TY  - JOUR
A1  - Jarick, I.
A1  - Volckmar, A. L.
A1  - Pütter, C.
A1  - Pechlivanis, S.
A1  - Nguyen, T. T.
A1  - Dauvermann, M. R.
A1  - Beck, S.
A1  - Albayrak, Ö.
A1  - Scherag, S.
A1  - Gilsbach, S.
A1  - Cichon, S.
A1  - Hoffmann, P.
A1  - Degenhardt, F.
A1  - Nöthen, M. M.
A1  - Schreiber, S.
A1  - Wichmann, H. E.
A1  - Jöckel, K. H.
A1  - Heinrich, J.
A1  - Tiesler, C. M. T.
A1  - Faraone, S. V.
A1  - Walitza, S.
A1  - Sinzig, J.
A1  - Freitag, C.
A1  - Meyer, J.
A1  - Herpertz-Dahlmann, B.
A1  - Lehmkuhl, G.
A1  - Renner, T. J.
A1  - Warnke, A.
A1  - Romanos, M.
A1  - Lesch, K. P.
A1  - Reif, A.
A1  - Schimmelmann, B. G.
A1  - Hebebrand, J.
A1  - Scherag, A.
A1  - Hinney, A.
T1  - Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder
JF  - Molecular Psychiatry
N2  - Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls \((P=2.8 × 10^{-4})\) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients \((P=1.2 × 10^{-3})\) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control \((P=4.3 × 10^{-2})\). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
KW  - children
KW  - ADHD
KW  - CNVs
KW  - GWAS
KW  - PARK2
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121131
VL  - 19
IS  - 19
ER  - 
TY  - JOUR
A1  - Brevik, Erlend J
A1  - van Donkelaar, Marjolein M. J.
A1  - Weber, Heike
A1  - Sánchez-Mora, Cristina
A1  - Jacob, Christian
A1  - Rivero, Olga
A1  - Kittel-Schneider, Sarah
A1  - Garcia-martinez, Iris
A1  - Aebi, Marcel
A1  - van Hulzen, Kimm
A1  - Cormand, Bru
A1  - Ramos-Quiroga, Josep A
A1  - Lesch, Klaus-Peter
A1  - Reif, Andreas
A1  - Ribases, Marta
A1  - Franke, Barbara
A1  - Posserud, Maj-Britt
A1  - Johansson, Stefan
A1  - Lundervold, Astri J.
A1  - Haavik, Jan
A1  - Zayats, Tetyana
T1  - Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder
JF  - American Journal of Medical Genetics Part B-Neuropsychiatric Genetics
N2  - Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders.
KW  - Large multicenter ADHD
KW  - Antisocial behavior
KW  - Diagnostic approach
KW  - Rating scale
KW  - Gene
KW  - Deficit/hyperactivity disorder
KW  - Susceptibility loci
KW  - Conduct disorder
KW  - Association
KW  - Adult
KW  - ADHD
KW  - Aggression
KW  - GWAS
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188116
VL  - 171B
IS  - 5
ER  - 
TY  - JOUR
A1  - Lopez-Arboleda, William Andres
A1  - Reinert, Stephan
A1  - Nordborg, Magnus
A1  - Korte, Arthur
T1  - Global genetic heterogeneity in adaptive traits
JF  - Molecular Biology and Evolution
N2  - Understanding the genetic architecture of complex traits is a major objective in biology. The standard approach for doing so is genome-wide association studies (GWAS), which aim to identify genetic polymorphisms responsible for variation in traits of interest. In human genetics, consistency across studies is commonly used as an indicator of reliability. However, if traits are involved in adaptation to the local environment, we do not necessarily expect reproducibility. On the contrary, results may depend on where you sample, and sampling across a wide range of environments may decrease the power of GWAS because of increased genetic heterogeneity. In this study, we examine how sampling affects GWAS in the model plant species Arabidopsis thaliana. We show that traits like flowering time are indeed influenced by distinct genetic effects in local populations. Furthermore, using gene expression as a molecular phenotype, we show that some genes are globally affected by shared variants, whereas others are affected by variants specific to subpopulations. Remarkably, the former are essentially all cis-regulated, whereas the latter are predominately affected by trans-acting variants. Our result illustrate that conclusions about genetic architecture can be extremely sensitive to sampling and population structure.
KW  - evolutionary genomics
KW  - GWAS
KW  - regulation of gene expression
KW  - genetic architecture
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270410
VL  - 38
IS  - 11
ER  -