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 - Todorov, Alexandre
N1 - Publisher Copyright:
© 2015 Wiley Periodicals, Inc.
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
C2 - 26061966
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 -