Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

AbstractAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids

Seasonal variation in environmental DNA detection in sediment and water samples

The use of aquatic environmental DNA (eDNA) to detect the presence of species depends on the seasonal activity of the species in the sampled habitat. eDNA may persist in sediments for longer than it does in water, and analysing sediment could potentially extend the seasonal window for species assessment. Using the great crested newt as a model, we compare how detection probability changes across the seasons in eDNA samples collected from both pond water and pond sediments. Detection of both aquatic and sedimentary eDNA varied through the year, peaking in the summer (July), with its lowest point in the winter (January): in all seasons, detection probability of eDNA from water exceeded that from sediment. Detection probability of eDNA also varied between study areas, and according to great crested newt habitat suitability and sediment type. As aquatic and sedimentary eDNA show the same seasonal fluctuations, the patterns observed in both sample types likely reflect current or recent presence of the target species. However, given the low detection probabilities found in the autumn and winter we would not recommend using either aquatic or sedimentary eDNA for year-round sampling without further refinement and testing of the methods

<i>ERBB4</i> Mutant Alleles May Drive <i>BRAF</i> WT Melanomas

AbstractMetastatic skin cutaneous melanomas that contain wild-type BRAF alleles (“BRAF WT melanomas”) remain a significant clinical challenge, primarily because of the paucity of targets for therapeutic intervention. In prior work, in silico analyses of The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) dataset suggested that elevated transcription of the gene that encodes the ERBB4 receptor tyrosine kinase may drive BRAF WT melanomas. Moreover, that prior work demonstrated that expression of the wild-type ERBB4 gene (WT ERBB4) stimulates clonogenic proliferation by the MEL-JUSO, MeWo, and IPC-298 human BRAF WT melanoma cell lines. Moreover, expression of a dominant-negative (K751M) ERBB4 mutant (ERBB4 DN) inhibits clonogenic proliferation by the MEL-JUSO and MeWo cell lines.Here we have extended these findings by investigating the role of ERBB4 mutant alleles in BRAF WT melanomas. In silico analyses of the TCGA-SKCM BRAF WT melanoma dataset indicates that ERBB4 missense mutant alleles occur in a non-random manner, suggesting that melanomagenesis selects for the ERBB4 missense mutant alleles. Specifically, ERBB4 missense mutant alleles affect amino acid residues that are weakly correlated with residues conserved in the ERBB3 extracellular domains and the EGFR tyrosine kinase domain. The occurrence of ERBB4 missense mutant alleles in the TCGA-SKCM BRAF WT melanoma dataset is weakly inversely correlated with events that cause ERBB4-independent PI3K pathway signaling and is strongly correlated with events that cause elevated RAS pathway signaling. Thus, the in silico analyses suggest that ERBB4 mutant alleles stimulate PI3K signaling, which cooperates with elevated RAS signaling to drive BRAF WT melanomas. Moreover, the in silico analyses have prioritized the ERBB4 mutant alleles as candidate drivers of BRAF WT melanomas. One of the prioritized ERBB4 mutant alleles (P759L) stimulates greater clonogenic proliferation of MEL-JUSO cells than does WT ERBB4. Thus, our in silico prioritization strategy may effectively identify ERBB4 mutants that drive BRAF WT melanomas. Finally, the results of our in silico analyses suggest that ERBB4-dependent, BRAF WT melanomas may be effectively treated by a combination of a PI3K pathway inhibitor and a RAS pathway inhibitor.</jats:p