RT Journal
A1 Kukurba, Kimberly R.
A1 Parsana, Princy
A1 Balliu, Brunilda
A1 Smith, Kevin S.
A1 Zappala, Zachary
A1 Knowles, David A.
A1 Favé, Marie-Julie
A1 Davis, Joe R.
A1 Li, Xin
A1 Zhu, Xiaowei
A1 Potash, James B.
A1 Weissman, Myrna M.
A1 Shi, Jianxin
A1 Kundaje, Anshul
A1 Levinson, Douglas F.
A1 Awadalla, Philip
A1 Mostafavi, Sara
A1 Battle, Alexis
A1 Montgomery, Stephen B.
T1 Impact of the X Chromosome and sex on regulatory variation
JF Genome Research 
JO Genome Research 
YR 2016 
FD June 01 
VO 26 
IS 6 
SP 768 
OP 777 
DO 10.1101/gr.197897.115 
UL http://genome.cshlp.org/content/26/6/768.abstract 
AB 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.