The genetic regulation of transcription in human endometrial tissue

Fung, Jenny N., Girling, Jane E., Lukowski, Samuel W., Sapkota, Yadav, Wallace, Leanne, Holdsworth-Carson, Sarah J., Henders, Anjali K., Healey, Martin, Rogers, Peter A. W., Powell, Joseph E. and Montgomery, Grant W. (2017) The genetic regulation of transcription in human endometrial tissue. Human Reproduction, 32 4: 893-904. doi:10.1093/humrep/dex006


Author Fung, Jenny N.
Girling, Jane E.
Lukowski, Samuel W.
Sapkota, Yadav
Wallace, Leanne
Holdsworth-Carson, Sarah J.
Henders, Anjali K.
Healey, Martin
Rogers, Peter A. W.
Powell, Joseph E.
Montgomery, Grant W.
Title The genetic regulation of transcription in human endometrial tissue
Journal name Human Reproduction   Check publisher's open access policy
ISSN 1460-2350
0268-1161
Publication date 2017-04-01
Year available 2009
Sub-type Article (original research)
DOI 10.1093/humrep/dex006
Open Access Status Not yet assessed
Volume 32
Issue 4
Start page 893
End page 904
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 2743 Reproductive Medicine
2742 Rehabilitation
2729 Obstetrics and Gynaecology
Abstract STUDY QUESTION Do genetic effects regulate gene expression in human endometrium SUMMARY ANSWER This study demonstrated strong genetic effects on endometrial gene expression and some evidence for genetic regulation of gene expression in a menstrual cycle stage-specific manner. WHAT IS KNOWN ALREADY Genetic effects on expression levels for many genes are tissue specific. Endometrial gene expression varies across menstrual cycle stages and between individuals, but there are limited data on genetic control of expression in endometrium. STUDY DESIGN, SIZE, DURATION We analysed genome-wide genotype and gene expression data to map cis expression quantitative trait loci (eQTL) in endometrium. PARTICIPANTS/MATERIALS, SETTING, METHODS We recruited 123 women of European ancestry. DNA samples from blood were genotyped on Illumina HumanCoreExome chips. Total RNA was extracted from endometrial tissues. Whole-transcriptome profiles were characterized using Illumina Human HT-12 v4.0 Expression Beadchips. We performed eQTL mapping with ∼8 000 000 genotyped and imputed single nucleotide polymorphisms (SNPs) and 12 329 genes. MAIN RESULTS AND THE ROLE OF CHANCE We identified a total of 18 595 cis SNP-probe associations at a study-wide level of significance (P < 1 × 10 -7), which correspond to independent eQTLs for 198 unique genes. The eQTLs with the largest effect in endometrial tissue were rs4902335 for CHURC1 (P = 1.05 × 10 -32) and rs147253019 for ZP3 (P = 8.22 × 10 -30). We further performed a context-specific eQTL analysis to investigate if genetic effects on gene expression regulation act in a menstrual cycle-specific manner. Interestingly, five cis-eQTLs were identified with a significant stage-by-genotype interaction. The strongest stage interaction was the eQTL for C10ORF33 (PYROXD2) with SNP rs2296438 (P = 2.0 × 10 -4), where we observe a 2-fold difference in the average expression levels of heterozygous samples depending on the stage of the menstrual cycle. LARGE SCALE DATA The summary eQTL results are publicly available to browse or download. LIMITATIONS, REASONS FOR CAUTION A limitation of the present study was the relatively modest sample size. It was not powered to identify trans-eQTLs and larger sample sizes will also be needed to provide better power to detect cis-eQTLs and cycle stage-specific effects, given the substantial changes in expression across the menstrual cycle for many genes. WIDER IMPLICATIONS OF THE FINDINGS Identification of endometrial eQTLs provides a platform for better understanding genetic effects on endometriosis risk and other endometrial-related pathologies.
Formatted abstract
Study question: Do genetic effects regulate gene expression in human endometrium

Summary answer: This study demonstrated strong genetic effects on endometrial gene expression and some evidence for genetic regulation of gene expression in a menstrual cycle stage-specific manner.

What is known already: Genetic effects on expression levels for many genes are tissue specific. Endometrial gene expression varies across menstrual cycle stages and between individuals, but there are limited data on genetic control of expression in endometrium.

Study design, size, duration: We analysed genome-wide genotype and gene expression data to map cis expression quantitative trait loci (eQTL) in endometrium.

Participants/materials, setting, methods: We recruited 123 women of European ancestry. DNA samples from blood were genotyped on Illumina HumanCoreExome chips. Total RNA was extracted from endometrial tissues. Whole-transcriptome profiles were characterized using Illumina Human HT-12 v4.0 Expression Beadchips. We performed eQTL mapping with ∼8 000 000 genotyped and imputed single nucleotide polymorphisms (SNPs) and 12 329 genes.

Main results and the role of chance: We identified a total of 18 595 cis SNP-probe associations at a study-wide level of significance (P < 1 × 10-7), which correspond to independent eQTLs for 198 unique genes. The eQTLs with the largest effect in endometrial tissue were rs4902335 for CHURC1 (P = 1.05 × 10-32) and rs147253019 for ZP3 (P = 8.22 × 10-30). We further performed a context-specific eQTL analysis to investigate if genetic effects on gene expression regulation act in a menstrual cycle-specific manner. Interestingly, five cis-eQTLs were identified with a significant stage-by-genotype interaction. The strongest stage interaction was the eQTL for C10ORF33 (PYROXD2) with SNP rs2296438 (P = 2.0 × 10-4), where we observe a 2-fold difference in the average expression levels of heterozygous samples depending on the stage of the menstrual cycle.

Large scale data: The summary eQTL results are publicly available to browse or download.

Limitations, reasons for caution: A limitation of the present study was the relatively modest sample size. It was not powered to identify trans-eQTLs and larger sample sizes will also be needed to provide better power to detect cis-eQTLs and cycle stage-specific effects, given the substantial changes in expression across the menstrual cycle for many genes.

Wider implications of the findings: Identification of endometrial eQTLs provides a platform for better understanding genetic effects on endometriosis risk and other endometrial-related pathologies.

Study funding/competing interest(s): Funding for this work was provided by NHMRC Project Grants GNT1026033,
GNT1049472, GNT1046880, GNT1050208, GNT1105321 and APP1083405. There are no competing interests.
Keyword Expression quantitative trait loci (eQTL)
Human endometrium
Genetics
Gene expression regulation
Context-specific eQTL
Menstrual cycle
Differential expression
Gene switching
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
 
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