Publications by authors named "Rick Jansen"

94 Publications

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 09 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 2021

WeFaceNano: a user-friendly pipeline for complete ONT sequence assembly and detection of antibiotic resistance in multi-plasmid bacterial isolates.

BMC Microbiol 2021 06 7;21(1):171. Epub 2021 Jun 7.

Department of Pathology, Clinical Bioinformatics Unit, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands.

Background: Bacterial plasmids often carry antibiotic resistance genes and are a significant factor in the spread of antibiotic resistance. The ability to completely assemble plasmid sequences would facilitate the localization of antibiotic resistance genes, the identification of genes that promote plasmid transmission and the accurate tracking of plasmid mobility. However, the complete assembly of plasmid sequences using the currently most widely used sequencing platform (Illumina-based sequencing) is restricted due to the generation of short sequence lengths. The long-read Oxford Nanopore Technologies (ONT) sequencing platform overcomes this limitation. Still, the assembly of plasmid sequence data remains challenging due to software incompatibility with long-reads and the error rate generated using ONT sequencing. Bioinformatics pipelines have been developed for ONT-generated sequencing but require computational skills that frequently are beyond the abilities of scientific researchers. To overcome this challenge, the authors developed 'WeFaceNano', a user-friendly Web interFace for rapid assembly and analysis of plasmid DNA sequences generated using the ONT platform. WeFaceNano includes: a read statistics report; two assemblers (Miniasm and Flye); BLAST searching; the detection of antibiotic resistance- and replicon genes and several plasmid visualizations. A user-friendly interface displays the main features of WeFaceNano and gives access to the analysis tools.

Results: Publicly available ONT sequence data of 21 plasmids were used to validate WeFaceNano, with plasmid assemblages and anti-microbial resistance gene detection being concordant with the published results. Interestingly, the "Flye" assembler with "meta" settings generated the most complete plasmids.

Conclusions: WeFaceNano is a user-friendly open-source software pipeline suitable for accurate plasmid assembly and the detection of anti-microbial resistance genes in (clinical) samples where multiple plasmids can be present.
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http://dx.doi.org/10.1186/s12866-021-02225-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186029PMC
June 2021

Metabolomic profiles discriminating anxiety from depression.

Acta Psychiatr Scand 2021 08 25;144(2):178-193. Epub 2021 May 25.

Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, the Netherlands.

Objective: Depression has been associated with metabolomic alterations. Depressive and anxiety disorders are often comorbid diagnoses and are suggested to share etiology. We investigated whether differential metabolomic alterations are present between anxiety and depressive disorders and which clinical characteristics of these disorders are related to metabolomic alterations.

Methods: Data were from the Netherlands Study of Depression and Anxiety (NESDA), including individuals with current comorbid anxiety and depressive disorders (N = 531), only a current depression (N = 304), only a current anxiety disorder (N = 548), remitted depressive and/or anxiety disorders (N = 897), and healthy controls (N = 634). Forty metabolites from a proton nuclear magnetic resonance lipid-based metabolomics panel were analyzed. First, we examined differences in metabolites between disorder groups and healthy controls. Next, we assessed whether depression or anxiety clinical characteristics (severity and symptom duration) were associated with metabolites.

Results: As compared to healthy controls, seven metabolomic alterations were found in the group with only depression, reflecting an inflammatory (glycoprotein acetyls; Cohen's d = 0.12, p = 0.002) and atherogenic-lipoprotein-related (e.g., apolipoprotein B: Cohen's d = 0.08, p = 0.03, and VLDL cholesterol: Cohen's d = 0.08, p = 0.04) profile. The comorbid group showed an attenuated but similar pattern of deviations. No metabolomic alterations were found in the group with only anxiety disorders. The majority of metabolites associated with depression diagnosis were also associated with depression severity; no associations were found with anxiety severity or disease duration.

Conclusion: While substantial clinical overlap exists between depressive and anxiety disorders, this study suggests that altered inflammatory and atherogenic-lipoprotein-related metabolomic profiles are uniquely associated with depression rather than anxiety disorders.
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http://dx.doi.org/10.1111/acps.13310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361773PMC
August 2021

Methods and Techniques to Facilitate the Development of NT as an Effective, Therapeutic Oncolytic Bacteria.

Front Microbiol 2021 29;12:624618. Epub 2021 Mar 29.

Cell and Molecular Biology Program, North Dakota State University, Fargo, ND, United States.

The tumor microenvironment is characterized by anomalous vascularization, hypoxia, and acidity at the core of solid tumors that culminates in concentrated necrosis and immune system dysregulation among other effects. While this environment presents several challenges for the development of oncotherapeutics that deliver their activity via the enhanced permeability and retention (EPR) effect of the leaky blood vessels around a tumor, oncolytic bacteria, or a class of bacteria with a noted capacity to lyse solid tumors, are attracted to the very environment found at the center of solid tumors that confounds other therapeutics. It is this capacity that allows for a potent, active penetration from the tumor margins into the core, and subsequent colonization to facilitate lysis and immune reactivation. in particular has recently shown great promise in preclinical and clinical trials when administered directly to the tumor. These studies indicate that is uniquely poised to effectively accomplish the long sought after "holy grail" of oncotherapeutics: selective tumor localization via intravenous delivery. This study reports the development of efficient methods that facilitate experimental work and therapeutic translation of including the ability to work with this obligate micro-anaerobe on the benchtop. Additionally, this study seeks to utilize this newfound experimental flexibility to address several gaps in the current knowledge regarding the efficacy of CRIPSR/Cas9-mediated gene insertion in this species to further develop this oncolytic bacteria and the genetic customization of bacteria in general.
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http://dx.doi.org/10.3389/fmicb.2021.624618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039391PMC
March 2021

Effects of dietary interventions on depressive symptom profiles: results from the MooDFOOD depression prevention study.

Psychol Med 2021 Apr 7:1-10. Epub 2021 Apr 7.

Department of Psychiatry, Amsterdam UMC, Vrije Universiteit, Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, The Netherlands.

Background: Dietary interventions did not prevent depression onset nor reduced depressive symptoms in a large multi-center randomized controlled depression prevention study (MooDFOOD) involving overweight adults with subsyndromal depressive symptoms. We conducted follow-up analyses to investigate whether dietary interventions differ in their effects on depressive symptom profiles (mood/cognition; somatic; atypical, energy-related).

Methods: Baseline, 3-, 6-, and 12-month follow-up data from MooDFOOD were used (n = 933). Participants received (1) placebo supplements, (2) food-related behavioral activation (F-BA) therapy with placebo supplements, (3) multi-nutrient supplements (omega-3 fatty acids and a multi-vitamin), or (4) F-BA therapy with multi-nutrient supplements. Depressive symptom profiles were based on the Inventory of Depressive Symptomatology.

Results: F-BA therapy was significantly associated with decreased severity of the somatic (B = -0.03, p = 0.014, d = -0.10) and energy-related (B = -0.08, p = 0.001, d = -0.13), but not with the mood/cognition symptom profile, whereas multi-nutrient supplementation was significantly associated with increased severity of the mood/cognition (B = 0.05, p = 0.022, d = 0.09) and the energy-related (B = 0.07, p = 0.002, d = 0.12) but not with the somatic symptom profile.

Conclusions: Differentiating depressive symptom profiles indicated that food-related behavioral interventions are most beneficial to alleviate somatic symptoms and symptoms of the atypical, energy-related profile linked to an immuno-metabolic form of depression, although effect sizes were small. Multi-nutrient supplements are not indicated to reduce depressive symptom profiles. These findings show that attention to clinical heterogeneity in depression is of importance when studying dietary interventions.
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http://dx.doi.org/10.1017/S0033291721000337DOI Listing
April 2021

Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response.

Cancer Res 2021 04 8;81(7):1667-1680. Epub 2021 Feb 8.

Target Discovery Institute, University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom.

Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies. SIGNIFICANCE: These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0177DOI Listing
April 2021

An integrative study of five biological clocks in somatic and mental health.

Elife 2021 Feb 9;10. Epub 2021 Feb 9.

Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, Netherlands.

Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants. Correlations between biological aging indicators were small (all < 0.2), indicating little overlap. The most consistent associations of advanced biological aging were found for male sex, higher body mass index (BMI), metabolic syndrome, smoking, and depression. As compared to the individual clocks, a composite index of all five clocks showed most pronounced associations with health determinants. The large effect sizes of the composite index and the low correlation between biological aging indicators suggest that one's biological age is best reflected by combining aging measures from multiple cellular levels.
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http://dx.doi.org/10.7554/eLife.59479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872513PMC
February 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 06 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Associations between oil development and sexually transmitted infections: Public health nurse perspectives.

Public Health Nurs 2021 01 20;38(1):4-12. Epub 2020 Nov 20.

Department of Public Health, North Dakota State University, Fargo, ND, USA.

Background: Oil development (OD) has been associated with increased sexually transmitted infection (STI) rates, with limited focus on the North Dakota (ND) oil boom. Public health (PH) nurse experiences can provide context related to health challenges during OD-related population booms.

Objective: To compare reported STI rates in ND oil-producing (OP) and non-oil-producing (NOP) counties before, during, and after the oil boom and describe PH nurse experiences during this time.

Design: We conducted secondary data analysis of oil production data and reported rates for chlamydia and gonorrhea, and conducted interviews with ND PH nurses.

Sample: PH nurses within ND counties geographically located in or near OD in the state.

Measurements: ND county-level OD data trends were compared to similarly timed reported rates of chlamydia and gonorrhea in OP and NOP counties. PH nurse interviews were conducted addressing their STI-related experiences working in PH during the oil boom.

Results: Significant findings include a correlation between OD and gonorrhea rates. PH nurses described a limited PH infrastructure to meet the health needs of a transient, increasing population.

Conclusions: Expanding the role of PH nurses in ND to implement STI screening and treatment would improve access to STI testing allowing for comprehensive reporting of STIs.
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http://dx.doi.org/10.1111/phn.12836DOI Listing
January 2021

Comparison of Illumina versus Nanopore 16S rRNA Gene Sequencing of the Human Nasal Microbiota.

Genes (Basel) 2020 09 21;11(9). Epub 2020 Sep 21.

Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center (Erasmus MC), 3015 CN Rotterdam, The Netherlands.

Illumina and nanopore sequencing technologies are powerful tools that can be used to determine the bacterial composition of complex microbial communities. In this study, we compared nasal microbiota results at genus level using both Illumina and nanopore 16S rRNA gene sequencing. We also monitored the progression of nanopore sequencing in the accurate identification of species, using pure, single species cultures, and evaluated the performance of the nanopore EPI2ME 16S data analysis pipeline. Fifty-nine nasal swabs were sequenced using Illumina MiSeq and Oxford Nanopore 16S rRNA gene sequencing technologies. In addition, five pure cultures of relevant bacterial species were sequenced with the nanopore sequencing technology. The Illumina MiSeq sequence data were processed using bioinformatics modules present in the Mothur software package. Albacore and Guppy base calling, a workflow in nanopore EPI2ME (Oxford Nanopore Technologies-ONT, Oxford, UK) and an in-house developed bioinformatics script were used to analyze the nanopore data. At genus level, similar bacterial diversity profiles were found, and five main and established genera were identified by both platforms. However, probably due to mismatching of the nanopore sequence primers, the nanopore sequencing platform identified in much lower abundance compared to Illumina sequencing. Further, when using default settings in the EPI2ME workflow, almost all sequence reads that seem to belong to the bacterial genus and a considerable part to the genus were only identified at family level. Nanopore sequencing of single species cultures demonstrated at least 88% accurate identification of the species at genus and species level for 4/5 strains tested, including improvements in accurate sequence read identification when the basecaller Guppy and Albacore, and when flowcell versions R9.4 (Oxford Nanopore Technologies-ONT, Oxford, UK) and R9.2 (Oxford Nanopore Technologies-ONT, Oxford, UK) were compared. In conclusion, the current study shows that the nanopore sequencing platform is comparable with the Illumina platform in detection bacterial genera of the nasal microbiota, but the nanopore platform does have problems in detecting bacteria within the genus . Although advances are being made, thorough validation of the nanopore platform is still recommendable.
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http://dx.doi.org/10.3390/genes11091105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565314PMC
September 2020

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference.

Genome Biol 2020 08 28;21(1):220. Epub 2020 Aug 28.

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.

Background: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.

Results: By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation.

Conclusion: We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.
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http://dx.doi.org/10.1186/s13059-020-02114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453518PMC
August 2020

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies.

Cancers (Basel) 2020 Aug 24;12(9). Epub 2020 Aug 24.

Leroy T. Canoles Jr. Cancer Research Center, Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA.

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.
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http://dx.doi.org/10.3390/cancers12092392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565566PMC
August 2020

Unmet Clinical Need: Developing Prognostic Biomarkers and Precision Medicine to Forecast Early Tumor Relapse, Detect Chemo-Resistance and Improve Overall Survival in High-Risk Breast Cancer.

Ann Breast Cancer Ther 2020 May;4(1):48-57

Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, USA.

Chemo-resistant breast cancer is a major barrier to curative treatment for a significant number of women with breast cancer. Neoadjuvant chemotherapy (NACT) is standard first- line treatment for most women diagnosed with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. Current clinical prognostic tools evaluate four clinicopathological factors: Tumor size, LN status, pathological stage, and tumor molecular subtype. However, many similarly treated patients with identical residual cancer burden (RCB) following NACT experience distinctly different tumor relapse rates, clinical outcomes and survival. This problem is particularly apparent for incomplete responders with a high-risk RCB classification following NACT. Therefore, there is a pressing need to identify new prognostic and predictive biomarkers, and develop novel curative therapies to augment current standard of care (SOC) treatment regimens to save more lives. Here, we will discuss these unmet needs and clinical challenges that stand in the way of precision medicine and personalized cancer therapy.
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http://dx.doi.org/10.36959/739/525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295150PMC
May 2020

Associations between depressive symptom profiles and immunometabolic characteristics in individuals with depression and their siblings.

World J Biol Psychiatry 2021 02 19;22(2):128-138. Epub 2020 May 19.

Department of Psychiatry, Amsterdam UMC, Department of Amsterdam Public Health research institute and Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Objectives: The present study examined associations between immunometabolic characteristics (IMCs) and depressive symptom profiles (DSPs) in probands with lifetime diagnoses of depression and/or anxiety disorders and their siblings.

Methods: Data were from the Netherlands Study of Depression and Anxiety, comprising 256 probands with lifetime diagnoses of depression and/or anxiety and their 380 siblings. Measured IMCs included blood pressure, waist circumference, and levels of glucose, triglycerides, HDL cholesterol, CRP, TNF-α and IL-6. DSPs included mood, cognitive, somatic and atypical-like profiles. We cross-sectionally examined whether DSPs were associated with IMCs within probands and within siblings, and whether DSPs were associated with IMCs between probands and siblings.

Results: Within probands and within siblings, higher BMI and waist circumference were associated with higher somatic and atypical-like profiles. Other IMCs (IL-6, glucose and HDL cholesterol) were significantly related to DSPs either within probands or within siblings. DSPs and IMCs were not associated between probands and siblings.

Conclusions: The results suggest that there is a familial component for each trait, but no common familial factors for the association between DSPs and IMCs. Alternative mechanisms, such as direct causal effects or non-shared environmental risk factors, may better fit these results.
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http://dx.doi.org/10.1080/15622975.2020.1761562DOI Listing
February 2021

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

Mol Psychiatry 2019 Dec 6. Epub 2019 Dec 6.

University Medical Centre Hamburg-Eppendorf, House W34, 3.OG, Martinistr. 52, 20246, Hamburg, Germany.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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http://dx.doi.org/10.1038/s41380-019-0605-zDOI Listing
December 2019

Epigenomics of Pancreatic Cancer: A Critical Role for Epigenome-Wide Studies.

Epigenomes 2019 Mar 19;3(1). Epub 2019 Jan 19.

Department of Public Health, North Dakota State University, Fargo, ND 58102, USA.

Several challenges present themselves when discussing current approaches to the prevention or treatment of pancreatic cancer. Up to 45% of the risk of pancreatic cancer is attributed to unknown causes, making effective prevention programs difficult to design. The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is generally diagnosed at a late stage, leading to a poor prognosis and 5-year survival estimate. PDAC tumors are heterogeneous, leading to many identified cell subtypes within one patient's primary tumor. This explains why there is a high frequency of tumors that are resistant to standard treatments, leading to high relapse rates. This review will discuss how epigenetic technologies and epigenome-wide association studies have been used to address some of these challenges and the future promises these approaches hold.
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http://dx.doi.org/10.3390/epigenomes3010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879055PMC
March 2019

Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies.

Genome Biol 2019 11 14;20(1):235. Epub 2019 Nov 14.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: A large number of analysis strategies are available for DNA methylation (DNAm) array and RNA-seq datasets, but it is unclear which strategies are best to use. We compare commonly used strategies and report how they influence results in large cohort studies.

Results: We tested the associations of DNAm and RNA expression with age, BMI, and smoking in four different cohorts (n = ~ 2900). By comparing strategies against the base model on the number and percentage of replicated CpGs for DNAm analyses or genes for RNA-seq analyses in a leave-one-out cohort replication approach, we find the choice of the normalization method and statistical test does not strongly influence the results for DNAm array data. However, adjusting for cell counts or hidden confounders substantially decreases the number of replicated CpGs for age and increases the number of replicated CpGs for BMI and smoking. For RNA-seq data, the choice of the normalization method, gene expression inclusion threshold, and statistical test does not strongly influence the results. Including five principal components or excluding correction of technical covariates or cell counts decreases the number of replicated genes.

Conclusions: Results were not influenced by the normalization method or statistical test. However, the correction method for cell counts, technical covariates, principal components, and/or hidden confounders does influence the results.
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http://dx.doi.org/10.1186/s13059-019-1878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857161PMC
November 2019

Resurgence of Syphilis in the United States: An Assessment of Contributing Factors.

Infect Dis (Auckl) 2019 16;12:1178633719883282. Epub 2019 Oct 16.

Department of Public Health, North Dakota State University, Fargo, ND, USA.

In the last decade, there has been a marked resurgence of syphilis in the United States despite the availability of effective treatments and previously reliable prevention strategies. The majority of cases are among the population of men who have sex with men (MSM); however, there has also been a recent increase among premenopausal women, coinciding with a concerning rise of congenital cases. The resurgence of syphilis can be largely attributed to changing social and behavioral factors, especially among young MSM. The biological association of syphilis with human immunodeficiency virus (HIV) transmission and acquisition is particularly alarming because of the increased individual and healthcare burden. In addition, some individual actions and public health efforts that are meant to reduce the risk of acquiring HIV may actually lead to risk compensation that facilitates the transmission of syphilis. Untreated syphilis is associated with detrimental health outcomes; therefore, both effective prevention strategies and treatment of this systemic disease have important short-term and long-term public health implications. This article offers a review of social and behavioral factors contributing to the current resurgence and recommendations for reducing syphilis incidence through medical and public health prevention strategies.
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http://dx.doi.org/10.1177/1178633719883282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798162PMC
October 2019

Disparities in Secondary Prevention of Atherosclerotic Heart Disease After Coronary Artery Bypass Grafting in Northern Plains American Indians.

Health Equity 2019 24;3(1):520-526. Epub 2019 Oct 24.

Department of Surgery, University of North Dakota School of Medicine and Health Sciences, Fargo, North Dakota.

Cardiovascular disease has become the leading cause of death in American Indians (AIs). For patients with severe disease requiring coronary artery bypass grafting (CABG), AIs have been demonstrated to present with increased risk factors. Guideline-directed medical therapy after CABG effectively reduces mortality and recurrent ischemic events in all patients and is especially important in high-risk populations such as AIs. Isolated CABG patients between 2012 and 2017 were studied and 74 AI patients were identified. Propensity matching was performed and the resulting 148 patients were followed for a year after surgery. Guideline-directed medical therapy (GDMT) for secondary prevention of atherosclerotic disease after CABG was detailed in all patients. GDMT was similar between groups (85% AI vs. 89% non-AI; =NS), and the incidence of prescribed antiplatelet medications, beta-blockers, and statins was similar. AIs were more likely to receive insulin therapy (=0.002) and opioids (=0.03) at discharge, while non-AIs were more likely to receive anti-arrhythmic medications (=0.002). One year after discharge, GDMT trended lower in AIs (75% AI vs. 85% non-AI; =0.2) and AIs were less likely to be on a statin 1 year after surgery (81% AI vs. 93% non-AI; =0.04). Opioid use trended higher after 1 year in AIs (28% AI vs. 18% non-AI; =NS) and fewer AI patients participated in cardiac rehabilitation (CR) after CABG. Disparities in GDMT for secondary prevention of coronary artery disease after CABG exist, with fewer AI patients receiving statins and undergoing CR 1 year after surgery. Increased use of opioids in AIs is troubling and deserves further investigation. Improved adherence to GDMT would be expected to improve long-term outcomes after CABG in this high risk population.
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http://dx.doi.org/10.1089/heq.2019.0030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814079PMC
October 2019

A characterization of cis- and trans-heritability of RNA-Seq-based gene expression.

Eur J Hum Genet 2020 02 26;28(2):253-263. Epub 2019 Sep 26.

Department of Biological Psychology, Amsterdam Public Health research institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Insights into individual differences in gene expression and its heritability (h) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h, composed of cis-heritability (h, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h, the residual variance explained by all other genome-wide variants). Mean h was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h = 0.14, p = 6.15 × 10). Mean h was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, ρ = 0.76, p < 10) and with estimates from earlier RNA-Seq-based studies. Mean h was 0.20 and correlated with the beta of the corresponding trans-eQTL (ρ = 0.04, p < 1.89 × 10) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 × 10), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.
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http://dx.doi.org/10.1038/s41431-019-0511-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974598PMC
February 2020

The effect of age on DNA methylation in whole blood among Bangladeshi men and women.

BMC Genomics 2019 Sep 10;20(1):704. Epub 2019 Sep 10.

Department of Public Health Sciences, University of Chicago, 5841 S. Maryland Ave., W264, MC2000, Chicago, IL, 60637, USA.

Background: It is well-known that methylation changes occur as humans age, however, understanding how age-related changes in DNA methylation vary by sex is lacking. In this study, we characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. We used the Illumina HumanMethylation 450 K array and DNA derived from whole blood for 400 adult participants (189 males and 211 females) from Bangladesh to identify age-associated CpG sites and regions and characterize the location of these age-associated sites with respect to CpG islands (vs. shore, shelf, or open sea) and gene regions (vs. intergenic). We conducted a genome-wide search for age-associated CpG sites (among 423,604 sites) using a reference-free approach to adjust for cell type composition (the R package RefFreeEWAS) and performed an independent replication analysis of age-associated CpGs.

Results: The number of age-associated CpGs (p < 5 x 10) were 986 among men and 3479 among women of which 2027(63.8%) and 572 (64.1%) replicated (using Bonferroni adjusted p < 1.2 × 10). For both sexes, age-associated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Although we observed strong correlation between chronological age and previously-developed epigenetic age models (r ≈ 0.8), among our top (based on lowest p-value) age-associated CpG sites only 12 for males and 44 for females are included in these prediction models, and the median chronological age compared to predicted age was 44 vs. 51.7 in males and 45 vs. 52.1 in females.

Conclusions: Our results describe genome-wide features of age-related changes in DNA methylation. The observed associations between age and methylation were generally consistent for both sexes, although the associations tended to be stronger among women. Our population may have unique age-related methylation changes that are not captured in the established methylation-based age prediction model we used, which was developed to be non-tissue-specific.
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http://dx.doi.org/10.1186/s12864-019-6039-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734473PMC
September 2019

A methylation study of long-term depression risk.

Mol Psychiatry 2020 06 9;25(6):1334-1343. Epub 2019 Sep 9.

Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.

Recurrent and chronic major depressive disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P = 2.0 × 10). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genome-wide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future.
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http://dx.doi.org/10.1038/s41380-019-0516-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061076PMC
June 2020

Involvement of inflammatory gene expression pathways in depressed patients with hyperphagia.

Transl Psychiatry 2019 08 20;9(1):193. Epub 2019 Aug 20.

Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health research institute and Amsterdam Neuroscience, Oldenaller 1, 1081 HJ, Amsterdam, the Netherlands.

The pathophysiology of major depressive disorder (MDD) is highly heterogeneous. Previous evidence at the DNA level as well as on the serum protein level suggests that the role of inflammation in MDD pathology is stronger in patients with hyperphagia during an active episode. Which inflammatory pathways differ in MDD patients with hyperphagia inflammatory pathways in terms of gene expression is unknown. We analyzed whole-blood gene expression profiles of 881 current MDD cases and 331 controls from the Netherlands Study of Depression and Anxiety (NESDA). The MDD patients were stratified according to patients with hyperphagia (characterized by increased appetite and/or weight, N = 246) or hypophagia (characterized by decreased appetite and/or weight, N = 342). Using results of differential gene expression analysis between controls and the MDD subgroups, enrichment of curated inflammatory pathways was estimated. The majority of the pathways were significantly (FDR < 0.1) enriched in the expression profiles of MDD cases with hyperphagia, including top pathways related to factors responsible for the onset of inflammatory response ('caspase', 'GATA3', 'NFAT', and 'inflammasomes' pathways). Only two pathways ('adaptive immune system' and 'IL-8- and CXCR2-mediated signaling') were enriched in the MDD with hypophagia subgroup, these were also enriched in the total current MDD group and the group with hyperphagia. This confirms the importance of inflammation in MDD pathology of patients with hyperphagia, and suggests that distinguishing more uniform MDD phenotypes can help in finding their pathophysiological basis.
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http://dx.doi.org/10.1038/s41398-019-0528-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702221PMC
August 2019

RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting.

BMC Biol 2019 06 24;17(1):50. Epub 2019 Jun 24.

Department of Biomedical Data Sciences, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.

Background: Identification of imprinted genes, demonstrating a consistent preference towards the paternal or maternal allelic expression, is important for the understanding of gene expression regulation during embryonic development and of the molecular basis of developmental disorders with a parent-of-origin effect. Combining allelic analysis of RNA-Seq data with phased genotypes in family trios provides a powerful method to detect parent-of-origin biases in gene expression.

Results: We report findings in 296 family trios from two large studies: 165 lymphoblastoid cell lines from the 1000 Genomes Project and 131 blood samples from the Genome of the Netherlands (GoNL) participants. Based on parental haplotypes, we identified > 2.8 million transcribed heterozygous SNVs phased for parental origin and developed a robust statistical framework for measuring allelic expression. We identified a total of 45 imprinted genes and one imprinted unannotated transcript, including multiple imprinted transcripts showing incomplete parental expression bias that was located adjacent to strongly imprinted genes. For example, PXDC1, a gene which lies adjacent to the paternally expressed gene FAM50B, shows a 2:1 paternal expression bias. Other imprinted genes had promoter regions that coincide with sites of parentally biased DNA methylation identified in the blood from uniparental disomy (UPD) samples, thus providing independent validation of our results. Using the stranded nature of the RNA-Seq data in lymphoblastoid cell lines, we identified multiple loci with overlapping sense/antisense transcripts, of which one is expressed paternally and the other maternally. Using a sliding window approach, we searched for imprinted expression across the entire genome, identifying a novel imprinted putative lncRNA in 13q21.2. Overall, we identified 7 transcripts showing parental bias in gene expression which were not reported in 4 other recent RNA-Seq studies of imprinting.

Conclusions: Our methods and data provide a robust and high-resolution map of imprinted gene expression in the human genome.
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http://dx.doi.org/10.1186/s12915-019-0674-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589892PMC
June 2019

An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.

Nat Commun 2019 06 13;10(1):2581. Epub 2019 Jun 13.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.
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http://dx.doi.org/10.1038/s41467-019-10487-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565679PMC
June 2019

Multivariate genome-wide analyses of the well-being spectrum.

Nat Genet 2019 03 14;51(3):445-451. Epub 2019 Jan 14.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (N = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.
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http://dx.doi.org/10.1038/s41588-018-0320-8DOI Listing
March 2019

Skewed X-inactivation is common in the general female population.

Eur J Hum Genet 2019 03 14;27(3):455-465. Epub 2018 Dec 14.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.
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http://dx.doi.org/10.1038/s41431-018-0291-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460563PMC
March 2019
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