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Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets.

ABSTRACT: 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.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.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.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.

SUBMITTER: Rahmioglu N

PROVIDER: S-EPMC4132588 | biostudies-literature | 2014 Sep-Oct

REPOSITORIES: biostudies-literature

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Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets.

Rahmioglu Nilufer N Nyholt Dale R DR Morris Andrew P AP Missmer Stacey A SA Montgomery Grant W GW Zondervan Krina T KT

Human reproduction update 20140327 5

<h4>Background</h4>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 ...[more]

PMID: 24676469

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Project description:CONTEXT:Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE:To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS:Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES:Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS:In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS:We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

Project description:BackgroundOvine footrot caused by Dichelobacter nodosus (D. nodosus) is a contagious disease with serious economic and welfare impacts in sheep production systems worldwide. A better understanding of the host genetic architecture regarding footrot resistance/susceptibility is crucial to develop disease control strategies that efficiently reduce infection and its severity. A genome-wide association study was performed using a customized SNP array (47,779 SNPs in total) to identify genetic variants associated to footrot resistance/susceptibility in two Portuguese native breeds, i.e. Merino Branco and Merino Preto, and a population of crossbred animals. A cohort of 1375 sheep sampled across 17 flocks, located in the Alentejo region (southern Portugal), was included in the analyses.ResultsPhenotypes were scored from 0 (healthy) to 5 (severe footrot) based on visual inspection of feet lesions, following the Modified Egerton System. Using a linear mixed model approach, three SNPs located on chromosome 24 reached genome-wide significance after a Bonferroni correction (p < 0.05). Additionally, six genome-wide suggestive SNPs were identified each on chromosomes 2, 4, 7, 8, 9 and 15. The annotation and KEGG pathway analyses showed that these SNPs are located within regions of candidate genes such as the nonsense mediated mRNA decay associated PI3K related kinase (SMG1) (chromosome 24) and the RALY RNA binding protein like (RALYL) (chromosome 9), both involved in immunity, and the heparan sulfate proteoglycan 2 (HSPG2) (chromosome 2) and the Thrombospodin 1 (THBS1) (chromosome 7) implicated in tissue repair and wound healing processes.ConclusionThis is the first attempt to identify molecular markers associated with footrot in Portuguese Merino sheep. These findings provide relevant information on a likely genetic association underlying footrot resistance/susceptibility and the potential candidate genes affecting this trait. Genetic selection strategies assisted on the information obtained from this study could enhance Merino sheep-breeding programs, in combination with farm management strategies, for a more effective and sustainable long-term solution for footrot control.

Project description:We have performed exome-wide association studies to identify single nucleotide polymorphisms that influence serum concentrations of triglycerides, high density lipoprotein (HDL)-cholesterol, or low density lipoprotein (LDL)-cholesterol or confer susceptibility to hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia in Japanese. Exome-wide association studies for serum triglycerides (13,414 subjects), HDL-cholesterol (14,119 subjects), LDL-cholesterol (13,577 subjects), hypertriglyceridemia (4742 cases, 8672 controls), hypo-HDL-cholesterolemia (2646 cases, 11,473 controls), and hyper-LDL-cholesterolemia (4489 cases, 9088 controls) were performed with HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. Twenty-four, 69, or 32 loci were significantly (P < 1.21 × 10-6) associated with serum triglycerides, HDL-cholesterol, or LDL-cholesterol, respectively, with 13, 16, or 9 of these loci having previously been associated with triglyceride-, HDL-cholesterol-, or LDL-cholesterol-related traits, respectively. Two single nucleotide polymorphisms (rs10790162, rs7350481) were significantly related to both serum triglycerides and hypertriglyceridemia; three polymorphisms (rs146515657, rs147317864, rs12229654) were significantly related to both serum HDL-cholesterol and hypo-HDL-cholesterolemia; and six polymorphisms (rs2853969, rs7771335, rs2071653, rs2269704, rs2269703, rs2269702) were significantly related to both serum LDL-cholesterol and hyper-LDL-cholesterolemia. Among polymorphisms identified in the present study, two polymorphisms (rs146515657, rs147317864) may be novel determinants of hypo-HDL-cholesterolemia, and six polymorphisms (rs2853969, rs7771335, rs2071653, rs2269704, rs2269703, rs2269702) may be new determinants of hyper-LDL-cholesterolemia. In addition, 12, 61, 23, or 3 polymorphisms may be new determinants of the serum triglyceride, HDL-cholesterol, or LDL-cholesterol concentrations or of hyper-LDL-cholesterolemia, respectively.

Project description:ObjectiveSulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction.Research design and methodsAs an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.ResultsAfter establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10-8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10-8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10-58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10-8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10-7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.ConclusionsWe have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.

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Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets.

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Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets.

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