Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10(-8): 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.

We conducted a genome-wide association study (GWAS) with replication in 36,180 Chinese individuals and performed further transancestry meta-analyses with data from the Psychiatry Genomics Consortium (PGC2). Approximately 95% of the genome-wide significant (GWS) index alleles (or their proxies) from the PGC2 study were overrepresented in Chinese schizophrenia cases, including ∼50% that achieved nominal significance and ∼75% that continued to be GWS in the transancestry analysis. The Chinese-only analysis identified seven GWS loci; three of these also were GWS in the transancestry analyses, which identified 109 GWS loci, thus yielding a total of 113 GWS loci (30 novel) in at least one of these analyses. We observed improvements in the fine-mapping resolution at many susceptibility loci. Our results provide several lines of evidence supporting candidate genes at many loci and highlight some pathways for further research. Together, our findings provide novel insight into the genetic architecture and biological etiology of schizophrenia.

Major depression disorder (MDD) is a debilitating mental illness with significant morbidity and mortality. Despite the growing number of studies that have emerged, the precise underlying mechanisms of MDD remain unknown. When studying MDD, tissue samples like peripheral blood or post-mortem brain samples are used to elucidate underlying mechanisms. Unfortunately, there are many uncontrollable factors with such samples such as medication history, age, time after death before post-mortem tissue was collected, age, sex, race, and living conditions. Although these factors are critical, they introduce confounding variables that can influence the outcome profoundly. In this regard, animal models provide a crucial approach to examine neural circuitry and molecular and cellular pathways in a controlled environment. Further, manipulations with pharmacological agents and gene editing are accepted methods of studying depression in animal models, which is impossible to employ in human patient studies. Here, we have reviewed the most widely used animal models of depression and delineated the salient features of each model in terms of behavioral and neurobiological outcomes. We have also illustrated the current challenges in using these models and have suggested strategies to delineate the underlying mechanism associated with vulnerability or resilience to developing depression.

Schizophrenia is a severe mental disorder affecting ~1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 patients and 6,468 healthy controls (1,578 cases and 1,592 controls from the Northern Han; 1,238 cases and 2,856 controls from the Central Han; 934 cases and 2,020 controls from the Southern Han); and we followed up the top association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese. Meta-analysis identified genome-wide significant association of common SNPs with schizophrenia on chromosome 8p12 (rs16887244, P=1.27×10−10) and 1q24.2 (rs10489202, P=9.50×10−9). Our findings provide new insights into the pathogenesis of schizophrenia.

These results provide strong evidence of interactions between FKBP5 genotypes and early-life stress, which could pose a significant risk factor for stress-associated disorders such as major depression and PTSD.

The National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), provides a suite of database resources to support worldwide research activities in both academia and industry. With the explosive growth of multi-omics data, CNCB-NGDC is continually expanding, updating and enriching its core database resources through big data deposition, integration and translation. In the past year, considerable efforts have been devoted to 2019nCoVR, a newly established resource providing a global landscape of SARS-CoV-2 genomic sequences, variants, and haplotypes, as well as Aging Atlas, BrainBase, GTDB (Glycosyltransferases Database), LncExpDB, and TransCirc (Translation potential for circular RNAs). Meanwhile, a series of resources have been updated and improved, including BioProject, BioSample, GWH (Genome Warehouse), GVM (Genome Variation Map), GEN (Gene Expression Nebulas) as well as several biodiversity and plant resources. Particularly, BIG Search, a scalable, one-stop, cross-database search engine, has been significantly updated by providing easy access to a large number of internal and external biological resources from CNCB-NGDC, our partners, EBI and NCBI. All of these resources along with their services are publicly accessible at https://bigd.big.ac.cn.

The data in this study provide mechanistic insights into the dysregulation of the TNF-α gene in the brains of individuals who died by suicide, which could potentially be involved in suicidal behavior.