Variability in proliferative and migratory defects in Hirschsprung disease-associated pathogenic variants.

Despite the extensive genetic heterogeneity of Hirschsprung disease (HSCR; congenital colonic aganglionosis) 72% of patients harbor pathogenic variants in 10 genes that form a gene regulatory network (GRN) controlling the development of the enteric nervous system (ENS). Among these genes, the receptor tyrosine kinase gene RET is the most significant contributor, accounting for pathogenic variants in 12%-50% of patients depending on phenotype. RET plays a critical role in the proliferation and migration of ENS precursors, and defects in these processes lead to HSCR.

RET enhancer haplotype-dependent remodeling of the human fetal gut development program.

Hirschsprung disease (HSCR) is associated with deficiency of the receptor tyrosine kinase RET, resulting in loss of cells of the enteric nervous system (ENS) during fetal gut development. The major contribution to HSCR risk is from common sequence variants in RET enhancers with additional risk from rare coding variants in many genes. Here, we demonstrate that these RET enhancer variants specifically alter the human fetal gut development program through significant decreases in gene expression of RET, members of the RET-EDNRB gene regulatory network (GRN), other HSCR genes, with an altered transcriptome of 2,382 differentially expressed genes across diverse neuronal and mesenchymal functions.

A multi-enhancer regulatory code is disrupted in Hirschsprung disease.

The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within -regulatory elements (CREs) of the receptor tyrosine kinase gene , which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce gene expression, and dysregulate other ENS and HSCR genes in the gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in CREs that affect its gene expression.

Gender Differences in Predictors of Self-Reported Physical Aggression: Exploring Theoretically Relevant Dimensions among Adolescents from Santiago, Chile.

Research findings remain unclear on whether different factors predict aggression for adolescent men and women. Given that aggression research is rarely conducted with Latin American populations, the current study used multiple imputation and linear regression to assess gender differences in levels and predictors of self-reported physical aggression among a community sample of young (ages 11 through 17) men (=504) and women ( = 471) from Santiago, Chile. Results revealed that adolescent women reported engaging in higher levels of physical aggression than men.

Racial/Ethnic group differences in bipolar symptomatology in a community sample of persons with bipolar I disorder.

To better understand the problems associated with diagnosis of bipolar disorder, especially problems related to race and ethnicity, this study compared whites, African Americans, and Latinos with bipolar I disorder in the presentation of manic symptoms, depressive episodes, functional impairments (Short Form-12), and self-reports of schizophrenia diagnosis. Data for this study were derived from the 2001 National Epidemiologic Survey on Alcohol and Related Conditions, which are nationally representative of United States households. African Americans and Latinos expressed similar rates in presentation of 14 out of 16 manic symptoms compared with whites, with the exception of grandiosity/self-esteem, in which they were more likely to exhibit this symptom compared with whites.