD phenotype relates to other human traits and growing potential to use genomic risk factors for understanding clinical trajectories and for precision medicine approaches.
- Published
- 2021
- Full Text
- View/download PDF
21. A polygenic risk score analysis of ASD and ADHD across emotion recognition subtypes.
- Author
-
Waddington F, Franke B, Hartman C, Buitelaar JK, Rommelse N, and Mota NR
- Subjects
- Emotions, Humans, Risk Factors, Siblings, Attention Deficit Disorder with Hyperactivity genetics, Autism Spectrum Disorder genetics
- Abstract
This study investigated the genetic components of ADHD and ASD by examining the cross-disorder trait of emotion recognition problems. The genetic burden for ADHD and ASD on previously identified emotion recognition factors (speed and accuracy of visual and auditory emotion recognition) and classes (Class 1: Average visual, impulsive auditory; Class 2: Average-strong visual & auditory; Class 3: Impulsive & imprecise visual, average auditory; Class 4: Weak visual & auditory) was assessed using ASD and ADHD polygenic risk scores (PRS). Our sample contained 552 participants: 74 with ADHD, 85 with ASD, 60 with ASD + ADHD, 177 unaffected siblings of ADHD or ASD probands, and 156 controls. ADHD- and ASD-PRS, calculated from the latest ADHD and ASD GWAS meta-analyses, were analyzed across these emotion recognition factors and classes using linear mixed models. Unexpectedly, the analysis of emotion recognition factors showed higher ASD-PRS to be associated with faster visual emotion recognition. The categorical analysis of emotion recognition classes showed ASD-PRS to be reduced in Class 3 compared to the other classes (p value threshold [pT] = 1, p = .021). A dimensional analysis identified a high ADHD-PRS reduced the probability of being assigned to the Class 1 or Class 3 (pT = .05, p = .028 and p = .044, respectively). Though these nominally significant results did not pass FDR correction, they potentially indicate different indirect causative chains from genetics via emotion recognition to ADHD and ASD, which need to be verified in future research., (© 2020 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
22. Genetic underpinnings of sociability in the general population.
- Author
-
Bralten J, Mota NR, Klemann CJHM, De Witte W, Laing E, Collier DA, de Kluiver H, Bauduin SEEC, Arango C, Ayuso-Mateos JL, Fabbri C, Kas MJ, van der Wee N, Penninx BWJH, Serretti A, Franke B, and Poelmans G
- Subjects
- Adult, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide genetics, Bipolar Disorder genetics, Depressive Disorder, Major, Schizophrenia genetics
- Abstract
Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h
2 of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits-loneliness and social anxiety-but not with bipolar disorder or Alzheimer's disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
23. Meta-analysis and systematic review of ADGRL3 (LPHN3) polymorphisms in ADHD susceptibility.
- Author
-
Bruxel EM, Moreira-Maia CR, Akutagava-Martins GC, Quinn TP, Klein M, Franke B, Ribasés M, Rovira P, Sánchez-Mora C, Kappel DB, Mota NR, Grevet EH, Bau CHD, Arcos-Burgos M, Rohde LA, and Hutz MH
- Subjects
- Adult, Child, Genetic Association Studies, Genetic Predisposition to Disease genetics, Humans, Polymorphism, Single Nucleotide genetics, Receptors, G-Protein-Coupled genetics, Receptors, Peptide genetics, Attention Deficit Disorder with Hyperactivity genetics
- Abstract
The gene encoding adhesion G protein-coupled receptor L3 (ADGRL3, also referred to as latrophilin 3 or LPHN3) has been associated with ADHD susceptibility in independent ADHD samples. We conducted a systematic review and a comprehensive meta-analysis to summarize the associations between the most studied ADGRL3 polymorphisms (rs6551665, rs1947274, rs1947275, and rs2345039) and both childhood and adulthood ADHD. Eight association studies (seven published and one unpublished) fulfilled criteria for inclusion in our meta-analysis. We also incorporated GWAS data for ADGRL3. In order to avoid overlapping samples, we started with summary statistics from GWAS samples and then added data from gene association studies. The results of our meta-analysis suggest an effect of ADGRL3 variants on ADHD susceptibility in children (n = 8724/14,644 cases/controls and 1893 families): rs6551665 A allele (Z score = -2.701; p = 0.0069); rs1947274 A allele (Z score = -2.033; p = 0.0421); rs1947275 T allele (Z score = 2.339; p = 0.0978); and rs2345039 C allele (Z score = 3.806; p = 0.0026). Heterogeneity was found in analyses for three SNPs (rs6551665, rs1947274, and rs2345039). In adults, results were not significant (n = 6532 cases/15,874 controls): rs6551665 A allele (Z score = 2.005; p = 0.0450); rs1947274 A allele (Z score = 2.179; p = 0.0293); rs1947275 T allele (Z score = -0.822; p = 0.4109); and rs2345039 C allele (Z score = -1.544; p = 0.1226). Heterogeneity was found just for rs6551665. In addition, funnel plots did not suggest publication biases. Consistent with ADGRL3's role in early neurodevelopment, our findings suggest that the gene is predominantly associated with childhood ADHD., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
- Full Text
- View/download PDF
24. Mapping relationships between ADHD genetic liability, stressful life events, and ADHD symptoms in healthy adults.
- Author
-
Li T, Franke B, AriasVasquez A, and Mota NR
- Subjects
- Adult, Chromosome Mapping methods, Cognition, Female, Genetic Association Studies methods, Genetic Predisposition to Disease genetics, Healthy Volunteers, Humans, Life Change Events, Longitudinal Studies, Male, Phenotype, Stress, Psychological metabolism, Attention Deficit Disorder with Hyperactivity genetics, Stress, Psychological genetics
- Abstract
Attention-deficit/hyperactivity disorder (ADHD) symptoms are continuously distributed in the general population, where both genetic and environmental factors play roles. Stressful life events (SLEs) have been associated with ADHD diagnosis, but the relationship between ADHD genetic liability, SLEs, and ADHD symptoms in healthy individuals is less clear. Using a sample of 1,531 healthy adults (average age 26.9 years; 55.8% female), we investigated relationships between ADHD polygenic risk scores (ADHD-PRSs), SLEs, and ADHD symptoms in a general population sample. Confirming earlier findings in an overlapping sample, all SLE-measures assessed (lifetime SLEs, recent SLEs, and childhood trauma (CT)) were significantly correlated with total ADHD, inattention (IA), and hyperactivity-impulsivity (HI) scores (r
2 range = .08-.15; all p < .005). ADHD-PRSs was associated with HI (R2 best-fit = .37%), lifetime SLEs (R2 best-fit = .56%), and CT (R2 best-fit = .40%). Mediation analyses showed that lifetime SLEs partially mediated the association between ADHD-PRSs and HI (indirect effect: β = 68.6, bias corrected accelerated 95% confident interval (BCa95%CI) [11.9, 131.0], p = .016, proportion mediated (PM ) =19.5%), with strongest effects contributed by CT (β = 34.4, BCa95%CI [0.4, 76.5], p = .040, PM = 9.8%). On the other hand, HI partially mediated the association between the ADHD-PRSs and lifetime SLEs (β = 42.9, BCa95%CI [7.3, 83.9], p = .014, PM = 18.8%). Our study observed a complex relationship of genetic and environmental risk factors contributing to ADHD symptoms in the healthy adult population., (© 2020 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)- Published
- 2021
- Full Text
- View/download PDF
25. Obesity and ADHD: Exploring the role of body composition, BMI polygenic risk score, and reward system genes.
- Author
-
Martins-Silva T, Vaz JDS, Genro JP, Hutz MH, Loret de Mola C, Mota NR, Oliveira I, Gigante DP, Pinheiro RT, Vitola E, Grevet E, Horta BL, Rohde LA, and Tovo-Rodrigues L
- Subjects
- Adult, Body Composition, Body Mass Index, Brazil, Humans, Obesity epidemiology, Obesity genetics, Reward, Risk Factors, Attention Deficit Disorder with Hyperactivity genetics
- Abstract
The association between obesity and attention-deficit hyperactivity disorder (ADHD) has been extensively reported in the literature. However, the potential mechanisms underlying this association are not completely understood. This study aimed to evaluate the association between body composition and ADHD and explore the possible genetic mechanisms involved. We used data from the 1982 Pelotas (Brazil) Birth Cohort at age 30-year follow-up (N = 3630). We first used logistic regression analysis to test whether body mass index (BMI), fat mass (FM), and fat-free mass (FFM) were associated with ADHD. We further tested the association between BMI polygenic risk score (BMI-PRS) and ADHD and the role of the genes upregulated in the reward system using a gene-set association approach. BMI (odds ratio [OR] = 1.05; 95% confidence interval [CI], 1.00-1.09; p = 0.038) and FM (OR = 1.04; 95% CI, 1.00-1.07; p = 0.043) were associated with ADHD. The BMI-PRS was associated with ADHD (using p-value threshold (P
T ) = 0.4; OR = 1.65; 95% CI, 1.02-2.65) at a nominal level. In gene-set analysis, the reward system genes were associated with BMI in subjects with a high BMI-PRS score, considering PT = 0.4 (p = 0.014). The results suggest that BMI genetic components, especially those genes related to the reward system, may be involved in this association., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
26. Contribution of Intellectual Disability-Related Genes to ADHD Risk and to Locomotor Activity in Drosophila .
- Author
-
Klein M, Singgih EL, van Rens A, Demontis D, Børglum AD, Mota NR, Castells-Nobau A, Kiemeney LA, Brunner HG, Arias-Vasquez A, Schenck A, van der Voet M, and Franke B
- Subjects
- Adult, Aged, Animals, Circadian Rhythm, Dopaminergic Neurons metabolism, Female, Gene Knockdown Techniques, Genome-Wide Association Study, Humans, Intellectual Disability genetics, MEF2 Transcription Factors genetics, Male, Middle Aged, Neurons metabolism, Sleep genetics, Attention Deficit Disorder with Hyperactivity genetics, Drosophila Proteins genetics, Drosophila melanogaster genetics, Intercellular Signaling Peptides and Proteins genetics, Locomotion genetics, Myogenic Regulatory Factors genetics, Sialyltransferases genetics
- Abstract
Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster ., Methods: Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits., Results: The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were MEF2C , ST3GAL3 , and TRAPPC9 . Performing functional characterization of the two evolutionarily conserved genes in Drosophila melanogaster , the authors found that their knockdown in dopaminergic ( dMEF2 ) and circadian neurons ( dTRAPPC9 ) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype., Conclusions: This study reveals that a large set of intellectual disability-related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified TRAPPC9 , MEF2C , and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.
- Published
- 2020
- Full Text
- View/download PDF
27. Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures.
- Author
-
Mota NR, Poelmans G, Klein M, Torrico B, Fernàndez-Castillo N, Cormand B, Reif A, Franke B, and Arias Vásquez A
- Subjects
- Body Mass Index, Humans, Obesity genetics, Signal Transduction genetics, Attention Deficit Disorder with Hyperactivity genetics, Dopamine physiology
- Abstract
Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N = 10,720-10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10
-3 ) and BMI (P = 1.63 × 10-5 ); the circadian rhythm was associated with BMI (P = 1.28 × 10-3 ). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P = 7.7 × 10-3 ; replication data P = 3.9 × 10-2 )-a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.- Published
- 2020
- Full Text
- View/download PDF
28. The genetic architecture of the human cerebral cortex.
- Author
-
Grasby KL, Jahanshad N, Painter JN, Colodro-Conde L, Bralten J, Hibar DP, Lind PA, Pizzagalli F, Ching CRK, McMahon MAB, Shatokhina N, Zsembik LCP, Thomopoulos SI, Zhu AH, Strike LT, Agartz I, Alhusaini S, Almeida MAA, Alnæs D, Amlien IK, Andersson M, Ard T, Armstrong NJ, Ashley-Koch A, Atkins JR, Bernard M, Brouwer RM, Buimer EEL, Bülow R, Bürger C, Cannon DM, Chakravarty M, Chen Q, Cheung JW, Couvy-Duchesne B, Dale AM, Dalvie S, de Araujo TK, de Zubicaray GI, de Zwarte SMC, den Braber A, Doan NT, Dohm K, Ehrlich S, Engelbrecht HR, Erk S, Fan CC, Fedko IO, Foley SF, Ford JM, Fukunaga M, Garrett ME, Ge T, Giddaluru S, Goldman AL, Green MJ, Groenewold NA, Grotegerd D, Gurholt TP, Gutman BA, Hansell NK, Harris MA, Harrison MB, Haswell CC, Hauser M, Herms S, Heslenfeld DJ, Ho NF, Hoehn D, Hoffmann P, Holleran L, Hoogman M, Hottenga JJ, Ikeda M, Janowitz D, Jansen IE, Jia T, Jockwitz C, Kanai R, Karama S, Kasperaviciute D, Kaufmann T, Kelly S, Kikuchi M, Klein M, Knapp M, Knodt AR, Krämer B, Lam M, Lancaster TM, Lee PH, Lett TA, Lewis LB, Lopes-Cendes I, Luciano M, Macciardi F, Marquand AF, Mathias SR, Melzer TR, Milaneschi Y, Mirza-Schreiber N, Moreira JCV, Mühleisen TW, Müller-Myhsok B, Najt P, Nakahara S, Nho K, Olde Loohuis LM, Orfanos DP, Pearson JF, Pitcher TL, Pütz B, Quidé Y, Ragothaman A, Rashid FM, Reay WR, Redlich R, Reinbold CS, Repple J, Richard G, Riedel BC, Risacher SL, Rocha CS, Mota NR, Salminen L, Saremi A, Saykin AJ, Schlag F, Schmaal L, Schofield PR, Secolin R, Shapland CY, Shen L, Shin J, Shumskaya E, Sønderby IE, Sprooten E, Tansey KE, Teumer A, Thalamuthu A, Tordesillas-Gutiérrez D, Turner JA, Uhlmann A, Vallerga CL, van der Meer D, van Donkelaar MMJ, van Eijk L, van Erp TGM, van Haren NEM, van Rooij D, van Tol MJ, Veldink JH, Verhoef E, Walton E, Wang M, Wang Y, Wardlaw JM, Wen W, Westlye LT, Whelan CD, Witt SH, Wittfeld K, Wolf C, Wolfers T, Wu JQ, Yasuda CL, Zaremba D, Zhang Z, Zwiers MP, Artiges E, Assareh AA, Ayesa-Arriola R, Belger A, Brandt CL, Brown GG, Cichon S, Curran JE, Davies GE, Degenhardt F, Dennis MF, Dietsche B, Djurovic S, Doherty CP, Espiritu R, Garijo D, Gil Y, Gowland PA, Green RC, Häusler AN, Heindel W, Ho BC, Hoffmann WU, Holsboer F, Homuth G, Hosten N, Jack CR Jr, Jang M, Jansen A, Kimbrel NA, Kolskår K, Koops S, Krug A, Lim KO, Luykx JJ, Mathalon DH, Mather KA, Mattay VS, Matthews S, Mayoral Van Son J, McEwen SC, Melle I, Morris DW, Mueller BA, Nauck M, Nordvik JE, Nöthen MM, O'Leary DS, Opel N, Martinot MP, Pike GB, Preda A, Quinlan EB, Rasser PE, Ratnakar V, Reppermund S, Steen VM, Tooney PA, Torres FR, Veltman DJ, Voyvodic JT, Whelan R, White T, Yamamori H, Adams HHH, Bis JC, Debette S, Decarli C, Fornage M, Gudnason V, Hofer E, Ikram MA, Launer L, Longstreth WT, Lopez OL, Mazoyer B, Mosley TH, Roshchupkin GV, Satizabal CL, Schmidt R, Seshadri S, Yang Q, Alvim MKM, Ames D, Anderson TJ, Andreassen OA, Arias-Vasquez A, Bastin ME, Baune BT, Beckham JC, Blangero J, Boomsma DI, Brodaty H, Brunner HG, Buckner RL, Buitelaar JK, Bustillo JR, Cahn W, Cairns MJ, Calhoun V, Carr VJ, Caseras X, Caspers S, Cavalleri GL, Cendes F, Corvin A, Crespo-Facorro B, Dalrymple-Alford JC, Dannlowski U, de Geus EJC, Deary IJ, Delanty N, Depondt C, Desrivières S, Donohoe G, Espeseth T, Fernández G, Fisher SE, Flor H, Forstner AJ, Francks C, Franke B, Glahn DC, Gollub RL, Grabe HJ, Gruber O, Håberg AK, Hariri AR, Hartman CA, Hashimoto R, Heinz A, Henskens FA, Hillegers MHJ, Hoekstra PJ, Holmes AJ, Hong LE, Hopkins WD, Hulshoff Pol HE, Jernigan TL, Jönsson EG, Kahn RS, Kennedy MA, Kircher TTJ, Kochunov P, Kwok JBJ, Le Hellard S, Loughland CM, Martin NG, Martinot JL, McDonald C, McMahon KL, Meyer-Lindenberg A, Michie PT, Morey RA, Mowry B, Nyberg L, Oosterlaan J, Ophoff RA, Pantelis C, Paus T, Pausova Z, Penninx BWJH, Polderman TJC, Posthuma D, Rietschel M, Roffman JL, Rowland LM, Sachdev PS, Sämann PG, Schall U, Schumann G, Scott RJ, Sim K, Sisodiya SM, Smoller JW, Sommer IE, St Pourcain B, Stein DJ, Toga AW, Trollor JN, Van der Wee NJA, van 't Ent D, Völzke H, Walter H, Weber B, Weinberger DR, Wright MJ, Zhou J, Stein JL, Thompson PM, and Medland SE
- Subjects
- Attention Deficit Disorder with Hyperactivity genetics, Brain Mapping, Cognition, Genetic Loci, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Organ Size genetics, Parkinson Disease genetics, Cerebral Cortex anatomy & histology, Genetic Variation
- Abstract
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
- Full Text
- View/download PDF
29. RICOPILI: Rapid Imputation for COnsortias PIpeLIne.
- Author
-
Lam M, Awasthi S, Watson HJ, Goldstein J, Panagiotaropoulou G, Trubetskoy V, Karlsson R, Frei O, Fan CC, De Witte W, Mota NR, Mullins N, Brügger K, Lee SH, Wray NR, Skarabis N, Huang H, Neale B, Daly MJ, Mattheisen M, Walters R, and Ripke S
- Subjects
- Algorithms, Genome, Genomics, Genome-Wide Association Study, Software
- Abstract
Summary: Genome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open-sourced Perl-based pipeline was developed to address the challenges of rapidly processing large-scale multi-cohort GWAS studies including quality control (QC), imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing environments. RICOPILI was created as the Psychiatric Genomics Consortium pipeline for GWAS and adopted by other users. The pipeline features (i) technical and genomic QC in case-control and trio cohorts, (ii) genome-wide phasing and imputation, (iv) association analysis, (v) meta-analysis, (vi) polygenic risk scoring and (vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work., Availability and Implementation: RICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press.)
- Published
- 2020
- Full Text
- View/download PDF
30. 30-year journey from the start of the Human Genome Project to clinical application of genomics in psychiatry: are we there yet?
- Author
-
Mota NR and Franke B
- Subjects
- Antipsychotic Agents adverse effects, Antipsychotic Agents therapeutic use, Humans, Obesity, Olanzapine adverse effects, Olanzapine therapeutic use, Weight Gain, Genomics trends, Human Genome Project organization & administration, Mental Disorders drug therapy, Mental Disorders genetics, Psychiatry
- Published
- 2020
- Full Text
- View/download PDF
31. Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response.
- Author
-
da Silva BS, Leffa DT, Beys-da-Silva WO, Torres ILS, Rovaris DL, Victor MM, Rohde LA, Mota NR, Oliveira C, Berger M, Yates JR 3rd, Sabnis R, Peña RD, Campos AR, Grevet EH, Santi L, Bau CHD, and Contini V
- Subjects
- Adult, Animals, Female, Humans, Male, Pharmacogenetics, Proteomics, Random Allocation, Rats, Rats, Inbred WKY, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit Disorder with Hyperactivity genetics, Central Nervous System Stimulants therapeutic use, Methylphenidate therapeutic use
- Abstract
Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < -1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.
- Published
- 2019
- Full Text
- View/download PDF
32. ADHD symptoms in the adult general population are associated with factors linked to ADHD in adult patients.
- Author
-
Li T, Mota NR, Galesloot TE, Bralten J, Buitelaar JK, IntHout J, AriasVasquez A, and Franke B
- Subjects
- Age Factors, Attention Deficit Disorder with Hyperactivity complications, Female, Humans, Hyperkinesis complications, Male, Middle Aged, Psychiatric Status Rating Scales, Self Report, Sex Factors, Attention, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity psychology, Healthy Volunteers psychology, Impulsive Behavior, Personality
- Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children and adults. It is characterized by inappropriate levels of inattention (IA) and/or hyperactivity and impulsivity (HI). The ADHD diagnosis is hypothesized to represent the extreme of a continuous distribution of ADHD symptoms in the general population. In this study, we investigated whether factors linked to adult ADHD as a disorder are associated with adult ADHD symptoms in the general population. Our population-based sample included 4987 adults (mean age 56.1 years; 53.8% female) recruited by the Nijmegen Biomedical Study (NBS). Participants completed the Dutch ADHD DSM-IV Rating Scale for current and childhood ADHD symptoms, the Symptom Check List-90-R (SCL-90-R) anxiety subscale, and the Eysenk Personality Questionnaire (EPQR-S). Partial Spearman correlation and Hurdle negative binomial regression analysis were used to assess how age, sex, childhood ADHD symptoms, anxiety symptoms, and personality traits (neuroticism, extraversion, and psychoticism) are associated with current IA and HI symptoms. Increasing age was associated with a lower proportion of participants reporting HI symptoms and with reduced levels of HI; IA levels remained fairly stable over the age-range, but the probability of reporting IA symptoms increased throughout middle/late adulthood. Females were more likely to report IA symptoms than males. Childhood ADHD symptoms, neuroticism, and psychoticism were positively associated with current IA and HI symptoms, while extraversion had an opposite association with these symptom domains. Anxiety symptoms affected HI symptoms in females. Our results indicate that factors associated with categorical ADHD are also correlated with ADHD symptoms in the adult population., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
33. Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD.
- Author
-
da Silva BS, Cupertino RB, Rovaris DL, Schuch JB, Kappel DB, Müller D, Bandeira CE, Victor MM, Karam RG, Mota NR, Rohde LA, Contini V, Grevet EH, and Bau CHD
- Subjects
- Adult, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit and Disruptive Behavior Disorders complications, Central Nervous System Stimulants, Exocytosis physiology, Female, Humans, Male, Methylphenidate pharmacology, Methylphenidate therapeutic use, Outcome Assessment, Health Care, Polymorphism, Genetic, Synaptotagmin I metabolism, Syntaxin 1 genetics, Syntaxin 1 metabolism, Treatment Outcome, Vesicle-Associated Membrane Protein 2 genetics, Vesicle-Associated Membrane Protein 2 metabolism, Attention Deficit Disorder with Hyperactivity genetics, Exocytosis genetics, Synaptotagmin I genetics
- Abstract
Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, P
FDR =0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, PFDR =0.028 and P=0.017, PFDR =0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, PFDR =0.048), and with months of treatment (P=0.002, PFDR =0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.- Published
- 2018
- Full Text
- View/download PDF
34. Evidence of sexual dimorphism of HTR1B gene on major adult ADHD comorbidities.
- Author
-
Müller D, Grevet EH, Panzenhagen AC, Cupertino RB, da Silva BS, Kappel DB, Mota NR, Blaya-Rocha P, Teche SP, Vitola ES, Rohde LA, Contini V, Rovaris DL, Schuch JB, and Bau CHD
- Subjects
- Adult, Anxiety Disorders epidemiology, Attention Deficit Disorder with Hyperactivity epidemiology, Comorbidity, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Tobacco Use Disorder epidemiology, Tobacco Use Disorder genetics, Young Adult, Anxiety Disorders genetics, Attention Deficit Disorder with Hyperactivity genetics, Receptor, Serotonin, 5-HT1B genetics, Sex Characteristics, Substance-Related Disorders genetics
- Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a very common psychiatric disorder across the life cycle and frequently presents comorbidities. Since ADHD is highly heritable, several studies have focused in the underlying genetic factors involved in its etiology. One of the major challenges in this search is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we differentially tested the influence of HTR1B SNPs (rs11568817, rs130058, rs6296 and rs13212041) on ADHD susceptibility and on its major comorbidities according to sex. The sample comprised 564 adults with ADHD diagnosed according to DSM-IV criteria and 635 controls. There was no association of any HTR1B SNPs tested in relation to ADHD susceptibility. As for the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (P
corr = 0.009 and Pcorr = 0.018, respectively) and for rs11568817 with nicotine dependence (Pcorr = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (Pcorr = 0.031). The observed effects of rs11568817 G allele presence conferring risk to either substance use disorders or generalized anxiety disorder according to sex, suggest an overall scenario where a higher transcriptional activity of HTR1B, resulting from the presence of this allele, is related to externalizing behaviors in men and internalizing behaviors in women. These results are consistent with and expand previous evidence of sexual dimorphism of the serotoninergic system., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
35. Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood.
- Author
-
Kappel DB, Schuch JB, Rovaris DL, da Silva BS, Cupertino RB, Winkler C, Teche SP, Vitola ES, Karam RG, Rohde LA, Bau CHD, Grevet EH, and Mota NR
- Subjects
- Adult, Attention Deficit Disorder with Hyperactivity physiopathology, Attention Deficit Disorder with Hyperactivity psychology, Disease Progression, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Male, Multigene Family, Phenotype, Polymorphism, Single Nucleotide, Retrospective Studies, Attention Deficit Disorder with Hyperactivity genetics, CD56 Antigen genetics, Protein Serine-Threonine Kinases genetics, Proteins genetics, Receptors, Dopamine D2 genetics, Receptors, G-Protein-Coupled genetics, Receptors, Peptide genetics
- Abstract
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
36. Trajectories of attention-deficit/hyperactivity disorder dimensions in adults.
- Author
-
Karam RG, Rovaris DL, Breda V, Picon FA, Victor MM, Salgado CAI, Vitola ES, Mota NR, Silva KL, Meller M, Rohde LA, Grevet EH, and Bau CHD
- Subjects
- Adult, Cognition Disorders epidemiology, Cognition Disorders physiopathology, Comorbidity, Female, Follow-Up Studies, Humans, Male, Attention Deficit Disorder with Hyperactivity physiopathology, Mental Health, Severity of Illness Index
- Abstract
Objective: There is a lack of available information on the trajectories of attention-deficit/hyperactivity disorder (ADHD) dimensions during adulthood. This study investigates the course and the predictors of change for each ADHD domain in a clinical sample of adults with ADHD., Method: Adults with ADHD (n = 344) were followed up for 7 years, with a final retention rate of 66.0%. Trajectories of inattention, hyperactivity, and impulsivity and their potential predictors were examined., Results: On average, symptoms declined in all ADHD domains during follow-up. Despite this, rises in inattentive, hyperactive, and impulsive symptoms were observed in approximately 13%, 25%, and 17% of patients respectively. Different predictors influenced the trajectory of each ADHD dimension. Oppositional defiant disorder and social phobia were associated with the maintenance of symptoms, while alcohol use disorder was associated with both maintenance and rise of symptoms., Conclusion: Unexpectedly, a rise in the symptoms after 7 years was not uncommon in adults with ADHD. Prevalent comorbidities have the potential to influence the neurodevelopment and the trajectory of ADHD. Therefore, such predictors should be investigated in population cohorts to better characterize the course of ADHD. Additionally, these findings may be relevant in prevention studies and in strategies for ADHD treatment., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
37. Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors.
- Author
-
Cupertino RB, Schuch JB, Bandeira CE, da Silva BS, Rovaris DL, Kappel DB, Contini V, Salatino-Oliveira A, Vitola ES, Karam RG, Hutz MH, Rohde LA, Grevet EH, Bau CHD, and Mota NR
- Subjects
- Antisocial Personality Disorder etiology, Case-Control Studies, Child, Conduct Disorder etiology, Female, Gene Frequency, Genetic Association Studies, Humans, Male, Attention Deficit Disorder with Hyperactivity complications, Attention Deficit Disorder with Hyperactivity genetics, Mental Disorders etiology, Polymorphism, Single Nucleotide genetics, Synaptotagmin I genetics
- Abstract
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
38. Erratum to: Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults.
- Author
-
de Azeredo LA, Rovaris DL, Mota NR, Polina ER, Marques FZ, Contini V, Vitola ES, Belmonte-de-Abreu P, Rohde LA, Grevet EH, and Bau CH
- Published
- 2016
- Full Text
- View/download PDF
39. Effects of corticotropin-releasing hormone receptor 1 SNPs on major depressive disorder are influenced by sex and smoking status.
- Author
-
da Silva BS, Rovaris DL, Schuch JB, Mota NR, Cupertino RB, Aroche AP, Bertuzzi GP, Karam RG, Vitola ES, Tovo-Rodrigues L, Grevet EH, and Bau CH
- Subjects
- Adult, Brazil, Cross-Sectional Studies, Depressive Disorder, Major etiology, Female, Genome-Wide Association Study, Haplotypes, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Sex Factors, White People, Young Adult, Depressive Disorder, Major genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Receptors, Corticotropin-Releasing Hormone genetics, Smoking adverse effects
- Abstract
Background: The corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status., Methods: The association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking status RESULTS: Among nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (P
corr =0.034) and rs878886 in men (Pcorr =0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDD LIMITATIONS: The lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups., Conclusions: Our results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD., (Copyright © 2016 Elsevier B.V. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
40. Exome chip analyses in adult attention deficit hyperactivity disorder.
- Author
-
Zayats T, Jacobsen KK, Kleppe R, Jacob CP, Kittel-Schneider S, Ribasés M, Ramos-Quiroga JA, Richarte V, Casas M, Mota NR, Grevet EH, Klein M, Corominas J, Bralten J, Galesloot T, Vasquez AA, Herms S, Forstner AJ, Larsson H, Breen G, Asherson P, Gross-Lesch S, Lesch KP, Cichon S, Gabrielsen MB, Holmen OL, Bau CH, Buitelaar J, Kiemeney L, Faraone SV, Cormand B, Franke B, Reif A, Haavik J, and Johansson S
- Subjects
- Adult, Brain metabolism, Female, Genetic Loci genetics, Genetic Variation, Genotype, Humans, Male, Open Reading Frames genetics, Attention Deficit Disorder with Hyperactivity genetics, Oligonucleotide Array Sequence Analysis, Polymorphism, Genetic genetics, Exome Sequencing
- 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
- View/download PDF
41. Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD.
- Author
-
Schuch JB, Polina ER, Rovaris DL, Kappel DB, Mota NR, Cupertino RB, Silva KL, Guimarães-da-Silva PO, Karam RG, Salgado CAI, White MJ, Rohde LA, Grevet EH, and Bau CHD
- Subjects
- Adult, Analysis of Variance, Female, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Multigene Family genetics, Neuropsychological Tests, Psychiatric Status Rating Scales, Attention Deficit Disorder with Hyperactivity genetics, Chromosomes, Human, Pair 15 genetics, Cognition Disorders genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Receptors, Nicotinic genetics, Tobacco Use Disorder genetics
- Abstract
Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster (Chr15q25) have been robustly associated with nicotine dependence, including genome-wide studies, as well as with cognitive and neuropsychological measures. In addition, cognitive processes can be influenced by nicotine use through nicotinic acetylcholine receptors (nAChRs). Here, we evaluated the effect of polymorphisms in CHRNA5-CHRNA3-CHRNB4 gene cluster and their interaction with tobacco smoking status on cognition in patients with Attention Deficit/Hyperactivity Disorder (ADHD). Eight SNPs from the CHRNA5-CHRNA3-CHRNB4 gene cluster were evaluated on a clinical sample of 403 adults with ADHD. Cognitive performance was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Analyses of covariance were used to assess the influence of single markers and their interaction with smoking status in the Vocabulary and Block Design subtests of WAIS-R. Correction for multiple comparisons was applied. Lifetime smoking was associated to Vocabulary subtest. The TT genotypes of CHRNA5 SNPs rs588765 and rs514743 showed a trend towards association with, respectively, higher and lower scores on the Vocabulary subtest. There was a significant interaction between intergenic SNP rs8023462 and smoking on Vocabulary scores. Our results are consistent with an influence of variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on cognitive measures. The overall scenario suggests a pleiotropic role of Chr15q25 nicotinic gene cluster with complex influences in ADHD, tobacco smoking and cognitive performance, characteristics that can be partially interdependent and may share underlying genetic factors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
42. Meta-analysis of the DRD5 VNTR in persistent ADHD.
- Author
-
Klein M, Berger S, Hoogman M, Dammers J, Makkinje R, Heister AJGAM, Galesloot TE, Kiemeney LALM, Weber H, Kittel-Schneider S, Lesch KP, Reif A, Ribase S M, Ramos-Quiroga JA, Cormand B, Zayats T, Hegvik TA, Jacobsen KK, Johansson S, Haavik J, Mota NR, Bau CHD, Grevet EH, Doyle A, Faraone SV, Arias-Va Squez A, and Franke B
- Subjects
- Genetic Predisposition to Disease, Humans, Attention Deficit Disorder with Hyperactivity genetics, Minisatellite Repeats, Receptors, Dopamine D5 genetics
- Abstract
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. DRD5, the gene encoding the dopamine receptor D5, was recently confirmed as a candidate gene for ADHD in children through meta-analysis. In this study, we aimed at studying the association of the ADHD-associated variable number tandem repeat (VNTR) polymorphism upstream of DRD5 with adult ADHD. We compiled data from six sites of the International Multicentre persistent ADHD CollaboraTion (IMpACT) and reached N=6979 (3344 cases and 3635 healthy participants), the largest sample investigated so far. We tested the association of the common DRD5 alleles with categorically defined ADHD and with inattentive and hyperactive/impulsive symptom counts. Our findings provide evidence that none of the common DRD5 alleles are associated with ADHD risk or ADHD symptom counts in adults., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
43. SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond.
- Author
-
Cupertino RB, Kappel DB, Bandeira CE, Schuch JB, da Silva BS, Müller D, Bau CH, and Mota NR
- Subjects
- Humans, Pharmacogenetics, Protein Processing, Post-Translational, Protein Transport physiology, SNARE Proteins genetics, Exocytosis physiology, Mental Disorders genetics, Mental Disorders metabolism, Mental Disorders pathology, Neurotransmitter Agents metabolism, SNARE Proteins metabolism
- Abstract
Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes.
- Published
- 2016
- Full Text
- View/download PDF
44. Does collateral retrospective information about childhood attention-deficit/hyperactivity disorder symptoms assist in the diagnosis of attention-deficit/hyperactivity disorder in adults? Findings from a large clinical sample.
- Author
-
Breda V, Rovaris DL, Vitola ES, Mota NR, Blaya-Rocha P, Salgado CA, Victor MM, Picon FA, Karam RG, Silva KL, Rohde LA, Bau CH, and Grevet EH
- Subjects
- Adolescent, Adult, Brazil, Child, Comorbidity, Demography, Diagnostic and Statistical Manual of Mental Disorders, Female, Humans, Male, Retrospective Studies, Self Report, Severity of Illness Index, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity drug therapy, Central Nervous System Stimulants therapeutic use, Methylphenidate therapeutic use
- Abstract
Objectives: In accordance with consolidated clinical practice, Diagnostic and Statistical Manual of Mental Disorders, 5th edition suggests a key role of collateral information in the evaluation of retrospective childhood attention-deficit/hyperactivity disorder symptoms in adults despite poor evidence supporting its use. This study aims to assess the incremental value of collateral information on the presence of childhood attention-deficit/hyperactivity disorder symptoms when evaluating adults with attention-deficit/hyperactivity disorder., Methods: Adult patients with attention-deficit/hyperactivity disorder (n = 449) and non-attention-deficit/hyperactivity disorder subjects (n = 143) underwent an extensive clinical assessment based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. For patients, retrospective collateral information regarding childhood attention-deficit/hyperactivity disorder was obtained and used to sort them into two groups: agreement (n = 277) and disagreement (n = 172) between self- and collateral reports. We compared demographic, clinical and response to treatment profiles among groups to test the relevance of collateral information on the specific issue of childhood attention-deficit/hyperactivity disorder symptoms., Results: Both attention-deficit/hyperactivity disorder groups had higher rates of several comorbidities (oppositional defiant, conduct, substance use and bipolar disorders; all p < 0.001) and impairments than controls. Disagreement between self- and collateral reports on childhood attention-deficit/hyperactivity disorder symptoms occurred in 38% of patients. Overall, attention-deficit/hyperactivity disorder disagreement and agreement groups had similar profiles in response to treatment and comorbidity, and the few differences detected in impairment measures were of small magnitude (Eta(2) < 0.05)., Conclusion: Although collateral report has an important role for diagnosing attention-deficit/hyperactivity disorder in children, it has no incremental value in the evaluation of childhood attention-deficit/hyperactivity disorder symptoms in adults with a self-reported history of attention-deficit/hyperactivity disorder assessed in clinical settings., (© The Royal Australian and New Zealand College of Psychiatrists 2015.)
- Published
- 2016
- Full Text
- View/download PDF
45. NOS1 and SNAP25 polymorphisms are associated with Attention-Deficit/Hyperactivity Disorder symptoms in adults but not in children.
- Author
-
Salatino-Oliveira A, Akutagava-Martins GC, Bruxel EM, Genro JP, Polanczyk GV, Zeni C, Kieling C, Karam RG, Rovaris DL, Contini V, Cupertino RB, Mota NR, Grevet EH, Bau CH, Rohde LA, and Hutz MH
- Subjects
- Adolescent, Adult, Child, Female, Genetic Association Studies, Genotype, Humans, Male, Middle Aged, Statistics, Nonparametric, Young Adult, Aging, Attention Deficit Disorder with Hyperactivity genetics, Nitric Oxide Synthase Type I genetics, Polymorphism, Genetic genetics, Synaptosomal-Associated Protein 25 genetics
- Abstract
Several investigations documented that Attention-Deficit/Hyperactivity Disorder (ADHD) is better conceptualized as a dimensional disorder. At the same time, the disorder seems to have different neurobiological underpinnings and phenotypic presentation in children compared to adults. Neurodevelopmental genes could explain, at least partly these differences. The aim of the present study was to examine possible associations between polymorphisms in SNAP25, MAP1B and NOS1 genes and ADHD symptoms in Brazilian samples of children/adolescents and adults with ADHD. The youth sample consisted of 301 patients whereas the adult sample comprises 485 individuals with ADHD. Diagnoses of ADHD and comorbidities were based on the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. The Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV) was applied by psychiatrists blinded to genotype. The total SNAP-IV scores were compared between genotypes. Impulsivity SNAP-IV scores were also compared according to NOS1 genotypes. Adult patients homozygous for the C allele at SNAP25 rs8636 showed significantly higher total SNAP-IV scores (F = 11.215; adjusted P-value = 0.004). Impulsivity SNAP-IV scores were also significantly different according to NOS1 rs478597 polymorphisms in adults with ADHD (F = 6.282; adjusted P-value = 0.026). These associations were not observed in children and adolescents with ADHD. These results suggest that SNAP25 and NOS1 genotypes influence ADHD symptoms only in adults with ADHD. Our study corroborates previous evidences for differences in the genetic contribution to adult ADHD compared with childhood ADHD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
46. NCAM1-TTC12-ANKK1-DRD2 gene cluster and the clinical and genetic heterogeneity of adults with ADHD.
- Author
-
Mota NR, Rovaris DL, Kappel DB, Picon FA, Vitola ES, Salgado CA, Karam RG, Rohde LA, Grevet EH, and Bau CH
- Abstract
Dysfunctions of the dopaminergic system have been implicated on the etiology of Attention Deficit/Hyperactivity Disorder (ADHD). Meta-analyses addressing the association of the dopamine receptor D2 (DRD2) gene and ADHD were inconclusive due to excessive heterogeneity across studies. Both the great phenotypic heterogeneity of ADHD and the complexity of the genomic region where DRD2 is located could contribute to the inconsistent findings. Most previous DRD2 studies focused on the well-known Taq1A (rs1800497) SNP, which is actually placed in a neighbor gene (ANKK1). These two genes, together with NCAM1 and TTC12, form the NTAD gene cluster on Chr11q22-23. In order to address the reasons for the high heterogeneity previously reported on DRD2 effects on ADHD, this study investigates the role of NTAD variants on ADHD susceptibility in adults and on the modulation of comorbidity and personality profiles in these patients. Functional polymorphisms from NTAD were analyzed, both individually and in haplotypes, on a sample of 520 adults with ADHD and 630 non-ADHD controls. No direct association of NTAD variants with ADHD susceptibility itself was observed. However, different NTAD polymorphisms and haplotypes were associated to various phenotypes relevant to the clinical heterogeneity of ADHD, including Major Depressive Disorder, Generalized Anxiety Disorder, and Harm Avoidance and Persistence temperament scores. Therefore, these findings represent a possible explanation for the multiple conflicting findings regarding polymorphisms in this genomic region in psychiatry. The NTAD cluster may comprise a variety of independent molecular influences on various brain and behavior characteristics eventually associated with ADHD comorbidities and personality traits. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
47. Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment.
- Author
-
Rovaris DL, Mota NR, Bertuzzi GP, Aroche AP, Callegari-Jacques SM, Guimarães LS, Pezzi JC, Viola TW, Bau CH, and Grassi-Oliveira R
- Subjects
- Adult, Child, Cross-Sectional Studies, Epistasis, Genetic, Female, Gene-Environment Interaction, Humans, Male, Mental Status Schedule, Young Adult, Child Abuse psychology, Cocaine-Related Disorders genetics, Cocaine-Related Disorders psychology, Cocaine-Related Disorders therapy, Crack Cocaine, Genetic Predisposition to Disease genetics, Inactivation, Metabolic genetics, Polymorphism, Single Nucleotide genetics, Receptors, Steroid genetics
- Abstract
The aim of this study was to analyze hypotheses-driven gene-environment and gene-gene interactions in smoked (crack) cocaine addiction by evaluating childhood neglect and polymorphisms in mineralocorticoid and glucocorticoid receptor genes (NR3C2 and NR3C1, respectively). One hundred thirty-nine crack/cocaine-addicted women who completed 3 weeks of follow-up during early abstinence composed our sample. Childhood adversities were assessed using the Childhood Trauma Questionnaire (CTQ), and withdrawal symptoms were assessed using the Cocaine Selective Severity Assessment (CSSA) scale. Conditional logistic regression with counterfactuals and generalized estimating equation modeling were used to test gene-environment and gene-gene interactions. We found an interaction between the rs5522-Val allele and childhood physical neglect, which altered the risk of crack/cocaine addiction (Odds ratio = 4.0, P = 0.001). Moreover, a NR3C2-NR3C1 interaction (P = 0.002) was found modulating the severity of crack/cocaine withdrawal symptoms. In the post hoc analysis, concomitant carriers of the NR3C2 rs5522-Val and NR3C1 rs6198-G alleles showed lower overall severity scores when compared to other genotype groups (P-values ≤ 0.035). This gene-environment interaction is consistent with epidemiological and human experimental findings demonstrating a strong relationship between early life stress and the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in cocaine addiction. Additionally, this study extended in crack/cocaine addiction the findings previously reported for tobacco smoking involving an interaction between NR3C2 and NR3C1 genes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
48. Persistence and remission of ADHD during adulthood: a 7-year clinical follow-up study.
- Author
-
Karam RG, Breda V, Picon FA, Rovaris DL, Victor MM, Salgado CA, Vitola ES, Silva KL, Guimarães-da-Silva PO, Mota NR, Caye A, Belmonte-de-Abreu P, Rohde LA, Grevet EH, and Bau CH
- Subjects
- Adolescent, Adult, Aged, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity epidemiology, Brazil epidemiology, Comorbidity, Follow-Up Studies, Hospitals, Teaching, Humans, Interview, Psychological, Middle Aged, Phobia, Social complications, Phobia, Social psychology, Regression Analysis, Remission Induction, Treatment Outcome, Young Adult, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit Disorder with Hyperactivity psychology, Central Nervous System Stimulants therapeutic use, Methylphenidate therapeutic use
- Abstract
Background: Course and predictors of persistence of attention deficit hyperactivity disorder (ADHD) in adults are still largely unknown. Neurobiological and clinical differences between child and adult ADHD raise the need for follow-up studies of patients diagnosed during adulthood. This study investigates predictors of ADHD persistence and the possibility of full remission 7 years after baseline assessment., Method: A 7-year follow-up study of adults with ADHD (n = 344, mean age 34.1 years, 49.9% males) was conducted. Variables from different domains (social demographics, co-morbidities, temperament, medication status, ADHD measures) were explored with the aim of finding potential predictors of ADHD persistence., Results: Retention rate was 66% (n = 227). Approximately a third of the sample (n = 70, 30.2%) did not maintain ADHD criteria and 28 (12.4%) presented full remission (<4 symptoms), independently of changes in co-morbidity or cognitive demand profiles. Baseline predictors of diagnostic persistence were higher number of inattention symptoms [odds ratio (OR) 8.05, 95% confidence interval (CI) 2.54-25.45, p < 0.001], number of hyperactivity/impulsivity symptoms (OR 1.18, 95% CI 1.04-1.34, p = 0.01), oppositional defiant disorder (OR 3.12, 95% CI 1.20-8.11, p = 0.02), and social phobia (OR 3.59, 95% CI 1.12-11.47, p = 0.03)., Conclusions: Despite the stage of brain maturation in adults suggests stability, approximately one third of the sample did not keep full DSM-IV diagnosis at follow-up, regardless if at early, middle or older adulthood. Although full remission is less common than in childhood, it should be considered as a possible outcome among adults.
- Published
- 2015
- Full Text
- View/download PDF
49. Cadherin-13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder.
- Author
-
Salatino-Oliveira A, Genro JP, Polanczyk G, Zeni C, Schmitz M, Kieling C, Anselmi L, Menezes AM, Barros FC, Polina ER, Mota NR, Grevet EH, Bau CH, Rohde LA, and Hutz MH
- Subjects
- Adolescent, Adult, Case-Control Studies, Child, Cohort Studies, Female, Follow-Up Studies, Genetic Association Studies, Humans, Life Style, Male, Phenotype, Prognosis, Psychiatric Status Rating Scales, Severity of Illness Index, alpha Catenin genetics, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity psychology, Cadherins genetics, Hyperkinesis genetics, Hyperkinesis psychology, Impulsive Behavior, Polymorphism, Single Nucleotide genetics
- Abstract
Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P ≥ 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P-value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P-value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
50. Lack of association between the GRM7 gene and attention deficit hyperactivity disorder.
- Author
-
Akutagava-Martins GC, Salatino-Oliveira A, Bruxel EM, Genro JP, Mota NR, Polanczyk GV, Zeni CP, Grevet EH, Bau CH, Rohde LA, and Hutz MH
- Subjects
- Adolescent, Humans, Attention Deficit Disorder with Hyperactivity genetics, Receptors, Metabotropic Glutamate genetics
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.