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The impact of sex on gene expression across human tissues.
Oliva M, Muñoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH, Cotter DJ, Parsana P, Kasela S, Balliu B, Viñuela A, Castel SE, Mohammadi P, Aguet F, Zou Y, Khramtsova EA, Skol AD, Garrido-Martín D, Reverter F, Brown A, Evans P, Gamazon ER, Payne A, Bonazzola R, Barbeira AN, Hamel AR, Martinez-Perez A, Soria JM, GTEx Consortium, Pierce BL, Stephens M, Eskin E, Dermitzakis ET, Segrè AV, Im HK, Engelhardt BE, Ardlie KG, Montgomery SB, Battle AJ, Lappalainen T, Guigó R, Stranger BE
(2020) Science 369:
MeSH Terms: Chromosomes, Human, X, Disease, Epigenesis, Genetic, Female, Gene Expression, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Promoter Regions, Genetic, Quantitative Trait Loci, Sex Characteristics, Sex Factors
Show Abstract · Added September 15, 2020
Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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15 MeSH Terms
Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic β-Cells.
Osipovich AB, Stancill JS, Cartailler JP, Dudek KD, Magnuson MA
(2020) Diabetes 69: 1476-1491
MeSH Terms: Animals, Calcium, Cells, Cultured, Diet, High-Fat, Female, Gene Expression Regulation, Glucose, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mitochondria, Overnutrition, Sex Characteristics, Transcriptome
Show Abstract · Added April 28, 2020
A sustained increase in intracellular Ca concentration (referred to hereafter as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic β-cell failure. To determine the additive effects of excitotoxicity and overnutrition on β-cell function and gene expression, we analyzed the impact of a high-fat diet (HFD) on knockout mice. Excitotoxicity caused β-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca channel blocker. Excitotoxicity, overnutrition, and the combination of both stresses caused similar but distinct alterations in the β-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid β-oxidation, and mitochondrial biogenesis and their key regulator Overnutrition worsened excitotoxicity-induced mitochondrial dysfunction, increasing metabolic inflexibility and mitochondrial damage. In addition, excitotoxicity and overnutrition, individually and together, impaired both β-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of β-cell epigenetic and transcriptional program. Sex had an impact on all β-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca, by altering mitochondrial function and impairing β-cell identity, augments overnutrition-induced β-cell failure.
© 2020 by the American Diabetes Association.
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BNST-insula structural connectivity in humans.
Flook EA, Feola B, Avery SN, Winder DG, Woodward ND, Heckers S, Blackford JU
(2020) Neuroimage 210: 116555
MeSH Terms: Adolescent, Adult, Cerebral Cortex, Diffusion Tensor Imaging, Echo-Planar Imaging, Female, Humans, Male, Middle Aged, Nerve Net, Septal Nuclei, Sex Characteristics, Sex Factors, Young Adult
Show Abstract · Added January 31, 2020
The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.
Published by Elsevier Inc.
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Diffusion time dependency along the human corpus callosum and exploration of age and sex differences as assessed by oscillating gradient spin-echo diffusion tensor imaging.
Tétreault P, Harkins KD, Baron CA, Stobbe R, Does MD, Beaulieu C
(2020) Neuroimage 210: 116533
MeSH Terms: Adult, Age Factors, Aged, Aging, Axons, Corpus Callosum, Diffusion Tensor Imaging, Female, Humans, Male, Middle Aged, Monte Carlo Method, Sex Characteristics, Young Adult
Show Abstract · Added March 5, 2020
Conventional diffusion imaging uses pulsed gradient spin echo (PGSE) waveforms with diffusion times of tens of milliseconds (ms) to infer differences of white matter microstructure. The combined use of these long diffusion times with short diffusion times (<10 ​ms) enabled by oscillating gradient spin echo (OGSE) waveforms can enable more sensitivity to changes of restrictive boundaries on the scale of white matter microstructure (e.g. membranes reflecting the axon diameters). Here, PGSE and OGSE images were acquired at 4.7 ​T from 20 healthy volunteers aged 20-73 years (10 males). Mean, radial, and axial diffusivity, as well as fractional anisotropy were calculated in the genu, body and splenium of the corpus callosum (CC). Monte Carlo simulations were also conducted to examine the relationship of intra- and extra-axonal radial diffusivity with diffusion time over a range of axon diameters and distributions. The results showed elevated diffusivities with OGSE relative to PGSE in the genu and splenium (but not the body) in both males and females, but the OGSE-PGSE difference was greater in the genu for males. Females showed positive correlations of OGSE-PGSE diffusivity difference with age across the CC, whereas there were no such age correlations in males. Simulations of radial diffusion demonstrated that for axon sizes in human brain both OGSE and PGSE diffusivities were dominated by extra-axonal water, but the OGSE-PGSE difference nonetheless increased with area-weighted outer-axon diameter. Therefore, the lack of OGSE-PGSE difference in the body is not entirely consistent with literature that suggests it is composed predominantly of axons with large diameter. The greater OGSE-PGSE difference in the genu of males could reflect larger axon diameters than females. The OGSE-PGSE difference correlation with age in females could reflect loss of smaller axons at older ages. The use of OGSE with short diffusion times to sample the microstructural scale of restriction implies regional differences of axon diameters along the corpus callosum with preliminary results suggesting a dependence on age and sex.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions.
Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS
(2020) J Clin Invest 130: 1336-1349
MeSH Terms: Animals, Antidepressive Agents, Female, GABAergic Neurons, Gene Knockout Techniques, Glutamate Decarboxylase, Interneurons, Ketamine, Male, Mice, Mice, Transgenic, Parvalbumins, Receptors, N-Methyl-D-Aspartate, Sex Characteristics, Somatostatin
Show Abstract · Added March 18, 2020
A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine's behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell-specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrated that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst) or parvalbumin (Pvalb), but not glutamate principle neurons in the medial prefrontal cortex (mPFC). Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.
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Sex differences in the genetic predictors of Alzheimer's pathology.
Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Bush WS, Gifford KA, Chibnik LB, Mukherjee S, De Jager PL, Kukull W, Crane PK, Resnick SM, Keene CD, Montine TJ, Schellenberg GD, Deming Y, Chao MJ, Huentelman M, Martin ER, Hamilton-Nelson K, Shaw LM, Trojanowski JQ, Peskind ER, Cruchaga C, Pericak-Vance MA, Goate AM, Cox NJ, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative, Bennett DA, Schneider JA, Jefferson AL, Hohman TJ
(2019) Brain 142: 2581-2589
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Sex Characteristics, tau Proteins
Show Abstract · Added March 30, 2020
Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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13 MeSH Terms
Long-term outcomes in mouse models of ischemia-reperfusion-induced acute kidney injury.
Scarfe L, Menshikh A, Newton E, Zhu Y, Delgado R, Finney C, de Caestecker MP
(2019) Am J Physiol Renal Physiol 317: F1068-F1080
MeSH Terms: Acute Kidney Injury, Animals, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Disease Models, Animal, Female, Fibrosis, Kidney Function Tests, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Nephrectomy, Reperfusion Injury, Sex Characteristics, Species Specificity
Show Abstract · Added May 10, 2020
Severe acute kidney injury has a high mortality and is a risk factor for progressive chronic kidney disease. None of the potential therapies that have been identified in preclinical studies have successfully improved clinical outcomes. This failure is partly because animal models rarely reflect the complexity of human disease: most preclinical studies are short term and are commonly performed in healthy, young, male mice. Therapies that are effective in preclinical models that share common clinical features seen in patients with acute kidney injury, including genetic diversity, different sexes, and comorbidities, and evaluate long-term outcomes are more likely to predict success in the clinic. Here, we evaluated susceptibility to chronic kidney disease after ischemia-reperfusion injury with delayed nephrectomy by monitoring long-term functional and histological responses to injury. We defined conditions required to induce long-term postinjury renal dysfunction and fibrosis without increased mortality in a reproducible way and evaluate effect of mouse strains, sexes, and preexisting diabetes on these responses.
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Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens.
Cadeddu Dessalvi C, Pepe A, Penna C, Gimelli A, Madonna R, Mele D, Monte I, Novo G, Nugara C, Zito C, Moslehi JJ, de Boer RA, Lyon AR, Tocchetti CG, Mercuro G
(2019) Heart Fail Rev 24: 915-925
MeSH Terms: Anthracyclines, Biomarkers, Cardiotonic Agents, Cardiotoxicity, Echocardiography, Female, Gonadal Steroid Hormones, Heart, Heart Failure, Humans, Magnetic Resonance Spectroscopy, Male, Mitochondria, Nuclear Medicine, Oxidative Stress, Prognosis, Reperfusion Injury, Risk Factors, Sex Characteristics
Show Abstract · Added November 12, 2019
Anthracyclines are the cornerstone for many oncologic treatments, but their cardiotoxicity has been recognized for several decades. Female subjects, especially before puberty and adolescence, or after menopause, seem to be more at increased risk, with the prognostic impact of this sex issue being less consistent compared to other cardiovascular risk factors. Several studies imply that sex differences could depend on the lack of the protective effect of sex hormones against the anthracycline-initiated damage in cardiac cells, or on differential mitochondria-related oxidative gene expression. This is also reflected by the results obtained with different diagnostic methods, such as cardiovascular biomarkers and imaging techniques (echocardiography, magnetic resonance, and nuclear medicine) in the diagnosis and monitoring of cardiotoxicity, confirming that sex differences exist. The same is true about protective strategies from anthracycline cardiotoxicity. Indeed, first studied to withstand oxidative damage in response to ischemia/reperfusion (I/R) injury, cardioprotection has different outcomes in men and women. A number of studies assessed the differences in I/R response between male and female hearts, with oxidative stress and apoptosis being shared mechanisms between the I/R and anthracyclines heart damage. Sex hormones can modulate these mechanisms, thus confirming their importance in the pathophysiology in cardioprotection not only from the ischemia/reperfusion damage, but also from anthracyclines, fueling further cardio-oncologic research on the topic.
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19 MeSH Terms
Sex modifies placental gene expression in response to metabolic and inflammatory stress.
Barke TL, Money KM, Du L, Serezani A, Gannon M, Mirnics K, Aronoff DM
(2019) Placenta 78: 1-9
MeSH Terms: Animals, Diabetes, Gestational, Diet, High-Fat, Female, Fetal Development, Fetus, Gene Expression, Inflammation, Male, Mice, Mice, Inbred C57BL, Obesity, Placenta, Pregnancy, Pregnancy Complications, Sex Characteristics, Stress, Physiological, Transcriptome
Show Abstract · Added April 15, 2019
INTRODUCTION - Metabolic stress (e.g., gestational diabetes mellitus (GDM) and obesity) and infections are common during pregnancy, impacting fetal development and the health of offspring. Such antenatal stresses can differentially impact male and female offspring. We sought to determine how metabolic stress and maternal immune activation (MIA), either alone or in combination, alters inflammatory gene expression within the placenta and whether the effects exhibited sexual dimorphism.
METHODS - Female C57BL/6 J mice were fed a normal diet or a high fat diet for 6 weeks prior to mating, with the latter diet inducing a GDM phenotype during pregnancy. Dams within each diet group at gestational day (GD) 12.5 received either an intraperitoneal injection of the viral mimic, polyinosinic:polycytidylic acid (poly(I:C)) or saline. Three hours post injection; placentae were collected and analyzed for changes in the expression of 248 unique immune genes.
RESULTS - Placental immune gene expression was significantly altered by GDM, MIA and the combination of the two (GDM+MIA). mRNA expression was generally lower in placentae of mice exposed to GDM alone compared with the other experimental groups, while mice exposed to MIA exhibited the highest transcript levels. Notably, fetal/placental sex influenced the responses of many immune genes to both metabolic and inflammatory stress.
DISCUSSION - GDM and MIA provoke inflammatory responses within the placenta and such effects exhibit sexual dimorphism. The combination of these stressors impacts the placenta differently than either condition alone. These findings may help explain sexual dimorphism observed in adverse pregnancy outcomes in human offspring exposed to similar stressors.
Copyright © 2019. Published by Elsevier Ltd.
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Sex-based differences in the incidence of inflammatory bowel diseases-pooled analysis of population-based studies from the Asia-Pacific region.
Shah SC, Khalili H, Chen CY, Ahn HS, Ng SC, Burisch J, Colombel JF
(2019) Aliment Pharmacol Ther 49: 904-911
MeSH Terms: Adolescent, Adult, Aged, Asia, Child, Child, Preschool, Cohort Studies, Female, Humans, Incidence, Infant, Infant, Newborn, Inflammatory Bowel Diseases, Male, Middle Aged, Pacific Ocean, Population Surveillance, Risk Factors, Sex Characteristics, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - There appear to be differences in risk factor profiles for IBD between Asia-Pacific and Western populations, which might suggest idiosyncrasies in pathogenesis. Recently, sex-based differences in IBD according to the age of diagnosis have been described in Western populations.
AIM - To identify whether sex-based differences in IBD incidence similarly exist across the age spectrum for Asia-Pacific populations.
METHODS - We identified Asia-Pacific population-based cohorts where IBD incidence data stratified by sex were available for the full age spectrum. Cohorts were included only if IBD diagnoses were confirmed and validated. We calculated incidence rate ratios of Crohn's disease (CD) and ulcerative colitis (UC) according to age and compared differences between males and females using random-effects meta-analysis.
RESULTS - Among 567.8 million people from 11 Asia-Pacific countries/provinces/nations, we identified 10 553 incident CD cases (7060 males; 3493 females) and 16 946 incident UC cases (9754 males; 7192 females). Starting in early adolescence until age 50 years, there was a 36%-64% higher incidence of CD in males vs females (P < 0.001). UC incidence ranged from 20%-42% higher in males vs females in the age groups between 15 and 65 years (P < 0.05).
CONCLUSIONS - In a pooled analysis of population-based studies from the Asia-Pacific region, we found a male predominance of both CD and UC for the majority of the age spectrum from adolescence to middle/late-middle age. Additional studies are needed to clarify biological and nonbiological determinants of sex differences in IBD, which might be distinct between Asia-Pacific and Western populations.
© 2019 John Wiley & Sons Ltd.
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20 MeSH Terms