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Background Cardiometabolic diseases are highly comorbid, but their relationship with female‐specific or overwhelmingly female‐predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross‐trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to women. Methods and Results Using electronic health record data from 71 008 ancestrally diverse women, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index, coronary artery disease, type 2 diabetes, and hypertension) by performing 4 analyses: (1) cross‐trait genetic correlation analyses to compare genetic architecture, (2) polygenic risk score–based association tests to characterize shared genetic effects on disease risk, (3) Mendelian randomization for significant associations to assess cross‐trait causal relationships, and (4) chronology analyses to visualize the timeline of events unique to groups of women with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. We observed 27 significant associations between cardiometabolic polygenic scores and obstetrical/gynecological conditions (body mass index and endometrial cancer, body mass index and polycystic ovarian syndrome, type 2 diabetes and gestational diabetes, type 2 diabetes and polycystic ovarian syndrome). Mendelian randomization analysis provided additional evidence of independent causal effects. We also identified an inverse association between coronary artery disease and breast cancer. High cardiometabolic polygenic scores were associated with early development of polycystic ovarian syndrome and gestational hypertension. Conclusions We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female‐specific health conditions.

Cigarette smoke (CS) is the leading risk factor to develop COPD. Therefore, the pathologic effects of whole CS on the differentiation of primary small airway epithelial cells (SAEC) were investigated, using cells from three healthy donors and three COPD patients, cultured under ALI (air-liquid interface) conditions. The analysis of the epithelial physiology demonstrated that CS impaired barrier formation and reduced cilia beat activity. Although, COPD-derived ALI cultures preserved some features known from COPD patients, CS-induced effects were similarly pronounced in ALI cultures from patients compared to healthy controls. RNA sequencing analyses revealed the deregulation of marker genes for basal and secretory cells upon CS exposure. The comparison between gene signatures obtained from the in vitro model (CS vs. air) with a published data set from human epithelial brushes (smoker vs. non-smoker) revealed a high degree of similarity between deregulated genes and pathways induced by CS. Taken together, whole cigarette smoke alters the differentiation of small airway basal cells in vitro. The established model showed a good translatability to the situation in vivo. Thus, the model can help to identify and test novel therapeutic approaches to restore the impaired epithelial repair mechanisms in COPD, which is still a high medical need.

Summary Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation., Graphical abstract, Highlights • A multicohort study identifies 52 previously unknown osteoarthritis genetic risk variants • Similarities and differences in osteoarthritis genetic risk depend on joint sites • Osteoarthritis genetic components are associated with pain-related phenotypes • High-confidence effector genes highlight potential targets for drug intervention, A multicohort genome-wide association meta-analysis of osteoarthritis highlights the impact of joint site types on the features of genetic risk variants and the link between osteoarthritis genetics and pain-related phenotypes, pointing toward potential targets for therapeutic intervention.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. "Bronchiolization", characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1+ club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1+MUC5B+ club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1+SCGB3A2high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.

Background The human small airway epithelium (SAE) plays a central role in the early events in the pathogenesis of most inherited and acquired lung disorders. Little is known about the molecular phenotypes of the specific cell populations comprising the SAE in humans, and the contribution of SAE specific cell populations to the risk for lung diseases. Methods Drop-seq single-cell RNA-sequencing was used to characterize the transcriptome of single cells from human SAE of nonsmokers and smokers by bronchoscopic brushing. Results Eleven distinct cell populations were identified, including major and rare epithelial cells, and immune/inflammatory cells. There was cell type-specific expression of genes relevant to the risk of the inherited pulmonary disorders, genes associated with risk of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and (non-mutated) driver genes for lung cancers. Cigarette smoking significantly altered the cell type-specific transcriptomes and disease risk-related genes. Conclusions This data provides new insights into the possible contribution of specific lung cells to the pathogenesis of lung disorders.

Embryonic germ cell migration is a vital component of the germline lifecycle. The translocation of germ cells from the place of origin to the developing somatic gonad involves several processes including passive movements with underlying tissues, transepithelial migration, cell adhesion dynamics, the establishment of environmental guidance cues and the ability to sustain directed migration. How germ cells accomplish these feats in established model organisms will be discussed in this review, with a focus on recent discoveries and themes conserved across species.

Directional neuronal migration is mediated by a dynamic SDF1a source generated through localized SDF1a expression followed by regulated mRNA and protein turnover., During animal development, SDF1 simultaneously guides various cell types to different targets. As many targets are in close proximity to one another, it is unclear how the system avoids mistargeting. Zebrafish trigeminal sensory neurons express the SDF1 receptor Cxcr4b and encounter multiple SDF1 sources during migration, but ignore all but the correct one. We show that miR-430 and Cxcr7b regulation of SDF1a are required for precise guidance. In the absence of miR-430 or Cxcr7b, neurons responded to ectopic SDF1a sources along their route and did not reach their target. This was due to a failure to clear SDF1a transcript and protein from sites of expression that the migrating neurons had already passed. Our findings suggest an “attractive path” model in which migrating cells closely follow a dynamic SDF1a source that is refined on a transcript and protein level by miR-430 and Cxcr7b, respectively.

Under normal physiological conditions, cells use oxidants, particularly H2O2, for signal transduction during processes such as proliferation and migration. Though recent progress has been made in determining the precise role H2O2 plays in these processes, many gaps still remain. To further understand this, we describe the use of a dominant enhancer screen to identify novel components of a redox-regulated cell migration and adhesion pathway in Drosophila melanogaster. Here, we discuss our methodology and progress as well as the benefits and limitations of applying such an approach to study redox-regulated pathways. Depending on the nature of these pathways, unbiased genetic modifier screens may prove a productive way to identify novel redox-regulated signaling components.

Identifying genotypes and phenotypes that enhance an organism's ability to survive stress is of interest. We used Caenorhabditis elegans mutants, RNA interference (RNAi), and the chemical 5-fluorodeoxyuridine (FUDR) to test the hypothesis that a reduction in progeny would increase oxygen deprivation (anoxia) survival. In the hermaphrodite gonad, germ line processes such as spermatogenesis and oogenesis can be simultaneously as well as independently disrupted by genetic mutations. We analyzed genetic mutants [ glp-1(q158), glp-4(bn2ts), plc-1(rx1), ksr-1(ku68), fog-2(q71), fem-3(q20), spe-9(hc52ts), fer-15(hc15ts)] with reduced progeny production due to various reproductive defects. Furthermore, we used RNAi to inhibit the function of gene products in the RTK/Ras/MAPK signaling pathway, which is known to be involved in a variety of developmental processes including gonad function. We determined that reduced progeny production or complete sterility enhanced anoxia survival except in the case of sterile hermaphrodites [ spe-9(hc52ts), fer-15(hc15ts)] undergoing oocyte maturation and ovulation as exhibited by the presence of laid unfertilized oocytes. Furthermore, the fog-2(q71) long-term anoxia survival phenotype was suppressed when oocyte maturation and ovulation were induced by mating with males that have functional or nonfunctional sperm. The mutants with a reduced progeny production survive long-term anoxia in a daf-16- and hif-1-independent manner. Finally, we determined that wild-type males were able to survive long-term anoxia in a daf-16-independent manner. Together, these results suggest that the insulin signaling pathway is not the only mechanism to survive oxygen deprivation and that altering gonad function, in particular oocyte maturation and ovulation, leads to a physiological state conducive for oxygen deprivation survival.