title: Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies HLA-F and TAP2 as Fecundability-Associated Genes.
abstract: Fertility traits in humans are heritable, however, little is known about the genes that influence reproductive outcomes or the genetic variants that contribute to differences in these traits between individuals, particularly women. To address this gap in knowledge, we performed an unbiased genome-wide expression quantitative trait locus (eQTL) mapping study to identify common regulatory (expression) single nucleotide polymorphisms (eSNPs) in mid-secretory endometrium. We identified 423 cis-eQTLs for 132 genes that were significant at a false discovery rate (FDR) of 1%. After pruning for strong LD (r2 >0.95), we tested for associations between eSNPs and fecundability (the ability to get pregnant), measured as the length of the interval to pregnancy, in 117 women. Two eSNPs were associated with fecundability at a FDR of 5%; both were in the HLA region and were eQTLs for the TAP2 gene (P = 1.3x10-4) and the HLA-F gene (P = 4.0x10-4), respectively. The effects of these SNPs on fecundability were replicated in an independent sample. The two eSNPs reside within or near regulatory elements in decidualized human endometrial stromal cells. Our study integrating eQTL mapping in a primary tissue with association studies of a related phenotype revealed novel genes and associated alleles with independent effects on fecundability, and identified a central role for two HLA region genes in human implantation success.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Courtney K
authors.identifier: 0000-0003-1715-1123
authors.initials: CK
authors.lastname: Burrows
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Gülüm
authors.initials: G
authors.lastname: Kosova
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Catherine
authors.identifier: 0000-0001-8087-1970
authors.initials: C
authors.lastname: Herman
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Kristen
authors.initials: K
authors.lastname: Patterson
authors.affiliation: Institute for Medicine and Public Health, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, Tennessee, United States of America.|Departments of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hartmann
authors.affiliation: Institute for Medicine and Public Health, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, Tennessee, United States of America.|Departments of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Digna R
authors.initials: DR
authors.lastname: Velez Edwards
authors.affiliation: Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Mary D
authors.initials: MD
authors.lastname: Stephenson
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Lynch
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.|Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
mesh_terms: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3 / Q000096:biosynthesis / Q000235:genetics*; D000328:Adult; D002874:Chromosome Mapping; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005298:Fertility / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D040641:Quantitative Trait Loci / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; C062341:HLA-F antigens; D015395:Histocompatibility Antigens Class I; C071692:TAP2 protein, human