Quality control and analytic best practices for testing genetic models of sex differences in large populations

Khramtsova, Ekaterina A.; Wilson, Melissa A.; Martin, Joanna; Winham, Stacey J.; He, Karen Y.; Davis, Lea K.; Stranger, Barbara Elaine

doi:10.1016/j.cell.2023.04.014

Cited by 13 publications

(15 citation statements)

References 122 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…How we should handle the allele dosage for males and females and whether allele dosage should be adjusted in the presence of escape is one of the technical difficulties associated with the X chromosome analysis 9,10 . Currently, many software for GWAS, such as PLINK2 35 , BOLT-LMM 36 , and REGINIE 37 , handle the dosage of alleles assuming the complete XCI in a default setting, while previous literature argued that in the presence of escape, the effective dosage on the female should increase 9,10 . In our comparisons of the eQTL effect sizes between sexes, we found no inter-sex differences in eQTL effects regardless of the quantified estimates of the escape.…”

Section: Discussionmentioning

confidence: 99%

“…Expression from Xi due to the escape can contribute to the sex differences of the gene expression and diseases, such as cancer 4 and autoimmune diseases 5–7 . Furthermore, escape can introduce changes in the effective allele dosage of females in the context of genotype-phenotype association analyses 8–10 (e.g. genome-wide association study [GWAS] and expression quantitative trait locus [eQTL] mapping).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Quantification of the escape from X chromosome inactivation with the million cell-scale human single-cell omics datasets reveals heterogeneity of escape across cell types and tissues

Tomofuji,

Edahiro,

Shirai

et al. 2023

Preprint

View full text Add to dashboard Cite

One of the two X chromosomes of females is silenced through X chromosome inactivation (XCI) to compensate for the difference in the dosage between sexes. Among the X-linked genes, several genes escape from XCI, which could contribute to the differential gene expression between the sexes. However, the differences in the escape across cell types and tissues are still poorly characterized because no methods could directly evaluate the escape under a physiological condition at the cell-cluster resolution with versatile technology. Here, we developed a method, single-cell Level inactivated X chromosome mapping (scLinaX), which directly quantifies relative gene expression from the inactivated X chromosome with droplet-based single-cell RNA-sequencing (scRNA-seq) data. The scLinaX and differentially expressed genes analyses with the scRNA-seq datasets of -1,000,000 blood cells consistently identified the relatively strong degree of escape in lymphocytes compared to myeloid cells. An extension of scLinaX for multi-modal datasets, scLinaX-multi, suggested a stronger degree of escape in lymphocytes than myeloid cells at the chromatin-accessibility level with a 10X multiome dataset. The scLinaX analysis with the human multiple-organ scRNA-seq datasets also identified the relatively strong degree of escape from XCI in lymphoid tissues and lymphocytes. Finally, effect size comparisons of genome-wide association studies between sexes identified the larger effect sizes of the PRKX gene locus-lymphocyte counts association in females than males. This could suggest evidence of the underlying impact of escape on the genotype-phenotype association in humans. Overall, scLinaX and the quantified catalog of escape identified the heterogeneity of escape across cell types and tissues and would contribute to expanding the current understanding of the XCI, escape, and sex differences in gene regulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantification of the escape from X chromosome inactivation with the million cell-scale human single-cell omics datasets reveals heterogeneity of escape across cell types and tissues

Tomofuji,

Edahiro,

Shirai

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Sex differences between measured heritability was assessed using Z-score and its associated P-value statistic (P Heri ) as suggested previously. 21…”

Section: Methodsmentioning

confidence: 99%

“…24 The effects of heterogeneous loci were categorized as sex-differential (effect in both sexes, but of different magnitude) or sex-specific (effect in one sex, but not the other), as suggested previously. 21 To account for possible confounding through LD, we performed statistical colocalization and tested the hypothesis of shared genetic signal (H4) using default prior probabilities as implemented in the R package coloc (v5.1.0). 25…”

Section: Methodsmentioning

confidence: 99%

“…Sex differences between measured heritability was assessed using Z-score and its associated P-value statistic (P Heri ) as suggested previously. 21 To identify single genetic variation associated with RV traits, we performed genome-wide association studies (GWAS) using BOLT-LMM (v2.4.1) which accounts for cryptic population structure and sample relatedness by fitting a linear mixed model with a Bayesian mixture prior. 22 We used again the full panel of hard-called genotypes to construct the genetic relationship matrix.…”

Section: Heritability and Genome-wide Association Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Sex-specific genetic determinants of right ventricular structure and function

Harbaum,

Hennigs,

Pott

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown. We used common genetic variation to provide biological insights into sex differences in the structure and function of the right ventricle (RV). Methods: RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank, based on a deep-learning approach, including end-diastolic, end-systolic, and stroke volumes, as well as ejection fraction. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured hemodynamics in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK National Institute for Health Research BioResource Rare Diseases study. Results: Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts and lung function. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men. These included two sex-specific candidate loci present in women only; namely, a locus for RV ejection fraction in BMPR1A and a locus for RV end-systolic volume near DMRT2. Epigenetic data indicate that variation at the BMPR1A locus likely alters transcriptional regulation in RV tissue. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size 0.16 l/min/m2), despite similar RV afterload among genotypic groups. Conclusions: We report sex-specific genetic loci for RV structure and function. BMPR1A has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH. Further studies are needed to explore the underlying biological pathways.

show abstract

Sex-stratified genome-wide association and transcriptome-wide Mendelian randomization studies reveal drug targets of heart failure

Yang,

et al. 2024

Cell Reports Medicine

View full text Add to dashboard Cite

Quality control and analytic best practices for testing genetic models of sex differences in large populations

Cited by 13 publications

References 122 publications

Quantification of the escape from X chromosome inactivation with the million cell-scale human single-cell omics datasets reveals heterogeneity of escape across cell types and tissues

Quantification of the escape from X chromosome inactivation with the million cell-scale human single-cell omics datasets reveals heterogeneity of escape across cell types and tissues

Sex-specific genetic determinants of right ventricular structure and function

Sex-stratified genome-wide association and transcriptome-wide Mendelian randomization studies reveal drug targets of heart failure

Contact Info

Product

Resources

About