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Articles by T. G Schulze
Total Records ( 2 ) for T. G Schulze
  R Uher , N Perroud , M. Y. M Ng , J Hauser , N Henigsberg , W Maier , O Mors , A Placentino , M Rietschel , D Souery , T Zagar , P. M Czerski , B Jerman , E. R Larsen , T. G Schulze , A Zobel , S Cohen Woods , K Pirlo , A. W Butler , P Muglia , M. R Barnes , M Lathrop< , A Farmer , G Breen , K. J Aitchison , I Craig , C. M Lewis and P. McGuffin
  Objective

The purpose of this study was to identify genetic variants underlying the considerable individual differences in response to antidepressant treatment. The authors performed a genome-wide association analysis of improvement of depression severity with two antidepressant drugs.

Method

High-quality Illumina Human610-quad chip genotyping data were available for 706 unrelated participants of European ancestry treated for major depression with escitalopram (N=394) or nortriptyline (N=312) over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, a partially randomized open-label pharmacogenetic trial.

Results

Single nucleotide polymorphisms in two intergenic regions containing copy number variants on chromosomes 1 and 10 were associated with the outcome of treatment with escitalopram or nortriptyline at suggestive levels of significance and with a high posterior likelihood of true association. Drug-specific analyses revealed a genome-wide significant association between marker rs2500535 in the uronyl 2-sulphotransferase gene and response to nortriptyline. Response to escitalopram was best predicted by a marker in the interleukin-11 (IL11) gene. A set of 72 a priori-selected candidate genes did not show pharmacogenetic associations above a chance level, but an association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11.

Conclusions

While limited statistical power means that a number of true associations may have been missed, these results suggest that efficacy of antidepressants may be predicted by genetic markers other than traditional candidates. Genome-wide studies, if properly replicated, may thus be important steps in the elucidation of the genetic basis of pharmacological response.

  J Schumacher , G Laje , R. A Jamra , T Becker , T. W Muhleisen , C Vasilescu , M Mattheisen , S Herms , P Hoffmann , A. M Hillmer , A Georgi , C Herold , T. G Schulze , P Propping , M Rietschel , F. J McMahon , M. M Nothen and S. Cichon
 

Association studies, as well as the initial translocation family study, identified the gene Disrupted-In-Schizophrenia-1 (DISC1) as a risk factor for schizophrenia. DISC1 encodes a multifunctional scaffold protein involved in neurodevelopmental processes implicated in the etiology of schizophrenia. The present study explores the contribution of the DISC locus to schizophrenia using three different approaches: (i) systematic association mapping aimed at detecting DISC risk variants in a schizophrenia sample from a central European population (556 SNPs, n = 1621 individuals). In this homogenous sample, a circumscribed DISC1 interval in intron 9 was significantly associated with schizophrenia in females (P = 4 x 10–5) and contributed most strongly to early-onset cases (P = 9 x 10–5). The odds ratios (ORs) were in the range of 1.46–1.88. (ii) The same sample was used to test for the locus-specific SNP–SNP interaction most recently associated with schizophrenia. Our results confirm the SNP interplay effect between rs1538979 and rs821633 that significantly conferred disease risk in male patients with schizophrenia (P = 0.016, OR 1.57). (iii) In order to detect additional schizophrenia variants, a meta-analysis was performed using nine schizophrenia samples from different European populations (50 SNPs, n = 10 064 individuals maximum, n = 3694 minimum). We found evidence for a common schizophrenia risk interval within DISC1 intron 4–6 (P = 0.002, OR 1.27). The findings point to a complex association between schizophrenia and DISC, including the presence of different risk loci and SNP interplay effects. Furthermore, our phenotype–genotype results—including the consideration of sex-specific effects—highlight the value of homogenous samples in mapping risk genes for schizophrenia in general, and at the DISC locus in particular.

 
 
 
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