TY  - JOUR
A1  - Palladino, Viola Stella
A1  - Chiocchetti, Andreas G.
A1  - Frank, Lukas
A1  - Haslinger, Denise
A1  - McNeill, Rhiannon
A1  - Radtke, Franziska
A1  - Till, Andreas
A1  - Haupt, Simone
A1  - Brüstle, Oliver
A1  - Günther, Katharina
A1  - Edenhofer, Frank
A1  - Hoffmann, Per
A1  - Reif, Andreas
A1  - Kittel-Schneider, Sarah
T1  - Energy metabolism disturbances in cell models of PARK2 CNV carriers with ADHD
JF  - Journal of Clinical Medicine
N2  - The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
KW  - ADHD
KW  - hiPSC
KW  - PARK2
KW  - mitochondria
KW  - disease modelling
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220074
SN  - 2077-0383
VL  - 9
IS  - 12
ER  - 
TY  - JOUR
A1  - Schulz, Herbert
A1  - Ruppert, Ann-Kathrin
A1  - Herms, Stefan
A1  - Wolf, Christiane
A1  - Mirza-Schreiber, Nazanin
A1  - Stegle, Oliver
A1  - Czamara, Darina
A1  - Forstner, Andreas J.
A1  - Sivalingam, Sugirthan
A1  - Schoch, Susanne
A1  - Moebus, Susanne
A1  - Pütz, Benno
A1  - Hillmer, Axel
A1  - Fricker, Nadine
A1  - Vatter, Hartmut
A1  - Müller-Myhsok, Bertram
A1  - Nöthen, Markus M.
A1  - Becker, Albert J.
A1  - Hoffmann, Per
A1  - Sander, Thomas
A1  - Cichon, Sven
T1  - Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus
JF  - Nature Communications
N2  - Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the \(cis\)-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify \(cis\)-meQTLs at 14,118 CpG methylation sites and \(cis\)-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal \(cis\)-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. \(Cis\)-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of \(cis\)-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.
KW  - psychiatry
KW  - epigenetics in the nervous system
KW  - epigenomics
KW  - gene expression
KW  - neurological disorders
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173168
VL  - 8
ER  -