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‣ Genetic analysis and gene fine mapping of aroma in rice (Oryza sativa L. Cyperales, Poaceae)

Sun,Shu Xia; Gao,Fang Yuan; Lu,Xian Jun; Wu,Xian Jun; Wang,Xu Dong; Ren,Guang Jun; Luo,Hong
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2008 Português
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We investigated inheritance and carried out gene fine mapping of aroma in crosses between the aromatic elite hybrid rice Oryza sativa indica variety Chuanxiang-29B (Ch-29B) and the non-aromatic rice O. sativa indica variety R2 and O. sativa japonica Lemont (Le). The F1 grains and leaves were non-aromatic while the F2 non-aroma to aroma segregation pattern was 3:1. The F3 segregation ratio was consistent with the expected 1:2:1 for a single recessive aroma gene in Ch-29B. Linkage analysis between simple sequence repeat (SSR) markers and the aroma locus for the aromatic F2 plants mapped the Ch-29B aroma gene to a chromosome 8 region flanked by SSR markers RM23120 at 0.52 cM and RM3459 at 1.23 cM, a replicate F2 population confirming these results. Three bacterial artificial chromosome (BAC) clones cover chromosome 8 markers RM23120 and RM3459. Our molecular mapping data from the two populations indicated that the aroma locus occurs in a 142.85 kb interval on BAC clones AP005301 or AP005537, implying that it might be the same gene reported by Bradbury et al (2005a; Plant Biotec J. 3:363-370). The flanking markers Aro7, RM23120 and RM3459 identified by us could greatly accelerate the efficiency and precision of aromatic rice breeding programs.

‣ Genomewide Scan and Fine-Mapping Linkage Studies in Four European Samples with Bipolar Affective Disorder Suggest a New Susceptibility Locus on Chromosome 1p35-p36 and Provides Further Evidence of Loci on Chromosome 4q31 and 6q24

Schumacher, Johannes; Kaneva, Radka; Jamra, Rami Abou; Diaz, Guillermo Orozco; Ohlraun, Stephanie; Milanova, Vihra; Lee, Young-Ae; Rivas, Fabio; Mayoral, Fermin; Fuerst, Robert; Flaquer, Antonia; Windemuth, Christine; Gay, Eudoxia; Sanz, Sebastian; Gonzá
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.

‣ Fine-mapping using the weighted average method for a case-control study

Song, Kijoung; Orloff, Mohammed S; Lu, Qing; Elston, Robert C
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 30/12/2005 Português
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We present a new method for fine-mapping a disease susceptibility locus using a case-control design. The new method, termed the weighted average (WA) statistic, averages the Cochran-Armitage (CA) trend test statistic and the difference between the Hardy-Weinberg disequilibrium test statistic for cases and controls (the HWD trend). The main characteristics of the WA statistic are that it improves on the weaknesses, and maintains the strengths, of both the CA trend test and the HWD trend test. Data from three different populations in the Genetic Analysis Workshop 14 (GAW14) simulated dataset (Aipotu, Karangar, and Danacaa) were first subjected to model-free linkage analysis to find regions exhibiting linkage. Then, for fine-scale mapping, 140 SNPs within the significant linkage regions were analyzed with the WA test statistic on replicates of the three populations, both separately and combined. The regions that were significant in the multipoint linkage analysis were also significant in this fine-scale mapping. The most significant regions that were obtained using the WA statistic were regions in chromosome 3 (B03T3056–B03T3058, p-value < 1 × 10-10 ) and chromosome 9 (B09T8332–B09T8334, p-value 1 × 10-6 ). Based on the results of the simulated GAW14 data...

‣ Comparison of false-discovery rate for genome-wide and fine mapping regions

Tabangin, Meredith E; Woo, Jessica G; Liu, Chunyan; Nick, Todd G; Martin, Lisa J
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 18/12/2007 Português
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With technological advances in high-throughput genotyping, it is not unusual to perform hundreds of thousands of tests for each phenotype. Thus, correction to control type I error is essential. The false-discovery rate (FDR) has been successfully used in genome-wide expression data. However, its performance has not been evaluated for association analysis. Our objective was to analyze the Genetic Analysis Workshop 15 simulated data set, with answers, to evaluate FDR for genome-wide association and fine mapping. In genome-wide analysis, FDR performed well, with good localization of positive results. However, in fine mapping, all tested methods performed poorly, producing a high proportion of significant results. Thus, caution should be used when employing FDR for fine mapping.

‣ Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility

Lou, Hong; Yeager, Meredith; Li, Hongchuan; Bosquet, Jesus Gonzalez; Hayes, Richard B.; Orr, Nick; Yu, Kai; Hutchinson, Amy; Jacobs, Kevin B.; Kraft, Peter; Wacholder, Sholom; Chatterjee, Nilanjan; Feigelson, Heather Spencer; Thun, Michael J.; Diver, W. R
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Two recent genome-wide association studies have independently identified a prostate cancer susceptibility locus on chromosome 10q11.2. The most significant single-nucleotide polymorphism (SNP) marker reported, rs10993994, is 57 bp centromeric of the first exon of the MSMB gene, which encodes β-microseminoprotein (prostatic secretory protein 94). In this study, a fine-mapping analysis using HapMap SNPs was conducted across a ≈65-kb region (chr10: 51168330–51234020) flanking rs10993994 with 13 tag SNPs in 6,118 prostate cancer cases and 6,105 controls of European origin from the Cancer Genetic Markers of Susceptibility (CGEMS) project. rs10993994 remained the most strongly associated marker with prostate cancer risk [P = 8.8 × 10−18; heterozygous odds ratio (OR) = 1.20, 95% confidence interval (CI): 1.11–1.30; homozygous OR = 1.64, 95% CI: 1.47–1.86 for the adjusted genotype test with 2 df]. In follow-up functional analyses, the T variant of rs10993994 significantly affected expression of in vitro luciferase reporter constructs. In electrophoretic mobility shift assays, the C allele of rs10993994 preferentially binds to the CREB transcription factor. Analysis of tumor cell lines with a CC or CT genotype revealed a high level of MSMB gene expression compared with cell lines with a TT genotype. These findings were specific to the alleles of rs10993994 and were not observed for other SNPs determined by sequence analysis of the proximal promoter. Together...

‣ Combining DNA pooling with selective recombinant genotyping for increased efficiency in fine mapping

Chi, Xiao-Fei; Lou, Xiang-Yang; Shu, Qing-Yao
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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One of the key steps in positional cloning and marker-aided selection is to identify marker(s) tightly linked to the target gene (i.e., fine mapping). Selective genotyping such as selective recombinant genotyping (SRG) is commonly used in fine mapping for cost-saving. To further decrease genotyping effort and rapidly screen for tightly linked markers, we propose here a combined DNA pooling and SRG strategy. A two-stage pooled genotyping can be used for identifying recombinants between a pair of flanking markers more efficiently, and a joint use of bulked DNA analysis and two-stage pooling can also save cost for genotyping recombinants. The combined DNA pooling and SRG strategy can further be extended to fine mapping for polygenic traits. The numerical results based on hypothetical scenarios and an illustrative application to fine mapping of a mutant gene, called xl(t), in rice suggest that the proposed strategy can remarkably reduce genotyping amount compared with the conventional SRG.

‣ Fine-mapping of colorectal cancer susceptibility loci at 8q23.3, 16q22.1 and 19q13.11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes

Carvajal-Carmona, Luis G.; Cazier, Jean-Baptiste; Jones, Angela M.; Howarth, Kimberley; Broderick, Peter; Pittman, Alan; Dobbins, Sara; Tenesa, Albert; Farrington, Susan; Prendergast, James; Theodoratou, Evi; Barnetson, Rebecca; Conti, David; Newcomb, Pol
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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We have previously identified several colorectal cancer (CRC)-associated polymorphisms using genome-wide association (GWA) analysis. We sought to fine-map the location of the functional variants for three of these regions at 8q23.3 (EIF3H), 16q22.1 (CDH1/CDH3) and 19q13.11 (RHPN2). We genotyped two case–control sets at high density in the selected regions and used existing data from four other case–control sets, comprising a total of 9328 CRC cases and 10 480 controls. To improve marker density, we imputed genotypes from the 1000 Genomes Project and Hapmap3 data sets. All three regions contained smaller areas in which a cluster of single nucleotide polymorphisms (SNPs) showed clearly stronger association signals than surrounding SNPs, allowing us to assign those areas as the most likely location of the disease-associated functional variant. Further fine-mapping within those areas was generally unhelpful in identifying the functional variation based on strengths of association. However, functional annotation suggested a relatively small number of functional SNPs, including some with potential regulatory function at 8q23.3 and 16q22.1 and a non-synonymous SNP in RPHN2. Interestingly, the expression quantitative trait locus browser showed a number of highly associated SNP alleles correlated with mRNA expression levels not of EIF3H and CDH1 or CDH3...

‣ Saturation of an Intra-Gene Pool Linkage Map: Towards a Unified Consensus Linkage Map for Fine Mapping and Synteny Analysis in Common Bean

Galeano, Carlos H.; Fernandez, Andrea C.; Franco-Herrera, Natalia; Cichy, Karen A.; McClean, Phillip E.; Vanderleyden, Jos; Blair, Matthew W.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 08/12/2011 Português
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Map-based cloning and fine mapping to find genes of interest and marker assisted selection (MAS) requires good genetic maps with reproducible markers. In this study, we saturated the linkage map of the intra-gene pool population of common bean DOR364×BAT477 (DB) by evaluating 2,706 molecular markers including SSR, SNP, and gene-based markers. On average the polymorphism rate was 7.7% due to the narrow genetic base between the parents. The DB linkage map consisted of 291 markers with a total map length of 1,788 cM. A consensus map was built using the core mapping populations derived from inter-gene pool crosses: DOR364×G19833 (DG) and BAT93×JALO EEP558 (BJ). The consensus map consisted of a total of 1,010 markers mapped, with a total map length of 2,041 cM across 11 linkage groups. On average, each linkage group on the consensus map contained 91 markers of which 83% were single copy markers. Finally, a synteny analysis was carried out using our highly saturated consensus maps compared with the soybean pseudo-chromosome assembly. A total of 772 marker sequences were compared with the soybean genome. A total of 44 syntenic blocks were identified. The linkage group Pv6 presented the most diverse pattern of synteny with seven syntenic blocks...

‣ Analysis of genome-wide structure, diversity and fine mapping of Mendelian traits in traditional and village chickens

Wragg, D; Mwacharo, J M; Alcalde, J A; Hocking, P M; Hanotte, O
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Extensive phenotypic variation is a common feature among village chickens found throughout much of the developing world, and in traditional chicken breeds that have been artificially selected for traits such as plumage variety. We present here an assessment of traditional and village chicken populations, for fine mapping of Mendelian traits using genome-wide single-nucleotide polymorphism (SNP) genotyping while providing information on their genetic structure and diversity. Bayesian clustering analysis reveals two main genetic backgrounds in traditional breeds, Kenyan, Ethiopian and Chilean village chickens. Analysis of linkage disequilibrium (LD) reveals useful LD (r2⩾0.3) in both traditional and village chickens at pairwise marker distances of ∼10 Kb; while haplotype block analysis indicates a median block size of 11–12 Kb. Association mapping yielded refined mapping intervals for duplex comb (Gga 2:38.55–38.89 Mb) and rose comb (Gga 7:18.41–22.09 Mb) phenotypes in traditional breeds. Combined mapping information from traditional breeds and Chilean village chicken allows the oocyan phenotype to be fine mapped to two small regions (Gga 1:67.25–67.28 Mb, Gga 1:67.28–67.32 Mb) totalling ∼75 Kb. Mapping the unmapped earlobe pigmentation phenotype supports previous findings that the trait is sex-linked and polygenic. A critical assessment of the number of SNPs required to map simple traits indicate that between 90 and 110K SNPs are required for full genome-wide analysis of haplotype block structure/ancestry...

‣ Efficiency of trans-ethnic genome-wide meta-analysis and fine-mapping

Twee-Hee Ong, Rick; Wang, Xu; Liu, Xuanyao; Teo, Yik-Ying
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Genome-wide association studies have seen unprecedented success in identifying genetic loci that correlate with disease susceptibility and severity. Early phases of these studies have predominantly been performed in the Caucasian populations. The next phase in medical genetics is to extend the exploration across genetically diverse populations to leverage on larger sample sizes for locating smaller effects that may be present in most human populations. However, discoveries from these studies do not actually reveal the underlying functional changes to the human genome, but only point to broad regions stipulated by the extent of linkage disequilibrium (LD). Fine-mapping the functional variants can, however, be hampered by extensive LD, which can yield multiple perfect surrogates that are not distinguishable from the underlying causal variants, although several studies have illustrated the value of relying on multiple genetically diverse populations to narrow the candidate regions where the functional variants can be found in. Here, we explore the efficiency of trans-ethnic meta-analysis in discovering genetic association and in fine-mapping the causal variants by asking: are there any population diversity metrics that will be useful for: (i) identifying the populations or genomic regions where meta-analysis are likely to be more successful for discovering associations?; (ii) identifying the populations or loci to perform deep targeted sequencing for the purpose of fine-mapping causal variants? Our results indicate that simple metrics like the FST or the population specificity of haplotypes are useful in trans-ethnic meta-analyses...

‣ Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Kote-Jarai, Zsofia; Saunders, Edward J.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Jugurnauth-Little, Sarah; Ross-Adams, Helen; Al Olama, Ali Amin; Benlloch, Sara; Halim, Silvia; Russel, Roslin; Dunning, Alison M.; Luccarini, Cr
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

‣ Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

Saunders, Edward J.; Dadaev, Tokhir; Leongamornlert, Daniel A.; Jugurnauth-Little, Sarah; Tymrakiewicz, Malgorzata; Wiklund, Fredrik; Al Olama, Ali Amin; Benlloch, Sara; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Giles, Graham G.; Severi, Gianl
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 13/02/2014 Português
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The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

‣ Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

Saunders, Edward J.; Dadaev, Tokhir; Leongamornlert, Daniel A.; Jugurnauth-Little, Sarah; Tymrakiewicz, Malgorzata; Wiklund, Fredrik; Al Olama, Ali Amin; Benlloch, Sara; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Giles, Graham G.; Severi, Gianl
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
57.394556%
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

‣ Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, L
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry...

‣ Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, L
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
57.517417%
We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry...

‣ A method for fine mapping quantitative trait loci in outbred animal stocks

Mott, Richard; Talbot, Christopher J.; Turri, Maria G.; Collins, Allan C.; Flint, Jonathan
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
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High-resolution mapping of quantitative trait loci (QTL) in animals has proved to be difficult because the large effect sizes detected in crosses between inbred strains are often caused by numerous linked QTLs, each of small effect. In a study of fearfulness in mice, we have shown it is possible to fine map small-effect QTLs in a genetically heterogeneous stock (HS). This strategy is a powerful general method of fine mapping QTLs, provided QTLs detected in crosses between inbred strains that formed the HS can be reliably detected in the HS. We show here that single-marker association analysis identifies only two of five QTLs expected to be segregating in the HS and apparently limits the strategy's usefulness for fine mapping. We solve this problem with a multipoint analysis that assigns the probability that an allele descends from each progenitor in the HS. The analysis does not use pedigrees but instead requires information about the HS founder haplotypes. With this method we mapped all three previously undetected loci [chromosome (Chr.) 1 logP 4.9, Chr. 10 logP 6.0, Chr. 15 logP 4.0]. We show that the reason for the failure of single-marker association to detect QTLs is its inability to distinguish opposing phenotypic effects when they occur on the same marker allele. We have developed a robust method of fine mapping QTLs in genetically heterogeneous animals and suggest it is now cost effective to undertake genomewide high-resolution analysis of complex traits in parallel on the same set of mice.

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

O'Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Dennis, Joe; Australian National Endometrial Cancer Study Group (ANECS); Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Ashton, Katie; Proietto, Tony; Otton, Geoff
Fonte: Society for Endocrinology Publicador: Society for Endocrinology
Tipo: Article; published version
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This is the final version of the article. It first appeared from the Society for Endocrinology via http://dx.doi.org/10.1530/ERC-15-0319; 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...

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

Carvajal-Carmona, Luis G.; O?Mara, Tracy A.; Painter, Jodie N.; Lose, Felicity A.; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; Pooley, Karen; Beesley, Jonathan; Cheng, Timothy; Jones, Ange
Fonte: Springer Berlin Heidelberg Publicador: Springer Berlin Heidelberg
Tipo: Article; published version
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This is the published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00439-014-1515-4.; 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...

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

Painter, Jodie N.; O?Mara, Tracy A.; Batra, Jyotsna; Cheng, Timothy; Lose, Felicity A.; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; Kaufmann, Susanne; Hillman, Kristine M.; Walpole, Carina
Fonte: Oxford Journals Publicador: Oxford Journals
Tipo: Article; published version
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This is the accepted manuscript. The final version is available from OUP at http://hmg.oxfordjournals.org/content/24/5/1478.; 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 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4?10-14, OR=0.86, 95% CI=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 tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD 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...

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

Thompson, Deborah J.; O?Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Folkerd, Elizabeth; Doody, Deborah; Dennis, Joe; Webb, Penelope M.; Australian National Endometrial Cancer Study Group (ANECS); Gorman, Maggie; Martin, Lynn; Hodgs
Fonte: Bioscientifica Publicador: Bioscientifica
Tipo: Article; published version
Português
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This is the author accepted manuscript. The final version is available from Bioscientifica via http://dx.doi.org/10.1530/ERC-15-0386; Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol concentrations. We analysed 2,937 SNPs in 6,608 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=4.8x10-11). SNP rs727479 was also among those most strongly associated with circulating estradiol concentrations in 2,767 post-menopausal controls (P=7.4x10- 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 estradiol concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by estradiol. 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.; Fine-mapping analysis was supported by NHMRC project grant [ID#1031333] to ABS...