Cushing’s disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the deubiquitinase gene USP8 occur in 35–62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.

Caregiving for people with mental illness (PwMI) could be burdensome, especially for informal caregivers. However, there is a scarcity of research investigating caregiving burden among informal caregivers of PwMI in China at the national level. To fill this gap, this study examined the prevalence of caregiving burden, depression, and anxiety, as well as their associated factors, among a cross-sectional sample of informal caregivers of PwMI in China. Data were collected via an online survey between June and November 2023. Caregiving burden, depression, and anxiety were measured by the Zarit Burden Interview, the Patient Health Questionnaire, and the Generalized Anxiety Disorder Scale. Information on caregivers’ sociodemographic, care recipients’ sociodemographic and disease-related, and caregiving-related characteristics was also collected. Hierarchical regression analyses were performed to identify associated factors of caregiving burden, depression, and anxiety. A total of 1,224 informal caregivers of PwMI in China were included in the final analysis. 72.1% of the participants had high caregiving burden, 53.5% had moderate to severe depression, and 43.1% had moderate to severe anxiety. Caregiving burden, depression, and anxiety were inter-correlated with each other but exhibited different profiles of associated factors. The most important factors associated with all the three outcomes were disease-related characteristics, particularly care recipients’ symptom stability, medication compliance, and insight. Informal caregivers of males with mental illness had higher levels of caregiving burden, depression, and anxiety than those of females. There was a lack of differentiation in caregiving burden, depression, and anxiety based on care recipients’ diagnosis. Formal or common-law marriage was a protective factor for caregiver depression and anxiety but not for caregiving burden. Informal caregivers of PwMI in China experienced a high level of caregiving burden, depression, and anxiety. Urgent actions are needed to relieve caregiving burden, depression, and anxiety among informal caregivers of PwMI in China.

Mutagenesis screening is a powerful forward genetic approach that has been successfully applied in lower-model organisms to discover genetic factors for biological processes. This phenotype-based approach has yet to be established in vertebrates for probing major human diseases, largely because of the complexity of colony management. Herein, we report a rapid strategy for identifying genetic modifiers of cardiomyopathy (CM). Based on the application of doxorubicin stress to zebrafish insertional cardiac (ZIC) mutants, we identified 4 candidate CM-modifying genes, of which 3 have been linked previously to CM. The long isoform of DnaJ (Hsp40) homolog, subfamily B, member 6b ( dnajb6b(L) ) was identified as a CM susceptibility gene, supported by identification of rare variants in its human ortholog DNAJB6 from CM patients. Mechanistic studies indicated that the deleterious, loss-of-function modifying effects of dnajb6b(L) can be ameliorated by inhibition of ER stress. In contrast, overexpression of dnajb6(L) exerts cardioprotective effects on both fish and mouse CM models. Together, our findings establish a mutagenesis screening strategy that is scalable for systematic identification of genetic modifiers of CM, feasible to suggest therapeutic targets, and expandable to other major human diseases.

Gout is a disease that manifests itself after decades of following a high-purine diet, with excessive alcohol consumption assumed to be one of the main contributors to the development of the disease. This study performs a Mendelian randomization (MR) analysis to determine whether alcohol consumption causally affects the risk of developing both hyperuricemia and gout. The results indicate that genetically predicted drinks consumed per week have no causal effect on neither the risk of gout (p = 0.35), nor serum uric acid levels (p = 0.73). For MR analysis in the other direction, genetic risk of gout was significantly associated with drinks per week (p = 0.03). Furthermore, the results of the MR analysis were verified in a cohort of individuals diagnosed with hyperuricemia and gout, comprising of alcohol-consuming and alcohol-abstaining subgroups. When split by alcohol status, the serum uric acid levels failed to show a significant difference in both gout (p = 0.92) and hyperuricemia (p = 0.23) subgroups. Overall, the results suggest that increased alcohol consumption does not play a causal role in the development of gout.

Background: A large schizophrenia genome-wide association study (GWAS) and a subsequent extensive replication study of individuals of European ancestry identified eight new loci with genome-wide significance and suggested that theMIR137-mediated pathway plays a role in the predisposition for schizophrenia.Aims: To validate the above findings in a Han Chinese population.Method: We analysed the single nucleotide polymorphisms (SNPs) in the newly identified schizophrenia candidate loci and predictedMIR137target genes based on our published Han Chinese populations (BIOX) GWAS data. We then analysed 18 SNPs from the candidate regions in an independent cohort that consisted of 3585 patients with schizophrenia and 5496 controls of Han Chinese ancestry.Results: We replicated the associations of five markers (P<0.05), including three that were located in the predictedMIR137target genes. Two loci (ITIH3/4: rs2239547,P=1.17×10^–10andCALN1: rs2944829,P=9.97×10^–9) exhibited genome-wide significance in the Han Chinese population.Conclusions: TheITIH3/4locus has been reported to be of genome-wide significance in the European population. The successful replication of this finding in a different ethnic group provides stronger evidence for the association between schizophrenia andITIH3/4. We detected the first genome-wide significant association of schizophrenia withCALN1, which is a predicted target ofMIR137, and thus provide new evidence for the associations betweenMIR137targets and schizophrenia.