Biology subjects

Stranger, B. E.

Publications and source records attributed to Stranger, B. E..

4 recordsLinked to original sources

bioRxiv2018

Sex differences in gene expression in response to ischemia in the human myocardium

Abstract and KeywordsO_ST_ABSBackgroundC_ST_ABSSex differences exist in the prevalence, presentation, and outcomes of ischemic heart disease. Females have higher risk of heart failure post myocardial infarction relative to males and the female sex is an independent risk factor for hospital and operative mortality after cardiac surgery. However, the mechanisms underlying this sexual dimorphism remain unclear. We examined sex differences in human myocardial gene expression in response to ischemia.\n\nMethodsLeft ventricular biopsies from 68 male and 46 female patients undergoing aortic valve replacement surgery were obtained at baseline and after a median 74 minutes of cold cardioplegic arrest/ischemia and respective transcriptomes were quantified by RNA-Seq. Sex-specific responses to ischemia were quantified by differential gene expression, expression quantitative trait loci (eQTL) and pathway and functional analysis. Cell-type enrichment analysis. was used to obtain an estimate of the identity and relative proportions of different cell types present in each sample.\n\nResultsA sex-specific response to ischemia was observed for 271 genes. Functional annotation analysis revealed sex-specific modulation of the oxytocin signaling pathway and common pathway of fibrin clot formation. The eQTL analysis identified variant-by-sex interaction eQTLs at baseline and post-ischemia, indicative of sex differences in the genotypic effects on gene expression, and cell-type enrichment analysis showed sex-bias in proportion of specific cell types.\n\nConclusionIn response to myocardial ischemia, the human left ventricle demonstrates changes in gene expression that differ between the sexes. These differences provide insight into the sexual dimorphism of ischemic heart disease and may aid in the development of sex-specific therapies that reduce myocardial injury.

genomics↗

bioRxiv2017

Sex differences in the genetic architecture of obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD), a highly heritable complex phenotype, demonstrates sexual dimorphism in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sexual-dimorphism including a sexually dimorphic liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, genetic and phenotypic heterogeneity, and sex-specific pleiotropic effects. We observed a strong genetic correlation between male and female OCD and no evidence for a sexually dimorphic liability threshold model. While we did not detect any sex-specific genome-wide associations, we observed that the SNPs with sexually dimorphic effects showed an enrichment of regulatory variants influencing expression of genes in immune tissues. Furthermore, top sex-specific genome-wide associations were enriched for regulatory variants in different tissues, suggesting evidence for potential sex difference in the biology underlying risk for OCD. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific risk factors for OCD, significantly advancing our understanding of the differences in the genetic basis of sexually dimorphic neuropsychiatric traits.

genomics↗

bioRxiv2017

Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection

While the impact of common genetic variants on gene expression response to cellular stimuli has been analyzed in depth, less is known about how stimulation modulates the genetic control of isoform usage. Analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to viral infection and stimulation with type I interferon. We identified more than a thousand single nucleotide polymorphisms associated with isoform usage (isoQTLs), > 40% of which are independent of expression QTLs for the same gene. Compared to eQTLs, isoQTLs are enriched for splice sites and untranslated regions, and depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs in stimulated cells explain a significant proportion of the disease heritability attributed to common genetic variants. At the IRF7 locus, we found alternative promoter usage in response to influenza as a possible mechanism by which DNA variants previously associated with immune-related disorders mediate disease risk. At the ERAP2 locus, we shed light on the function of the major haplotype that has been maintained under long-term balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with absence of ERAP2 expression while the minor haplotype, known to increase Crohns disease risk, is associated with high ERAP2 expression. Surprisingly, in response to influenza infection, the major haplotype results in the expression of two uncharacterized, alternatively transcribed, spliced and translated short isoforms. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in the innate immune response, and in the case of ERAP2, may confer a historical fitness advantage in response to virus.

genomics↗

bioRxiv2017

Polygenic selection underlies evolution of human brain structure and behavioral traits

Seemingly paradoxical characteristics of psychiatric disorders, including moderate to high prevalence, reduced fecundity, and high heritability have motivated explanations for the persistence of common risk alleles for severe psychiatric phenotypes throughout human evolution. Proposed mechanisms include balancing selection, drift, and weak polygenic adaptation acting either directly, or indirectly through selection on correlated traits. While many mechanisms have been proposed, few have been empirically tested. Leveraging publicly available data of unprecedented sample size, we studied twenty-five traits (i.e., ten neuropsychiatric disorders, three personality traits, total intracranial volume, seven subcortical brain structure volume traits, and four complex traits without neuropsychiatric associations) for evidence of several different signatures of selection over a range of evolutionary time scales. Consistent with the largely polygenic architecture of neuropsychiatric traits, we found no enrichment of trait-associated single-nucleotide polymorphisms (SNPs) in regions of the genome that underwent classical selective sweeps (i.e., events which would have driven selected alleles to near fixation). However, we discovered that SNPs associated with some, but not all, behaviors and brain structure volumes are enriched in genomic regions under selection since divergence from Neanderthals ~600,000 years ago, and show further evidence for signatures of ancient and recent polygenic adaptation. Individual subcortical brain structure volumes demonstrate genome-wide evidence in support of a mosaic theory of brain evolution while total intracranial volume and height appear to share evolutionary constraints consistent with concerted evolution. We further characterized the biological processes potentially targeted by selection, through expression Quantitative Trait Locus (eQTL) and Gene Ontology (GO) enrichment analyses and found evidence for the role of regulatory functions among selected SNPs in immune and brain tissues. Taken together, our results suggest that alleles associated with neuropsychiatric, behavioral, and brain volume phenotypes have experienced both ancient and recent polygenic adaptation in human evolution, acting through neurodevelopmental and immune-mediated pathways.

evolutionary biology↗