title: Impact of the X Chromosome and sex on regulatory variation.
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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kukurba
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA;
authors.forename: Princy
authors.initials: P
authors.lastname: Parsana
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Brunilda
authors.initials: B
authors.lastname: Balliu
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Smith
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Zachary
authors.initials: Z
authors.lastname: Zappala
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA;
authors.forename: David A
authors.initials: DA
authors.lastname: Knowles
authors.affiliation: Sainte-Justine University Hospital Research Centre, Department of Pediatrics, University of Montreal, Montreal, Québec H3T 1J4, Canada;
authors.forename: Marie-Julie
authors.initials: MJ
authors.lastname: Favé
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Joe R
authors.initials: JR
authors.lastname: Davis
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Psychiatry, University of Iowa Hospitals & Clinics, Iowa City, Iowa 52242, USA;
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.affiliation: Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, New York 10032, USA;
authors.forename: Myrna M
authors.initials: MM
authors.lastname: Weissman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA;
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Computer Science, Stanford University, Stanford, California 94305, USA;
authors.forename: Anshul
authors.initials: A
authors.lastname: Kundaje
authors.affiliation: Department of Psychiatry, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Levinson
authors.affiliation: Sainte-Justine University Hospital Research Centre, Department of Pediatrics, University of Montreal, Montreal, Québec H3T 1J4, Canada;
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
authors.affiliation: Department of Statistics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Mostafavi
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA; ajbattle@cs.jhu.edu smontgom@stanford.edu.
authors.forename: Alexis
authors.initials: A
authors.lastname: Battle
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Computer Science, Stanford University, Stanford, California 94305, USA; ajbattle@cs.jhu.edu smontgom@stanford.edu.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012727:Sex Characteristics; D059467:Transcriptome