Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (N cases = 270/N controls = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (P discovery+replication = 2.19 × 10 −12 , OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10 −8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10 −17 , HR = 0.91 [95% CI :0.89-0.93], for MI) and Million Veteran Program (P = 9.33 × 10 −36 , OR = 0.95 [95% CI: 0.94-0.96], for CAD; P = 3.35 × 10 −6 , OR = 0.96 [95% CI: 0.95-0.98] for MI). Here we report that SCADrelated MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.

Background: For over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These "bred High Responder" (bHR) and "bred Low Responder" (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders. Methods:Our study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n=46, P7: n=22, P14: n=49, P21: n=21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype.Results: Genetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8. Conclusion:These candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment..

2For over 16 years, we have selectively-bred rats to react differently to a novel, anxiety-3 inducing environment, exhibiting either high or low exploratory activity. These "bred High 4 Responder" (bHR) and "bred Low Responder" (bLR) rats serve as a general model for extreme 5 manifestations of behavioral inhibition and temperament, showing large differences in a variety 6 of internalizing and externalizing behaviors relevant to both mood and substance abuse 7 disorders. The current study elucidated persistent differences in gene expression related to 8 bHR/bLR phenotype across development (P7, P14, P21) and adulthood within the 9 hippocampus, a brain structure critical for emotional regulation. To do this, we meta-analyzed 10 eight transcriptional profiling datasets (microarray and RNA-Seq) spanning 43 generations of 11 selective breeding (n=2-6 rats per group per dataset; total n per meta-analysis: adult: n=46, P7: 12 n=22, P14: n=49, P21: n=21). By cross-referencing these results with a concurrent exome 13 sequencing study performed on our colony, we pinpointed several genes that are strongly 14 implicated in bHR/bLR behavioral phenotype, including two genes previously associated with 15 energy metabolism and mood: Thyrotropin releasing hormone receptor (Trhr) and the 16 mitochondrial protein Uncoupling protein 2 (Ucp2). Our meta-analysis also highlighted robust 17 bHR/bLR functional differences in the hippocampus, including a network essential for 18 neurodevelopmental programming, cell proliferation, and differentiation, which centered on the 19 hub genes Bone morphogenetic protein 4 (Bmp4) and the canonical Marker of proliferation 20 (Mki67). Another functional theme was microglial activation and phagocytosis, including 21 differential expression of pro-inflammatory Complement C1q A chain (C1qa) and the anti- 22inflammatory Milk fat globule-EGF factor 8 (Mfge8), situated within a chromosomal loci 23 implicated by our concurrent genetic study. Given the newly-discovered role of microglia in 24 synaptic pruning in relationship to neuronal activity during both development and adulthood, we 25 propose that these functional pathways have the capability to not only direct bHR and bLR rats 26 along a different developmental trajectory, but to set the stage for a widely-different reactivity to 27 the environment. 28 29 30 35 36 Both mood disorders and substance abuse disorders affect approximately 8-10% of 37 adults in the United States each year (1, 2). Due to high comorbidity, these disorders are often 38 classified as either internalizing and externalizing. Internalizing disorders are associated with 39 neuroticism, anxiety, and depression, whereas externalizing disorders are associated with 40 greater risk-taking and novelty-seeking, as seen in mania, substance abuse, and impulse-41 control disorders (3). This pattern of comorbidity is thought to represent a spectrum of latent 42 liability, which arises from a complex interplay of genetic risk and environmental factors, such as 43 stress and childhood adversity...

Crosstalk between multiple components underlies the formation of mature vessels. Although the players involved in angiogenesis have been identified, mechanisms underlying the crosstalk between them are still unclear. Using the ex vivo aortic ring assay, we set out to dissect the interactions between two key angiogenic signaling pathways, vascular endothelial growth factor (VEGF) and transforming growth factor β (TGFβ), with members of the lysyl oxidase (LOX) family of matrix modifying enzymes. We find an interplay between VEGF, TGFβ, and the LOXs is essential for the formation of mature vascular smooth muscle cells (vSMC)‐coated vessels. RNA sequencing analysis further identified an interaction with the endothelin‐1 pathway. Our work implicates endothelin‐1 downstream of TGFβ in vascular maturation and demonstrate the complexity of processes involved in generating vSMC‐coated vessels.

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva, and operative tissue when available, were collected. Among the 102 children were 13 having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection and RNASeq analysis of NF1, MAPK pathway genes, and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina, and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation, and increased MCP1 expression. In summary, NF-1 related RVH in children is rare but often severe and progressive and as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.