@article{DoerkPeterlongoMannermaaetal.2019, author = {D{\"o}rk, Thilo and Peterlongo, Peter and Mannermaa, Arto and Bolla, Manjeet K. and Wang, Qin and Dennis, Joe and Ahearn, Thomas and Andrulis, Irene L. and Anton-Culver, Hoda and Arndt, Volker and Aronson, Kristan J. and Augustinsson, Annelie and Beane Freeman, Laura E. and Beckmann, Matthias W. and Beeghly-Fadiel, Alicia and Behrens, Sabine and Bermisheva, Marina and Blomqvist, Carl and Bogdanova, Natalia V. and Bojesen, Stig E. and Brauch, Hiltrud and Brenner, Hermann and Burwinkel, Barbara and Canzian, Federico and Chan, Tsun L. and Chang-Claude, Jenny and Chanock, Stephen J. and Choi, Ji-Yeob and Christiansen, Hans and Clarke, Christine L. and Couch, Fergus J. and Czene, Kamila and Daly, Mary B. and dos-Santos-Silva, Isabel and Dwek, Miriam and Eccles, Diana M. and Ekici, Arif B. and Eriksson, Mikael and Evans, D. Gareth and Fasching, Peter A. and Figueroa, Jonine and Flyger, Henrik and Fritschi, Lin and Gabrielson, Marike and Gago-Dominguez, Manuela and Gao, Chi and Gapstur, Susan M. and Garc{\´i}a-Closas, Montserrat and Garc{\´i}a-S{\´a}enz, Jos{\´e} A. and Gaudet, Mia M. and Giles, Graham G. and Goldberg, Mark S. and Goldgar, David E. and Guen{\´e}l, Pascal and Haeberle, Lothar and Haimann, Christopher A. and H{\aa}kansson, Niclas and Hall, Per and Hamann, Ute and Hartman, Mikael and Hauke, Jan and Hein, Alexander and Hillemanns, Peter and Hogervorst, Frans B. L. and Hooning, Maartje J. and Hopper, John L. and Howell, Tony and Huo, Dezheng and Ito, Hidemi and Iwasaki, Motoki and Jakubowska, Anna and Janni, Wolfgang and John, Esther M. and Jung, Audrey and Kaaks, Rudolf and Kang, Daehee and Kapoor, Pooja Middha and Khusnutdinova, Elza and Kim, Sung-Won and Kitahara, Cari M. and Koutros, Stella and Kraft, Peter and Kristensen, Vessela N. and Kwong, Ava and Lambrechts, Diether and Le Marchand, Loic and Li, Jingmei and Lindstr{\"o}m, Sara and Linet, Martha and Lo, Wing-Yee and Long, Jirong and Lophatananon, Artitaya and Lubiński, Jan and Manoochehri, Mehdi and Manoukian, Siranoush and Margolin, Sara and Martinez, Elena and Matsuo, Keitaro and Mavroudis, Dimitris and Meindl, Alfons and Menon, Usha and Milne, Roger L. and Mohd Taib, Nur Aishah and Muir, Kenneth and Mulligan, Anna Marie and Neuhausen, Susan L. and Nevanlinna, Heli and Neven, Patrick and Newman, William G. and Offit, Kenneth and Olopade, Olufunmilayo I. and Olshan, Andrew F. and Olson, Janet E. and Olsson, H{\aa}kan and Park, Sue K. and Park-Simon, Tjoung-Won and Peto, Julian and Plaseska-Karanfilska, Dijana and Pohl-Rescigno, Esther and Presneau, Nadege and Rack, Brigitte and Radice, Paolo and Rashid, Muhammad U. and Rennert, Gad and Rennert, Hedy S. and Romero, Atocha and Ruebner, Matthias and Saloustros, Emmanouil and Schmidt, Marjanka K. and Schmutzler, Rita K. and Schneider, Michael O. and Schoemaker, Minouk J. and Scott, Christopher and Shen, Chen-Yang and Shu, Xiao-Ou and Simard, Jaques and Slager, Susan and Smichkoska, Snezhana and Southey, Melissa C. and Spinelli, John J. and Stone, Jennifer and Surowy, Harald and Swerdlow, Anthony J. and Tamimi, Rulla M. and Tapper, William J. and Teo, Soo H. and Terry, Mary Beth and Toland, Amanda E. and Tollenaar, Rob A. E. M. and Torres, Diana and Torres-Mej{\´i}a, Gabriela and Troester, Melissa A. and Truong, Th{\´e}r{\`e}se and Tsugane, Shoichiro and Untch, Michael and Vachon, Celine M. and van den Ouweland, Ans M. W. and van Veen, Elke M. and Vijai, Joseph and Wendt, Camilla and Wolk, Alicja and Yu, Jyh-Cherng and Zheng, Wei and Ziogas, Argyrios and Ziv, Elad and Dunnig, Alison and Pharaoh, Paul D. P. and Schindler, Detlev and Devilee, Peter and Easton, Douglas F.}, title = {Two truncating variants in FANCC and breast cancer risk}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, organization = {ABCTB Investigators, NBCS Collaborators}, doi = {10.1038/s41598-019-48804-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222838}, year = {2019}, abstract = {Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95\%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.}, language = {en} } @article{ManchiaAdliAkulaetal.2013, author = {Manchia, Mirko and Adli, Mazda and Akula, Nirmala and Arda, Raffaella and Aubry, Jean-Michel and Backlund, Lena and Banzato, Claudio E. M. and Baune, Bernhard T. and Bellivier, Frank and Bengesser, Susanne and Biernacka, Joanna M. and Brichant-Petitjean, Clara and Bui, Elise and Calkin, Cynthia V. and Cheng, Andrew Tai Ann and Chillotti, Caterina and Cichon, Sven and Clark, Scott and Czerski, Piotr M. and Dantas, Clarissa and Del Zompo, Maria and DePaulo, J. Raymond and Detera-Wadleigh, Sevilla D. and Etain, Bruno and Falkai, Peter and Fris{\´e}n, Louise and Frye, Mark A. and Fullerton, Jan and Gard, S{\´e}bastien and Garnham, Julie and Goes, Fernando S. and Grof, Paul and Gruber, Oliver and Hashimoto, Ryota and Hauser, Joanna and Heilbronner, Urs and Hoban, Rebecca and Hou, Liping and Jamain, St{\´e}phane and Kahn, Jean-Pierre and Kassem, Layla and Kato, Tadafumi and Kelsoe, John R. and Kittel-Schneider, Sarah and Kliwicki, Sebastian and Kuo, Po-Hsiu and Kusumi, Ichiro and Laje, Gonzalo and Lavebratt, Catharina and Leboyer, Marion and Leckband, Susan G. and L{\´o}pez Jaramillo, Carlos A. and Maj, Mario and Malafosse, Alain and Martinsson, Lina and Masui, Takuya and Mitchell, Philip B. and Mondimore, Frank and Monteleone, Palmiero and Nallet, Audrey and Neuner, Maria and Nov{\´a}k, Tom{\´a}s and O'Donovan, Claire and {\"O}sby, Urban and Ozaki, Norio and Perlis, Roy H. and Pfennig, Andrea and Potash, James B. and Reich-Erkelenz, Daniela and Reif, Andreas and Reininghaus, Eva and Richardson, Sara and Rouleau, Guy A. and Rybakowski, Janusz K. and Schalling, Martin and Schofield, Peter R. and Schubert, Oliver K. and Schweizer, Barbara and Seem{\"u}ller, Florian and Grigoroiu-Serbanescu, Maria and Severino, Giovanni and Seymour, Lisa R. and Slaney, Claire and Smoller, Jordan W. and Squassina, Alessio and Stamm, Thomas and Steele, Jo and Stopkova, Pavla and Tighe, Sarah K. and Tortorella, Alfonso and Turecki, Gustavo and Wray, Naomi R. and Wright, Adam and Zandi, Peter P. and Zilles, David and Bauer, Michael and Rietschel, Marcella and McMahon, Francis J. and Schulze, Thomas G. and Alda, Martin}, title = {Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0065636}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130938}, pages = {e65636}, year = {2013}, abstract = {Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.}, language = {en} } @article{RaynerColemanPurvesetal.2019, author = {Rayner, Christopher and Coleman, Jonathan R. I. and Purves, Kirstin L. and Hodsoll, John and Goldsmith, Kimberley and Alpers, Georg W. and Andersson, Evelyn and Arolt, Volker and Boberg, Julia and B{\"o}gels, Susan and Creswell, Cathy and Cooper, Peter and Curtis, Charles and Deckert, J{\"u}rgen and Domschke, Katharina and El Alaoui, Samir and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Grocholewski, Anja and Hahlweg, Kurt and Hamm, Alfons and Hedman, Erik and Heiervang, Einar R. and Hudson, Jennifer L. and J{\"o}hren, Peter and Keers, Robert and Kircher, Tilo and Lang, Thomas and Lavebratt, Catharina and Lee, Sang-hyuck and Lester, Kathryn J. and Lindefors, Nils and Margraf, J{\"u}rgen and Nauta, Maaike and Pan{\´e}-Farr{\´e}, Christiane A. and Pauli, Paul and Rapee, Ronald M. and Reif, Andreas and Rief, Winfried and Roberts, Susanna and Schalling, Martin and Schneider, Silvia and Silverman, Wendy K. and Str{\"o}hle, Andreas and Teismann, Tobias and Thastum, Mikael and Wannem{\"u}ller, Andre and Weber, Heike and Wittchen, Hans-Ulrich and Wolf, Christiane and R{\"u}ck, Christian and Breen, Gerome and Eley, Thalia C.}, title = {A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, number = {150}, doi = {10.1038/s41398-019-0481-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225048}, pages = {1-13}, year = {2019}, abstract = {Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.}, language = {en} } @article{GabrielJirůHillmannKraftetal.2020, author = {Gabriel, Katharina M. A. and J{\´i}rů-Hillmann, Steffi and Kraft, Peter and Selig, Udo and R{\"u}cker, Victoria and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Keidel, Matthias and Soda, Hassan and Rascher, Alexandra and Schneider, Rolf and Pfau, Mathias and Hoffmann, Roy and Stenzel, Joachim and Benghebrid, Mohamed and Goebel, Tobias and Doerck, Sebastian and Kramer, Daniela and Haeusler, Karl Georg and Volkmann, Jens and Heuschmann, Peter U. and Fluri, Felix}, title = {Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke)}, series = {BMC Neurology}, volume = {20}, journal = {BMC Neurology}, doi = {10.1186/s12883-020-01676-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229214}, year = {2020}, abstract = {Background Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. Methods The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. Results Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4\% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31\%), mainly in secondary stroke prevention; b) improvement over time (44\%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25\%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. Conclusion The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.}, language = {en} } @article{MarenholzEsparzaGordilloRueschendorfetal.2015, author = {Marenholz, Ingo and Esparza-Gordillo, Jorge and R{\"u}schendorf, Franz and Bauerfeind, Anja and Strachan, David P. and Spycher, Ben D. and Baurecht, Hansj{\"o}rg and Magaritte-Jeannin, Patricia and S{\"a}{\"a}f, Annika and Kerkhof, Marjan and Ege, Markus and Baltic, Svetlana and Matheson, Melanie C. and Li, Jin and Michel, Sven and Ang, Wei Q. and McArdle, Wendy and Arnold, Andreas and Homuth, Georg and Demenais, Florence and Bouzigon, Emmanuelle and S{\"o}derh{\"a}ll, Cilla and Pershagen, G{\"o}ran and de Jongste, Johan C. and Postma, Dirkje S. and Braun-Fahrl{\"a}nder, Charlotte and Horak, Elisabeth and Ogorodova, Ludmila M. and Puzyrev, Valery P. and Bragina, Elena Yu and Hudson, Thomas J. and Morin, Charles and Duffy, David L. and Marks, Guy B. and Robertson, Colin F. and Montgomery, Grant W. and Musk, Bill and Thompson, Philip J. and Martin, Nicholas G. and James, Alan and Sleiman, Patrick and Toskala, Elina and Rodriguez, Elke and F{\"o}lster-Holst, Regina and Franke, Andre and Lieb, Wolfgang and Gieger, Christian and Heinzmann, Andrea and Rietschel, Ernst and Keil, Thomas and Cichon, Sven and N{\"o}then, Markus M. and Pennel, Craig E. and Sly, Peter D. and Schmidt, Carsten O. and Matanovic, Anja and Schneider, Valentin and Heinig, Matthias and H{\"u}bner, Norbert and Holt, Patrick G. and Lau, Susanne and Kabesch, Michael and Weidinger, Stefan and Hakonarson, Hakon and Ferreira, Manuel A. R. and Laprise, Catherine and Freidin, Maxim B. and Genuneit, Jon and Koppelman, Gerard H. and Mel{\´e}n, Erik and Dizier, Marie-H{\´e}l{\`e}ne and Henderson, A. John and Lee, Young Ae}, title = {Meta-analysis identifies seven susceptibility loci involved in the atopic march}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {8804}, doi = {10.1038/ncomms9804}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139835}, year = {2015}, abstract = {Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.}, language = {en} } @article{ArltBiehlTayloretal.2011, author = {Arlt, Wiebke and Biehl, Michael and Taylor, Angela E. and Hahner, Stefanie and Lib{\´e}, Rossella and Hughes, Beverly A. and Schneider, Petra and Smith, David J. and Stiekema, Han and Krone, Nils and Porfiri, Emilio and Opocher, Giuseppe and Bertherat, Jer{\^o}me and Mantero, Franco and Allolio, Bruno and Terzolo, Massimo and Nightingale, Peter and Shackleton, Cedric H. L. and Bertagna, Xavier and Fassnacht, Martin and Stewart, Paul M.}, title = {Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors}, series = {The Journal of Clinical Endocrinology \& Metabolism}, volume = {96}, journal = {The Journal of Clinical Endocrinology \& Metabolism}, number = {12}, doi = {10.1210/jc.2011-1565}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154682}, pages = {3775 -- 3784}, year = {2011}, abstract = {Context: Adrenal tumors have a prevalence of around 2\% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2-11\% of incidentally discovered adrenal masses. Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values. Objective: Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy. Design: Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19-84 yr) and 45 ACC patients (20-80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up [median duration 52 (range 26-201) months] without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids. Results: Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90\% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88\% (area under the curve = 0.96) when using only the nine most differentiating markers. Conclusions: Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas.}, language = {en} } @article{GrimmWeberKittelSchneideretal.2020, author = {Grimm, Oliver and Weber, Heike and Kittel-Schneider, Sarah and Kranz, Thorsten M. and Jacob, Christian P. and Lesch, Klaus-Peter and Reif, Andreas}, title = {Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk}, series = {Frontiers in Psychiatry}, volume = {11}, journal = {Frontiers in Psychiatry}, issn = {1664-0640}, doi = {10.3389/fpsyt.2020.557160}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219751}, year = {2020}, abstract = {While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70\% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive-neurotic type, an adventurous-hyperactive type with a stronger genetic component, and an anxious-inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.}, language = {en} } @article{BrevikvanDonkelaarWeberetal.2016, author = {Brevik, Erlend J and van Donkelaar, Marjolein M. J. and Weber, Heike and S{\´a}nchez-Mora, Cristina and Jacob, Christian and Rivero, Olga and Kittel-Schneider, Sarah and Garcia-martinez, Iris and Aebi, Marcel and van Hulzen, Kimm and Cormand, Bru and Ramos-Quiroga, Josep A and Lesch, Klaus-Peter and Reif, Andreas and Ribases, Marta and Franke, Barbara and Posserud, Maj-Britt and Johansson, Stefan and Lundervold, Astri J. and Haavik, Jan and Zayats, Tetyana}, title = {Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder}, series = {American Journal of Medical Genetics Part B-Neuropsychiatric Genetics}, volume = {171B}, journal = {American Journal of Medical Genetics Part B-Neuropsychiatric Genetics}, number = {5}, organization = {IMAGE Consortium}, doi = {10.1002/ajmg.b.32434}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188116}, pages = {733-747}, year = {2016}, abstract = {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.}, language = {en} } @article{HollaenderSchwenderBoehmeetal.2021, author = {Holl{\"a}nder, Olivia and Schwender, Kristina and B{\"o}hme, Petra and Fleckhaus, Jan and Haas, Cordula and Han, Yang and Heidorn, Frank and Klein-Unseld, Rachel and Lichtenwald, Julia and Naue, Jana and Neubauer, Jacqueline and Poetsch, Micaela and Schneider, Peter M. and Wagner, Wolfgang and Vennemann, Marielle}, title = {Forensische DNA-Methylierungsanalyse}, series = {Rechtsmedizin}, volume = {31}, journal = {Rechtsmedizin}, number = {3}, organization = {Arbeitsgemeinschaft Molekulare Alterssch{\"a}tzung der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM)}, issn = {0937-9819}, doi = {10.1007/s00194-021-00492-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307131}, pages = {192-201}, year = {2021}, abstract = {Die quantitative Analyse der relativen DNA-Methylierung gilt als eine der vielversprechendsten Methoden der molekularen Alterssch{\"a}tzung. Viele Studien der letzten Jahre identifizierten geeignete Positionen im Genom, deren DNA-Methylierung sich altersabh{\"a}ngig ver{\"a}ndert. F{\"u}r den Einsatz dieser Methode in der Routine- bzw. Fallarbeit ist es von großer Bedeutung, angewandte Analysetechniken zu validieren. Als ein Teilaspekt dieser Validierung sollte die Vergleichbarkeit der Analyseergebnisse zur DNA-Methylierung mithilfe der Mini- und Pyrosequenzierung zwischen verschiedenen Laboren evaluiert werden. Die Arbeitsgruppe „Molekulare Alterssch{\"a}tzung" der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM) f{\"u}hrte hierzu den ersten, technischen Ringversuch durch, der 4 Positionen in den Genen PDE4C, EDARADD, SST und KLF14 umfasste. Diese Marker waren in vorangegangenen Studien als altersabh{\"a}ngige Biomarker charakterisiert worden. Am Ringversuch nahmen 12 Labore teil, wobei jedes die Wahl zwischen der Minisequenzierung und/oder der Pyrosequenzierung f{\"u}r die quantitative Methylierungsanalyse hatte. Jedem teilnehmenden Labor wurden Blut- und Speichelproben von 3 Personen unterschiedlichen Alters {\"u}bersandt. Die Wahl der Reagenzien f{\"u}r die Probenbearbeitung wurde den Teilnehmern freigestellt. Die Ergebnisse der Minisequenzierung zeigten systematische Abweichungen zwischen den Laboren, die am ehesten auf die Verwendung unterschiedlicher Reagenzien und Analyseplattformen zur{\"u}ckzuf{\"u}hren sein k{\"o}nnen. Die Resultate der Pyrosequenzierung hingegen wiesen nicht auf systematische Abweichungen zwischen den Laboren hin, hier zeigte sich jedoch die Tendenz einer markerabh{\"a}ngigen Abweichung. Dar{\"u}ber hinaus konnten Unterschiede hinsichtlich technischer Probleme zwischen Laboren mit mehr Erfahrung in der jeweiligen Sequenzierungsmethode und Laboren mit weniger Erfahrung festgestellt werden. Sowohl die Beobachtung von systematischen als auch die von markerabh{\"a}ngigen Abweichungen l{\"a}sst den Schluss zu, dass eine {\"U}bertragung von Analysemethoden zwischen Laboren grunds{\"a}tzlich m{\"o}glich ist, eine Anpassung des jeweiligen Modells zur Alterssch{\"a}tzung jedoch notwendig sein kann.}, language = {de} } @article{NauePfeiferAugustinetal.2021, author = {Naue, Jana and Pfeifer, Manuel and Augustin, Christa and Becker, Julia and Fleckhaus, Jan and Grabm{\"u}ller, Melanie and Han, Yang and Heidorn, Frank and Hollaender, Olivia and Klein-Unseld, Rachel and Kulstein, Galina and Lichtenwald, Julia and Neubauer, Jacqueline and Suarez, Philippe and Haas, Cordula and Schneider, Peter M. and Vennemann, Marielle and B{\"o}hme, Petra}, title = {Forensische DNA-Methylierungsanalyse}, series = {Rechtsmedizin}, volume = {31}, journal = {Rechtsmedizin}, number = {3}, organization = {Arbeitsgemeinschaft Molekulare Alterssch{\"a}tzung der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM)}, issn = {0937-9819}, doi = {10.1007/s00194-021-00493-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307129}, pages = {202-216}, year = {2021}, abstract = {Mit der Entdeckung altersabh{\"a}ngiger epigenetischer Ver{\"a}nderungen, der DNA-Methylierung (DNAm), hat sich eine neue M{\"o}glichkeit aufgezeigt, das Alter eines Individuums zu sch{\"a}tzen. Die Methode wurde intensiv erforscht und ihre Anwendung in der forensischen Fallarbeit durch die Aktualisierung des \S 81e der Strafprozessordnung (StPO) in Deutschland reguliert. Zur Untersuchung des DNAm-Grades m{\"u}ssen neue Techniken etabliert und validiert werden. Dies macht die Pr{\"u}fung der Vergleichbarkeit von Messergebnissen aus verschiedenen forensischen Laboren erforderlich. Hierzu f{\"u}hrte die Arbeitsgruppe „Molekulare Alterssch{\"a}tzung" der Deutschen Gesellschaft f{\"u}r Rechtsmedizin (DGRM) im Winter 2019/2020 den 2. Ringversuch (RV) zur quantitativen DNAm-Analyse mithilfe der Mini- und der Pyrosequenzierung durch. Dieser basierte auf den Erfahrungen des 1. RV 2018/2019, dessen Ergebnisse in dieser Ausgabe ebenfalls vorgestellt werden. Die aktuelle Studie umfasst Analyseergebnisse aus 12 Laboren (ingesamt 14 teilnehmende Labore), von denen einige beide Methoden angewandt haben. Zus{\"a}tzlich f{\"u}hrten 4 Labore eine Alterssch{\"a}tzung an den RV-Proben mit eigenen Markerkombinationen und Modellen durch. Da diese auf unterschiedlichen Referenzdaten und Markerkombinationen beruhen, erfolgte kein qualitativer Vergleich der Modelle, sondern das grunds{\"a}tzliche Potenzial der Methodik wurde verdeutlicht. Ziele des RV waren die Evaluierung der Vergleichbarkeit der DNAm-Messungen und die Bewertung m{\"o}glicher Einflussfaktoren, wie Extraktionsmethode und verwendetes Ger{\"a}t. Die Ergebnisse zeigen, dass sich die gemessenen DNAm-Werte der untersuchten Marker sowohl zwischen Mini- und Pyrosequenzierung als auch innerhalb der jeweiligen Methode zwischen den Laboren unterscheiden k{\"o}nnen, sodass mit Schwankungen gerechnet werden muss.}, language = {de} }