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1. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Author

Demontis, D., Walters, G.B., Athanasiadis, G., Walters, R., Therrien, K., Nielsen, T.T., Farajzadeh, L., Voloudakis, G., Bendl, J., Zeng, B., Zhang, W, Grove, J, Als, T.D., Duan, J., Satterstrom, F.K., Bybjerg-Grauholm, J., Bækved-Hansen, M., Gudmundsson, O.O., Magnusson, S.H., Baldursson, G., Davidsdottir, K., Haraldsdottir, G.S., Agerbo, E., Hoffman, G.E., Dalsgaard, S., Martin, J., Ribasés, M., Boomsma, D.I., Soler Artigas, M., Roth Mota, N., Howrigan, D., Medland, S.E., Zayats, T., Rajagopal, V.M., Nordentoft, M., Mors, O., Hougaard, D.M., Mortensen, P.B., Daly, M.J., Faraone, S.V, Stefansson, H., Roussos, P., Franke, B., Werge, T., Neale, B.M., Stefansson, K., Børglum, A.D., Demontis, D., Walters, G.B., Athanasiadis, G., Walters, R., Therrien, K., Nielsen, T.T., Farajzadeh, L., Voloudakis, G., Bendl, J., Zeng, B., Zhang, W, Grove, J, Als, T.D., Duan, J., Satterstrom, F.K., Bybjerg-Grauholm, J., Bækved-Hansen, M., Gudmundsson, O.O., Magnusson, S.H., Baldursson, G., Davidsdottir, K., Haraldsdottir, G.S., Agerbo, E., Hoffman, G.E., Dalsgaard, S., Martin, J., Ribasés, M., Boomsma, D.I., Soler Artigas, M., Roth Mota, N., Howrigan, D., Medland, S.E., Zayats, T., Rajagopal, V.M., Nordentoft, M., Mors, O., Hougaard, D.M., Mortensen, P.B., Daly, M.J., Faraone, S.V, Stefansson, H., Roussos, P., Franke, B., Werge, T., Neale, B.M., Stefansson, K., and Børglum, A.D.

Abstract

01 februari 2023, Item does not contain fulltext, Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Published
2023

5. Understanding the heterogeneity and comorbidity of ASD and ADHD. A study of emotion recognition from genes to behaviour

Author

Franke, B., Buitelaar, J.K., Lambregts-Rommelse, N.N.J., Roth Mota, N., Waddington, F.L.V., Franke, B., Buitelaar, J.K., Lambregts-Rommelse, N.N.J., Roth Mota, N., and Waddington, F.L.V.

Abstract

Radboud University, 19 april 2022, Promotores : Franke, B., Buitelaar, J.K., Lambregts-Rommelse, N.N.J. Co-promotor : Roth Mota, N., Contains fulltext : 247713.pdf (Publisher’s version ) (Open Access)

Published
2022

6. The link between cognition and somatic conditions related to insulin resistance in the UK Biobank study cohort: a systematic review

Author

Fanelli, G., Roth Mota, N., Salas-Salvadó, J., Bulló, M., Fernandez-Aranda, F., Camacho-Barcia, L., Testa, G., Jiménez-Murcia, S., Bertaina-Anglade, V., Franke, B., Poelmans, G.J.V., Gils, V. van, Jansen, W.J., Vos, S.J.B., Wimberley, T., Dalsgaard, S., Barta, C., Serretti, A., Fabbri, C., Bralten, J.B., Fanelli, G., Roth Mota, N., Salas-Salvadó, J., Bulló, M., Fernandez-Aranda, F., Camacho-Barcia, L., Testa, G., Jiménez-Murcia, S., Bertaina-Anglade, V., Franke, B., Poelmans, G.J.V., Gils, V. van, Jansen, W.J., Vos, S.J.B., Wimberley, T., Dalsgaard, S., Barta, C., Serretti, A., Fabbri, C., and Bralten, J.B.

Abstract

Item does not contain fulltext, 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

7. Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

Author

Tielbeek, J.J., Uffelmann, E., Williams, B.S., Colodro-Conde, L., Gagnon, É., Mallard, T.T., Levitt, B.E., Jansen, P.R., Johansson, A, Sallis, H.M., Pistis, G., Saunders, G.R.B., Allegrini, A.G., Rimfeld, K., Konte, B., Klein, M., Hartmann, A.M., Salvatore, J.E., Nolte, I.M., Demontis, D., Malmberg, A.L.K., Burt, S.A., Savage, J.E., Sugden, K., Poulton, R., Harris, K.M., Vrieze, S., McGue, M., Iacono, W.G., Roth Mota, N., Mill, J., Viana, J.F., Mitchell, B.L., Morosoli, J.J., Andlauer, T.F.M., Ouellet-Morin, I., Tremblay, R.E., Côté, S.M., Gouin, J.-P., Brendgen, M.R., Dionne, G., Vitaro, F., Lupton, M.K., Martin, N.G., Porjesz, B., Hesselbrock, V., Foroud, T., Agrawal, A., Edenberg, H.J., Liu, Y, Plawecki, M.H., Kuperman, S., Kramer, J.R., Meyers, J.M., Kamarajan, C., Pandey, A., Bierut, L., Rice, J., Bucholz, K.K., Schuckit, M.A., Tischfield, J., Hart, R., Almasy, L., Goate, A., Slesinger, P., Scott, D., Castelao, E., Räikkönen, K., Eriksson, J.G., Lahti, J., Hartman, C.A, Oldehinkel, A.J., Snieder, H., Liu, H., Preisig, M., Whipp, A., Vuoksimaa, E., Lu, Y., Jern, P., Rujescu, D., Giegling, I., Palviainen, T., Kaprio, J., Harden, K.P., Munafò, M.R., Morneau-Vaillancourt, G., Plomin, R., Viding, E., Boutwell, B.B., Aliev, F., Dick, D.M., Popma, A., Faraone, S.V, Børglum, A.D., Medland, S.E., Franke, B., Boivin, M., Pingault, J.-B., Glennon, J.C., Barnes, J.C., Fisher, S.E., Tielbeek, J.J., Uffelmann, E., Williams, B.S., Colodro-Conde, L., Gagnon, É., Mallard, T.T., Levitt, B.E., Jansen, P.R., Johansson, A, Sallis, H.M., Pistis, G., Saunders, G.R.B., Allegrini, A.G., Rimfeld, K., Konte, B., Klein, M., Hartmann, A.M., Salvatore, J.E., Nolte, I.M., Demontis, D., Malmberg, A.L.K., Burt, S.A., Savage, J.E., Sugden, K., Poulton, R., Harris, K.M., Vrieze, S., McGue, M., Iacono, W.G., Roth Mota, N., Mill, J., Viana, J.F., Mitchell, B.L., Morosoli, J.J., Andlauer, T.F.M., Ouellet-Morin, I., Tremblay, R.E., Côté, S.M., Gouin, J.-P., Brendgen, M.R., Dionne, G., Vitaro, F., Lupton, M.K., Martin, N.G., Porjesz, B., Hesselbrock, V., Foroud, T., Agrawal, A., Edenberg, H.J., Liu, Y, Plawecki, M.H., Kuperman, S., Kramer, J.R., Meyers, J.M., Kamarajan, C., Pandey, A., Bierut, L., Rice, J., Bucholz, K.K., Schuckit, M.A., Tischfield, J., Hart, R., Almasy, L., Goate, A., Slesinger, P., Scott, D., Castelao, E., Räikkönen, K., Eriksson, J.G., Lahti, J., Hartman, C.A, Oldehinkel, A.J., Snieder, H., Liu, H., Preisig, M., Whipp, A., Vuoksimaa, E., Lu, Y., Jern, P., Rujescu, D., Giegling, I., Palviainen, T., Kaprio, J., Harden, K.P., Munafò, M.R., Morneau-Vaillancourt, G., Plomin, R., Viding, E., Boutwell, B.B., Aliev, F., Dick, D.M., Popma, A., Faraone, S.V, Børglum, A.D., Medland, S.E., Franke, B., Boivin, M., Pingault, J.-B., Glennon, J.C., Barnes, J.C., and Fisher, S.E.

Abstract

Item does not contain fulltext

Published
2022

9. Mapping relationships between ADHD genetic liability, stressful life events, and ADHD symptoms in healthy adults

Author

Li, T., Franke, B., Arias Vasquez, A., Roth Mota, N., Li, T., Franke, B., Arias Vasquez, A., and Roth Mota, N.

Abstract

Item does not contain fulltext, 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 (R(2) (best-fit) = .37%), lifetime SLEs (R(2) (best-fit) = .56%), and CT (R(2) (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 (P(M) ) =19.5%), with strongest effects contributed by CT (β = 34.4, BCa95%CI [0.4, 76.5], p = .040, P(M) = 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, P(M) = 18.8%). Our study observed a complex relationship of genetic and environmental risk factors contributing to ADHD symptoms in the healthy adult population.

Published
2021

10. A polygenic risk score analysis of ASD and ADHD across emotion recognition subtypes

Author

Waddington, F.L.V., Franke, B., Hartman, C., Buitelaar, J.K., Rommelse, N.N.J., Roth Mota, N., Waddington, F.L.V., Franke, B., Hartman, C., Buitelaar, J.K., Rommelse, N.N.J., and Roth Mota, N.

Abstract

Contains fulltext : 243902.pdf (Publisher’s version ) (Open Access), 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.

Published
2021

11. Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes

Author

Li, T., Rooij, D. van, Roth Mota, N., Buitelaar, J.K., Hoogman, M., Arias Vasquez, A., Franke, B., Li, T., Rooij, D. van, Roth Mota, N., Buitelaar, J.K., Hoogman, M., Arias Vasquez, A., and Franke, B.

Abstract

Contains fulltext : 237820.pdf (Publisher’s version ) (Open Access), BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD's etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes. METHODS: Using the large ENIGMA-ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks. RESULTS: Exploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case-control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men. CONCLUSIONS: Our results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups.

Published
2021

12. Genetic underpinnings of sociability in the general population

Author

Bralten, J.B., Roth Mota, N., Klemann, C.J.H.M., Witte, Ward De, Laing, E., Collier, D.A., Kluiver, H. de, Bauduin, S., Arango, C., Ayuso-Mateos, J.L., Fabbri, C., Kas, M.J., Wee, N. van der, Penninx, B., Serretti, A., Franke, B., Poelmans, G.J.V., Bralten, J.B., Roth Mota, N., Klemann, C.J.H.M., Witte, Ward De, Laing, E., Collier, D.A., Kluiver, H. de, Bauduin, S., Arango, C., Ayuso-Mateos, J.L., Fabbri, C., Kas, M.J., Wee, N. van der, Penninx, B., Serretti, A., Franke, B., and Poelmans, G.J.V.

Abstract

Item does not contain fulltext, 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.

Published
2021

14. Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes

Author

Li, T, van Rooij, D, Roth Mota, N, Buitelaar, JK, Hoogman, M, Arias Vasquez, A, Franke, B, Ambrosino, S, Banaschewski, T, Bandeira, CE, Bau, CHD, Baumeister, S, Baur-Streubel, R, Bellgrove, MA, Biederman, J, Bralten, J, Bramati, IE, Brandeis, D, Berm, S, Busatto, GF, Calvo, A, Castellanos, FX, Cercignani, M, Chantiluke, KC, Christakou, A, Coghill, D, Conzelmann, A, Cubillo, AI, Cupertino, RB, de Zeeuw, P, Durston, S, Earl, EA, Epstein, JN, Ethofer, T, Fallgatter, AJ, Fair, DA, Faraone, SV, Frodl, T, Gabel, MC, Gogberashvili, T, Grevet, EH, Haavik, J, Harrison, NA, Hartman, CA, Heslenfeld, DJ, Hoekstra, PJ, Høvik, MF, Jahanshad, N, Kardatzki, B, Karkashadze, G, Kelly, C, Kohls, G, Konrad, K, Kuntsi, J, Lazaro, L, Lera-Miguel, S, Lesch, KP, Louza, MR, Lundervold, AJ, Malpas, CB, Mattos, P, McCarthy, H, Nicolau, R, Nigg, JT, O'Gorman Tuura, RL, Oosterlaan, J, Oranje, B, Paloyelis, Y, Pauli, P, Picon, FA, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Rosa, PGP, Rubia, K, Schrantee, A, Schweren, LJS, Seitz, J, Shaw, P, Silk, Tim, Skokauskas, N, Carlos Soliva Vila, J, Soloveva, A, Stevens, MC, Sudre, G, Tamm, L, Thompson, PM, Tovar-Moll, F, van Erp, TGM, Vance, A, Vilarroya, O, Vives-Gilabert, Y, von Polier, GG, Walitza, S, Yoncheva, YN, Zanetti, MV, Ziegler, GC, Anikin, A, Asherson, P, Li, T, van Rooij, D, Roth Mota, N, Buitelaar, JK, Hoogman, M, Arias Vasquez, A, Franke, B, Ambrosino, S, Banaschewski, T, Bandeira, CE, Bau, CHD, Baumeister, S, Baur-Streubel, R, Bellgrove, MA, Biederman, J, Bralten, J, Bramati, IE, Brandeis, D, Berm, S, Busatto, GF, Calvo, A, Castellanos, FX, Cercignani, M, Chantiluke, KC, Christakou, A, Coghill, D, Conzelmann, A, Cubillo, AI, Cupertino, RB, de Zeeuw, P, Durston, S, Earl, EA, Epstein, JN, Ethofer, T, Fallgatter, AJ, Fair, DA, Faraone, SV, Frodl, T, Gabel, MC, Gogberashvili, T, Grevet, EH, Haavik, J, Harrison, NA, Hartman, CA, Heslenfeld, DJ, Hoekstra, PJ, Høvik, MF, Jahanshad, N, Kardatzki, B, Karkashadze, G, Kelly, C, Kohls, G, Konrad, K, Kuntsi, J, Lazaro, L, Lera-Miguel, S, Lesch, KP, Louza, MR, Lundervold, AJ, Malpas, CB, Mattos, P, McCarthy, H, Nicolau, R, Nigg, JT, O'Gorman Tuura, RL, Oosterlaan, J, Oranje, B, Paloyelis, Y, Pauli, P, Picon, FA, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Rosa, PGP, Rubia, K, Schrantee, A, Schweren, LJS, Seitz, J, Shaw, P, Silk, Tim, Skokauskas, N, Carlos Soliva Vila, J, Soloveva, A, Stevens, MC, Sudre, G, Tamm, L, Thompson, PM, Tovar-Moll, F, van Erp, TGM, Vance, A, Vilarroya, O, Vives-Gilabert, Y, von Polier, GG, Walitza, S, Yoncheva, YN, Zanetti, MV, Ziegler, GC, Anikin, A, and Asherson, P

Published
2021

16. Contribution of Intellectual Disability-Related Genes to ADHD Risk and to Locomotor Activity in Drosophila

Author

Klein, M., Singgih, E.L., Rens, A.B. van, Demontis, Ditte, Borglum, Anders D., Roth Mota, N., Castells Nobau, A., Kiemeney, L.A., Brunner, H.G., Arias Vasquez, A., Schenck, A., Voet, M. van der, Franke, B., Klein, M., Singgih, E.L., Rens, A.B. van, Demontis, Ditte, Borglum, Anders D., Roth Mota, N., Castells Nobau, A., Kiemeney, L.A., Brunner, H.G., Arias Vasquez, A., Schenck, A., Voet, M. van der, and Franke, B.

Abstract

Contains fulltext : 219830.pdf (Publisher’s version ) (Closed access)

Published
2020

17. Genetic Markers of ADHD-Related Variations in Intracranial Volume

Author

Klein, M., Walters, R.K., Demontis, D., Stein, J.L., Hibar, D.P., Adams, H.H.H., Bralten, J.B., Roth Mota, N., Schachar, R., Sonuga-Barke, E., Mattheisen, M., Neale, B.M., Thompson, P.M., Medland, S.E., Borglum, A.D., Faraone, S.V, Arias-Vasquez, A., Franke, B., Klein, M., Walters, R.K., Demontis, D., Stein, J.L., Hibar, D.P., Adams, H.H.H., Bralten, J.B., Roth Mota, N., Schachar, R., Sonuga-Barke, E., Mattheisen, M., Neale, B.M., Thompson, P.M., Medland, S.E., Borglum, A.D., Faraone, S.V, Arias-Vasquez, A., and Franke, B.

Abstract

Contains fulltext : 202907.pdf (publisher's version ) (Closed access), OBJECTIVE:: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder. METHODS:: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level. RESULTS:: Analyses revealed a significant negative genetic correlation between ADHD and ICV (rg=-0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes. CONCLUSIONS:: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.

Published
2019

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

Author

Pagerols, M., Richarte, Vanesa, Sanchez-Mora, Cristina, Rovira, P., Soler Artigas, M., Garcia-Martinez, Iris, Roth Mota, N., Antoni Ramos-Quiroga, Josep, Ribases, Marta, Pagerols, M., Richarte, Vanesa, Sanchez-Mora, Cristina, Rovira, P., Soler Artigas, M., Garcia-Martinez, Iris, Roth Mota, N., Antoni Ramos-Quiroga, Josep, and Ribases, Marta

Abstract

Contains fulltext : 198316.pdf (publisher's version ) (Open Access)

Published
2018

19. Exploring the genetic architecture of brain structure and ADHD using polygenic neuroimaging-derived scores.

Author

van der Es T, Soheili-Nezhad S, Roth Mota N, Franke B, Buitelaar J, and Sprooten E

Abstract

Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of neuropsychiatric disorders and highlighted their complexity. Careful consideration of the polygenicity and complex genetic architecture could aid in the understanding of the underlying brain mechanisms. We introduce an innovative approach to polygenic scoring, utilizing imaging-derived phenotypes (IDPs) to predict a clinical phenotype. We leveraged IDP GWAS data from the UK Biobank, to create polygenic imaging-derived scores (PIDSs). As a proof-of-concept, we assessed genetic variations in brain structure between individuals with ADHD and unaffected controls across three NeuroIMAGE waves (n = 954). Out of the 94 PIDS, 72 exhibited significant associations with their corresponding IDPs in an independent sample. Notably, several global measures, including cerebellum white matter, cerebellum cortex, and cerebral white matter, displayed substantial variance explained for their respective IDPs, ranging from 3% to 5.7%. Conversely, the associations between each IDP and the clinical ADHD phenotype were relatively weak. These findings highlight the growing power of GWAS in structural neuroimaging traits, enabling the construction of polygenic scores that accurately reflect the underlying polygenic architecture. However, to establish robust connections between PIDS and behavioral or clinical traits such as ADHD, larger samples are needed. Our novel approach to polygenic risk scoring offers a valuable tool for researchers in the field of psychiatric genetics., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Published
2024
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20. Shared genetics linking sociability with the brain's default mode network.

Author

Fanelli G, Robinson J, Fabbri C, Bralten J, Roth Mota N, Arenella M, Sprooten E, Franke B, Kas M, Andlauer TF, and Serretti A

Abstract

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. In the present study, we examined the genetic relationship between sociability and DMN-related resting-state functional magnetic resonance imaging (rs-fMRI) traits. To this end, we used genome-wide association summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N=34,691-342,461). First, we examined global and local genetic correlations between sociability and the rs-fMRI traits. Second, to assess putatively causal relationships between the traits, we conducted bi-directional Mendelian randomisation (MR) analyses. Finally, we prioritised genes influencing both sociability and rs-fMRI traits by combining three methods: gene-expression eQTL MR analyses, the CELLECT framework using single-nucleus RNA-seq data, and network propagation in the context of a protein-protein interaction network. Significant local genetic correlations were found between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the frontal/cingulate and angular/temporal cortices. Sociability affected 12 rs-fMRI traits when allowing for weakly correlated genetic instruments. Combing all three methods for gene prioritisation, we defined 17 highly prioritised genes, with DRD2 and LINGO1 showing the most robust evidence across all analyses. By integrating genetic and transcriptomics data, our gene prioritisation strategy may serve as a blueprint for future studies. The prioritised genes could be explored as potential biomarkers for social dysfunction in the context of neuropsychiatric disorders and as drug target genes., Competing Interests: AS is or has been a consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer Ingelheim, 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. All other authors report no biomedical financial interests or potential conflicts of interest.

Published
2024
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21. Author Correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Author

Demontis D, Walters GB, Athanasiadis G, Walters R, Therrien K, Nielsen TT, Farajzadeh L, Voloudakis G, Bendl J, Zeng B, Zhang W, Grove J, Als TD, Duan J, Satterstrom FK, Bybjerg-Grauholm J, Bækved-Hansen M, Gudmundsson OO, Magnusson SH, Baldursson G, Davidsdottir K, Haraldsdottir GS, Agerbo E, Hoffman GE, Dalsgaard S, Martin J, Ribasés M, Boomsma DI, Soler Artigas M, Roth Mota N, Howrigan D, Medland SE, Zayats T, Rajagopal VM, Nordentoft M, Mors O, Hougaard DM, Mortensen PB, Daly MJ, Faraone SV, Stefansson H, Roussos P, Franke B, Werge T, Neale BM, Stefansson K, and Børglum AD

Published
2023
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22. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Author

Demontis D, Walters GB, Athanasiadis G, Walters R, Therrien K, Nielsen TT, Farajzadeh L, Voloudakis G, Bendl J, Zeng B, Zhang W, Grove J, Als TD, Duan J, Satterstrom FK, Bybjerg-Grauholm J, Bækved-Hansen M, Gudmundsson OO, Magnusson SH, Baldursson G, Davidsdottir K, Haraldsdottir GS, Agerbo E, Hoffman GE, Dalsgaard S, Martin J, Ribasés M, Boomsma DI, Soler Artigas M, Roth Mota N, Howrigan D, Medland SE, Zayats T, Rajagopal VM, Nordentoft M, Mors O, Hougaard DM, Mortensen PB, Daly MJ, Faraone SV, Stefansson H, Roussos P, Franke B, Werge T, Neale BM, Stefansson K, and Børglum AD

Subjects
Humans, Brain, Cognition, Genetic Predisposition to Disease, Genome-Wide Association Study, Attention Deficit Disorder with Hyperactivity genetics
Abstract

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2023
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23. Dissecting the heterogeneous subcortical brain volume of autism spectrum disorder using community detection.

Author

Li T, Hoogman M, Roth Mota N, Buitelaar JK, Vasquez AA, Franke B, and van Rooij D

Subjects
Adolescent, Adult, Brain diagnostic imaging, Case-Control Studies, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Autism Spectrum Disorder diagnostic imaging
Abstract

Structural brain alterations in autism spectrum disorder (ASD) are heterogeneous, with limited effect sizes overall. In this study, we aimed to identify subgroups in ASD, based on neuroanatomical profiles; we hypothesized that the effect sizes for case/control differences would be increased in the newly defined subgroups. Analyzing a large data set from the ENIGMA-ASD working group (n = 2661), we applied exploratory factor analysis (EFA) to seven subcortical volumes of individuals with and without ASD to uncover the underlying organization of subcortical structures. Based on earlier findings and data availability, we focused on three age groups: boys (<=14 years), male adolescents (15-22 years), and adult men (> = 22 years). The resulting factor scores were used in a community detection (CD) analysis to cluster participants into subgroups. Three factors were found in each subsample; the factor structure in adult men differed from that in boys and male adolescents. From these factors, CD uncovered four distinct communities in boys and three communities in adolescents and adult men, irrespective of ASD diagnosis. The effect sizes for case/control comparisons were more pronounced than in the combined sample, for some communities. A significant group difference in ADOS scores between communities was observed in boys and male adolescents with ASD. We succeeded in stratifying participants into more homogeneous subgroups based on subcortical brain volumes. This stratification enhanced our ability to observe case/control differences in subcortical brain volumes in ASD, and may help to explain the heterogeneity of previous findings in ASD. LAY SUMMARY: Structural brain alterations in ASD are heterogeneous, with overall limited effect sizes. Here we aimed to identify subgroups in ASD based on neuroimaging measures. We tested whether the effect sizes for case/control differences would be increased in the newly defined subgroups. Based on neuroanatomical profiles, we succeeded in stratifying our participants into more homogeneous subgroups. The effect sizes of case/control differences were more pronounced in some subgroups than those in the whole sample., (© 2021 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Published
2022
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24. Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes.

Author

Li T, van Rooij D, Roth Mota N, Buitelaar JK, Hoogman M, Arias Vasquez A, and Franke B

Subjects
Adult, Brain diagnostic imaging, Case-Control Studies, Female, Humans, Magnetic Resonance Imaging, Male, Thalamus diagnostic imaging, Attention Deficit Disorder with Hyperactivity diagnostic imaging, Attention Deficit Disorder with Hyperactivity epidemiology
Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD's etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes., Methods: Using the large ENIGMA-ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks., Results: Exploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case-control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men., Conclusions: Our results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups., (© 2021 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
2021
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25. Genetic Markers of ADHD-Related Variations in Intracranial Volume.

Author

Klein M, Walters RK, Demontis D, Stein JL, Hibar DP, Adams HH, Bralten J, Roth Mota N, Schachar R, Sonuga-Barke E, Mattheisen M, Neale BM, Thompson PM, Medland SE, Børglum AD, Faraone SV, Arias-Vasquez A, and Franke B

Subjects
Amygdala pathology, Attention Deficit Disorder with Hyperactivity etiology, Attention Deficit Disorder with Hyperactivity pathology, Case-Control Studies, Caudate Nucleus pathology, Genetic Markers genetics, Genome-Wide Association Study, Hippocampus pathology, Humans, Linkage Disequilibrium genetics, Nucleus Accumbens pathology, Organ Size genetics, Polymorphism, Single Nucleotide genetics, Putamen pathology, Quantitative Trait Loci genetics, Attention Deficit Disorder with Hyperactivity genetics, Brain pathology
Abstract

Objective: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder., Methods: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level., Results: Analyses revealed a significant negative genetic correlation between ADHD and ICV (r g =-0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes., Conclusions: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.

Published
2019
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