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

doi:10.1016/j.isci.2024.109047

Sex-dependent placental methylation quantitative trait loci provide insight into the prenatal origins of childhood onset traits and conditions

iScience. 2024 Jan 26;27(2):109047. doi: 10.1016/j.isci.2024.109047. eCollection 2024 Feb 16.

Authors

William Casazza^{1

2

3}, Amy M Inkster^{3

4}, Giulia F Del Gobbo^{3

4

5}, Victor Yuan^{3

4}, Fabien Delahaye⁶, Carmen Marsit⁷, Yongjin P Park^{8

9}, Wendy P Robinson^{3

4}, Sara Mostafavi^{1

10}, Jessica K Dennis^{1

2

3

4}

Affiliations

¹ Centre for Molecular Medicine and Therapeutics, BC Children's Hospital, Vancouver, BC, Canada.
² Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada.
³ BC Children's Hospital Research Institute, Vancouver, BC, Canada.
⁴ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
⁵ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
⁶ Albert Einstein College of Medicine, The Bronx, NY, USA.
⁷ Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁸ Department of Statistics, University of British Columbia, Vancouver, BC, Canada.
⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁰ Paul Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA.

Abstract

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.

Keywords: Association analysis; Developmental genetics; Human Genetics; Quantitative genetics.

Abstract

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