Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
24676469
TITLE
Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition.
METHODS NlmCategory: METHODS
Meta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations.
RESULTS NlmCategory: RESULTS
Meta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10(-8)), including rs12700667 on 7p15.2 (P = 1.6 × 10(-9)), rs7521902 near WNT4 (P = 1.8 × 10(-15)), rs10859871 near VEZT (P = 4.7 × 10(-15)), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10(-8)), rs7739264 near ID4 (P = 6.2 × 10(-10)) and rs13394619 in GREB1 (P = 4.5 × 10(-8)). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10(-8)) and rs4141819 on 2p14 (P = 9.2 × 10(-8)). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis.
CONCLUSIONS NlmCategory: CONCLUSIONS
Our meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways.
© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
DATE PUBLISHED
2014 Sep-Oct
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2014/03/27
entrez 2014/03/29 06:00
pubmed 2014/03/29 06:00
medline 2014/10/21 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Rahmioglu N Rahmioglu Nilufer N Wellcome Trust Center for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK nilufer.rahmioglu@well.ox.ac.uk krina.zondervan@well.ox.ac.uk.
Nyholt DR Nyholt Dale R DR Neurogenetics, QIMR Berghofer Medical Research Institute, Brisbane QLD 4029, Australia.
Morris AP Morris Andrew P AP Wellcome Trust Center for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
Missmer SA Missmer Stacey A SA Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Montgomery GW Montgomery Grant W GW Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane QLD 4029, Australia.
Zondervan KT Zondervan Krina T KT Wellcome Trust Center for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
INVESTIGATORS
JOURNAL
VOLUME: 20
ISSUE: 5
TITLE: Human reproduction update
ISOABBREVIATION: Hum. Reprod. Update
YEAR:
MONTH:
DAY:
MEDLINEDATE: 2014 Sep-Oct
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2369
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Hum Reprod Update
COUNTRY: England
ISSNLINKING: 1355-4786
NLMUNIQUEID: 9507614
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
084766 Wellcome Trust United Kingdom
085235 Wellcome Trust United Kingdom
090532 Wellcome Trust United Kingdom
MR/K011480/1 Medical Research Council United Kingdom
WT085235/Z/08/Z Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
KEYWORD
GWAS
endometriosis
genetics
heterogeneity
sub-phenotypes
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Endometriosis genetics
European Continental Ancestry Group genetics
Female genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study genetics
Humans genetics
Phenotype genetics
Risk genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
PMC4132588 NLM