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Julian B Maller,
Gilean McVean,
Jake Byrnes,
Damjan Vukcevic,
Kimmo Palin,
Zhan Su,
Joanna M M Howson,
Adam Auton,
Simon Myers,
Andrew Morris, [......],
Miles Parkes,
Nazneen Rahman,
Audrey Duncanson,
John A Todd,
Dominic P Kwiatkowski,
Nilesh J Samani,
Stephen C L Gough,
Mark I McCarthy, Panagiotis Deloukas,
Peter Donnelly
[show abstract]
[hide abstract]
ABSTRACT: To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.
Nature Genetics 10/2012; · 35.53 Impact Factor
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Zari Dastani,
Marie-France Hivert,
Nicholas Timpson,
John R B Perry,
Xin Yuan,
Robert A Scott,
Peter Henneman,
Iris M Heid,
Jorge R Kizer,
Leo-Pekka Lyytikäinen, [......],
Eric E Schadt,
David P Strachan,
Muredach P Reilly,
Nilesh J Samani,
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Sekar Kathiresan
[show abstract]
[hide abstract]
ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
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Lisette Stolk,
John R B Perry,
Daniel I Chasman,
Chunyan He,
Massimo Mangino,
Patrick Sulem,
Maja Barbalic,
Linda Broer,
Enda M Byrne,
Florian Ernst, [......],
Elizabeth A Streeten,
Unnur Thorsteinsdottir,
Manuela Uda,
G Uitterlinden,
Cornelia M van Duijn,
Henry,
Anna Murray,
Joanne M Murabito,
Jenny A Visser,
Kathryn L Lunetta
Nature Genetics 01/2012; 44(3):260-268. · 35.53 Impact Factor
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Amy Gerrish,
Giancarlo Russo,
Alexander Richards,
Valentina Moskvina,
Dobril Ivanov,
Denise Harold,
Rebecca Sims,
Richard Abraham,
Paul Hollingworth,
Jade Chapman, [......],
Norman Klopp,
H-Erich Wichmann,
Minerva M Carrasquillo,
Shane Pankratz,
Steven G Younkin,
Lesley Jones,
Peter A Holmans,
Michael C O 'donovan,
Michael J Owen,
Julie Williams
Journal of Alzheimer's disease: JAD 01/2012; 28:377-387. · 3.74 Impact Factor
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Lisette Stolk,
John R B Perry,
Daniel I Chasman,
Chunyan He,
Massimo Mangino,
Patrick Sulem,
Maja Barbalic,
Linda Broer,
Enda M Byrne,
Florian Ernst, [......],
Elizabeth A Streeten,
Unnur Thorsteinsdottir,
Manuela Uda,
André G Uitterlinden,
Cornelia M van Duijn,
Henry Völzke,
Anna Murray,
Joanne M Murabito,
Jenny A Visser,
Kathryn L Lunetta
[show abstract]
[hide abstract]
ABSTRACT: To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
Nature Genetics 01/2012; 44(3):260-8. · 35.53 Impact Factor
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Amy Gerrish,
Giancarlo Russo,
Alexander Richards,
Valentina Moskvina,
Dobril Ivanov,
Denise Harold,
Rebecca Sims,
Richard Abraham,
Paul Hollingworth,
Jade Chapman, [......],
Norman Klopp,
H-Erich Wichmann,
Minerva M Carrasquillo,
V Shane Pankratz,
Steven G Younkin,
Lesley Jones,
Peter A Holmans,
Michael C O'Donovan,
Michael J Owen,
Julie Williams
[show abstract]
[hide abstract]
ABSTRACT: Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
Journal of Alzheimer's disease: JAD 01/2012; 28(2):377-87. · 3.74 Impact Factor
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Paul Hollingworth,
Denise Harold,
Rebecca Sims,
Amy Gerrish,
Jean-Charles Lambert,
Minerva M Carrasquillo,
Richard Abraham,
Marian L Hamshere,
Jaspreet Singh Pahwa,
Valentina Moskvina, [......],
Lesley Jones,
Peter A Holmans,
Thorlakur Jonsson,
Matthias Riemenschneider,
Kevin Morgan,
Steven G Younkin,
Michael J Owen,
Michael O'Donovan,
Philippe Amouyel,
Julie Williams
[show abstract]
[hide abstract]
ABSTRACT: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
Nature Genetics 04/2011; 43(5):429-35. · 35.53 Impact Factor
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Dawn M Waterworth,
Sally L Ricketts,
Kijoung Song,
Li Chen,
Jing Hua Zhao,
Samuli Ripatti,
Yurii S Aulchenko,
Weihua Zhang,
Xin Yuan,
Noha Lim, [......],
Nilesh J Samani,
David P Strachan,
Philip Barter,
Cornelia M van Duijn,
Jaspal S Kooner,
Leena Peltonen,
Nicholas J Wareham,
Ruth McPherson,
Vincent Mooser,
Manjinder S Sandhu
[show abstract]
[hide abstract]
ABSTRACT: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.
We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)).
We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
Arteriosclerosis Thrombosis and Vascular Biology 11/2010; 30(11):2264-76. · 6.37 Impact Factor
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
[show abstract]
[hide abstract]
ABSTRACT: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Nature 08/2010; 466(7307):707-13. · 36.28 Impact Factor
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Clare Turnbull,
Elizabeth A Rapley,
Sheila Seal,
David Pernet,
Anthony Renwick,
Deborah Hughes,
Michelle Ricketts,
Rachel Linger,
Jeremie Nsengimana, Panagiotis Deloukas,
Robert A Huddart,
D Timothy Bishop,
Douglas F Easton,
Michael R Stratton,
Nazneen Rahman
[show abstract]
[hide abstract]
ABSTRACT: We conducted a genome-wide association study for testicular germ cell tumor, genotyping 298,782 SNPs in 979 affected individuals and 4,947 controls from the UK and replicating associations in a further 664 cases and 3,456 controls. We identified three new susceptibility loci, two of which include genes that are involved in telomere regulation. We identified two independent signals within the TERT-CLPTM1L locus on chromosome 5, which has previously been associated with multiple other cancers (rs4635969, OR=1.54, P=1.14x10(-23); rs2736100, OR=1.33, P=7.55x10(-15)). We also identified a locus on chromosome 12 (rs2900333, OR=1.27, P=6.16x10(-10)) that contains ATF7IP, a regulator of TERT expression. Finally, we identified a locus on chromosome 9 (rs755383, OR=1.37, P=1.12x10(-23)), containing the sex determination gene DMRT1, which has been linked to teratoma susceptibility in mice.
Nature Genetics 07/2010; 42(7):604-7. · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: High-throughput measurement of allele-specific expression (ASE) is a relatively new and exciting application area for array-based technologies. In this paper, we explore several data sets which make use of Illumina's GoldenGate BeadArray technology to measure ASE. This platform exploits coding SNPs to obtain relative expression measurements for alleles at approximately 1500 positions in the genome.
We analyze data from a mixture experiment where genomic DNA samples from pairs of individuals of known genotypes are pooled to create allelic imbalances at varying levels for the majority of SNPs on the array. We observe that GoldenGate has less sensitivity at detecting subtle allelic imbalances (around 1.3 fold) compared to extreme imbalances, and note the benefit of applying local background correction to the data. Analysis of data from a dye-swap control experiment allowed us to quantify dye-bias, which can be reduced considerably by careful normalization. The need to filter the data before carrying out further downstream analysis to remove non-responding probes, which show either weak, or non-specific signal for each allele, was also demonstrated. Throughout this paper, we find that a linear model analysis of the data from each SNP is a flexible modelling strategy that allows for testing of allelic imbalances in each sample when replicate hybridizations are available.
Our analysis shows that local background correction carried out by Illumina's software, together with quantile normalization of the red and green channels within each array, provides optimal performance in terms of false positive rates. In addition, we strongly encourage intensity-based filtering to remove SNPs which only measure non-specific signal. We anticipate that a similar analysis strategy will prove useful when quantifying ASE on Illumina's higher density Infinium BeadChips.
BMC Bioinformatics 01/2010; 11:280. · 2.75 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
High-throughput measurement of allele-specific expression (ASE) is a relatively new and exciting application area for array-based technologies. In this paper, we explore several data sets which make use of Illumina's GoldenGate BeadArray technology to measure ASE. This platform exploits coding SNPs to obtain relative expression measurements for alleles at approximately 1500 positions in the genome.
Results
We analyze data from a mixture experiment where genomic DNA samples from pairs of individuals of known genotypes are pooled to create allelic imbalances at varying levels for the majority of SNPs on the array. We observe that GoldenGate has less sensitivity at detecting subtle allelic imbalances (around 1.3 fold) compared to extreme imbalances, and note the benefit of applying local background correction to the data. Analysis of data from a dye-swap control experiment allowed us to quantify dye-bias, which can be reduced considerably by careful normalization. The need to filter the data before carrying out further downstream analysis to remove non-responding probes, which show either weak, or non-specific signal for each allele, was also demonstrated. Throughout this paper, we find that a linear model analysis of the data from each SNP is a flexible modelling strategy that allows for testing of allelic imbalances in each sample when replicate hybridizations are available.
Conclusions
Our analysis shows that local background correction carried out by Illumina's software, together with quantile normalization of the red and green channels within each array, provides optimal performance in terms of false positive rates. In addition, we strongly encourage intensity-based filtering to remove SNPs which only measure non-specific signal. We anticipate that a similar analysis strategy will prove useful when quantifying ASE on Illumina's higher density Infinium BeadChips.
BMC Bioinformatics. 01/2010;
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J Brent Richards,
Fotini K Kavvoura,
Fernando Rivadeneira,
Unnur Styrkársdóttir,
Karol Estrada,
Bjarni V Halldórsson,
Yi-Hsiang Hsu,
M Carola Zillikens,
Scott G Wilson,
Benjamin H Mullin, [......],
Frances M K Williams,
Yanhua Zhou,
Stuart H Ralston,
Gudmar Thorleifsson,
Cornelia M van Duijn,
Douglas P Kiel,
Kari Stefansson,
André G Uitterlinden,
John P A Ioannidis,
Tim D Spector
[show abstract]
[hide abstract]
ABSTRACT: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.
To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.
Large-scale meta-analysis of genome-wide association data.
5 international, multicenter, population-based studies.
Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.
Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.
150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.
In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.
Annals of internal medicine 10/2009; 151(8):528-37. · 16.73 Impact Factor
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Denise Harold,
Richard Abraham,
Paul Hollingworth,
Rebecca Sims,
Amy Gerrish,
Marian L Hamshere,
Jaspreet Singh Pahwa,
Valentina Moskvina,
Kimberley Dowzell,
Amy Williams, [......],
Karl-Heinz Jöckel,
Norman Klopp,
H-Erich Wichmann,
Minerva M Carrasquillo,
V Shane Pankratz,
Steven G Younkin,
Peter A Holmans,
Michael O'Donovan,
Michael J Owen,
Julie Williams
[show abstract]
[hide abstract]
ABSTRACT: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).
Nature Genetics 10/2009; 41(10):1088-93. · 35.53 Impact Factor
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Fernando Rivadeneira,
Unnur Styrkársdottir,
Karol Estrada,
Bjarni V Halldórsson,
Yi-Hsiang Hsu,
J Brent Richards,
M Carola Zillikens,
Fotini K Kavvoura,
Najaf Amin,
Yurii S Aulchenko, [......],
Frances M K Williams,
Scott G Wilson,
Yanhua Zhou,
Stuart H Ralston,
Cornelia M van Duijn,
Timothy Spector,
Douglas P Kiel,
Kari Stefansson,
John P A Ioannidis,
André G Uitterlinden
[show abstract]
[hide abstract]
ABSTRACT: Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 x 10(-8)), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.
Nature Genetics 10/2009; 41(11):1199-206. · 35.53 Impact Factor
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Denise Harold,
Richard Abraham,
Paul Hollingworth,
Rebecca Sims,
Amy Gerrish,
Marian L Hamshere,
Jaspreet Singh Pahwa,
Valentina Moskvina,
Kimberley Dowzell,
Amy Williams, [......],
Karl-Heinz J|[ouml]|ckel,
Norman Klopp,
H-Erich Wichmann,
Minerva M Carrasquillo,
V Shane Pankratz,
Steven G Younkin,
Peter A Holmans,
Michael O'Donovan,
Michael J Owen,
Julie Williams
Nature Genetics 09/2009; 41(10):1156-1156. · 35.53 Impact Factor
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Denise Harold,
Richard Abraham,
Paul Hollingworth,
Rebecca Sims,
Amy Gerrish,
Marian L Hamshere,
Jaspreet Singh Pahwa,
Valentina Moskvina,
Kimberley Dowzell,
Amy Williams, [......],
Karl-Heinz J|[ouml]|ckel,
Norman Klopp,
H-Erich Wichmann,
Minerva M Carrasquillo,
V Shane Pankratz,
Steven G Younkin,
Peter A Holmans,
Michael O'Donovan,
Michael J Owen,
Julie Williams
[show abstract]
[hide abstract]
ABSTRACT: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (
Nature Genetics 09/2009; 41(10):1088-1093. · 35.53 Impact Factor
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Elizabeth A Rapley,
Clare Turnbull,
Ali Amin Al Olama,
Emmanouil T Dermitzakis,
Rachel Linger,
Robert A Huddart,
Anthony Renwick,
Deborah Hughes,
Sarah Hines,
Sheila Seal,
Jonathan Morrison,
Jeremie Nsengimana, Panagiotis Deloukas,
Nazneen Rahman,
D Timothy Bishop,
Douglas F Easton,
Michael R Stratton
[show abstract]
[hide abstract]
ABSTRACT: We conducted a genome-wide association study for testicular germ cell tumor (TGCT), genotyping 307,666 SNPs in 730 cases and 1,435 controls from the UK and replicating associations in a further 571 cases and 1,806 controls. We found strong evidence for susceptibility loci on chromosome 5 (per allele OR = 1.37 (95% CI = 1.19-1.58), P = 3 x 10(-13)), chromosome 6 (OR = 1.50 (95% CI = 1.28-1.75), P = 10(-13)) and chromosome 12 (OR = 2.55 (95% CI = 2.05-3.19), P = 10(-31)). KITLG, encoding the ligand for the receptor tyrosine kinase KIT, which has previously been implicated in the pathogenesis of TGCT and the biology of germ cells, may explain the association on chromosome 12.
Nature Genetics 08/2009; 41(7):807-10. · 35.53 Impact Factor
