TY  - JOUR
A1  - Biernacka, J. M.
A1  - Sangkuhl, K.
A1  - Jenkins, G.
A1  - Whaley, R. M.
A1  - Barman, P.
A1  - Batzler, A.
A1  - Altman, R. B.
A1  - Arolt, V.
A1  - Brockmöller, J.
A1  - Chen, C. H.
A1  - Domschke, K.
A1  - Hall-Flavin, D. K.
A1  - Hong, C. J.
A1  - Illi, A.
A1  - Ji, Y.
A1  - Kampman, O.
A1  - Kinoshita, T.
A1  - Leinonen, E.
A1  - Liou, Y. J.
A1  - Mushiroda, T.
A1  - Nonen, S.
A1  - Skime, M. K.
A1  - Wang, L.
A1  - Baune, B. T.
A1  - Kato, M.
A1  - Liu, Y. L.
A1  - Praphanphoj, V.
A1  - Stingl, J. C.
A1  - Tsai, S. J.
A1  - Kubo, M.
A1  - Klein, T. E.
A1  - Weinshilboum, R.
T1  - The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response
JF  - Translational Psychiatry
N2  - Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.
KW  - major depressive disorder
KW  - genetic variation
KW  - schizophrenia
KW  - neuregulin-1
KW  - population
KW  - microcephalin 1
KW  - susceptibility
KW  - metaanalysis
KW  - MCPH1
KW  - loci
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143223
VL  - 5
IS  - e553
ER  - 
TY  - JOUR
A1  - Leich, E.
A1  - Weißbach, S.
A1  - Klein, H.-U.
A1  - Grieb, T.
A1  - Pischimarov, J.
A1  - Stühmer, T.
A1  - Chatterjee, M.
A1  - Steinbrunn, T.
A1  - Langer, C.
A1  - Eilers, M.
A1  - Knop, S.
A1  - Einsele, H.
A1  - Bargou, R.
A1  - Rosenwald, A.
T1  - Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules
JF  - Blood Cancer Journal
N2  - Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.
KW  - multiple myeloma
KW  - somatic mutations
KW  - whole-exome sequencing
KW  - adhesion
KW  - receptor tyrosine kinases
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128663
VL  - 3
IS  - e102
ER  -