@article{ZayatsJacobsenKleppeetal.2016,
  author    = {Zayats, T and Jacobsen, KK and Kleppe, R and Jacob, CP and Kittel-Schneider, S and Ribas{\´e}s, M and Ramos-Quiroga, JA and Richarte, V and Casas, M and Mota, NR and Grevet, EH and Klein, M and Corominas, J and Bralten, J and Galesloot, T and Vasquez, AA and Herms, S and Forstner, AJ and Larsson, H and Breen, G and Asherson, P and Gross-Lesch, S and Lesch, KP and Cichon, S and Gabrielsen, MB and Holmen, OL and Bau, CHD and Buitelaar, J and Kiemeney, L and Faraone, SV and Cormand, B and Franke, B and Reif, A and Haavik, J and Johansson, S},
  title     = {Exome chip analyses in adult attention deficit hyperactivity disorder},
  series = {Translational Psychiatry},
  volume    = {6},
  journal   = {Translational Psychiatry},
  number    = {e923},
  doi       = {10.1038/tp.2016.196},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168297},
  year      = {2016},
  abstract  = {Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1\%); (2) single marker association tests of common variants (MAF⩾1\%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.},
  language  = {en}
}
@article{LanghauserCasasDaoetal.2018,
  author    = {Langhauser, Friederike and Casas, Ana I. and Dao, Vu-Thao-Vi and Guney, Emre and Menche, J{\"o}rg and Geuss, Eva and Kleikers, Pamela W. M. and L{\´o}pez, Manuela G. and Barab{\´a}si, Albert-L. and Kleinschnitz, Christoph and Schmidt, Harald H. H. W.},
  title     = {A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection},
  series = {npj Systems Biology and Applications},
  volume    = {4},
  journal   = {npj Systems Biology and Applications},
  doi       = {10.1038/s41540-017-0039-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236381},
  year      = {2018},
  abstract  = {Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease-disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.},
  language  = {en}
}