Converging evidence does not support GIT1 as an ADHD risk gene

Psychiatric Genomics Consortium ADHD Working Group; Marieke Klein; Monique van der Voet; Benjamin Harich; Kimm J.E. van Hulzen; A. Marten H. Onnink; Martine Hoogman; Tulio Guadalupe; Marcel Zwiers; Johanne M. Groothuismink; Alicia Verberkt; Bonnie Nijhof; Anna Castells-Nobau; Stephen V. Faraone; Jan K. Buitelaar; Annette Schenck; Alejandro Arias-Vasquez; Barbara Franke; Richard J.L. Anney; Alejandro Arias Vasquez; Philip Asherson; Tobias Banaschewski; Mònica Bayés; Joseph Biederman; Miguel Casas; Alice Charach; Bru Cormand; Jennifer Crosbie; Mark J. Daly; Alysa E. Doyle; Richard P. Ebstein; Josephine Elia; Christine Freitag; Michael Gill; Hakon Hakonarson; Johannes Hebebrand; Anke Hinney; Peter Holmans; Lindsey Kent; Jonna Kuntsi; Nanda Lambregts-Rommelse; Kate Langley; Klaus Peter Lesch; Sandra K. Loo; James J. McGough; Sarah E. Medland; Jobst Meyer; Eric Mick; Ana Miranda; Fernando Mulas; Benjamin M. Neale

doi:10.1002/ajmg.b.32327

Converging evidence does not support GIT1 as an ADHD risk gene

Psychiatric Genomics Consortium ADHD Working Group, Marieke Klein, Monique van der Voet, Benjamin Harich, Kimm J.E. van Hulzen, A. Marten H. Onnink, Martine Hoogman, Tulio Guadalupe, Marcel Zwiers, Johanne M. Groothuismink, Alicia Verberkt, Bonnie Nijhof, Anna Castells-Nobau, Stephen V. Faraone, Jan K. Buitelaar, Annette Schenck, Alejandro Arias-Vasquez, Barbara Franke^*, Richard J.L. Anney, Alejandro Arias VasquezPhilip Asherson, Tobias Banaschewski, Mònica Bayés, Joseph Biederman, Miguel Casas, Alice Charach, Bru Cormand, Jennifer Crosbie, Mark J. Daly, Alysa E. Doyle, Richard P. Ebstein, Josephine Elia, Christine Freitag, Michael Gill, Hakon Hakonarson, Johannes Hebebrand, Anke Hinney, Peter Holmans, Lindsey Kent, Jonna Kuntsi, Nanda Lambregts-Rommelse, Kate Langley, Klaus Peter Lesch, Sandra K. Loo, James J. McGough, Sarah E. Medland, Jobst Meyer, Eric Mick, Ana Miranda, Fernando Mulas, Benjamin M. Neale

^*Corresponding author for this work

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

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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
DOIs	https://doi.org/10.1002/ajmg.b.32327
Publication status	Published - 1 Sept 2015

Keywords

ADHD
Brain imaging genetics
Drosophila melanogaster
EQTL
GIT1

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Psychiatric Genomics Consortium ADHD Working Group, 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., ... Neale, B. M. (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

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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 = "ADHD, Brain imaging genetics, Drosophila melanogaster, EQTL, GIT1",

author = "{Psychiatric Genomics Consortium ADHD Working Group} and Marieke Klein and {van der Voet}, Monique and Benjamin Harich and {van Hulzen}, {Kimm J.E.} and Onnink, {A. Marten H.} and Martine Hoogman and Tulio Guadalupe and Marcel Zwiers and Groothuismink, {Johanne M.} and Alicia Verberkt and Bonnie Nijhof and Anna Castells-Nobau and Faraone, {Stephen V.} and Buitelaar, {Jan K.} and Annette Schenck and Alejandro Arias-Vasquez and Barbara Franke and Anney, {Richard J.L.} and Vasquez, {Alejandro Arias} and Philip Asherson and Tobias Banaschewski and M{\`o}nica Bay{\'e}s and Joseph Biederman and Miguel Casas and Alice Charach and Bru Cormand and Jennifer Crosbie and Daly, {Mark J.} and Doyle, {Alysa E.} and Ebstein, {Richard P.} and Josephine Elia and Christine Freitag and Michael Gill and Hakon Hakonarson and Johannes Hebebrand and Anke Hinney and Peter Holmans and Lindsey Kent and Jonna Kuntsi and Nanda Lambregts-Rommelse and Kate Langley and Lesch, {Klaus Peter} and Loo, {Sandra K.} and McGough, {James J.} and Medland, {Sarah E.} and Jobst Meyer and Eric Mick and Ana Miranda and Fernando Mulas and Neale, {Benjamin M.}",

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year = "2015",

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

language = "English",

volume = "168",

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Psychiatric Genomics Consortium ADHD Working Group, 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, Casas, M, Charach, A, Cormand, B, Crosbie, J, Daly, MJ, Doyle, AE, Ebstein, RP, Elia, J, Freitag, C, Gill, M, Hakonarson, H, Hebebrand, J, Hinney, A, Holmans, P, Kent, L, Kuntsi, J, Lambregts-Rommelse, N, Langley, K, Lesch, KP, Loo, SK, McGough, JJ, Medland, SE, Meyer, J, Mick, E, Miranda, A, Mulas, F & Neale, BM 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 - Psychiatric Genomics Consortium ADHD Working Group

AU - Klein, Marieke

AU - van der Voet, Monique

AU - Harich, Benjamin

AU - van Hulzen, Kimm J.E.

AU - Onnink, A. Marten H.

AU - Hoogman, Martine

AU - Guadalupe, Tulio

AU - Zwiers, Marcel

AU - Groothuismink, Johanne M.

AU - Verberkt, Alicia

AU - Nijhof, Bonnie

AU - Castells-Nobau, Anna

AU - Faraone, Stephen V.

AU - Buitelaar, Jan K.

AU - Schenck, Annette

AU - Arias-Vasquez, Alejandro

AU - Franke, Barbara

AU - Anney, Richard J.L.

AU - Vasquez, Alejandro Arias

AU - Asherson, Philip

AU - Banaschewski, Tobias

AU - Bayés, Mònica

AU - Biederman, Joseph

AU - Casas, Miguel

AU - Charach, Alice

AU - Cormand, Bru

AU - Crosbie, Jennifer

AU - Daly, Mark J.

AU - Doyle, Alysa E.

AU - Ebstein, Richard P.

AU - Elia, Josephine

AU - Freitag, Christine

AU - Gill, Michael

AU - Hakonarson, Hakon

AU - Hebebrand, Johannes

AU - Hinney, Anke

AU - Holmans, Peter

AU - Kent, Lindsey

AU - Kuntsi, Jonna

AU - Lambregts-Rommelse, Nanda

AU - Langley, Kate

AU - Lesch, Klaus Peter

AU - Loo, Sandra K.

AU - McGough, James J.

AU - Medland, Sarah E.

AU - Meyer, Jobst

AU - Mick, Eric

AU - Miranda, Ana

AU - Mulas, Fernando

AU - Neale, Benjamin M.

PY - 2015/9/1

Y1 - 2015/9/1

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 - ADHD

KW - Brain imaging genetics

KW - Drosophila melanogaster

KW - EQTL

KW - GIT1

UR - http://www.scopus.com/inward/record.url?scp=84939573349&partnerID=8YFLogxK

U2 - 10.1002/ajmg.b.32327

DO - 10.1002/ajmg.b.32327

M3 - Article

AN - SCOPUS:84939573349

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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