Novel risk factors for craniofacial microsomia and assessment of their utility in clinic diagnosis.

Craniofacial microsomia (CFM, OMIM%164 210) is one of the most common congenital facial abnormalities worldwide, but it's genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify 15 significant (P < 5 × 10-8) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene Ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate that nine of them show dramatic expression change during early cranial NCC development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk-predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. Single-nucleotide polymorphism-based PRS is significantly associated with CFM [P = 7.22 × 10-58, odds ratio = 3.15, 95% confidence interval (CI) 2.74-3.63], and the top fifth percentile has a 6.8-fold CFM risk comparing with the 10th percentile. Father's smoking increases CFM risk as evidenced by interaction parameter of -0.324 (95% CI -0.578 to -0.070, P = 0.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction, and father's smoking is a key environmental risk factor for CFM through interacting with genetic factors.

Research progress on neural crest cells and neurocristopathies and its pathogenesis.

Neural crest cells (NCCs) are multipotent progenitor cells unique to vertebrates, and they have the ability to differentiate into a variety of cells, such as chondrocytes, neurons, and melanocytes. The formation, migration, and differentiation of NCCs are tightly regulated, and the disruption of NCC development results in abnormal embryo development. Neurocristopathies (NCPs) refer to a group of diseases that develop in response to abnormal development of NCCs. NCPs are of various types and exhibit complex phenotypes, which can affect many parts of the human body, such as the craniofacial structure, heart, intestine, and skin. NCPs negatively impact the physical function and mental health of the affected patients. NCPs account for one third of the defects in children with birth defects. Genetic factors are the main risk factors for NCPs, but environmental factors and abnormal gene-environment interactions can also lead to the development of NCPs. In this review, we introduce NCCs, NCPs, and their pathogenesis, so as to provide a reference point for a systematic understanding of NCPs and NCC development, and to provide scientific support for understanding the etiology of NCPs and their effective prevention and control.

Single-Cell RNA-Seq Reveals a Population of Smooth Muscle Cells Responsible for Atherogenesis.

Understanding the regional propensity differences of atherosclerosis (AS) development is hindered by the lack of animal models suitable for the study of the disease process. In this paper, we used 3S-ASCVD dogs, an ideal large animal human-like models for AS, to interrogate the heterogeneity of AS-prone and AS-resistant arteries; and at the single-cell level, identify the dominant cells involved in AS development. Here we present data from 3S-ASCVD dogs which reliably mimic human AS pathophysiology, predilection for lesion sites, and endpoint events. Our analysis combined bulk RNA-seq with single-cell RNA-seq to depict the transcriptomic profiles and cellular atlas of AS-prone and AS-resistant arteries in 3S-ASCVD dogs. Our results revealed the integral role of smooth muscle cells (SMCs) in regional propensity for AS. Notably, TNC+ SMCs were major contributors to AS development in 3S-ASCVD dogs, indicating enhanced extracellular matrix remodeling and transition to myofibroblasts during the AS process. Moreover, TNC+ SMCs were also present in human AS-prone carotid plaques, suggesting a potential origin of myofibroblasts and supporting the relevance of our findings. Our study provides a promising large animal model for pre-clinical studies of ASCVD and add novel insights surrounding the regional propensity of AS development in humans, which may lead to interventions that delay or prevent lesion progression and adverse clinical events.

Coding Variants are Relevant to the Expression of Obesity-Related Genes for Pediatric Adiposity.

OBJECTIVE: Heredity has a remarkable effect on obesity in an obesogenic environment. Despite the numerous genetic variants that contribute to obesity-related traits, none has been identified in Chinese children. This study aimed to identify novel variants associated with childhood obesity in China. METHODS: Promising single-nucleotide variants were obtained using whole-exome sequencing from 76 children who had obesity and 74 children with normal weight, and their associations with obesity-related traits in an additional 6,334-child cohort were investigated. The effects of the genome-wide significant (P < 5E-8) variants on the expression of the implicated genes in blood and adipose tissue were then depicted using transcriptome sequencing. RESULTS: Two coding variants associated with obesity with genome-wide significance were identified: rs1059491 (P = 2.57E-28) in SULT1A2 and rs189326455 (P = 8.98E-12) in MAP3K21. In addition, rs1059491 was also significantly associated with several obesity traits. Transcriptome sequencing demonstrated that rs1059491 and rs189326455 were expression quantitative trait loci relevant to the expression levels of several obesity-related genes, such as SULT1A2, ATXN2L, TUFM, and MAP3K21. CONCLUSIONS: This work identified two coding variants that were significantly associated with pediatric adiposity and were expression quantitative trait loci for obesity-related genes. This study provides new insights into the pathophysiology of Chinese childhood obesity.