Publications by authors named "Jodie N Painter"

52 Publications

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

Ten years of enhancing neuro-imaging genetics through meta-analysis: An overview from the ENIGMA Genetics Working Group.

Hum Brain Mapp 2022 Jan 10;43(1):292-299. Epub 2020 Dec 10.

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey, California, USA.

Here we review the motivation for creating the enhancing neuroimaging genetics through meta-analysis (ENIGMA) Consortium and the genetic analyses undertaken by the consortium so far. We discuss the methodological challenges, findings, and future directions of the genetics working group. A major goal of the working group is tackling the reproducibility crisis affecting "candidate gene" and genome-wide association analyses in neuroimaging. To address this, we developed harmonized analytic methods, and support their use in coordinated analyses across sites worldwide, which also makes it possible to understand heterogeneity in results across sites. These efforts have resulted in the identification of hundreds of common genomic loci robustly associated with brain structure. We have found both pleiotropic and specific genetic effects associated with brain structures, as well as genetic correlations with psychiatric and neurological diseases.
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http://dx.doi.org/10.1002/hbm.25311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675405PMC
January 2022

The genetic architecture of sporadic and multiple consecutive miscarriage.

Nat Commun 2020 11 25;11(1):5980. Epub 2020 Nov 25.

University of Queensland, St Lucia, QLD, Australia.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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http://dx.doi.org/10.1038/s41467-020-19742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689465PMC
November 2020

Comparison of Genome-Wide Association Scans for Quantitative and Observational Measures of Human Hair Curvature.

Twin Res Hum Genet 2020 10;23(5):271-277

Psychiatric Genetics, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Previous genetic studies on hair morphology focused on the overall morphology of the hair using data collected by self-report or researcher observation. Here, we present the first genome-wide association study (GWAS) of a micro-level quantitative measure of hair curvature. We compare these results to GWAS results obtained using a macro-level classification of observable hair curvature performed in the same sample of twins and siblings of European descent. Observational data were collected by trained observers, while quantitative data were acquired using an Optical Fibre Diameter Analyser (OFDA). The GWAS for both the observational and quantitative measures of hair curvature resulted in genome-wide significant signals at chromosome 1q21.3 close to the trichohyalin (TCHH) gene, previously shown to harbor variants associated with straight hair morphology in Europeans. All genetic variants reaching genome-wide significance for both GWAS (quantitative measure lead single-nucleotide polymorphism [SNP] rs12130862, p = 9.5 × 10-09; observational measure lead SNP rs11803731, p = 2.1 × 10-17) were in moderate to very high linkage disequilibrium (LD) with each other (minimum r2 = .45), indicating they represent the same genetic locus. Conditional analyses confirmed the presence of only one signal associated with each measure at this locus. Results from the quantitative measures reconfirmed the accuracy of observational measures.
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http://dx.doi.org/10.1017/thg.2020.78DOI Listing
October 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

The psychosocial impact of nausea and vomiting during pregnancy as a predictor of postpartum depression.

J Health Psychol 2021 06 27;26(7):1061-1072. Epub 2019 Jun 27.

QIMR Berghofer Medical Research Institute, Australia.

This study examined the extent to which psychosocial impact of nausea and vomiting during pregnancy predicts postpartum depression using a retrospective design. Data from a cross-sectional survey investigating women's experiences of nausea and vomiting during pregnancy were used ( = 861). Hierarchical logistic regression models revealed that the psychosocial impact of nausea and vomiting in pregnancy appears to be predictive of postpartum depression, independent of depression status before and during pregnancy. Our findings indicate that assessing the psychosocial impact of nausea and vomiting in pregnancy during antenatal care may identify women at risk of postpartum depression.
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http://dx.doi.org/10.1177/1359105319859048DOI Listing
June 2021

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Identification of 55,000 Replicated DNA Methylation QTL.

Sci Rep 2018 12 4;8(1):17605. Epub 2018 Dec 4.

The Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.

DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation from whole blood measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n = 614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1 Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5' UTR regions. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1 × 10), ulcerative colitis (p = 2 × 10), Crohn's disease (p = 6 × 10) and coronary artery disease (p = 5.5 × 10) when compared to a random sample of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs.
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http://dx.doi.org/10.1038/s41598-018-35871-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279736PMC
December 2018

Identification of 55,000 Replicated DNA Methylation QTL.

Sci Rep 2018 12 4;8(1):17605. Epub 2018 Dec 4.

The Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.

DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation from whole blood measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n = 614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1 Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5' UTR regions. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1 × 10), ulcerative colitis (p = 2 × 10), Crohn's disease (p = 6 × 10) and coronary artery disease (p = 5.5 × 10) when compared to a random sample of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs.
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http://dx.doi.org/10.1038/s41598-018-35871-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279736PMC
December 2018

Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses.

Cancer Med 2018 05 2;7(5):1978-1987. Epub 2018 Apr 2.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals KU Leuven, University of Leuven, Leuven, Belgium.

Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r = 0.23, P = 9.3 × 10 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10 ) and concordance in effect direction (P = 2.0 × 10 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
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http://dx.doi.org/10.1002/cam4.1445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943470PMC
May 2018

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Hum Mol Genet 2018 02;27(4):742-756

FIMM Institute for Molecular Medicine Finland, Helsinki University, Helsinki FI-00014, Finland.

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
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http://dx.doi.org/10.1093/hmg/ddx429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886200PMC
February 2018

Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339.

Hum Mol Genet 2016 11;25(22):5046-5058

Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 individuals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54; 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.
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http://dx.doi.org/10.1093/hmg/ddw320DOI Listing
November 2016

Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer.

Cancer Epidemiol Biomarkers Prev 2016 11 22;25(11):1503-1510. Epub 2016 Aug 22.

Department of Gynaecology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.

Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.

Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.

Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10). There was evidence of directional pleiotropy (P = 1.5 × 10). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.

Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.

Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093082PMC
November 2016

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

Int J Epidemiol 2016 06 10;45(3):884-95. Epub 2016 Jul 10.

Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.

Background: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.

Methods: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.

Results: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).

Conclusions: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.
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http://dx.doi.org/10.1093/ije/dyw158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644573PMC
June 2016

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.

Am J Hum Genet 2016 06;98(6):1159-1169

QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address:

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908177PMC
June 2016

Five endometrial cancer risk loci identified through genome-wide association analysis.

Nat Genet 2016 06 2;48(6):667-674. Epub 2016 May 2.

Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
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http://dx.doi.org/10.1038/ng.3562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907351PMC
June 2016

GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer.

Hum Mol Genet 2016 06 23;25(12):2612-2620. Epub 2016 Mar 23.

Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt - Ingram Cancer Center, Vanderbilt University Medical Center, Nashville TN 27232, USA.

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 ) at 6p22.3 (rs1740828; P = 2.29 × 10 , OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.
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http://dx.doi.org/10.1093/hmg/ddw092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868213PMC
June 2016

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

JAMA 2016 Mar;315(11):1129-40

QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Australia.

Importance: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.

Objective: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.

Design, Setting, And Participants: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.

Exposures: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.

Main Outcome And Measure: Offspring birth weight from 18 studies.

Results: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.

Conclusions And Relevance: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
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http://dx.doi.org/10.1001/jama.2016.1975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811305PMC
March 2016

Nausea and Vomiting During Pregnancy is Highly Heritable.

Behav Genet 2016 07 22;46(4):481-91. Epub 2016 Jan 22.

Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Nausea and vomiting during pregnancy (NVP) affects about 70 % of all expectant mothers and commonly impacts their physical health and psychosocial functioning. The aim of this study was to estimate the heritability of the presence, duration and severity of NVP. The sample consisted of 1723 women (M age = 41.78, SD = 11.67) including twins in both complete and incomplete pairs and their sisters from two cohorts participating in the NVP Genetics Consortium. The sample comprised 159 monozygotic and 140 dizygotic complete twin pairs, and 69 twin-sister pairs. We applied an extended twin design using OpenMx and Mx for secondary analysis. Individual differences in NVP were best explained by additive genetic and unique environmental effects. Heritability estimates were 73 % (95 % CIs = 57-84 %) for presence, 51 % (95 % CIs = 36-63 %) for duration and 53 % (95 % CIs = 38-65 %) for severity of NVP. The genetic correlation between duration and severity was almost perfect. Our results show that genes play an important role in different aspects of NVP and justify the importance of searching for genetic variants.
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http://dx.doi.org/10.1007/s10519-016-9781-7DOI Listing
July 2016

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer.

Endocr Relat Cancer 2016 Feb 16;23(2):77-91. Epub 2015 Nov 16.

Department of Public Health and Primary CareCentre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, Cambridge CB1 8RN, UKDepartment of Genetics and Computational BiologyQIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, AustraliaWellcome Trust Centre for Human GeneticsUniversity of Oxford, Oxford OX3 7BN, UKAcademic Department of BiochemistryRoyal Marsden Hospital, London SW3 6JJ, UKDepartment of Clinical GeneticsSt George's Hospital Medical School, London SW17 0RE, UKDepartment of OncologyCentre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UKDepartment of Medical Epidemiology and BiostatisticsKarolinska Institutet, Stockholm SE-171 77, SwedenDepartment of MedicineDivision of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USADepartment of Gynecology and ObstetricsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyInstitute of Human GeneticsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyGynaecology Research UnitHannover Medical School, Hannover 30625, GermanyClinics of Gynaecology and ObstetricsHannover Medical School, Hannover 30625, GermanyDepartment of GynaecologyJena University Hospital - Friedrich Schiller University, Jena 07743, GermanyVesalius Research CenterLeuven 3000, BelgiumLaboratory for Translational GeneticsDepartment of Oncology, University Hospitals Leuven, Leuven 3000, BelgiumDepartment of Obstetrics and GynecologyDivision of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Leuven 3000, BelgiumDepartment of Health Sciences ResearchMayo Clinic, Rochester, Minnesota 55905, USADepartment of BiostatisticsUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USADepartment of Obstetrics and GynecologyDivision of G

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
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http://dx.doi.org/10.1530/ERC-15-0386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697192PMC
February 2016

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.

Endocr Relat Cancer 2015 Oct;22(5):851-61

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia Wellcome Trust Centre for Human Genetics University of Oxford, Oxford OX3 7BN, UK Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK Hunter Medical Research Institute John Hunter Hospital, Newcastle, New South Wales 2305, Australia School of Medicine and Public Health Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Newcastle, New South Wales 2305, Australia Hunter Area Pathology Service John Hunter Hospital, Newcastle, New South Wales 2305, Australia Centre for Information Based Medicine School of Biomedical Sciences and Pharmacy School of Medicine and Public Health University of Newcastle, Newcastle, New South Wales 2308, Australia Department of Oncology Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK Department of Clinical Genetics St George's, University of London, London SW17 0RE, UK Division of Hematology/Oncology Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA Department of Gynecology and Obstetrics University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen 91054, Germany Institute of Human Genetics University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, Germany Department of Medical Epidemiology and Biostatistics Karolinska Institutet, Stockholm SE-171 77, Sweden Department of Gynaecology Jena University Hospital - Friedrich Schiller University, Jena 07743, Germany Hannover Medical School Clinics of Gynaecology and Obstetrics, Hannover 30625, Germany Gynaecology Research Unit Hannover Medical School, Hannover 30625, Germany Vesalius Research Center Leuven 3000, Belgium Laboratory for Translational Genetics

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.
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http://dx.doi.org/10.1530/ERC-15-0319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559752PMC
October 2015

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

Hum Mol Genet 2015 Oct 30;24(20):5955-64. Epub 2015 Jul 30.

Department of Pathology and.

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.
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http://dx.doi.org/10.1093/hmg/ddv306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581608PMC
October 2015

Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis.

J Natl Cancer Inst 2015 Sep 1;107(9). Epub 2015 Jul 1.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK (KTN, SJS, AB, JRBP, LAL, CL, NJW, RAS); Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (KTN); Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK (DJT, DFE, PDPP); Queensland Institute of Medical Research, Brisbane, Australia (JNP, ANECS, TO, ABS); University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge, UK (DBS, RKS); Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia (JA, EH, RJS); Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, The University of Newcastle, Newcastle, Australia (JA, MM); Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK (AMD, DFE, PDPP); Centre for Information Based Medicine, School of Medicine and Public Health, University of Newcastle, Australia (EH, RJS).

Background: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer.

Methods: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants.

Results: Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6)).

Conclusion: This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk.
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http://dx.doi.org/10.1093/jnci/djv178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572886PMC
September 2015

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Hum Genet 2015 Feb 9;134(2):231-45. Epub 2014 Dec 9.

Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, 95616, USA,

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
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http://dx.doi.org/10.1007/s00439-014-1515-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291520PMC
February 2015

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Hum Mol Genet 2015 Mar 6;24(5):1478-92. Epub 2014 Nov 6.

Department of Genetics, Portuguese Oncology Institute, Porto, Portugal, Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
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http://dx.doi.org/10.1093/hmg/ddu552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321445PMC
March 2015

Contribution of genetic variation to transgenerational inheritance of DNA methylation.

Genome Biol 2014 May 29;15(5):R73. Epub 2014 May 29.

Background: Despite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood. The genetic heritability of DNA methylation has been estimated using twin pairs, although concern has been expressed whether the underlying assumption of equal common environmental effects are applicable due to intrauterine differences between monozygotic and dizygotic twins. We estimate the heritability of DNA methylation on peripheral blood leukocytes using Illumina HumanMethylation450 array using a family based sample of 614 people from 117 families, allowing comparison both within and across generations.

Results: The correlations from the various available relative pairs indicate that on average the similarity in DNA methylation between relatives is predominantly due to genetic effects with any common environmental or zygotic effects being limited. The average heritability of DNA methylation measured at probes with no known SNPs is estimated as 0.187. The ten most heritable methylation probes were investigated with a genome-wide association study, all showing highly statistically significant cis mQTLs. Further investigation of one of these cis mQTL, found in the MHC region of chromosome 6, showed the most significantly associated SNP was also associated with over 200 other DNA methylation probes in this region and the gene expression level of 9 genes.

Conclusions: The majority of transgenerational similarity in DNA methylation is attributable to genetic effects, and approximately 20% of individual differences in DNA methylation in the population are caused by DNA sequence variation that is not located within CpG sites.
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http://dx.doi.org/10.1186/gb-2014-15-5-r73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072933PMC
May 2014

Common variants in the CYP2C19 gene are associated with susceptibility to endometriosis.

Fertil Steril 2014 Aug 3;102(2):496-502.e5. Epub 2014 May 3.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Objective: To follow-up previous studies highlighting a possible role for cytochrome P450, family 2, subfamily C, 19 (CYP2C19) in susceptibility to endometriosis by searching for additional variants in the CYP2C19 gene that may be associated with the disease.

Design: Case-control study.

Setting: Academic research.

Subject(s): The cases comprised 2,271 women with surgically confirmed endometriosis; the controls comprised 939 women with self-report of no endometriosis and 1,770 unscreened population samples.

Intervention(s): Sequencing of the CYP2C19 region and follow-up of 80 single nucleotide polymorphisms (SNPs) in two case-control samples.

Main Outcome Measure(s): Allele frequency differences between cases and controls.

Result(s): Sequencing of the CYP2C19 gene region resulted in the detection of a large number of known and novel SNPs. Genotyping of 80 polymorphic SNPs in 901 endometriosis cases and 939 controls resulted in study-wide significant association signals for SNPs in moderate or complete linkage disequilibrium with rs4244285, a functional SNP in exon 5 that abrogates CYP2C19 function through the creation of an alternative splice site. Evidence of association was also detected for another functional SNP in the CYP2C19 promoter, rs12248560, which was highlighted in our previous study.

Conclusion(s): Functional variants in CYP2C19 may contribute to endometriosis susceptibility in both familial and sporadic cases.
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http://dx.doi.org/10.1016/j.fertnstert.2014.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150687PMC
August 2014

Fine mapping of variants associated with endometriosis in the WNT4 region on chromosome 1p36.

Int J Mol Epidemiol Genet 2013 28;4(4):193-206. Epub 2013 Nov 28.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute Brisbane, Queensland, Australia.

Genome-wide association studies show strong evidence of association with endometriosis for markers on chromosome 1p36 spanning the potential candidate genes WNT4, CDC42 and LINC00339. WNT4 is involved in development of the uterus, and the expression of CDC42 and LINC00339 are altered in women with endometriosis. We conducted fine mapping to examine the role of coding variants in WNT4 and CDC42 and determine the key SNPs with strongest evidence of association in this region. We identified rare coding variants in WNT4 and CDC42 present only in endometriosis cases. The frequencies were low and cannot account for the common signal associated with increased risk of endometriosis. Genotypes for five common SNPs in the region of chromosome 1p36 show stronger association signals when compared with rs7521902 reported in published genome scans. Of these, three SNPs rs12404660, rs3820282, and rs55938609 were located in DNA sequences with potential functional roles including overlap with transcription factor binding sites for FOXA1, FOXA2, ESR1, and ESR2. Functional studies will be required to identify the gene or genes implicated in endometriosis risk.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852639PMC
December 2013
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