Sex differences in the human peripheral blood transcriptome

Abstract

Background: Genomes of men and women differ in only a limited number of genes located on the sex chromosomes, whereas the transcriptome is far more sex-specific. Identification of sex-biased gene expression will contribute to understanding the molecular basis of sex-differences in complex traits and common diseases.

Results: Sex differences in the human peripheral blood transcriptome were characterized using microarrays in 5,241 subjects, accounting for menopause status and hormonal contraceptive use. Sex-specific expression was observed for 582 autosomal genes, of which 57.7% was upregulated in women (female-biased genes). Female-biased genes were enriched for several immune system GO categories, genes linked to rheumatoid arthritis (16%) and genes regulated by estrogen (18%). Male-biased genes were enriched for genes linked to renal cancer (9%). Sex-differences in gene expression were smaller in postmenopausal women, larger in women using hormonal contraceptives and not caused by sex-specific eQTLs, confirming the role of estrogen in regulating sex-biased genes.

Conclusions: This study indicates that sex-bias in gene expression is extensive and may underlie sex-differences in the prevalence of common diseases.

Figure 1

Characterization of female- and male-biased genes. For each of the 47,122 transcripts the sex effect was determined using a mixed model, resulting in 3.1% sex-biased genes. A) Transcripts were selected based on a threshold for mean expression, the percentage of sex-biased genes increases with the threshold that is used: in genes that are highly expressed there are more (up to 13%) sex-biased genes than in genes that have low expression. Nonetheless, also large male/female fold changes were observed in genes with low (B) and moderate (C) expression. D) For each transcript fold changes were computed; on the autosomes 57.7% of the sex-biased genes was female-biased, and absolute log_e fold changes ranged from 0 to 0.2. E) For each chromosome, the number of male- and female-biased genes was computed, only the Y and X chromosomes were enriched for male- and female-biased genes, respectively.

Figure 2

Between transcript correlations are higher in males than in females for 2 modules. WGCNA (Weighted Gene Co-Expression Network Analysis) resulted in 9 modules with correlated transcripts, two of which were highly enriched for female-biased genes, and 3 for male-biased genes. From the latter three, two modules contained genes from which the pair-wise correlations were stronger in males compared to females. A) Module #6 contained 45 genes, 76% of the correlations computed in males (y axis) were larger than those computed in females (x axis). B) Module #9 contained 35 genes, 92% of the correlations computed in males (y axis) were larger than those computed in females (x axis).

Figure 3

Sex-differences in gene expression are increased by the use of hormonal contraceptives, and decreased during menopause. Women were divided in three groups: postmenopausal, hormonal contraceptive using (HC), and non hormonal contraceptive using (NHC) women. For the 993 sex-biased transcripts identified in the comparison between males and NHC women, fold changes were computed for the difference between the three groups of women and the men. Positive fold changes are from female-biased genes, negative fold changes correspond to male-biased genes. A) Fold changes are for 80% larger in NHC women as compared to postmenopausal women. B) Fold changes in HC women are for 66% larger than those observed in NHC women, and the negative fold changes (male-biased genes) were for 88% larger in HC women.