Sex-biased genetic effects on gene regulation in humans

Dimas, Antigone S.; Nica, Alexandra C.; Montgomery, Stephen B.; Stranger, Barbara Elaine; Raj, Towfique; Buil, Alfonso; Giger, Thomas; Lappalainen, Tuuli; Gutiérrez‐Arcelus, María; McCarthy, Mark I.; Dermitzakis, Emmanouil T.

doi:10.1101/gr.134981.111

Cited by 88 publications

(86 citation statements)

References 38 publications

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“…We observed no significant enrichment of genes with sex-specific expression for the top 100 sex-interacting eQTLs (odds ratio = 0.4 [0.05-1.58], P-value = 3.3 × 10 −1 , Fisher's exact test) compared to the background of genes expressed in whole blood. Concordant with a previous study (Dimas et al 2012), this demonstrates that sex-interacting eQTLs likely do not arise as a consequence of expression differences between the sexes and may result from other factors that differ in a sex-specific matter, such as transcription factor activity, hormone receptors, and chromatin accessibility.…”

Section: Regulatory Variation Onsupporting

confidence: 72%

“…Our study overcomes several limitations of previous eQTL and sex-specific eQTL studies which have either ignored the X Chromosome, conducted analyses in cell lines which may inaccurately reflect in vivo sex differences (Dimas et al 2012), had insufficient power to detect sex-specific eQTLs (Trabzuni et al 2013), or focused on only specific variants for sex-specific eQTL analysis (Castagne et al 2011;Yao et al 2014). We extend these studies to describe the characteristics of eQTL on the X Chromosome versus the autosomes, address the relationship between sex-specific gene expression and chromatin accessibility, and identify the contribution of multiple eQTLs to informing sex-biased disease risks.…”

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confidence: 99%

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Impact of the X Chromosome and sex on regulatory variation

et al. 2016

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The X Chromosome, with its unique mode of inheritance, contributes to differences between the sexes at a molecular level, including sex-specific gene expression and sex-specific impact of genetic variation. Improving our understanding of these differences offers to elucidate the molecular mechanisms underlying sex-specific traits and diseases. However, to date, most studies have either ignored the X Chromosome or had insufficient power to test for the sex-specific impact of genetic variation. By analyzing whole blood transcriptomes of 922 individuals, we have conducted the first large-scale, genome-wide analysis of the impact of both sex and genetic variation on patterns of gene expression, including comparison between the X Chromosome and autosomes. We identified a depletion of expression quantitative trait loci (eQTL) on the X Chromosome, especially among genes under high selective constraint. In contrast, we discovered an enrichment of sex-specific regulatory variants on the X Chromosome. To resolve the molecular mechanisms underlying such effects, we generated chromatin accessibility data through ATAC-sequencing to connect sex-specific chromatin accessibility to sex-specific patterns of expression and regulatory variation. As sex-specific regulatory variants discovered in our study can inform sex differences in heritable disease prevalence, we integrated our data with genome-wide association study data for multiple immune traits identifying several traits with significant sex biases in genetic susceptibilities. Together, our study provides genome-wide insight into how genetic variation, the X Chromosome, and sex shape human gene regulation and disease.

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Section: Regulatory Variation Onsupporting

confidence: 72%

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confidence: 99%

Impact of the X Chromosome and sex on regulatory variation

et al. 2016

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“…Recent studies by Dimas et al (23) and Kentet al (22) formally tested genotype × sex (or genotype × age) interaction in 379 lymphoblastoid cell lines and 1240 peripheral mononuclear cell samples, respectively. We were unable to replicate their findings of sex interaction of rs167769 and rs2872507 or age interaction for UBQLNL.…”

Section: Discussionmentioning

confidence: 99%

“…Among genes that display sex-specific or age-related changes in expression, a subset may exhibit genotype interaction with sex or age. While some sex-specific (16,17) and numerous age-related expression changes (18)(19)(20)(21) have been identified, few studies have yet considered sex-and age-interactions in eQTL analysis (22,23).…”

Section: Introductionmentioning

confidence: 99%

Sex- and age-interacting eQTLs in human complex diseases

Yao

Joehanes

Johnson

et al. 2013

Human Molecular Genetics

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Many complex human diseases exhibit sex or age differences in gene expression. However, the presence and the extent of genotype-specific variations in gene regulation are largely unknown. Here, we report results of a comprehensive analysis of expression regulation of genetic variation related to 11 672 complex disease-associated SNPs as a function of sex and age in whole-blood-derived RNA from 5254 individuals. At false discovery rate <0.05, we identified 14 sex-and 10 age-interacting expression quantitative trait loci (eQTLs). We show that these eQTLs are also associated with many sex-or age-associated traits. These findings provide important context regarding the regulation of phenotypes by genotype -environment interaction.

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“…1 There is evidence to suggest that the effect of genetic factors on disease risk may be influenced by sex. 5,6 Dimas et al found that 12-15% of autosomal gene expression quantitative trait loci were sexually dimorphic, and these sex-specific differences in gene regulation are likely to have sex-specific effects on disease. 5,6 Thus, we hypothesized that some JIA risk loci may affect disease risk differentially in females and males.…”

Section: Introductionmentioning

confidence: 98%

The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females

Chiaroni-Clarke

Munro

et al. 2015

Genes Immun

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A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.

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Sex-biased genetic effects on gene regulation in humans

Cited by 88 publications

References 38 publications

Impact of the X Chromosome and sex on regulatory variation

Impact of the X Chromosome and sex on regulatory variation

Sex- and age-interacting eQTLs in human complex diseases

The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females

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