Impact of the X Chromosome and sex on regulatory variation
- Kimberly R. Kukurba1,2,
- Princy Parsana3,
- Brunilda Balliu1,
- Kevin S. Smith1,
- Zachary Zappala1,2,
- David A. Knowles3,
- Marie-Julie Favé4,
- Joe R. Davis1,2,
- Xin Li1,
- Xiaowei Zhu5,
- James B. Potash6,
- Myrna M. Weissman7,
- Jianxin Shi8,
- Anshul Kundaje2,9,
- Douglas F. Levinson5,
- Philip Awadalla4,
- Sara Mostafavi10,
- Alexis Battle3,11 and
- Stephen B. Montgomery1,2,9,11
- 1Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
- 2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
- 3Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA;
- 4Sainte-Justine University Hospital Research Centre, Department of Pediatrics, University of Montreal, Montreal, Québec H3T 1J4, Canada;
- 5Department of Psychiatry, Stanford University School of Medicine, Stanford, California 94305, USA;
- 6Department of Psychiatry, University of Iowa Hospitals & Clinics, Iowa City, Iowa 52242, USA;
- 7Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, New York 10032, USA;
- 8Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA;
- 9Department of Computer Science, Stanford University, Stanford, California 94305, USA;
- 10Department of Statistics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
- Corresponding authors: ajbattle{at}cs.jhu.edu, smontgom{at}stanford.edu
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↵11 These authors contributed equally to this work.
Abstract
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.197897.115.
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Freely available online through the Genome Research Open Access option.
- Received August 6, 2015.
- Accepted April 18, 2016.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
