TY  - JOUR
A1  - Ronchi, Cristina L.
A1  - Leich, Ellen
A1  - Sbiera, Silviu
A1  - Weismann, Dirk
A1  - Rosenwald, Andreas
A1  - Allolio, Bruno
A1  - Fassnacht, Martin
T1  - Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways
JF  - Neoplasia
N2  - The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (>= 20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.
KW  - kinase
KW  - comparative genomic hybridization
KW  - high-resolution analysis
KW  - Cushings syndrome
KW  - neutral loss
KW  - tumors
KW  - serum
KW  - expression
KW  - carcinoma
KW  - catenin
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134953
VL  - 14
IS  - 3
ER  - 
TY  - JOUR
A1  - Havik, Bjarte
A1  - Degenhardt, Franziska A.
A1  - Johansson, Stefan
A1  - Fernandes, Carla P. D.
A1  - Hinney, Anke
A1  - Scherag, André
A1  - Lybaek, Helle
A1  - Djurovic, Srdjan
A1  - Christoforou, Andrea
A1  - Ersland, Kari M.
A1  - Giddaluru, Sudheer
A1  - O'Donovan, Michael C.
A1  - Owen, Michael J.
A1  - Craddock, Nick
A1  - Mühleisen, Thomas W.
A1  - Mattheisen, Manuel
A1  - Schimmelmann, Benno G.
A1  - Renner, Tobias
A1  - Warnke, Andreas
A1  - Herpertz-Dahlmann, Beate
A1  - Sinzig, Judith
A1  - Albayrak, Özgür
A1  - Rietschel, Marcella
A1  - Nöthen, Markus M.
A1  - Bramham, Clive R.
A1  - Werge, Thomas
A1  - Hebebrand, Johannes
A1  - Haavik, Jan
A1  - Andreassen, Ole A.
A1  - Cichon, Sven
A1  - Steen, Vidar M.
A1  - Le Hellard, Stephanie
T1  - DCLK1 Variants Are Associated across Schizophrenia and Attention Deficit/Hyperactivity Disorder
JF  - PLoS One
N2  - Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4x10\(^{-5}\) and 4x10\(^{-6}\), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity.
KW  - psychosis
KW  - deficit hyperactivity disorder
KW  - genome-wide association
KW  - bipolar disorder
KW  - VAL66MET polymorphism
KW  - doublecortine-like
KW  - genes
KW  - kinase
KW  - BDNF
KW  - endophenotype
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135285
VL  - 7
IS  - 4
ER  -