Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age

Zito, Antonino; Davies, Matthew N.; Tsai, Pei-Chien; Roberts, Stephen K.; Andres-Ejarque, Rosa; Nardone, Stefano; Bell, Jordana T.; Wong, Chloe; Small, Kerrin S.

doi:10.1038/s41467-019-13340-w

Cited by 52 publications

(68 citation statements)

References 84 publications

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“…Chromosome X genotypes were called from low depth 7x sequencing as part of the UK10K project, as previously described 65 and were available for 490 of 765 TwinsUK participants for whom adipose tissue gene expression data were available. 39 participants were excluded from cis-eQTL analyses due to skewing of X chromosome inactivation 66 . In METSIM and FUSION, HRC-imputed genotypes (HRC version 1.1) were available for all chromosomes including the X in all participants 46,64 .…”

Section: Genotype Data Imputation and Quality Controlmentioning

confidence: 99%

ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition

Moustafa

Jackson

Brotman

et al. 2020

Preprint

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COVID-19 severity has varied widely, with demographic and cardio-metabolic factors increasing risk of severe reactions to SARS-CoV-2 infection, but the underlying mechanisms for this remain uncertain. We investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), which has been shown to act as a receptor for SARS-CoV-2 cellular entry. In a meta-analysis of three independent studies including up to 1,471 participants, lower adipose tissue ACE2 expression was associated with adverse cardio-metabolic health indices including type 2 diabetes (T2D) and obesity status, higher serum fasting insulin and BMI, and lower serum HDL levels (P<5.32x10-4). ACE2 expression levels were also associated with estimated proportions of cell types in adipose tissue; lower ACE2 expression was associated with a lower proportion of microvascular endothelial cells (P=4.25x10-4) and higher macrophage proportion (P=2.74x10-5), suggesting a link to inflammation. Despite an estimated heritability of 32%, we did not identify any proximal or distal genetic variants (eQTLs) associated with adipose tissue ACE2 expression. Our results demonstrate that at-risk individuals have lower background ACE2 levels in this highly relevant tissue. Further studies will be required to establish how this may contribute to increased COVID-19 severity.

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Section: Genotype Data Imputation and Quality Controlmentioning

confidence: 99%

ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition

Moustafa

Jackson

Brotman

et al. 2020

Preprint

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“…The choice of which X is inactivated is generally random resulting in an average 50:50 pattern across cells within a tissue 58 ; however, this is not always the case and the ratio of expression can be highly skewed with the majority of cells within a tissue expressing the same copy of X, known as “skewed X-inactivation.” The degree of skewed X-inactivation is variable both between and within individuals, and varies with age, smoking status, cell type, sub-cell type, and disease status. 59 The large variation in skewed X-inactivation means that whereas the linear model in our XWAS codes female heterozygotes as having one copy of the effect allele, there will be much variability in the relative expression and effective gene dosage, depending on the degree of skewed X-inactivation in the IOP relevant tissues. This increased variance in heterozygotes will cause an increase in the standard error for the linear regression during association analysis, and thus a less significant P value, whereas the slope/estimate of effect size will be relatively unchanged as the homozygotes at each end of the slope will be the same.…”

Section: Discussionmentioning

confidence: 99%

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects

Simcoe

Khawaja

Mahroo

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to identify genetic variants on chromosome X associated with intraocular pressure (IOP) and determine if they possess any sex-specific effects. Methods Association analyses were performed across chromosome X using 102,407 participants from the UK Biobank. Replication and validation analyses were conducted in an additional 6599 participants from the EPIC-Norfolk cohort, and an independent 331,682 participants from the UK Biobank. Results We identified three loci associated with IOP at genomewide significance ( P < 5 × 10 −8 ), located within or near the following genes: MXRA5 (rs2107482, P = 7.1 × 10 −11 ), GPM6B (rs66819623, P = 6.9 × 10 −10 ), NDP , and EFHC2 (rs12558081, P = 4.9 × 10 −11 ). Alleles associated with increased IOP were also associated with increased risk for primary open-angle glaucoma in an independent sample. Finally, our results indicate that chromosome X genetics most likely do not illicit sex-specific effects on IOP. Conclusions In this study, we report the results of genomewide levels of association of three loci on chromosome X with IOP, and provide a framework to include chromosome X in large-scale genomewide association analyses for complex phenotypes.

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“…Moreover, Zito et al (2019), studied the heritability of skewed X‐inactivation pattern in twins and found that this phenomenon is tissue specific and associated with age. They reported that in an individual, skewed‐XCI differs between blood, adipose tissue, and epithelial tissue, but that XCI pattern is shared among immune system cells.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis for carrier diagnosis in hemophilia A and B in the Mexican population: 25 years of experience

González-Ramos¹,

Mantilla-Capacho²,

Luna-Záizar

et al. 2020

American J of Med Genetics Pt C

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Our 25 years of experience in carrier diagnosis of hemophilia A (HA) and B (HB) in Mexican population comprises linkage analysis of intragenic F8/F9 neutral variants along with, in severe HA (SHA), detection of F8 int22h and int1h inversions. In symptomatic carriers (SCs) we explored Lyonization to explain their symtomatology. From a DNA-Bank of 3,000 samples, intragenic restriction fragment length (RFLPs) and short tandem repeats (STRs) of F8/F9 genes were assessed by PCR-PAGE and GeneScan. In SHA patients, F8 inversions were detected by inverse shifting-PCR/ diagnostic and complementary tests. In SCs, we evaluated hemorrhagic symptoms, clotting FVIII/FIX and X-chromosome inactivation (XCI) patterns were assessed by HUMARA assay and the search of XIST promoter pathogenic variants. Informativeness of linkage analysis for HA carrier diagnosis with RFLP's/STR's increased to 74% and reached 80% with five RFLPs for HB. Combined Inv22/Inv1 diagnosed 113 possible carriers, three de novo Inv22-1, and confirmed 45 mothers as obligate or sporadic carriers. Among 21 SCs, four showed extreme skewed XCI pattern (80:20) but had normal karyotype and no C43G pathogenic variant in XIST promoter. Clotting FVIII/ FIX correlated with the active X in leukocytes. Our data integrate the largest comprehensive research worldwide on the molecular diagnosis of HA and HB carriers in terms of the number of studied and diagnosed cases, in addition to the genetic analysis in SCs. Intragenic RFLPs and STRs of F8/F9 genes along with F8 int22h/int1h inversions in SHA emerge as optimal variants for molecular diagnosis in Mexican population. In counseling SCs, inheritance of skewed X-inactivation should be considered.

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Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age

Cited by 52 publications

References 84 publications

ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition

ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects

Genetic analysis for carrier diagnosis in hemophilia A and B in the Mexican population: 25 years of experience

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