[Pharmacogenetics in psychiatry: state of the art]. / Pharmakogenetik in der Psychiatrie: eine Standortbestimmung.

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

High loading of polygenic risk in cases with chronic schizophrenia.

Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.

Identification and functional characterization of rare SHANK2 variants in schizophrenia.

Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.

The Problem of Mammographic Breast Density - The Position of the DEGUM Working Group on Breast Ultrasound.

Mammographic breast density correlates with breast cancer risk and also with the number of false-negative calls. In the USA these facts lead to the "Breast Density and Mammography Reporting Act" of 2011. In the case of mammographically dense breasts, the Working Group on Breast Ultrasound in Germany recommends explaining the advantages of adjunct imaging to women, depending on the individual breast cancer risk. Due to the particular structure of German healthcare, quality-assured breast ultrasound would be the first choice. Possible overdiagnosis, costs, potentially increased emotional stress should be addressed. In high familial breast cancer risk, genetic counselling and an intensified early detection program should be performed.

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

[Sonoelastography usage among German DEGUM-certified breast ultrasound specialists]. / Einsatz der Sonoelastografie in der Mammadiagnostik: Analyse unter DEGUM-zertifizierten Untersuchern.

PURPOSE: Sonoelastography of the breast is an emerging technology with evident data in the literature suggesting diagnostic advantages. Our study investigates the current usage of sonoelastography among German DEGUM-certified breast ultrasound specialists. MATERIALS AND METHODS: We used a standardized questionnaire with 18 items. In 2012, the survey was sent to all members of the breast ultrasound section of the DEGUM (n = 654). RESULTS: The group of survey participants (n = 208) performs 193 025 breast ultrasound examinations and examines 20 110 breast cancers per year. 21.2 % of the participants in the survey use sonoelastography, mainly for diagnostic purposes in BI-RADS®-US 3 and 4 lesions, less often for other categories or under study conditions. The most commonly applied criteria for the evaluation of the elastogram are the Tsukuba Elasticity Score (43.2 %), the fat-lesion ratio (29.5 %) and the determination of tissue stiffness with shear wave elastography expressed in kilopascal (25.0 %). The majority of non-users of elastography (58.6 %) would like to have the option of using sonoelastography in the future. CONCLUSION: Sonoelastography is a feasible and helpful method in the evaluation of breast lesions. A significant number of German ultrasound specialists already apply this technology today. We expect a growing number of sonographers to perform sonoelastography in the near future, provided that they have the necessary ultrasound system and that they are trained in the method. Evidence from the literature and the recommendations of the medical societies support this development.

[Evaluation of the nationwide DEGUM breast ultrasound training program]. / Evaluation der DEGUM-Mammasonografiekurse nach objektivierbaren Kriterien.

PURPOSE: The aim of this study was to evaluate the quality standard of the nationwide breast ultrasound training program of the German Society of Ultrasound in Medicine (DEGUM) through objective parameters. MATERIALS AND METHODS: 10 quality criteria, based on the recommendations of The National Association of Statutory Health Insurance Physicians (KBV), were defined for this study. All training units of the DEGUM received a questionnaire. The questionnaires and training material were analyzed. RESULTS: All units met the required criteria pertaining to the trainer's qualification, duration per training course and the maximum number of participants per ultrasound machine. Only 1 course did not fulfill the required 50 % practical training time. The requirements to participate in the graduate course (200 self-made and documented cases) were not clearly conceived and a defined training log could be improved. CONCLUSION: DEGUM breast ultrasound training offers trainees a high level of education based on the requirements of the KBV. Despite the high quality of training, the content of course announcements could be improved and an official and structured educational index could be meaningful.

Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder.

We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset < or =21 years (AO < or =21 years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO < or =21 years and AO>21 years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO < or =21 years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO < or = 21 years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO< or = 21 years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.

Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe.

Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.

The biology of malignant breast tumors has an impact on the presentation in ultrasound: an analysis of 315 cases.

BACKGROUND: The aim of this study was to evaluate the relation of some ultrasound morphological parameters to biological characteristics in breast carcinoma. METHODS: Ultrasound data from 315 breast masses were collected. We analyzed the ultrasound features of the tumors according to the ACR BI-RADS®-US classification system stratified by hormone receptor status, HER2 status, histology grade, tumor type (ductal versus lobular), triple-negativity, breast density, tumor size, lymph node involvement and patient's age. RESULTS: We found a variety of ultrasound features that varied between the groups. Invasive lobular tumors were more likely to have an angulated margin (39% versus 22%, p = 0.040) and less likely to show posterior acoustic enhancement (3% versus 16%, p = 0.023) compared to invasive ductal carcinoma. G3 tumors were linked to a higher chance of posterior acoustic enhancement and less shadowing and the margin of G3 tumors was more often described as lobulated or microlobulated compared to G1/G2 tumors (67% versus 46%, p = 0.001). Tumors with an over-expression of HER2 exhibited a higher rate of architectural distortions in the surrounding tissue, but there were no differences regarding the other features. Hormone receptor negative tumors were more likely to exhibit a lobulated or microlobulated margin (67% versus 50%, p = 0.037) and less likely to have an echogenic halo (39% versus 64%, p = 0.001). Furthermore, the posterior acoustic feature was more often described as enhancement (33% versus 13%, p = 0.001) and less often as shadowing (20% versus 47%, p < 0.001) compared to hormone receptor positive tumors. CONCLUSION: Depending on their biological and clinical profile, breast cancers are more or less likely to exhibit the typical criteria for malignancy in ultrasound. Moreover, certain types of breast cancer tend to possess criteria that are usually associated with benign masses. False-negative diagnosis may result in serious consequences for the patient. For the sonographer it is essential to be well aware of potential variations in the ultrasound morphology of breast tumors, as described in this paper.

Interdisciplinary consensus recommendations for the use of vacuum-assisted breast biopsy under sonographic guidance: first update 2012.

PURPOSE: The vacuum biopsy of the breast under sonographic guidance (VB) was introduced in Germany in the year 2000 and the first consensus recommendations were published by Krainick-Strobel et al. in 2005. Since then, many clinical studies on this technique have been published. The purpose of this publication is to update the consensus recommendations from 2005 regarding the latest literature. MATERIALS AND METHODS: The consensus statements were the result of two preliminary meetings after the review of the latest literature by members of the Minimally Invasive Breast Intervention Study Group from the German Society of Senology. The final consensus text was review by all members of the working group. The statements listed under results obtained complete acceptance (consensus 100 %). RESULTS: The consensus recommendations describe the indications, investigator qualifications, technical requirements, documentation, quality assurance and follow-up intervals regarding the latest literature. CONCLUSION: The VB is a safe method for extracting breast tissue for histological workup. The technique allows the resection of breast tissue up to 8 cm3. Besides the diagnostic indications, the method qualifies for a therapeutic resection of symptomatic benign lesions (e. g. fibroadenomas). The technique should be used in specialized breast centers working in a multidisciplinary setup. This paper is an expert's recommendation for the use of VB under sonographic guidance. It is not formulated as a nationwide guideline.

Susceptibility variants on chromosome 7p21.1 suggest HDAC9 as a new candidate gene for male-pattern baldness.

BACKGROUND: Male-pattern baldness (androgenetic alopecia, AGA) is the most common form of hair loss among humans. Research has shown that it is caused by genetic factors. Numerous studies have unequivocally identified two major genetic risk loci for AGA: the X-chromosomal AR/EDA2R locus, and the PAX1/FOXA2 locus on chromosome 20. OBJECTIVES: To identify further candidate genes for AGA, and thus gain further insights into this phenotype. METHODS: A German sample of 581 severely affected cases and 617 controls was used to perform a genome-wide association study. The identified associated locus was further analysed by fine-mapping, and then independently replicated in an Australian sample. Expression and pathway analyses were performed to characterize the susceptibility gene identified. RESULTS: The most significant association signal was obtained for rs756853 (P = 1·64 × 10(-7) ), which is located intronically in the histone deacetylase 9 (HDAC9) gene. Fine-mapping and a family-based analysis revealed that rs756853 and the 6-kb distal rs2249817 were the most highly associated single nucleotide polymorphisms. The association finding was replicated in an independent Australian sample, when the analysis was restricted to severely affected cases and unaffected controls (P = 0·026). Analysis of rs2249817 in a combined sample of severely affected German and Australian cases and unaffected controls revealed a strong association signal (P = 9·09 × 10(-8) ). Tissue expression studies demonstrated HDAC9 expression in various tissues, including tissues of relevance to AGA. No strong genotypic effects were observed in genotype-specific expression or splice studies. Pathway analyses supported the hypothesis that HDAC9 plays a functional role in AGA via interaction with the AR gene. CONCLUSIONS: The present study suggests that HDAC9 is the third AGA susceptibility gene.

[Diagnostic value of strain ratio measurement in the differentiation of malignant and benign breast lesions]. / Diagnostische Aussagekraft der Strain-Ratio-Messung zur Unterscheidung zwischen malignen und benignen Brusttumoren.

PURPOSE: The aim of this study was to evaluate the strain ratio measurement of breast lesions, to calculate the diagnostic value and to provide practically oriented recommendations concerning execution. MATERIALS AND METHODS: 117 breast lesions in 98 patients were included in the study. All lesions were examined by B-mode ultrasound and elastography using strain ratio measurement. The preinterventional findings of the different methods were compared to the final histopathological results. The sensitivity, specificity, positive and negative predictive value and the diagnostic accuracy were calculated for each method. RESULTS: There was a significant difference between the strain ratio of malignant (mean 6.50; sd 3.03; 95 %-CI 5.68 - 7.33) and benign (mean 1.79; sd 3.83; 95 %-CI 0.92 - 2.75) lesions. The strain ratio showed a sensitivity of 92.6 % (95 %-CI 82.1 - 97.9) and a specificity of 95.2 % (95 %-CI 86.7 - 99.0). The positive and negative predictive values were 94.3 % and 93.7 %. B-mode ultrasound achieved a sensitivity of 94.4 % (95 %-CI 84.6 - 98.8) and a specificity of 87.3 % (95 %-CI 76.5 - 94.3). The positive and negative predictive values were 86.4 % and 94.8 %. CONCLUSION: Strain ratio measurement of breast lesions is a standardized fast method for analyzing the stiffness inside the examined areas. Used as an additional tool to B-mode ultrasound, it helps to increase the specificity of the examination.

Multicenter study of ultrasound real-time tissue elastography in 779 cases for the assessment of breast lesions: improved diagnostic performance by combining the BI-RADS®-US classification system with sonoelastography.

PURPOSE: Hitachi real-time tissue elastography (HI-RTE) is an ultrasound technique that facilitates the estimation of tissue elasticity. Our study evaluates whether sonoelastography improves the differentiation of benign and malignant breast lesions. MATERIALS AND METHODS: In a multicenter approach sonoelastography of focal breast lesions was carried out in 779 patients with subsequent histological confirmation. We present data from 3 study centers (Berlin, Bielefeld, Homburg/Saar) focusing on the sensitivity (SE), specificity (SP) and the positive (PPV) and negative predictive value (NPV) of sonoelastography. In addition we performed an analysis of the diagnostic performance, expressed by the pretest and posttest probability of disease (POD), in BI-RADS®-US 3 or 4 lesions as these categories can imply both malignant and benign lesions and a more precise prediction would be a preferable aim. RESULTS: Sonoelastography demonstrated an improved SP (89.5 %) and an excellent PPV (86.8 %) compared to B-mode ultrasound (76.1 % and 77.2 %). Especially in dense breasts ACR III-IV, the SP was even higher (92.8 %). In BI-RADS-US 3 lesions, a suspicious elastogram significantly modified the POD from 8.3 % to a posttest POD of 45.5 %. In BI-RADS-US 4 lesions, we found a pretest POD of 56.6 %. The posttest POD changed significantly to 24.2 % with a normal elastogram and to 81.5 % with a suspicious elastogram. CONCLUSION: Our data demonstrates that the complementary use of sonoelastography definitely improves the performance in breast diagnostics. Finally we present a protocol of how sonoelastography can be integrated into our daily practice.

The effect of 5-HTTLPR and a serotonergic multi-marker score on amygdala, prefrontal and anterior cingulate cortex reactivity and habituation in a large, healthy fMRI cohort.

Major depressive disorder (MDD) is characterized by low mood for at least two weeks. Impaired emotion regulation has been suggested to be the consequence of dysfunctional serotonergic regulation of limbic and prefrontal regions, especially the amygdala, the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC). The impact of genetic variation on brain function can be investigated with intermediate phenotypes. A suggested intermediate phenotype of MDD is emotion recognition: The 5-HTTLPR polymorphism of SLC6A4 as well as other serotonergic genes have been associated with amygdala and prefrontal function during emotion recognition. Previously, it has been suggested that habituation is a more reliable index of emotion recognition than functional activation. We examined the relationship of genes involved in serotonergic signaling with amygdala as well as prefrontal functional activation and habituation during an emotion recognition task in 171 healthy subjects. While effects of 5-HTTLPR and of a serotonergic multi-marker score (5-HTTLPR, TPH1(rs1800532), TPH2(rs4570625), HTR1A(rs6295) and HTR2A(rs6311)) on amygdala activation did not withstand correction for multiple regions of interest, we observed a strong correlation of the multi-marker score and habituation in the amygdala, DLPFC, and ACC. We replicated a well-studied intermediate phenotype for association with 5-HTTLPR and provided additional evidence for polygenic involvement. Furthermore, we showed that task habituation may be influenced by genetic variation in serotonergic signaling, particularly by a serotonergic multi-marker score. We provided preliminary evidence that PFC activation is an important intermediate phenotype of MDD. Future studies are needed to corroborate the results in larger samples.

Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi-episode schizophrenia.

Preliminary studies suggest that, besides improving cognition, aerobic exercise might increase hippocampal volume in schizophrenia patients; however, results are not consistent. Individual mechanisms of volume changes are unknown but might be connected to the load of risk genes. Genome-wide association studies have uncovered the polygenic architecture of schizophrenia. The secondary analysis presented here aimed to determine the modulatory role of schizophrenia polygenic risk scores (PRSs) on volume changes in the total hippocampus and cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG) and subiculum over time. We studied 20 multi-episode schizophrenia patients and 23 healthy controls who performed aerobic exercise (endurance training) combined with cognitive remediation for 3 months and 21 multi-episode schizophrenia patients allocated to a control intervention (table soccer) combined with cognitive remediation. Magnetic resonance imaging-based assessments were performed at baseline and after 3 months with FreeSurfer. No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis. We hypothesize that a high polygenic risk may negatively influence neuroplasticity in CA4/DG during aerobic exercise in schizophrenia.