Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ⩾40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.

The goal of this study is to investigate the familial transmission of the spectrum of bipolar disorder in a nonclinical sample of probands with a broad range of manifestations of mood disorders. The sample included a total of 447 probands recruited from a clinically enriched community screening and their 2082 adult living and deceased first-degree relatives. A best estimate diagnostic procedure that was based on either direct semistructured interview or structured family history information from multiple informants regarding non-interviewed relatives was employed. Results revealed that there was specificity of familial aggregation of bipolar I (BP I; odds ratio (OR)=8.40; 3.27-20.97; h2=0.83) and major depressive disorder (OR=2.26; 1.58-3.22; h2=0.20), but not BP II. The familial aggregation of BP I was primarily attributable to the familial specificity of manic episodes after adjusting for both proband and relative comorbid anxiety and substance use disorders. There was no significant cross-aggregation between mood disorder subtypes suggesting that the familial transmission of manic and major depressive episodes is independent despite the high magnitude of comorbidity between these mood states. These findings confirm those of earlier studies of the familial aggregation of bipolar disorder and major depression in the first nonclinical sample, and the largest family study of bipolar disorder in the USA using contemporary nonhierarchical diagnostic criteria for mood and anxiety disorders. The results suggest that these major components of bipolar disorder may represent distinct underlying pathways rather than increasingly severe manifestations of a common underlying diathesis. Therefore, dissection of the broad bipolar phenotype in genetic studies could actually generate new findings that could index novel biologic pathways underlying bipolar disorder.

Background Bladder cancer (BCa) can be divided into muscle‐invasive BCa (MIBC) and non−muscle‐invasive BCa (NMIBC). Whether the tumor infiltrates the detrusor muscle is a critical determinant of disease management in patients with BCa. However, the current preoperative diagnostic accuracy of muscular invasiveness is less than satisfactory. The authors report a radiomic‐clinical nomogram for the individualized preoperative differentiation of MIBC from NMIBC. Methods In total, 2602 radiomics features were extracted from whole bladder tumors and the basal part of the lesions on T2‐weighted magnetic resonance imaging. Then, a radiomics signature was constructed using the least absolute shrinkage and selection operator algorithm in the training set (n = 130). Furthermore, a radiomic‐clinical nomogram was developed incorporating the radiomics signature and selected clinical predictors based on a multivariable logistic regression analysis. The performance of the nomogram (discrimination, calibration, and clinical usefulness) was assessed and validated in an independent validation set (n = 69). Results The radiomics signature, consisting of 23 selected features, showed good discrimination in the training and validation sets (area under the curve [AUC], 0.913 and 0.874, respectively). Incorporating the radiomics signature and magnetic resonance imaging‐determined tumor size, the radiomic‐clinical nomogram showed favorable calibration and discrimination in the training set with an AUC of 0.922, which was confirmed in the validation set (AUC, 0.876). Decision curve analysis and net reclassification improvement and integrated discrimination improvement indices (net reclassification improvement, 0.338, integrated discrimination improvement, 0.385) demonstrated the clinical usefulness of the nomogram. Conclusions The proposed noninvasive radiomic‐clinical nomogram can increase the accuracy of preoperatively discriminating MIBC from NMIBC, which may aid in clinical decision making and improve patient prognosis.

Background: Metastasis is a major obstacle in the treatment of bladder cancer (BC). Circular RNAs exert various functions in the aggressive biological behaviour of cancers. In this study, we aimed to elucidate how circPICALM influences BC metastasis. Methods: The expression of circPICALM was analysed by real-time PCR. The tumourigenic properties of BC cells were evaluated using in vitro migration, invasion, and wound healing assays and an in vivo footpad model. The interaction between circPICALM and miR-1265 was confirmed by pull-down and dualluciferase reporter assays and biotin-labelled miRNA capture. The interaction of STEAP4 and focal adhesion kinase (FAK) was confirmed by co-immunoprecipitation. Findings: CircPICALM was downregulated in BC tissues, and low circPICALM expression was related to advanced T stage, high grade, lymph node positivity and poor overall survival. Overexpression of circPI-CALM inhibited the metastasis of BC cells, and DHX9 negatively regulated circPICALM levels. CircPICALM colocalized with miR-1265 and acted as a sponge for this miRNA, and the pro-invasion effect of miR-1265 was abolished by circPICALM overexpression. STEAP4, a target of miR-1265, suppressed metastasis; it bound to FAK to prevent autophosphorylation at Y397 and influenced EMT in BC cells. Interpretation: CircPICALM can inhibit BC metastasis and bind to miR-1265 to block its pro-invasion activity. STEAP4 is a target of miR-1265 and is related to FAK phosphorylation and EMT.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as “response” (n = 514) or “non-response” (n = 290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top SNP was rs17162912 (P = 1.76×10−8) which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P <10−5) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877, and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave p-values of 2.86×10−6 and 8.41×10−6, respectively. The other 35 variations with signals of potential significance (P <10−4) involve multiple genes expressed in the brain, including GRIN2B, PCDH10, and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (FDR = 0.0097) and the serotonergic system (FDR = 0.0213). While the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Circular RNAs (circRNAs) are broad and diverse endogenous non-coding RNAs. Emerging evidence has revealed that circR-NAs play pivotal roles in cancers, regulating the gene expression by acting as a microRNA (miRNA) sponge. However, the biological functions of circRNAs in bladder cancer (BCa) remain largely unknown. In this study, we identified an altered circRNA, termed circFUT8, by screening RNA sequencing data generated from three BCa tissues and matched adjacent normal bladder tissues. Quantitative real-time PCR analysis demonstrated that circFUT8 was downregulated in BCa tissues and correlated with patients' prognosis, histological grade, and lymph node (LN) metastasis. Functionally, gainand loss-of-function assays indicated that circFUT8 inhibited the migration and invasion of BCa cell lines in vitro and LN metastasis in vivo. Mechanistically, circFUT8 directly bound to miR-570-3p and partially abrogated its oncogenic role, and miR-570-3p could suppress the expression of tumor suppressor gene Krüpple-like factor 10 (KLF10) by binding its 3 0 untranslated region (3 0 UTR). Moreover, we found that circ-FUT8 promoted the expression of KLF10 by competitively sponging miR-570-3p. In conclusion, circFUT8 functions as a tumor suppressor in BCa cells by targeting the miR-570-3p/ KLF10 axis and may serve as a potential biomarker and therapeutic target for the management of BCa patients with LN metastasis.

Background Alterations in the brain cortical structures of patients with chronic kidney disease (CKD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of kidney damage on brain cortical structure. Methods Genome-wide association studies summary data of estimated glomerular filtration rate (eGFR) in 480,698 participants from the CKDGen Consortium were used to identify genetically predicted eGFR. Data from 567,460 individuals from the CKDGen Consortium were used to assess genetically determined CKD; 302,687 participants from the UK Biobank were used to evaluate genetically predicted albuminuria. Further, data from 51,665 patients from the ENIGMA Consortium were used to assess the relationship between genetic predisposition and reduced eGFR, CKD, and progressive albuminuria with alterations in cortical thickness (TH) or surficial area (SA) of the brain. Magnetic resonance imaging was used to measure the SA and TH globally and in 34 functional regions. Inverse-variance weighted was used as the primary estimate whereas MR Pleiotropy RESidual Sum and Outlier, MR-Egger and weighted median were used to detect heterogeneity and pleiotropy. Findings At the global level, albuminuria decreased TH (β = −0.07 mm, 95% CI: −0.12 mm to −0.02 mm, P = 0.004); at the functional level, albuminuria reduced TH of pars opercularis gyrus without global weighted (β = −0.11 mm, 95% CI: −0.16 mm to −0.07 mm, P = 3.74×10 −6 ). No pleiotropy was detected. Interpretation Kidney damage causally influences the cortex structure which suggests the existence of a kidney-brain axis. Funding This study was supported by the Science and Technology Planning Project of Guangdong Province (Grant No. 2020A1515111119 and 2017B020227007), the National Key Research and Development Program of China (Grant No. 2018YFA0902803), the National Natural Science Foundation of China (Grant No. 81825016, 81961128027, 81772719, 81772728), the Key Areas Research and Development Program of Guangdong (Grant No. 2018B010109006), Guangdong Special Support Program (2017TX04R246), Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, and Grants from the Guangdong Science and Technology Department (2020B1212060018).

BackgroundClinical outcome of adrenocortical carcinoma (ACC) varies because of its heterogeneous nature and reliable prognostic prediction model for adult ACC patients is limited. The objective of this study was to develop and externally validate a nomogram for overall survival (OS) prediction in adult patients with ACC after surgery.MethodsBased on the data from the Surveillance Epidemiology, and End Results (SEER) database, adults patients diagnosed with ACC between January 1988 and December 2015 were identified and classified into a training set, comprised of 404 patients diagnosed between January 2007 and December 2015, and an internal validation set, comprised of 318 patients diagnosed between January 1988 and December 2006. The endpoint of this study was OS. The nomogram was developed using a multivariate Cox proportional hazards regression algorithm in the training set and its performance was evaluated in terms of its discriminative ability, calibration, and clinical usefulness. The nomogram was then validated using the internal SEER validation, also externally validated using the Cancer Genome Atlas set (TCGA, 82 patients diagnosed between 1998 and 2012) and a Chinese multicenter cohort dataset (82 patients diagnosed between December 2002 and May 2018), respectively.ResultsAge at diagnosis, T stage, N stage, and M stage were identified as independent predictors for OS. A nomogram incorporating these four predictors was constructed using the training set and demonstrated good calibration and discrimination (C-index 95% confidence interval [CI], 0.715 [0.679–0.751]), which was validated in the internal validation set (C-index [95% CI], 0.672 [0.637–0.707]), the TCGA set (C-index [95% CI], 0.810 [0.732–0.888]) and the Chinese multicenter set (C-index [95% CI], 0.726 [0.633–0.819]), respectively. Encouragingly, the nomogram was able to successfully distinguished patients with a high-risk of mortality in all enrolled patients and in the subgroup analyses. Decision curve analysis indicated that the nomogram was clinically useful and applicable.ConclusionsThe study presents a nomogram that incorporates clinicopathological predictors, which can accurately predict the OS of adult ACC patients after surgery. This model and the corresponding risk classification system have the potential to guide therapy decisions after surgery.