Sex-dependent placental methylation quantitative trait loci provide insight into the prenatal origins of childhood onset traits and conditions
William Casazza,
Amy M. Inkster,
Giulia F. Del Gobbo,
Victor Yuan,
Fabien Delahaye,
Carmen Marsit,
Yongjin P. Park,
Wendy P. Robinson,
Sara Mostafavi,
Jessica K. Dennis
Affiliations
William Casazza
Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital, Vancouver, BC, Canada; Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
Amy M. Inkster
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
Giulia F. Del Gobbo
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Victor Yuan
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
Fabien Delahaye
Albert Einstein College of Medicine, The Bronx, NY, USA
Carmen Marsit
Rollins School of Public Health, Emory University, Atlanta, GA, USA
Yongjin P. Park
Department of Statistics, University of British Columbia, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
Wendy P. Robinson
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
Sara Mostafavi
Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital, Vancouver, BC, Canada; Paul Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA
Jessica K. Dennis
Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital, Vancouver, BC, Canada; Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Corresponding author
Summary: Molecular quantitative trait loci (QTLs) allow us to understand the biology captured in genome-wide association studies (GWASs). The placenta regulates fetal development and shows sex differences in DNA methylation. We therefore hypothesized that placental methylation QTL (mQTL) explain variation in genetic risk for childhood onset traits, and that effects differ by sex. We analyzed 411 term placentas from two studies and found 49,252 methylation (CpG) sites with mQTL and 2,489 CpG sites with sex-dependent mQTL. All mQTL were enriched in regions that typically affect gene expression in prenatal tissues. All mQTL were also enriched in GWAS results for growth- and immune-related traits, but male- and female-specific mQTL were more enriched than cross-sex mQTL. mQTL colocalized with trait loci at 777 CpG sites, with 216 (28%) specific to males or females. Overall, mQTL specific to male and female placenta capture otherwise overlooked variation in childhood traits.
