Genetic effects influencing risk for major depressive disorder in China and Europe.

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+ (IgM+) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, EµSV-BCL2-22 and H2-Ld-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2+IL6+AID- and found that they developed-with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)-a severe IgM+ lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2+IL6+AID- model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM.

Exome chip analyses in adult attention deficit hyperactivity disorder.

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.

Correlation of fetal scalp blood sampling pH with neonatal outcome umbilical artery pH value.

PURPOSE: Fetal scalp blood sampling is considered as a complimentary tool in addition to cardiotocography to assess fetal well-being. This blood sampling is important as the obstetrician has to judge and make decisions regarding the further management of the delivery based on this pH result. The aim of this study was to analyze the correlation between fetal scalp blood pH and the umbilical artery pH after birth. Furthermore, it was investigated whether tocolysis, a performed episiotomy or cord encirclement have an influence on the umbilical artery pH. METHODS: This retrospective study over a period of 11 years included all singleton pregnancies without fetal anomalies, which were monitored by fetal scalp blood sampling during labor. RESULTS: 844 out of 1502 deliveries were included for analysis. The analysis demonstrates a good correlation between fetal scalp pH value and outcome pH value. Subgroup analysis with fetal scalp blood pH <7.20 showed a difference in 40 of 82 cases, with an outcome pH value ≥7.20, but this difference was statistically insignificant. Neither did tocolysis, episiotomy or the presence of cord encirclement show an overall effect, nor did they have an impact on the subgroup. CONCLUSION: Obstetricians must consider that the values of fetal scalp blood are not always reliable and can be false. However, on the basis of CTG and fetal scalp blood pH, decisions are made regarding delivery interventions. Therefore, we would encourage the consideration of taking two samples routinely at every attempt of fetal blood sampling.

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

GWAS-based pathway analysis differentiates between fluid and crystallized intelligence.

Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) - the ability to reason in novel situations - and general crystallized intelligence (gC) - the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.

Strong association of variants around FOXE1 and orofacial clefting.

Nonsyndromic orofacial clefting (nsOFC) is a common, complex congenital disorder. The most frequent forms are nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO). Although they are generally considered distinct entities, a recent study has implicated a region around the FOXE1 gene in both nsCL/P and nsCPO. To investigate this hypothesis, we analyzed the 2 most strongly associated markers (rs3758249 and rs4460498) in 2 independent samples of differing ethnicities: Central European (949 nsCL/P cases, 155 nsCPO cases, 1163 controls) and Mayan Mesoamerican (156 nsCL/P cases, 10 nsCPO cases, 338 controls). While highly significant associations for both single-nucleotide polymorphisms were obtained in nsCL/P (rs4460498: p Europe = 6.50 × 10(-06), p Mayan = .0151; rs3758249: p Europe = 2.41 × 10(-05), p Mayan = .0299), no association was found in nsCPO (p > .05). Genotyping of rs4460498 in 472 independent European trios revealed significant associations for nsCL/P (p = .016) and nsCPO (p = .043). A meta-analysis of all data revealed a genomewide significant result for nsCL/P (p = 1.31 × 10(-08)), which became more significant when nsCPO cases were added (p nsOFC = 1.56 × 10(-09)). These results strongly support the FOXE1 locus as a risk factor for nsOFC. With the data of the initial study, there is now considerable evidence that this locus is the first conclusive risk factor shared between nsCL/P and nsCPO.

The transcriptome of the human mast cell leukemia cells HMC-1.2: an approach to identify specific changes in the gene expression profile in KitD816V systemic mastocytosis.

To circumvent the costly isolation procedure associated with tissue mast cells, human mast cell lines such as HMC-1 are employed in mastocytosis research, but their relation to mutated mast cells in systemic mastocytosis has not been investigated systematically. In the present study, we determined the transcriptome of HMC-1.2 cells and compared the expression data with those reported in the literature for normal human resting lung and tonsillar mast cells as well as leukocytes from peripheral blood and mononuclear cells from bone marrow aspirates of patients with D816 V-positive systemic mastocytosis. Our results suggest that HMC-1.2 cells are an appropriate model for the investigation of this variant of systemic mast cell activation disease. The data confirm previous suggestions that the pathologically increased activity of mast cells in patients with D816 V-positive systemic mastocytosis can be deduced from the detection of mutation-related changes in the gene expression profile in leukocytes from peripheral blood and in mononuclear cells from bone marrow aspirates. Thus, mutation-related changes of the expression profile can serve as surrogates (besides clustering of mast cells, expression of CD25, and increased release of tryptase) for the presence of the mutation D816 V in tyrosine kinase Kit in patients with systemic mastocytosis according to the WHO criteria. Whether this also holds true for systemic mast cell activation disease caused by other mutations in Kit or other mast cell activity-related genes is a subject for future studies.

Investigation of the male pattern baldness major genetic susceptibility loci AR/EDA2R and 20p11 in female pattern hair loss.

BACKGROUND: The aetiology of female pattern hair loss (FPHL) is largely unknown. However, it is hypothesized that FPHL and male pattern baldness (AGA) share common susceptibility alleles. The two major susceptibility loci for AGA are the androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus on the X-chromosome, and a locus on chromosome 20p11, for which no candidate gene has yet been identified. OBJECTIVES: To examine the role of the AR/EDA2R and 20p11 loci in the development of FPHL using 145 U.K. and 85 German patients with FPHL, 179 U.K. supercontrols and 150 German blood donors. METHODS: Patients and controls were genotyped for 25 single nucleotide polymorphisms (SNPs) at the AR/EDA2R locus and five SNPs at the 20p11 locus. RESULTS: Analysis of the AR/EDA2R locus revealed no significant association in the German sample. However, a nominally significant association for a single SNP (rs1397631) was found in the U.K. sample. Subgroup analysis of the U.K. patients revealed significant association for seven markers in patients with an early onset (P = 0·047 after adjustment for the testing of multiple SNPs by Monte Carlo simulation). No significant association was obtained for the five 20p11 variants, either in the overall samples or in the analysis of subgroups. CONCLUSIONS: The observed association suggests that the AR/EDA2R locus confers susceptibility to early-onset FHPL. Our results do not implicate the 20p11 locus in the aetiology of FPHL.

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.

Caspase recruitment domain 15 gene haplotypes in sarcoidosis.

Sarcoidosis is a systematic granulomatous disorder. Genetic susceptibility could play a central role in the disease development and progression. In this study, we investigated whether caspase recruitment domain 15 (CARD15) gene haplotypes are associated with the onset or the clinical course of sarcoidosis. Three hundred Caucasian sarcoidosis patients and 381 matched controls were included. Eight haplotype-tagging single nucleotide polymorphisms (SNPs) in the CARD15 gene were examined by mass spectrometry-based SNP genotyping. By haplotype analysis, mutations located in between tested SNPs can also be identified. Therefore, we can conclude that there is no association between the CARD15 gene and the development or a special phenotype of sarcoidosis in our cohort.

The penetration of ciprofloxacin into human pancreatic and peripancreatic necroses in acute necrotizing pancreatitis.

BACKGROUND: Antibiotic prophylaxis in necrotizing pancreatitis has recently gained acceptance. Published studies, however, used different antibiotic regimes and some antibiotics penetrated pancreatic tissue or pancreatic necroses only poorly. The aim of this study was to assess the penetration of ciprofloxacin (CIP) into necrotic pancreatic and peripancreatic tissue. PATIENTS AND METHODS: Serum, pancreatic necroses, peripancreatic fat tissue necroses and infected omental fluid levels of CIP were measured after 51 operations in 14 patients. RESULTS: The median penetration ratio of CIP was 137.5% (range 11-196%) in infected omental bursa fluid, 59.6% (3-214%) in pancreatic necroses and 67.1% (1-250%) in peripancreatic necroses. Chemotherapeutical ratios of CIP as a marker for antimicrobial potency were high against most relevant pathogens in necrotizing pancreatitis. CONCLUSION: Due to its antimicrobial spectrum and the good penetration into the relevant compartments, CIP may be useful in preventing local infection in necrotizing pancreatitis.

[Epididymal adenomatoid tumors. 2 new cases]. / Tumores adenomatoides del epidídimo. Dos nuevas aportaciones.

OBJECTIVE: To review the different aspects of epididymal tumors, with special reference to adenomatoid tumor of the epididymis (mesothelial neoplasm). Two such cases are reported herein. METHODS: Two cases of adenomatoid tumor of the epididymis are described. The clinical features, diagnosis and treatment are discussed, within the context of the algorithm recently presented by Pellicé and co-workers. RESULTS/CONCLUSION: Most of the epididymal tumors are benign and treatment using a scrotal approach will suffice. However, inguinotomy should be performed when the benign nature of the tumor cannot be established unequivocally.

[Gynecomastia and Leydig cell tumor, clinically occult]. / Ginecomastía y tumor de células de Leydig, clínicamente oculto.

OBJECTIVES: An uncommon case of clinically occult Leydig cell tumor of the testis is described. The literature is reviewed with special reference to the difficulty encountered in making the diagnosis. METHODS/RESULTS: The clinical data of a patient with occult Leydig cell tumor of the testis, whose only remarkable feature was a long history of gynecomastia, are presented. CONCLUSIONS: A hormonal study and scrotal ultrasound evaluation are essential in the diagnosis of this tumor type and should be performed even in the absence of testicular anomalies on palpation.

[Fibrous pseudotumor of the epididymis]. / Pseudotumor fibroso de epidídimo.

Presentation of one case of fibrous pseudotumor of epididymis in a 33 year-old patient. Final diagnosis was achieved after surgical exeresis and its pathoanatomical examination. Etiopathogeny, clinic presentation and therapeutical approach are reviewed. Considering, in general, the clinical inespecificity of intrascrotal processes, we believe it is important to know this entity in order to be in a position to address differential diagnosis with truly neoplastic processes.

[Urinary tract involvement as the first clinical manifestation of adenocarcinoma of the colon]. / Afectación de la vía urinaria como primera manifestación clínica de un adenocarcinoma de colon.

A patient with a previous history of left renal colic and no evidence of passing calculi was admitted to hospital for exacerbation of the urinary condition. The IVP and US evaluation revealed a ureteral stop which appeared to be extrinsic on retrograde uretero-pyelography. Surgery disclosed a large urinoma in the lumbar fossa. The compromised ureteral segment was removed and the pathological analysis of the surgical specimen revealed infiltration from adenocarcinoma. A primary tumor was sought early postoperatively due to irregular constipation referred by the patient. Finally, adenocarcinoma of the sigmoid colon was found. Only 8 similar cases of urinoma from extravasation due to ureteral obstruction secondary to a tumor have been reported in the literature up to 1982.

[Acquired cystic renal disease, bilateral spontaneous renal hemorrhage, and functional renal transplantation. Review of the literature and report of a case]. / Enfermedad quística renal adquirida, hemorragia renal espontánea bilateral y trasplante renal funcionante. Revisión de la literatura y aportación de un caso.

Presentation of one case of bilateral, retroperitoneal, intracystic and spontaneous renal haematoma in a patient with acquired renal cystic disease (ARCD) and renal transplantation with functioning graft. A literature review is made with regard to the association of ARCD and spontaneous renal haematoma in dialysed patients; also an analysis of the etiopathogenic factors, as well as diagnostic and therapeutical approaches to the above association. No reference has been found in the literature of concomitant ARCD, bilateral spontaneous renal haemorrhage and renal transplantation with functioning graft.

[Nephrectomy following treatment with ESWL of staghorn lithiasis complicated with urinoma]. / Nefrectomía tras tratamiento con ESWL de una litiasis coraliforme complicada con urinoma.

We report on a female patient that had undergone extracorporeal shock wave lithotripsy for a staghorn stone. We describe the endourological maneuvers that were performed, but had failed to avoid nephrectomy due to renal fistula with urinoma.