Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10-61), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

A genome-wide association study of corneal astigmatism:The CREAM Consortium

Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08–1.16), p=5.55×10−9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans—claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.peerReviewe

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a highly heritable disease (h2 = 0.42 ± 0.09). Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG ris

Le site protohistorique du Mont Joui à Florensac (Hérault)

An emergency excavation, carried out in 1975 in the place known as Montjoui in Florensac (Hérault), gave much information concerning the main stages of habitation in this small protohistoric dwelling place which was very busy during the 6th century and early 5th century B.C. After a thorough exploration of the bottom of a hut, a large number of pieces of archeological stuff were discovered ; they are a genuine sample for reference for the early 5th century. A heavy basalt structure could be the foundation of a rampart.Une fouille d'urgence effectuée en 1975 au lieu-dit Montjoui à Florensac (Hérault) a permis de préciser les grandes phases d'occupation de ce petit habitat protohistorique activement fréquenté au VIe et au début du Ve s. av. J.-C. L'exploration extensive d'un fond de cabane a notamment livré un très important lot de mobilier, véritable échantillon de référence pour le début du Ve s. Une puissante structure en basalte pourrait correspondre au soubassement d'un rempart.Nickels André. Le site protohistorique du Mont Joui à Florensac (Hérault). In: Revue archéologique de Narbonnaise, tome 20, 1987. pp. 3-41

Les maisons à abside d'époque grecque archaïque de La Monédière, à Bessan (Hérault)

Nickels André. Les maisons à abside d'époque grecque archaïque de La Monédière, à Bessan (Hérault). In: Gallia, tome 34, fascicule 1, 1976. pp. 95-128

Contribution à l’étude de la céramique grise archaïque en Languedoc-Roussillon

Au cours des dix dernières années, les recherches concernant la céramique grise monochrome, dite phocéenne, se sont progressivement trouvées au centre des débats sur la colonisation grecque en Gaule méridionale. Grâce en particulier à F. Benoit, les questions posées par son origine — locale ou importée — par sa répartition et par l’existence de deux faciès régionaux bien individualisés en Languedoc et en Provence ont pu trouver leurs premiers éléments de réponse. Si, à la suite de cette premi..

Les Grecs en Gaule : l'exemple du Languedoc

Les recherches archéologiques récentes menées en Languedoc, dans la région d'Agde en particulier, montrent que les rapports entre Grecs et indigènes évoluent très sensiblement entre le milieu du VIIe s. et la conquête romaine. À une phase d'exploration, marquée par des contacts sporadiques au cours de la deuxième moitié du VIIe s. et au début du VIe s. succèdent des contacts réguliers, qui débouchent au cours du VIe s. sur des tentatives d'installation. Après une période de profonde mutation au cours du Ve s., encore mal connue, on assiste, à partir de la fin du Ve s., à une véritable mainmise massaliète sur le Languedoc, grâce à la création de la colonie d'Agde, qui se maintiendra, face à un environnement sans doute très hostile, jusqu'à la conquête romaine.Nickels André. Les Grecs en Gaule : l'exemple du Languedoc. In: Modes de contacts et processus de transformation dans les sociétés anciennes. Actes du colloque de Cortone (24-30 mai 1981) Rome : École Française de Rome, 1983. pp. 409-428. (Publications de l'École française de Rome, 67

Recherches sur la topographie de la ville antique d'Agde (Hérault)

Nickels André. Recherches sur la topographie de la ville antique d'Agde (Hérault). In: Documents d'Archéologie Méridionale, vol. 4, 1981. pp. 29-50