TY  - JOUR
A1  - Drgonova, Jana
A1  - Walther, Donna
A1  - Hartstein, G Luke
A1  - Bukhari, Mohammad O
A1  - Baumann, Michael H
A1  - Katz, Jonathan
A1  - Hall, F Scott
A1  - Arnold, Elizabeth R
A1  - Flax, Shaun
A1  - Riley, Anthony
A1  - Rivero, Olga
A1  - Lesch, Klaus-Peter
A1  - Troncoso, Juan
A1  - Ranscht, Barbara
A1  - Uhl, George R
T1  - Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice
JF  - Molecular Medicine
N2  - The Cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.
KW  - Cadherin (CDH13)
KW  - CDH13 mRNA
KW  - Attention Deficit Hyperactivity Disorder (ADHD)
KW  - CDH13 Expression
KW  - Human CDH13
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165842
VL  - 22
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  -