TY  - JOUR
A1  - Zayats, T
A1  - Jacobsen, KK
A1  - Kleppe, R
A1  - Jacob, CP
A1  - Kittel-Schneider, S
A1  - Ribasés, M
A1  - Ramos-Quiroga, JA
A1  - Richarte, V
A1  - Casas, M
A1  - Mota, NR
A1  - Grevet, EH
A1  - Klein, M
A1  - Corominas, J
A1  - Bralten, J
A1  - Galesloot, T
A1  - Vasquez, AA
A1  - Herms, S
A1  - Forstner, AJ
A1  - Larsson, H
A1  - Breen, G
A1  - Asherson, P
A1  - Gross-Lesch, S
A1  - Lesch, KP
A1  - Cichon, S
A1  - Gabrielsen, MB
A1  - Holmen, OL
A1  - Bau, CHD
A1  - Buitelaar, J
A1  - Kiemeney, L
A1  - Faraone, SV
A1  - Cormand, B
A1  - Franke, B
A1  - Reif, A
A1  - Haavik, J
A1  - Johansson, S
T1  - Exome chip analyses in adult attention deficit hyperactivity disorder
JF  - Translational Psychiatry
N2  - 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.
KW  - chip analyses
KW  - ADHD
KW  - adulthood
KW  - Illumina Human Exome Bead Chip
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168297
VL  - 6
IS  - e923
ER  - 
TY  - JOUR
A1  - Lueken, U
A1  - Kuhn, M
A1  - Yang, Y
A1  - Straube, B
A1  - Kircher, T
A1  - Wittchen, H-U
A1  - Pfleiderer, B
A1  - Arolt, V
A1  - Wittmann, A
A1  - Ströhle, A
A1  - Weber, H
A1  - Reif, A
A1  - Domschke, K
A1  - Deckert, J
A1  - Lonsdorf, TB
T1  - Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach
JF  - Translational Psychiatry
N2  - Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain’s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.
KW  - glycine receptor beta subunit
KW  - neural fear network activation
KW  - intermediate phenotype approach
KW  - defensive system reactivity
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-182381
VL  - 7
IS  - e1227
ER  -