Converging evidence does not support GIT1 as an ADHD risk gene

M. Klein; M. van der Voet; B. Harich; K.J.E. van Hulzen; A.M.H. Onnink; M. Hoogman; T. Guadalupe; M. Zwiers; J.M. Groothuismink; A. Verberkt; B. Nijhof; A. Castells-Nobau; S.V. Faraone; J.K. Buitelaar; A. Schenck; A. Arias-Vasquez; B. Franke; R.J.L. Anney; A.A. Vasquez; P. Asherson; T. Banaschewski; M. Bayés; J. Biederman; J.K. Buitelaar; M. Casas; A. Charach; B. Cormand; J. Crosbie; M.J. Daly; A.E. Doyle; R.P. Ebstein; J. Elia; S.V. Faraone; B. Franke; C. Freitag; M. Gill; H. Hakonarson; J. Hebebrand; A. Hinney; P. Holmans; L. Kent; J. Kuntsi; N. Lambregts-Rommelse; K. Langley; K.-P. Lesch; S.K. Loo; J.J. McGough; S.E. Medland; J. Meyer; E. Mick; A. Miranda; F. Mulas; B.M. Neale; S.F. Nelson; M.C. O'Donovan; R.D. Oades; M.J. Owen; H. Palmason; Q. Qian; J.A. Ramos-Quiroga; A. Reif; T.J. Renner; M. Ribasés; S. Ripke; H. Roeyers; M. Romanos; J. Romanos; A. Rothenberger; C. Sánchez-Mora; R. Schachar; A. Scherag; S. Scherag; J. Sergeant; S.L. Smalley; J.S. Edmund; [No Value] Sonuga-Barke; H.-C. Steinhausen; A. Thapar; A. Todorov; I. Waldman; S. Walitza; Y. Wang; A. Warnke; N. Williams; L. Yang

doi:10.1002/ajmg.b.32327

Converging evidence does not support GIT1 as an ADHD risk gene

M. Klein, M. van der Voet, B. Harich, K.J.E. van Hulzen, A.M.H. Onnink, M. Hoogman, T. Guadalupe, M. Zwiers, J.M. Groothuismink, A. Verberkt, B. Nijhof, A. Castells-Nobau, S.V. Faraone, J.K. Buitelaar, A. Schenck, A. Arias-Vasquez, B. Franke, R.J.L. Anney, A.A. Vasquez, P. AshersonT. Banaschewski, M. Bayés, J. Biederman, J.K. Buitelaar, M. Casas, A. Charach, B. Cormand, J. Crosbie, M.J. Daly, A.E. Doyle, R.P. Ebstein, J. Elia, S.V. Faraone, B. Franke, C. Freitag, M. Gill, H. Hakonarson, J. Hebebrand, A. Hinney, P. Holmans, L. Kent, J. Kuntsi, N. Lambregts-Rommelse, K. Langley, K.-P. Lesch, S.K. Loo, J.J. McGough, S.E. Medland, J. Meyer, E. Mick, A. Miranda, F. Mulas, B.M. Neale, S.F. Nelson, M.C. O'Donovan, R.D. Oades, M.J. Owen, H. Palmason, Q. Qian, J.A. Ramos-Quiroga, A. Reif, T.J. Renner, M. Ribasés, S. Ripke, H. Roeyers, M. Romanos, J. Romanos, A. Rothenberger, C. Sánchez-Mora, R. Schachar, A. Scherag, S. Scherag, J. Sergeant, S.L. Smalley, J.S. Edmund, [No Value] Sonuga-Barke, H.-C. Steinhausen, A. Thapar, A. Todorov, I. Waldman, S. Walitza, Y. Wang, A. Warnke, N. Williams, L. Yang

Research output: Contribution to journal › Article › peer-review

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N=19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N=225), and (3) the Brain Imaging Genetics cohort (BIG, N=1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences.

Original language	English
Pages (from-to)	492-507
Number of pages	16
Journal	American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Volume	168
Issue number	6
Early online date	10 Jun 2015
DOIs	https://doi.org/10.1002/ajmg.b.32327
Publication status	Published - Sept 2015

Keywords

GIT1
ADHD
Brain imaging genetics
eQTL
Drosophilia melanogaster

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Klein, M., van der Voet, M., Harich, B., van Hulzen, K. J. E., Onnink, A. M. H., Hoogman, M., Guadalupe, T., Zwiers, M., Groothuismink, J. M., Verberkt, A., Nijhof, B., Castells-Nobau, A., Faraone, S. V., Buitelaar, J. K., Schenck, A., Arias-Vasquez, A., Franke, B., Anney, R. J. L., Vasquez, A. A., ... Yang, L. (2015). Converging evidence does not support GIT1 as an ADHD risk gene. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics , 168(6), 492-507. https://doi.org/10.1002/ajmg.b.32327

@article{0531fbe74d9a43b08ffc88ae067d563d,

title = "Converging evidence does not support GIT1 as an ADHD risk gene",

abstract = "Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N=19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N=225), and (3) the Brain Imaging Genetics cohort (BIG, N=1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences.",

keywords = "GIT1, ADHD, Brain imaging genetics, eQTL, Drosophilia melanogaster",

author = "M. Klein and {van der Voet}, M. and B. Harich and {van Hulzen}, K.J.E. and A.M.H. Onnink and M. Hoogman and T. Guadalupe and M. Zwiers and J.M. Groothuismink and A. Verberkt and B. Nijhof and A. Castells-Nobau and S.V. Faraone and J.K. Buitelaar and A. Schenck and A. Arias-Vasquez and B. Franke and R.J.L. Anney and A.A. Vasquez and P. Asherson and T. Banaschewski and M. Bay{\'e}s and J. Biederman and J.K. Buitelaar and M. Casas and A. Charach and B. Cormand and J. Crosbie and M.J. Daly and A.E. Doyle and R.P. Ebstein and J. Elia and S.V. Faraone and B. Franke and C. Freitag and M. Gill and H. Hakonarson and J. Hebebrand and A. Hinney and P. Holmans and L. Kent and J. Kuntsi and N. Lambregts-Rommelse and K. Langley and K.-P. Lesch and S.K. Loo and J.J. McGough and S.E. Medland and J. Meyer and E. Mick and A. Miranda and F. Mulas and B.M. Neale and S.F. Nelson and M.C. O'Donovan and R.D. Oades and M.J. Owen and H. Palmason and Q. Qian and J.A. Ramos-Quiroga and A. Reif and T.J. Renner and M. Ribas{\'e}s and S. Ripke and H. Roeyers and M. Romanos and J. Romanos and A. Rothenberger and C. S{\'a}nchez-Mora and R. Schachar and A. Scherag and S. Scherag and J. Sergeant and S.L. Smalley and J.S. Edmund and Sonuga-Barke, {[No Value]} and H.-C. Steinhausen and A. Thapar and A. Todorov and I. Waldman and S. Walitza and Y. Wang and A. Warnke and N. Williams and L. Yang",

year = "2015",

month = sep,

doi = "10.1002/ajmg.b.32327",

language = "English",

volume = "168",

pages = "492--507",

journal = "American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics ",

issn = "1552-4841",

publisher = "Wiley-Liss",

number = "6",

}

Klein, M, van der Voet, M, Harich, B, van Hulzen, KJE, Onnink, AMH, Hoogman, M, Guadalupe, T, Zwiers, M, Groothuismink, JM, Verberkt, A, Nijhof, B, Castells-Nobau, A, Faraone, SV, Buitelaar, JK, Schenck, A, Arias-Vasquez, A, Franke, B, Anney, RJL, Vasquez, AA, Asherson, P, Banaschewski, T, Bayés, M, Biederman, J, Buitelaar, JK, Casas, M, Charach, A, Cormand, B, Crosbie, J, Daly, MJ, Doyle, AE, Ebstein, RP, Elia, J, Faraone, SV, Franke, B, Freitag, C, Gill, M, Hakonarson, H, Hebebrand, J, Hinney, A, Holmans, P, Kent, L, Kuntsi, J, Lambregts-Rommelse, N, Langley, K, Lesch, K-P, Loo, SK, McGough, JJ, Medland, SE, Meyer, J, Mick, E, Miranda, A, Mulas, F, Neale, BM, Nelson, SF, O'Donovan, MC, Oades, RD, Owen, MJ, Palmason, H, Qian, Q, Ramos-Quiroga, JA, Reif, A, Renner, TJ, Ribasés, M, Ripke, S, Roeyers, H, Romanos, M, Romanos, J, Rothenberger, A, Sánchez-Mora, C, Schachar, R, Scherag, A, Scherag, S, Sergeant, J, Smalley, SL, Edmund, JS, Sonuga-Barke, NV, Steinhausen, H-C, Thapar, A, Todorov, A, Waldman, I, Walitza, S, Wang, Y, Warnke, A, Williams, N & Yang, L 2015, 'Converging evidence does not support GIT1 as an ADHD risk gene', American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics , vol. 168, no. 6, pp. 492-507. https://doi.org/10.1002/ajmg.b.32327

TY - JOUR

T1 - Converging evidence does not support GIT1 as an ADHD risk gene

AU - Klein, M.

AU - van der Voet, M.

AU - Harich, B.

AU - van Hulzen, K.J.E.

AU - Onnink, A.M.H.

AU - Hoogman, M.

AU - Guadalupe, T.

AU - Zwiers, M.

AU - Groothuismink, J.M.

AU - Verberkt, A.

AU - Nijhof, B.

AU - Castells-Nobau, A.

AU - Faraone, S.V.

AU - Buitelaar, J.K.

AU - Schenck, A.

AU - Arias-Vasquez, A.

AU - Franke, B.

AU - Anney, R.J.L.

AU - Vasquez, A.A.

AU - Asherson, P.

AU - Banaschewski, T.

AU - Bayés, M.

AU - Biederman, J.

AU - Buitelaar, J.K.

AU - Casas, M.

AU - Charach, A.

AU - Cormand, B.

AU - Crosbie, J.

AU - Daly, M.J.

AU - Doyle, A.E.

AU - Ebstein, R.P.

AU - Elia, J.

AU - Faraone, S.V.

AU - Franke, B.

AU - Freitag, C.

AU - Gill, M.

AU - Hakonarson, H.

AU - Hebebrand, J.

AU - Hinney, A.

AU - Holmans, P.

AU - Kent, L.

AU - Kuntsi, J.

AU - Lambregts-Rommelse, N.

AU - Langley, K.

AU - Lesch, K.-P.

AU - Loo, S.K.

AU - McGough, J.J.

AU - Medland, S.E.

AU - Meyer, J.

AU - Mick, E.

AU - Miranda, A.

AU - Mulas, F.

AU - Neale, B.M.

AU - Nelson, S.F.

AU - O'Donovan, M.C.

AU - Oades, R.D.

AU - Owen, M.J.

AU - Palmason, H.

AU - Qian, Q.

AU - Ramos-Quiroga, J.A.

AU - Reif, A.

AU - Renner, T.J.

AU - Ribasés, M.

AU - Ripke, S.

AU - Roeyers, H.

AU - Romanos, M.

AU - Romanos, J.

AU - Rothenberger, A.

AU - Sánchez-Mora, C.

AU - Schachar, R.

AU - Scherag, A.

AU - Scherag, S.

AU - Sergeant, J.

AU - Smalley, S.L.

AU - Edmund, J.S.

AU - Sonuga-Barke, [No Value]

AU - Steinhausen, H.-C.

AU - Thapar, A.

AU - Todorov, A.

AU - Waldman, I.

AU - Walitza, S.

AU - Wang, Y.

AU - Warnke, A.

AU - Williams, N.

AU - Yang, L.

PY - 2015/9

Y1 - 2015/9

N2 - Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N=19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N=225), and (3) the Brain Imaging Genetics cohort (BIG, N=1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences.

AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N=19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N=225), and (3) the Brain Imaging Genetics cohort (BIG, N=1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences.

KW - GIT1

KW - ADHD

KW - Brain imaging genetics

KW - eQTL

KW - Drosophilia melanogaster

U2 - 10.1002/ajmg.b.32327

DO - 10.1002/ajmg.b.32327

M3 - Article

SN - 1552-4841

VL - 168

SP - 492

EP - 507

JO - American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics

JF - American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics

IS - 6

ER -

Converging evidence does not support GIT1 as an ADHD risk gene

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