No abstract

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 fifteen 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 nine of them show dramatic expression change during early cranial NCCs 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. SNP-based PRS is significantly associated with CFM (P = 7.22 × 10−58, OR = 3.15, 95% CI 2.74 to 3.63) and the top fifth percentile has a 6.8-fold CFM risk comparing to the tenth 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 smoking is a key environmental risk factor for CFM through interacting with genetic factors.

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.

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.

Treacher Collins syndrome (TCS, MIM #154500) is a severe congenital disorder implicated in particular dysplasia of the craniofacial bones, accompanied by downslanting palpebral fissures, lower eyelid colobomas, microtia, or other craniofacial malformations. However, the underlying pathogenic mutations in TCS are still unknown, and elucidating these is of primary importance for TCS researchers. We collected samples from a Chinese TCS family, including the proband and two parents. Sequencing, genotyping, and in silico analyses were employed to detect pathogenic mutations in the pedigree. In the proband, a de novo frameshift mutation of TCOF1 c.1562_1574del (p.A521fs) was identified as a pathogenic candidate, while the parents showed no mutations. The frameshift mutation results in TCOF1 truncation and damages the central repeat domain, which is the binding site for transcriptional factors. In conclusion, we identified a novel mutation TCOF1 c.1562_1574del, which is likely a pathogenic mutation for TCS, thereby expanding the mutation spectrum of TCS.