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1. A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context

Author

Gallois, Apolline, Mefford, Joel, Ko, Arthur, Vaysse, Amaury, Julienne, Hanna, Ala-Korpela, Mika, Laakso, Markku, Zaitlen, Noah, Pajukanta, Päivi, and Aschard, Hugues

Subjects
Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Aged, Amino Acids, Cohort Studies, Fatty Acids, Gene Regulatory Networks, Genetic Pleiotropy, Genome-Wide Association Study, Humans, Lipoproteins, HDL, Lipoproteins, IDL, Lipoproteins, LDL, Lipoproteins, VLDL, Magnetic Resonance Spectroscopy, Male, Metabolic Syndrome, Metabolome, Middle Aged, Polymorphism, Single Nucleotide
Abstract

Genetic studies of metabolites have identified thousands of variants, many of which are associated with downstream metabolic and obesogenic disorders. However, these studies have relied on univariate analyses, reducing power and limiting context-specific understanding. Here we aim to provide an integrated perspective of the genetic basis of metabolites by leveraging the Finnish Metabolic Syndrome In Men (METSIM) cohort, a unique genetic resource which contains metabolic measurements, mostly lipids, across distinct time points as well as information on statin usage. We increase effective sample size by an average of two-fold by applying the Covariates for Multi-phenotype Studies (CMS) approach, identifying 588 significant SNP-metabolite associations, including 228 new associations. Our analysis pinpoints a small number of master metabolic regulator genes, balancing the relative proportion of dozens of metabolite levels. We further identify associations to changes in metabolic levels across time as well as genetic interactions with statin at both the master metabolic regulator and genome-wide level.

Published
2019

2. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance

Author

de Oliveira Alves, Nilmara, primary, Dalmasso, Guillaume, additional, Nikitina, Darja, additional, Vaysse, Amaury, additional, Ruez, Richard, additional, Ledoux, Lea, additional, Pedron, Thierry, additional, Bergsten, Emma, additional, Boulard, Olivier, additional, Autier, Lora, additional, Allam, Sofian, additional, Motreff, Laurence, additional, Sauvanet, Pierre, additional, Letourneur, Diane, additional, Kashyap, Pragya, additional, Gagnière, Johan, additional, Pezet, Denis, additional, Godfraind, Catherine, additional, Salzet, Michel, additional, Lemichez, Emmanuel, additional, Bonnet, Mathilde, additional, Najjar, Imène, additional, Malabat, Christophe, additional, Monot, Marc, additional, Mestivier, Denis, additional, Barnich, Nicolas, additional, Yadav, Pankaj, additional, Fournier, Isabelle, additional, Kennedy, Sean, additional, Mettouchi, Amel, additional, Bonnet, Richard, additional, Sobhani, Iradj, additional, and Chamaillard, Mathias, additional

Published
2024
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4. Parvimonas micra , an oral pathobiont associated with colorectal cancer, epigenetically reprograms human colonocytes

Author

Bergsten, Emma, primary, Mestivier, Denis, additional, Donnadieu, Francoise, additional, Pedron, Thierry, additional, Barau, Caroline, additional, Meda, Landry Tsoumtsa, additional, Mettouchi, Amel, additional, Lemichez, Emmanuel, additional, Gorgette, Olivier, additional, Chamaillard, Mathias, additional, Vaysse, Amaury, additional, Volant, Stevenn, additional, Doukani, Abiba, additional, Sansonetti, Philippe J., additional, Sobhani, Iradj, additional, and Nigro, Giulia, additional

Published
2023
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5. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author

Demenais, Florence, Margaritte-Jeannin, Patricia, Barnes, Kathleen C., Cookson, William O. C., Altmüller, Janine, Ang, Wei, Barr, R. Graham, Beaty, Terri H., Becker, Allan B., Beilby, John, Bisgaard, Hans, Bjornsdottir, Unnur Steina, Bleecker, Eugene, Bønnelykke, Klaus, Boomsma, Dorret I., Bouzigon, Emmanuelle, Brightling, Christopher E., Brossard, Myriam, Brusselle, Guy G., Burchard, Esteban, Burkart, Kristin M., Bush, Andrew, Chan-Yeung, Moira, Chung, Kian Fan, Couto Alves, Alexessander, Curtin, John A., Custovic, Adnan, Daley, Denise, de Jongste, Johan C., Del-Rio-Navarro, Blanca E., Donohue, Kathleen M., Duijts, Liesbeth, Eng, Celeste, Eriksson, Johan G., Farrall, Martin, Fedorova, Yuliya, Feenstra, Bjarke, Ferreira, Manuel A., Freidin, Maxim B., Gajdos, Zofia, Gauderman, Jim, Gehring, Ulrike, Geller, Frank, Genuneit, Jon, Gharib, Sina A., Gilliland, Frank, Granell, Raquel, Graves, Penelope E., Gudbjartsson, Daniel F., Haahtela, Tari, Heckbert, Susan R., Heederik, Dick, Heinrich, Joachim, Heliövaara, Markku, Henderson, John, Himes, Blanca E., Hirose, Hiroshi, Hirschhorn, Joel N., Hofman, Albert, Holt, Patrick, Hottenga, Jouke, Hudson, Thomas J., Hui, Jennie, Imboden, Medea, Ivanov, Vladimir, Jaddoe, Vincent W. V., James, Alan, Janson, Christer, Jarvelin, Marjo-Riitta, Jarvis, Deborah, Jones, Graham, Jonsdottir, Ingileif, Jousilahti, Pekka, Kabesch, Michael, Kähönen, Mika, Kantor, David B., Karunas, Alexandra S., Khusnutdinova, Elza, Koppelman, Gerard H., Kozyrskyj, Anita L., Kreiner, Eskil, Kubo, Michiaki, Kumar, Rajesh, Kumar, Ashish, Kuokkanen, Mikko, Lahousse, Lies, Laitinen, Tarja, Laprise, Catherine, Lathrop, Mark, Lau, Susanne, Lee, Young-Ae, Lehtimäki, Terho, Letort, Sébastien, Levin, Albert M., Li, Guo, Liang, Liming, Loehr, Laura R., London, Stephanie J., Loth, Daan W., Manichaikul, Ani, Marenholz, Ingo, Martinez, Fernando J., Matheson, Melanie C., Mathias, Rasika A., Matsumoto, Kenji, Mbarek, Hamdi, McArdle, Wendy L., Melbye, Mads, Melén, Erik, Meyers, Deborah, Michel, Sven, Mohamdi, Hamida, Musk, Arthur W., Myers, Rachel A., Nieuwenhuis, Maartje A. E., Noguchi, Emiko, O’Connor, George T., Ogorodova, Ludmila M., Palmer, Cameron D., Palotie, Aarno, Park, Julie E., Pennell, Craig E., Pershagen, Göran, Polonikov, Alexey, Postma, Dirkje S., Probst-Hensch, Nicole, Puzyrev, Valery P., Raby, Benjamin A., Raitakari, Olli T., Ramasamy, Adaikalavan, Rich, Stephen S., Robertson, Colin F., Romieu, Isabelle, Salam, Muhammad T., Salomaa, Veikko, Schlünssen, Vivi, Scott, Robert, Selivanova, Polina A., Sigsgaard, Torben, Simpson, Angela, Siroux, Valérie, Smith, Lewis J., Solodilova, Maria, Standl, Marie, Stefansson, Kari, Strachan, David P., Stricker, Bruno H., Takahashi, Atsushi, Thompson, Philip J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiesler, Carla M. T., Torgerson, Dara G., Tsunoda, Tatsuhiko, Uitterlinden, André G., van der Valk, Ralf J. P., Vaysse, Amaury, Vedantam, Sailaja, von Berg, Andrea, von Mutius, Erika, Vonk, Judith M., Waage, Johannes, Wareham, Nick J., Weiss, Scott T., White, Wendy B., Wickman, Magnus, Widén, Elisabeth, Willemsen, Gonneke, Williams, L. Keoki, Wouters, Inge M., Yang, James J., Zhao, Jing Hua, Moffatt, Miriam F., Ober, Carole, and Nicolae, Dan L.

Published
2018
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6. Spatially-resolved metabolomic identifies colibactin-specific principles of reprogrammed lipid metabolism to promote cancer progression

Author

de Oliveira Alves, Nilmara, primary, Boulard, Olivier, additional, Vaysse, Amaury, additional, Dalmasso, Guillaume, additional, Nikitina, Darja, additional, Ruez, Richard, additional, Pedron, Thierry, additional, Bergstein, Emma, additional, Sauvanet, Pierre, additional, Letourneur, Diane, additional, Godfraind, Catherine, additional, Najjar, Imène, additional, Lemichez, Emmanuel, additional, Iovanna, Juan Lucio, additional, Mestivier, Denis, additional, Barnich, Nicolas, additional, Sansonetti, Philippe, additional, Malabat, Christophe, additional, Monot, Marc, additional, Kennedy, Sean, additional, Mettouchi, Amel, additional, Bonnet, Richard, additional, Sobhani, Iradj, additional, and Chamaillard, Mathias, additional

Published
2023
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7. IRF8 regulates efficacy of therapeutic anti‐CD20 monoclonal antibodies

Author

Grzelak, Ludivine, primary, Roesch, Ferdinand, additional, Vaysse, Amaury, additional, Biton, Anne, additional, Legendre, Rachel, additional, Porrot, Françoise, additional, Commère, Pierre‐Henri, additional, Planchais, Cyril, additional, Mouquet, Hugo, additional, Vignuzzi, Marco, additional, Bruel, Timothée, additional, and Schwartz, Olivier, additional

Published
2022
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8. Multitrait GWAS to connect disease variants and biological mechanisms

Author

Julienne, Hanna, Laville, Vincent, Mccaw, Zachary, He, Zihuai, Guillemot, Vincent, Lasry, Carla, Ziyatdinov, Andrey, Nerin, Cyril, Vaysse, Amaury, Lechat, Pierre, Ménager, Hervé, Le Goff, Wilfried, Dube, Marie-Pierre, Kraft, Peter, Ionita-Laza, Iuliana, Vilhjálmsson, Bjarni, Aschard, Hugues, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Harvard T.H. Chan School of Public Health, Stanford University School of Medicine [CA, USA], Stanford University, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Montreal Heart Institute - Institut de Cardiologie de Montréal, Columbia University [New York], Aarhus University [Aarhus], This work has been conducted as part of the INCEPTION program (ANR-16-CONV-0005) (HA). It was also supported by NIH grant R03DE025665 to HA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Aschard, hugues, and Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID

Subjects
Single Nucleotide Polymorphisms, QH426-470, Biochemistry, [STAT.AP] Statistics [stat]/Applications [stat.AP], Medicine and Health Sciences, Genetics of the Immune System, Cluster Analysis, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], RISK, [STAT.AP]Statistics [stat]/Applications [stat.AP], [STAT.ME] Statistics [stat]/Methodology [stat.ME], Covariance, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Genomics, Lipids, STATISTICS, Phenotypes, Cholesterol, Phenotype, DENSITY-LIPOPROTEIN CHOLESTEROL, Physical Sciences, [STAT.ME]Statistics [stat]/Methodology [stat.ME], MESH: Computational Biology, TRIGLYCERIDES, Research Article, Immunology, Quantitative Trait Loci, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Polymorphism, Single Nucleotide, ESTER TRANSFER PROTEIN, Genetics, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, MESH: Humans, CORRELATED TRAITS, MORTALITY, Biology and Life Sciences, Computational Biology, Human Genetics, Random Variables, Genome Analysis, Probability Theory, MESH: Cluster Analysis, MESH: Quantitative Trait Loci, MODEL, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Genome-Wide Association Study, Genetics of Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Clinical Immunology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Clinical Medicine, Mathematics, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have uncovered a wealth of associations between common variants and human phenotypes. Here, we present an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link with biological mechanisms. Our framework incorporates multitrait association mapping along with an investigation of the breakdown of genetic associations into clusters of variants harboring similar multitrait association profiles. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how genetic variants within clusters can be mapped to biological pathways and disease mechanisms. Finally, for the metabolism set, we investigate the link between gene cluster assignment and the success of drug targets in randomized controlled trials., Author summary Genome-wide association studies (GWAS) established numerous associations between genetic variants and human traits. The anonymized summary of GWAS results is generally made publicly available to the scientific community and can be explored further. Amongst the many possible secondary analyses, one is to study the effect of a genetic variant on several traits (multi-trait GWAS) rather than a unique trait. We compared several tests to conduct multi-trait GWAS on simulated and real data. We detected 322 new associations that were not previously reported by standard univariate GWAS. We then detected clusters of genetic variants having a similar effect across several traits. Focusing on two subsets of immunity and metabolism traits, we demonstrate how genetic variants within clusters can be mapped to biological pathways and disease mechanisms. Finally, for the metabolism set, we investigate the link between gene cluster and success of drug targets in randomized controlled trials. We propose this method for improving the functional interpretation of GWAS results.

Published
2021

12. New susceptibility loci for cutaneous melanoma risk and progression revealed using a porcine model

Author

Bourneuf, Emmanuelle, Jordi Estellé, Jordi, Blin, Amandine, Créchet, Francoise, Schneider, Maria-Del-Pilar, Gilbert, Hélène, Brossard, Myriam, Vaysse, Amaury, Lathrop, Mark, Vincent-Naulleau, Silvia, Demenais, Florence, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), DRF/IRCM/SREIT/LREG, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM), Taxonomie - Collections (TC), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (COMUE) (USPC), Innovation Centre, P&G, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-École nationale supérieure agronomique de Toulouse (ENSAT), Université de Toulouse (UT)-Université de Toulouse (UT), and Université de Toulouse (UT)

Subjects
pig, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV]Life Sciences [q-bio], melanoma, GWAS, [INFO]Computer Science [cs], comparative genomics, Research Paper, biomedical model
Abstract

International audience; Despite major advances, it is estimated that a large part of melanoma predisposing genes remains to be discovered. Animal models of spontaneous diseases are valuable tools and experimental crosses can be used to identify and fine-map new susceptibility loci associated with melanoma. We performed a Genome-Wide Association Study (GWAS) of melanoma occurrence and progression (clinical ulceration and presence of metastasis) in a porcine model of spontaneous melanoma, the MeLiM pig. Five loci on chromosomes 2, 5, 7, 8 and 16 showed genome-wide significant associations ( p < 5 × 10 –6 ) with either one of these phenotypes. Suggestive associations ( p < 5 × 10 –5 ) were also found at 16 additional loci. Moreover, comparison of the porcine results to those reported by human melanoma GWAS indicated shared association signals notably at CDKAL1 and TERT loci but also nearby CCND1 , FTO, PLA2G6 and TMEM 38B-RAD23B loci. Extensive search of the literature revealed a potential key role of genes at the identified porcine loci in tumor invasion ( DST , PLEKHA5, CBY1 , LIMK2 and ETV5 ) and immune response modulation ( ETV5 , HERC3 and DICER1 ) of the progression phenotypes. These biological processes are consistent with the clinico-pathological features of MeLiM tumors and can open new routes for future melanoma research in humans.

Published
2018

14. Multitrait genetic-phenotype associations to connect disease variants and biological mechanisms

Author

Julienne, Hanna, primary, Laville, Vincent, additional, McCaw, Zachary R., additional, He, Zihuai, additional, Guillemot, Vincent, additional, Lasry, Carla, additional, Ziyatdinov, Andrey, additional, Vaysse, Amaury, additional, Lechat, Pierre, additional, Ménager, Hervé, additional, Goff, Wilfried Le, additional, Dube, Marie-Pierre, additional, Kraft, Peter, additional, Ionita-Laza, Iuliana, additional, Vilhjálmsson, Bjarni J., additional, and Aschard, Hugues, additional

Published
2020
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17. RNA profiles of rat olfactory epithelia: individual and age related variations

Author

Vaysse Amaury, Robin Stéphanie, Rimbault Maud, and Galibert Francis

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Mammalian genomes contain a large number (~1000) of olfactory receptor (OR) genes, many of which (20 to 50%) are pseudogenes. OR gene transcription is not restricted to the olfactory epithelium, but is found in numerous tissues. Using microarray hybridization and RTqPCR, we analyzed the mRNA profiles of the olfactory epithelium of male and female Brown Norway rats of different origins and ages (newborn, adult and old). Results (1) We observed very little difference between males and females and between rats from two different suppliers. (2) Different OR genes were expressed at varying levels, rather than uniformly across the four endoturbinates. (3) A large proportion of the gene transcripts (2/3 of all probes) were detected in all three age groups. Adult and older rats expressed similar numbers of OR genes, both expressing more OR genes than newborns. (4) Comparisons of whole transcriptomes or transcription profiles of expressed OR genes only showed a clear clustering of the samples as a function of age. (5) Most OR genes were expressed at lower levels at birth than in older animals, but a small number of OR genes were expressed specifically or were overexpressed in newborns. Conclusion Not all OR genes are expressed at a detectable level. Pups expressed fewer OR genes than adult rats, and generally at a lower level; however, a small subset of OR genes were more strongly expressed in these newborn rats. The reasons for these differences are not understood. However, the specific expression of some OR genes in newborn olfactory epithelia may be related to the blindness and deafness of pups at birth, when these pups are heavily reliant on olfaction and their mother.

Published
2009
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18. Revisiting the missing protein-coding gene catalog of the domestic dog

Author

Galibert Francis, Ostrander Elaine A, André Catherine, Vaysse Amaury, Thézé Julien, Derrien Thomas, and Hitte Christophe

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Among mammals for which there is a high sequence coverage, the whole genome assembly of the dog is unique in that it predicts a low number of protein-coding genes, ~19,000, compared to the over 20,000 reported for other mammalian species. Of particular interest are the more than 400 of genes annotated in primates and rodent genomes, but missing in dog. Results Using over 14,000 orthologous genes between human, chimpanzee, mouse rat and dog, we built multiple pairwise synteny maps to infer short orthologous intervals that were targeted for characterizing the canine missing genes. Based on gene prediction and a functionality test using the ratio of replacement to silent nucleotide substitution rates (dN/dS), we provide compelling structural and functional evidence for the identification of 232 new protein-coding genes in the canine genome and 69 gene losses, characterized as undetected gene or pseudogenes. Gene loss phyletic pattern analysis using ten species from chicken to human allowed us to characterize 28 canine-specific gene losses that have functional orthologs continuously from chicken or marsupials through human, and 10 genes that arose specifically in the evolutionary lineage leading to rodent and primates. Conclusion This study demonstrates the central role of comparative genomics for refining gene catalogs and exploring the evolutionary history of gene repertoires, particularly as applied for the characterization of species-specific gene gains and losses.

Published
2009
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19. Genetic diversity of canine olfactory receptors

Author

Hitte Christophe, André Catherine, Dréano Stéphane, Vaysse Amaury, Rimbault Maud, Tacher Sandrine, Robin Stéphanie, and Galibert Francis

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Evolution has resulted in large repertoires of olfactory receptor (OR) genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity of olfactory receptors is essential if we are to understand the differences in olfactory sensory capability between individuals. Canine breeds constitute an attractive model system for such investigations. Results We sequenced 109 OR genes considered representative of the whole OR canine repertoire, which consists of more than 800 genes, in a cohort of 48 dogs of six different breeds. SNP frequency showed the overall level of polymorphism to be high. However, the distribution of SNP was highly heterogeneous among OR genes. More than 50% of OR genes were found to harbour a large number of SNP, whereas the rest were devoid of SNP or only slightly polymorphic. Heterogeneity was also observed across breeds, with 25% of the SNP breed-specific. Linkage disequilibrium within OR genes and OR clusters suggested a gene conversion process, consistent with a mean level of polymorphism higher than that observed for introns and intergenic sequences. A large proportion (47%) of SNP induced amino-acid changes and the Ka/Ks ratio calculated for all alleles with a complete ORF indicated a low selective constraint with respect to the high level of redundancy of the olfactory combinatory code and an ongoing pseudogenisation process, which affects dog breeds differently. Conclusion Our demonstration of a high overall level of polymorphism, likely to modify the ligand-binding capacity of receptors distributed differently within the six breeds tested, is the first step towards understanding why Labrador Retrievers and German Shepherd Dogs have a much greater potential for use as sniffer dogs than Pekingese dogs or Greyhounds. Furthermore, the heterogeneity in OR polymorphism observed raises questions as to why, in a context in which most OR genes are highly polymorphic, a subset of these genes is not? This phenomenon may be related to the nature of their ligands and their importance in everyday life.

Published
2009
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21. A novel role for ciliary function in atopy: ADGRV1 and DNAH5 interactions

Author

Sugier, Pierre-Emmanuel, primary, Brossard, Myriam, additional, Sarnowski, Chloé, additional, Vaysse, Amaury, additional, Morin, Andréanne, additional, Pain, Lucile, additional, Margaritte-Jeannin, Patricia, additional, Dizier, Marie-Hélène, additional, Cookson, William O.C.M., additional, Lathrop, Mark, additional, Moffatt, Miriam F., additional, Laprise, Catherine, additional, Demenais, Florence, additional, and Bouzigon, Emmanuelle, additional

Published
2018
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22. Melanoma Expression Genes Identified through Genome-Wide Association Study of Breslow Tumor Thickness

Author

Fang, Shenying, primary, Vaysse, Amaury, additional, Brossard, Myriam, additional, Wang, Yuling, additional, Deng, Defeng, additional, Liu, Quan, additional, Zhang, Peter, additional, Xu, Kejing, additional, Li, Ming, additional, Feng, Runhua, additional, Liu, Huey, additional, Dang, Yifang, additional, Chen, Wei, additional, Prieto, Victor, additional, Gershenwald, Jeffrey E., additional, Ross, Merrick I., additional, Matejka, Brenna, additional, Malke, Jared, additional, Haydu, Lauren E., additional, Reveille, John D., additional, Sui, Dawen, additional, Bassett, Roland L., additional, Koshkina, Nadya, additional, Avril, Marie Françoise, additional, Lu, Mason, additional, Wei, Qingyi, additional, Demenais, Florence, additional, Amos, Christopher I., additional, and Lee, Jeffrey E., additional

Published
2017
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23. A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction betweenCDC42andSCINgenetic variants

Author

Vaysse, Amaury, primary, Fang, Shenying, additional, Brossard, Myriam, additional, Wei, Qingyi, additional, Chen, Wei V., additional, Mohamdi, Hamida, additional, Vincent-Fetita, Lynda, additional, Margaritte-Jeannin, Patricia, additional, Lavielle, Nolwenn, additional, Maubec, Eve, additional, Lathrop, Mark, additional, Avril, Marie-Françoise, additional, Amos, Christopher I., additional, Lee, Jeffrey E., additional, and Demenais, Florence, additional

Published
2016
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24. Haplotype-based method for detecting regions under selection in domestic dog

Author

Jean-Baptiste-Adolphe , H., Emily , Mathieu, Vaysse , Amaury, André , C., Hitte , Christophe, Centre de Recherche de Statistiques - Rennes 2, Université de Rennes 2 (UR2), Institut de Recherche Mathématique de Rennes (IRMAR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Inria Rennes, François Coste, Denis Tagu, Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Institut de Recherche Mathématique de Rennes ( IRMAR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST-École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National des Sciences Appliquées ( INSA ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
[MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], [ MATH.MATH-ST ] Mathematics [math]/Statistics [math.ST]
Abstract

ISBN : 13 978-2-7261-1301-1; International audience

Published
2012

25. Identification des signatures génétiques de la sélection chez le chien

Author

Vaysse, Amaury, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Rennes 1, Christophe Hitte, Erhel, Sébastien, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Génomique comparative, Evolution, Population genetics, Polymorphisme génétique, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, comparative genomics, Chien, Genetic polymorphisms, Sélection artificielle, Domestication, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Bioinformatique, Génétique des populations, Dog, Evolution (biologie)
Abstract

The canine species is the oldest domesticated species about, 15,000 years ago, and today consists of more than 350 breeds resulting from a drastic artificial selection and inbreeding practices during centuries. My PhD thesis is dedicated to the study of the period dominated by natural selection during the evolution of canids and the recent period of breeds creation by intense artificial selection. We have identified the catalog of genes under positive selection in 10 species (dog, Human, marmoset, macaque, orangutan, chimpanzee, mouse, rat, horse and cow) from 10,730 genes in orthology relationship type 1: 1. The canine species has more genes under positive selection in common with Laurasatheria and rodents than the expected. We then identified the catalog of regions of allelic differentiation between dog breeds using genotype data of 170,000 SNPs in 456 dogs of 30 breeds, in collaboration with the team of Dr. Matthew Webster ( University of Uppsala, Sweden) as part of the European consortium of dog genetics named LUPA. These regions are candidates to be targets of the artificial selection. This project is continuing by the comparison of natural and artificial selection to determine whether there are regions of the genome that are constantly affected by the selection, and to determine whether the canine species may be considered as a reduced, but accelerated simulation of the mammals radiation., L'espèce canine est la plus ancienne espèce domestiquée, il y a environ 15.000 ans, et se compose aujourd'hui de plus de 350 races issues d'une sélection artificielle drastique et de croisements consanguins pratiqués durant les derniers siècles. Mon travail de thèse a pour objectif l'étude de la période dominée par la sélection naturelle au cours de l'évolution des canidés et la période récente de la création des races par une sélection artificielle intense. Nous avons identifié le catalogue des gènes sous sélection positive dans 10 espèces (chien, Homme, ouistiti, macaque, orang-outan, chimpanzé, souris, rat, cheval et vache) à partir de 10.730 gènes en relation d'orthologie de type 1:1. L'espèce canine présente plus de gènes sous sélection positive en commun avec les Laurasatheria et les rongeurs qu'à l'attendu. Nous avons ensuite identifié le catalogue des régions de différenciation alléliques entre races de chien à partir de données de génotypage de 170.000 SNPs de 456 chiens de 30 races, en collaboration avec l'équipe du Dr Matthew Webster (Université d'Uppsala en Suède) dans le cadre du consortium européen de génétique du chien LUPA. Ces régions sont candidates pour être les cibles de la sélection artificielle. Ce projet se poursuit actuellement afin de comparer les sélections naturelles et artificielles et de déterminer s'il existe des régions du génome qui sont constamment affectés par la sélection ; et de déterminer si l'espèce canine peut-elle être considérée comme une simulation réduite, mais accélérée de la radiation des mammifères.

Published
2011

26. A Spontaneous KRT16 Mutation in a Dog Breed: A Model for Human Focal Non-Epidermolytic Palmoplantar Keratoderma (FNEPPK)

Author

Plassais, Jocelyn, primary, Guaguère, Eric, additional, Lagoutte, Laetitia, additional, Guillory, Anne-Sophie, additional, de Citres, Caroline Dufaure, additional, Degorce-Rubiales, Frédérique, additional, Delverdier, Maxence, additional, Vaysse, Amaury, additional, Quignon, Pascale, additional, Bleuart, Céline, additional, Hitte, Christophe, additional, Fautrel, Alain, additional, Kaerle, Cecile, additional, Bellaud, Pascale, additional, Bensignor, Emmanuel, additional, Queney, Guillaume, additional, Bourrat, Emmanuelle, additional, Thomas, Anne, additional, and André, Catherine, additional

Published
2015
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27. Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

Author

Broad Institute of MIT and Harvard, Sigurdsson, Snaever, Sigurdsson, Snaevar, Karlsson, Elinor K., Lindblad-Toh, Kerstin, Vaysse, Amaury, Ratnakumar, Abhirami, Derrien, Thomas, Axelsson, Erik, Pielberg, Gerli Rosengren, Fall, Tove, Seppälä, Eija H., Hansen, Mark S. T., Lawley, Cindy T., Bannasch, Danika L., Vilà, Carles, Lohi, Hannes, Galibert, Francis, Fredholm, Merete, Häggström, Jens, Hedhammar, Åke, André, Catherine, Hitte, Christophe, Webster, Matthew T., Broad Institute of MIT and Harvard, Sigurdsson, Snaever, Sigurdsson, Snaevar, Karlsson, Elinor K., Lindblad-Toh, Kerstin, Vaysse, Amaury, Ratnakumar, Abhirami, Derrien, Thomas, Axelsson, Erik, Pielberg, Gerli Rosengren, Fall, Tove, Seppälä, Eija H., Hansen, Mark S. T., Lawley, Cindy T., Bannasch, Danika L., Vilà, Carles, Lohi, Hannes, Galibert, Francis, Fredholm, Merete, Häggström, Jens, Hedhammar, Åke, André, Catherine, Hitte, Christophe, and Webster, Matthew T.

Abstract

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease., LUPA Consortium

Published
2012

28. Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping

Author

Vaysse, Amaury, Ratnakumar, Abhirami, Derrien, Thomas, Axelsson, Erik, Rosengren Pielberg, Gerli, Sigurdsson, Snaevar, Fall, Tove, Seppälä, Eija H, Hansen, Mark S T, Lawley, Cindy T, Karlsson, Elinor K, Bannasch, Danika, Vilà, Carles, Lohi, Hannes, Galibert, Francis, Fredholm, Merete, Häggström, Jens, Hedhammar, Ake, André, Catherine, Lindblad-Toh, Kerstin, Hitte, Christophe, Webster, Matthew Thomas, Vaysse, Amaury, Ratnakumar, Abhirami, Derrien, Thomas, Axelsson, Erik, Rosengren Pielberg, Gerli, Sigurdsson, Snaevar, Fall, Tove, Seppälä, Eija H, Hansen, Mark S T, Lawley, Cindy T, Karlsson, Elinor K, Bannasch, Danika, Vilà, Carles, Lohi, Hannes, Galibert, Francis, Fredholm, Merete, Häggström, Jens, Hedhammar, Ake, André, Catherine, Lindblad-Toh, Kerstin, Hitte, Christophe, and Webster, Matthew Thomas

Abstract

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

Published
2011
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29. Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

Author

University of Helsinki, Research Program of Molecular Medicine, University of Helsinki, Faculty of Veterinary Medicine, Vaysse, Amaury, Ratnakumar, Abhirami, Derrien, Thomas, Axelsson, Erik, Pielberg, Gerli Rosengren, Sigurdsson, Snaevar, Fall, Tove, Seppala, Eija H., Hansen, Mark S. T., Lawley, Cindy T., Karlsson, Elinor K., Bannasch, Danika, Vila, Carles, Lohi, Hannes, Galibert, Francis, Fredholm, Merete, Haggstrom, Jens, Hedhammar, Ake, Andre, Catherine, Lindblad-Toh, Kerstin, Hitte, Christophe, Webster, Matthew T., LUPA Consortium, University of Helsinki, Research Program of Molecular Medicine, University of Helsinki, Faculty of Veterinary Medicine, Vaysse, Amaury, Ratnakumar, Abhirami, Derrien, Thomas, Axelsson, Erik, Pielberg, Gerli Rosengren, Sigurdsson, Snaevar, Fall, Tove, Seppala, Eija H., Hansen, Mark S. T., Lawley, Cindy T., Karlsson, Elinor K., Bannasch, Danika, Vila, Carles, Lohi, Hannes, Galibert, Francis, Fredholm, Merete, Haggstrom, Jens, Hedhammar, Ake, Andre, Catherine, Lindblad-Toh, Kerstin, Hitte, Christophe, Webster, Matthew T., and LUPA Consortium

Published
2011

30. A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants.

Author

Vaysse, Amaury, Fang, Shenying, Brossard, Myriam, Wei, Qingyi, Chen, Wei V., Mohamdi, Hamida, Vincent‐Fetita, Lynda, Margaritte‐Jeannin, Patricia, Lavielle, Nolwenn, Maubec, Eve, Lathrop, Mark, Avril, Marie‐Françoise, Amos, Christopher I., Lee, Jeffrey E., and Demenais, Florence

Abstract

Breslow thickness (BT) is a major prognostic factor of cutaneous melanoma (CM), the most fatal skin cancer. The genetic component of BT has only been explored by candidate gene studies with inconsistent results. Our objective was to uncover the genetic factors underlying BT using an hypothesis-free genome-wide approach. Our analysis strategy integrated a genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) for BT followed by pathway analysis of GWAS outcomes using the gene-set enrichment analysis (GSEA) method and epistasis analysis within BT-associated pathways. This strategy was applied to two large CM datasets with Hapmap3-imputed SNP data: the French MELARISK study for discovery (966 cases) and the MD Anderson Cancer Center study (1,546 cases) for replication. While no marginal effect of individual SNPs was revealed through GWAS, three pathways, defined by gene ontology (GO) categories were significantly enriched in genes associated with BT (false discovery rate ≤5% in both studies): hormone activity, cytokine activity and myeloid cell differentiation. Epistasis analysis, within each significant GO, identified a statistically significant interaction between CDC42 and SCIN SNPs ( pmeta-int =2.2 × 10−6, which met the overall multiple-testing corrected threshold of 2.5 × 10−6). These two SNPs (and proxies) are strongly associated with CDC42 and SCIN gene expression levels and map to regulatory elements in skin cells. This interaction has important biological relevance since CDC42 and SCIN proteins have opposite effects in actin cytoskeleton organization and dynamics, a key mechanism underlying melanoma cell migration and invasion. [ABSTRACT FROM AUTHOR]

Published
2016
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34. Genetic diversity of canine olfactory receptors

Author

Robin, Stéphanie, primary, Tacher, Sandrine, additional, Rimbault, Maud, additional, Vaysse, Amaury, additional, Dréano, Stéphane, additional, André, Catherine, additional, Hitte, Christophe, additional, and Galibert, Francis, additional

Published
2009
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36. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Fang, Jun, Jia, Jinping, Makowski, Matthew, Xu, Mai, Wang, Zhaoming, Zhang, Tongwu, Hoskins, Jason W., Choi, Jiyeon, Han, Younghun, Zhang, Mingfeng, Thomas, Janelle, Kovacs, Michael, Collins, Irene, Dzyadyk, Marta, Thompson, Abbey, O'Neill, Maura, Das, Sudipto, Lan, Qi, Koster, Roelof, Canzian, Federico, Kooperberg, Charles, Arslan, Alan A, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Jacobs, Eric J, Kamineni, Aruna, Van Den Eeden, Stephen, Klein, Alison P, Kolonel, Laurence N, Li, Donghui, Olson, Sara H, Risch, Harvey A, Sesso, Howard D, Visvanathan, Kala, Zheng, Wei, Albanes, Demetrius, Austin, Melissa A, Boutron-Ruault, Marie-Christine, Bueno-de-Mesquita, H Bas, Cotterchio, Michelle, Gaziano, J Michael, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Hassan, Manal, Helzlsouer, Kathy J, Holly, Elizabeth A, Hunter, David J, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay-Tee, Krogh, Vittorio, Kurtz, Robert C, LaCroix, Andrea, Le Marchand, Loic, Mannisto, Satu, Patel, Alpa V, Peeters, Petra H M, Riboli, Elio, Shu, Xiao-Ou, Sund, Malin, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Wactawski-Wende, Jean, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Hoover, Robert, Hartge, Patricia, Fuchs, Charles, Chanock, Stephen J, Stevens, Victoria, Albanes, Demetrios, Caporaso, Neil E, Brennan, Paul, McKay, James, Wu, Xifeng, Hung, Rayjean J, McLaughlin, John R, Bickeboller, Heike, Risch, Angela, Wichmann, Erich, Houlston, Richard, Mann, Graham, Hopper, John, Aitken, Joanne, Armstrong, Bruce, Giles, Graham, Holland, Elizabeth, Kefford, Richard, Cust, Anne, Jenkins, Mark, Schmid, Helen, Puig, Susana, Aguilera, Paula, Badenas, Celia, Barreiro, Alicia, Carrera, Cristina, Gabriel, Daniel, Xavier, Pol Gimenez, Iglesias-Garcia, Pablo, Malvehy, Josep, Mila, Montse, Pigem, Ramon, Potrony, Miriam, Batille, Joan-AntonPuig, Marti, Gemma Tell, Hayward, Nick, Martin, Nicholas, Montgomery, Grant, Duffy, David, Whiteman, David, Gregor, Stuart Mac, Calista, Donato, Landi, Giorgi, Minghetti, Paola, Arcangeli, Fabio, Bertazzi, Pier Alberto, Ghiorzo, Paola, Scarra, Giovanna Bianchi, Pastorino, Lorenze, Bruno, William, Andreotti, Virginia, Queirolo, Paola, Spagnolo, Francesco, Mackie, Rona, Lang, Julie, Gruis, Nelleke, van Nieuwpoort, Frans A, Out, Coby, Bergman, Wilma, Kukutsch, Nicole, Bavinck, Jan Nico Bouwes, Bakker, Bert, van der Stoep, Nienke, ter Huurne, Jeanet, van der Rhee, Han, Bekkenk, Marcel, Snels, Dyon, van Praag, Marinus, Brochez, Lieve, Gerritsen, Rianne, Crijns, Marianne, Vasen, Hans, Janssen, Bart, Ingvar, Christian, Olsson, Hakan, Jonsson, Goran, Borg, Ake, Harbst, Katja, Nielsen, Kari, Zander, Anita Schmidt, Molvern, Anders, Helsing, Per, Andresen, Per Arne, Rootwelt, Helge, Akslen, Lars A, Bressac-de Paillerets, Brigitte, Demenais, Florence, Avril, Marie-Francoise, Chaudru, Valerie, Jeannin, Patricia, Lesueur, Fabienne, Maubec, Eve, Mohamdi, Hamida, Bossard, Myriam, Vaysse, Amaury, Boitier, Francoise, Caron, Oliver, Caux, Frederic, Dalle, Stephane, Dereure, Oliviier, Leroux, Dominique, Martin, Ludovic, Mateus, Christine, Robert, Caroline, Stoppa-Lyonnet, Dominique, Thomas, Luc, Wierzbicka, Eva, Elder, David, Ming, Michael, Mitra, Nandita, Debniak, Tadeusz, Lubinski, Jan, Hocevar, Marko, Novakovic, Srdjan, Peric, Barbara, Skerl, Petra, Hansson, Johan, Hoiom, Veronica, Freidman, Eitan, Azizi, Esther, Baron-Epel, Orna, Scope, Alon, Pavlotsky, Felix, Cohen-Manheim, Irit, Laitman, Yael, Harland, Mark, Randerson-Moor, Juliette, Laye, Jon, Davies, John, Nsengimana, Jeremie, O'Shea, Sally, Chan, May, Gascoyne, Jo, Tucker, Margaret A, Goldstein, Alisa M, Yang, Xiaohong R, Stolzenberg-Solomon, Rachael S., Kraft, Peter, Wolpin, Brian M., Jansen, Pascal W. T. C., Olson, Sara, McGlynn, Katherine A., Kanetsky, Peter A., Chatterjee, Nilanjan, Barrett, Jennifer H., Dunning, Alison M., Taylor, John C., Newton-Bishop, Julia A., Bishop, D. Timothy, Andresson, Thorkell, Petersen, Gloria M., Amos, Christopher I., Iles, Mark M., Nathanson, Katherine L., Landi, Maria Teresa, Vermeulen, Michiel, Brown, Kevin M., and Amundadottir, Laufey T.

Abstract

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.

Published
2017
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37. Network-assisted analysis of GWAS data identifies a functionally-relevant gene module for childhood-onset asthma

Author

Liu, Yuanlong, Brossard, Myriam, Sarnowski, Chloé, Vaysse, Amaury, Moffatt, Miriam, Margaritte-Jeannin, Patricia, Llinares-López, Felipe, Dizier, Marie-Helene, Lathrop, Mark, Cookson, William, Bouzigon, Emmanuelle, and Demenais, Florence

Subjects
3. Good health
Abstract

The number of genetic factors associated with asthma remains limited. To identify new genes with an undetected individual effect but collectively influencing asthma risk, we conducted a network-assisted analysis that integrates outcomes of genome-wide association studies (GWAS) and protein-protein interaction networks. We used two GWAS datasets, each consisting of the results of a meta-analysis of nine childhood-onset asthma GWASs (5,924 and 6,043 subjects, respectively). We developed a novel method to compute gene-level P-values (fastCGP), and proposed a parallel dense-module search and cross-selection strategy to identify an asthma-associated gene module. We identified a module of 91 genes with a significant joint effect on childhood-onset asthma (P, Scientific Reports, 7, ISSN:2045-2322

38. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author

Demenais, Florence, Margaritte-Jeannin, Patricia, Barnes, Kathleen C., Cookson, William O. C., Altmüller, Janine, Ang, Wei, Barr, R. Graham, Beaty, Terri H., Becker, Allan B., Beilby, John, Bisgaard, Hans, Bjornsdottir, Unnur Steina, Bleecker, Eugene, Bønnelykke, Klaus, Boomsma, Dorret I., Bouzigon, Emmanuelle, Brightling, Christopher E., Brossard, Myriam, Brusselle, Guy G., Burchard, Esteban, Burkart, Kristin M., Bush, Andrew, Chan-Yeung, Moira, Chung, Kian Fan, Couto Alves, Alexessander, Curtin, John A., Custovic, Adnan, Daley, Denise, de Jongste, Johan C., Del-Rio-Navarro, Blanca E., Donohue, Kathleen M., Duijts, Liesbeth, Eng, Celeste, Eriksson, Johan G., Farrall, Martin, Fedorova, Yuliya, Feenstra, Bjarke, Ferreira, Manuel A., Gajdos, Zofia, Freidin, Maxim B., Gauderman, Jim, Gehring, Ulrike, Geller, Frank, Genuneit, Jon, Gharib, Sina A., Gilliland, Frank, Granell, Raquel, Graves, Penelope E., Gudbjartsson, Daniel F., Haahtela, Tari, Heckbert, Susan R., Heederik, Dick, Heinrich, Joachim, Heliövaara, Markku, Henderson, John, Himes, Blanca E., Hirose, Hiroshi, Hirschhorn, Joel N., Hofman, Albert, Holt, Patrick, Hottenga, Jouke, Hudson, Thomas J., Hui, Jennie, Imboden, Medea, Ivanov, Vladimir, Jaddoe, Vincent W. V., James, Alan, Janson, Christer, Jarvelin, Marjo-Riitta, Jarvis, Deborah, Jones, Graham, Jonsdottir, Ingileif, Jousilahti, Pekka, Kabesch, Michael, Kähönen, Mika, Kantor, David B., Karunas, Alexandra S., Khusnutdinova, Elza, Koppelman, Gerard H., Kozyrskyj, Anita L., Kreiner, Eskil, Kubo, Michiaki, Kumar, Rajesh, Kumar, Ashish, Kuokkanen, Mikko, Lahousse, Lies, Laitinen, Tarja, Laprise, Catherine, Lathrop, Mark, Lau, Susanne, Lee, Young-Ae, Lehtimäki, Terho, Letort, Sébastien, Levin, Albert M., Li, Guo, Liang, Liming, Loehr, Laura R., London, Stephanie J., Loth, Daan W., Manichaikul, Ani, Marenholz, Ingo, Martinez, Fernando J., Matheson, Melanie C., Mathias, Rasika A., Matsumoto, Kenji, Mbarek, Hamdi, McArdle, Wendy L., Melbye, Mads, Melén, Erik, Meyers, Deborah, Michel, Sven, Mohamdi, Hamida, Musk, Arthur W., Myers, Rachel A., Nieuwenhuis, Maartje A. E., Noguchi, Emiko, O'Connor, George T., Ogorodova, Ludmila M., Palmer, Cameron D., Palotie, Aarno, Park, Julie E., Pennell, Craig E., Pershagen, Göran, Polonikov, Alexey, Postma, Dirkje S., Probst-Hensch, Nicole, Puzyrev, Valery P., Raby, Benjamin A., Raitakari, Olli T., Ramasamy, Adaikalavan, Rich, Stephen S., Robertson, Colin F., Romieu, Isabelle, Salam, Muhammad T., Salomaa, Veikko, Schlünssen, Vivi, Scott, Robert, Selivanova, Polina A., Sigsgaard, Torben, Simpson, Angela, Siroux, Valérie, Smith, Lewis J., Solodilova, Maria, Standl, Marie, Stefansson, Kari, Strachan, David P., Stricker, Bruno H., Takahashi, Atsushi, Thompson, Philip J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiesler, Carla M. T., Torgerson, Dara G., Tsunoda, Tatsuhiko, Uitterlinden, André G., van der Valk, Ralf J. P., Vaysse, Amaury, Vedantam, Sailaja, von Berg, Andrea, von Mutius, Erika, Vonk, Judith M., Waage, Johannes, Wareham, Nick J., Weiss, Scott T., White, Wendy B., Wickman, Magnus, Widén, Elisabeth, Willemsen, Gonneke, Williams, L. Keoki, Wouters, Inge M., Yang, James J., Zhao, Jing Hua, Moffatt, Miriam F., Ober, Carole, and Nicolae, Dan L.

Subjects
3. Good health

39. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author

Demenais, Florence, Margaritte-Jeannin, Patricia, Barnes, Kathleen C, Cookson, William OC, Altmüller, Janine, Ang, Wei, Barr, R Graham, Beaty, Terri H, Becker, Allan B, Beilby, John, Bisgaard, Hans, Bjornsdottir, Unnur Steina, Bleecker, Eugene, Bønnelykke, Klaus, Boomsma, Dorret I, Bouzigon, Emmanuelle, Brightling, Christopher E, Brossard, Myriam, Brusselle, Guy G, Burchard, Esteban, Burkart, Kristin M, Bush, Andrew, Chan-Yeung, Moira, Chung, Kian Fan, Couto Alves, Alexessander, Curtin, John A, Custovic, Adnan, Daley, Denise, De Jongste, Johan C, Del-Rio-Navarro, Blanca E, Donohue, Kathleen M, Duijts, Liesbeth, Eng, Celeste, Eriksson, Johan G, Farrall, Martin, Fedorova, Yuliya, Feenstra, Bjarke, Ferreira, Manuel A, Australian Asthma Genetics Consortium (AAGC) Collaborators, Freidin, Maxim B, Gajdos, Zofia, Gauderman, Jim, Gehring, Ulrike, Geller, Frank, Genuneit, Jon, Gharib, Sina A, Gilliland, Frank, Granell, Raquel, Graves, Penelope E, Gudbjartsson, Daniel F, Haahtela, Tari, Heckbert, Susan R, Heederik, Dick, Heinrich, Joachim, Heliövaara, Markku, Henderson, John, Himes, Blanca E, Hirose, Hiroshi, Hirschhorn, Joel N, Hofman, Albert, Holt, Patrick, Hottenga, Jouke, Hudson, Thomas J, Hui, Jennie, Imboden, Medea, Ivanov, Vladimir, Jaddoe, Vincent WV, James, Alan, Janson, Christer, Jarvelin, Marjo-Riitta, Jarvis, Deborah, Jones, Graham, Jonsdottir, Ingileif, Jousilahti, Pekka, Kabesch, Michael, Kähönen, Mika, Kantor, David B, Karunas, Alexandra S, Khusnutdinova, Elza, Koppelman, Gerard H, Kozyrskyj, Anita L, Kreiner, Eskil, Kubo, Michiaki, Kumar, Rajesh, Kumar, Ashish, Kuokkanen, Mikko, Lahousse, Lies, Laitinen, Tarja, Laprise, Catherine, Lathrop, Mark, Lau, Susanne, Lee, Young-Ae, Lehtimäki, Terho, Letort, Sébastien, Levin, Albert M, Li, Guo, Liang, Liming, Loehr, Laura R, London, Stephanie J, Loth, Daan W, Manichaikul, Ani, Marenholz, Ingo, Martinez, Fernando J, Matheson, Melanie C, Mathias, Rasika A, Matsumoto, Kenji, Mbarek, Hamdi, McArdle, Wendy L, Melbye, Mads, Melén, Erik, Meyers, Deborah, Michel, Sven, Mohamdi, Hamida, Musk, Arthur W, Myers, Rachel A, Nieuwenhuis, Maartje AE, Noguchi, Emiko, O'Connor, George T, Ogorodova, Ludmila M, Palmer, Cameron D, Palotie, Aarno, Park, Julie E, Pennell, Craig E, Pershagen, Göran, Polonikov, Alexey, Postma, Dirkje S, Probst-Hensch, Nicole, Puzyrev, Valery P, Raby, Benjamin A, Raitakari, Olli T, Ramasamy, Adaikalavan, Rich, Stephen S, Robertson, Colin F, Romieu, Isabelle, Salam, Muhammad T, Salomaa, Veikko, Schlünssen, Vivi, Scott, Robert, Selivanova, Polina A, Sigsgaard, Torben, Simpson, Angela, Siroux, Valérie, Smith, Lewis J, Solodilova, Maria, Standl, Marie, Stefansson, Kari, Strachan, David P, Stricker, Bruno H, Takahashi, Atsushi, Thompson, Philip J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiesler, Carla MT, Torgerson, Dara G, Tsunoda, Tatsuhiko, Uitterlinden, André G, Van Der Valk, Ralf JP, Vaysse, Amaury, Vedantam, Sailaja, Von Berg, Andrea, Von Mutius, Erika, Vonk, Judith M, Waage, Johannes, Wareham, Nick J, Weiss, Scott T, White, Wendy B, Wickman, Magnus, Widén, Elisabeth, Willemsen, Gonneke, Williams, L Keoki, Wouters, Inge M, Yang, James J, Zhao, Jing Hua, Moffatt, Miriam F, Ober, Carole, and Nicolae, Dan L

Subjects
Risk, Rhinitis, Allergic, Seasonal, Asthma, respiratory tract diseases, 3. Good health, Epigenesis, Genetic, Histone Code, Enhancer Elements, Genetic, Phenotype, immune system diseases, Genetic Loci, Leukocytes, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Alleles, Genome-Wide Association Study
Abstract

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

40. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author

Joachim Heinrich, Arthur W. Musk, Dan L. Nicolae, Magnus Wickman, Anita L. Kozyrskyj, George T. O'Connor, Sven Michel, John Beilby, Nicole Probst-Hensch, André G. Uitterlinden, Ulrike Gehring, Eugene R. Bleecker, Markku Heliövaara, Christer Janson, Janine Altmüller, Tatsuhiko Tsunoda, Kathleen C. Barnes, Johan G. Eriksson, Alexey Polonikov, Penelope E. Graves, Andrea von Berg, Philip J. Thompson, Sina A. Gharib, Johan C. de Jongste, Miriam F. Moffatt, Adaikalavan Ramasamy, Kristin M. Burkart, Thomas J. Hudson, Marjo-Riitta Järvelin, Rasika A. Mathias, Kathleen M. Donohue, Gonneke Willemsen, Yuliya Fedorova, Michael Kabesch, Jing Hua Zhao, Ashok Kumar, Kenji Matsumoto, Vivi Schlünssen, Dara G. Torgerson, Terri H. Beaty, Florence Demenais, Julie E. Park, Tari Haahtela, Aarno Palotie, Elisabeth Widen, Hamida Mohamdi, Vladimir P. Ivanov, Tarja Laitinen, Emiko Noguchi, Lewis J. Smith, Valérie Siroux, Christopher E. Brightling, P. A. Selivanova, Frank D. Gilliland, Johannes Waage, Deborah A. Meyers, Unnur Thorsteinsdottir, Melanie C. Matheson, Hiroshi Hirose, Sébastien Letort, Andrew Bush, Alan James, Kari Stefansson, Robert A. Scott, Isabelle Romieu, Mads Melbye, Albert M. Levin, Laura R. Loehr, Guo Li, Veikko Salomaa, Celeste Eng, Esteban G. Burchard, Ralf J. P. van der Valk, Bjarke Feenstra, Daan W. Loth, Atsushi Takahashi, Lies Lahousse, Denise Daley, Stephen S. Rich, Carla M. T. Tiesler, Liming Liang, L. Keoki Williams, Susanne Lau, Nicholas J. Wareham, Erik Melén, Cameron D. Palmer, Medea Imboden, Patricia Margaritte-Jeannin, Unnur S. Bjornsdottir, Ludmila M. Ogorodova, Erika von Mutius, Gerard H. Koppelman, Susan R. Heckbert, Rachel A. Myers, Martin Farrall, Moira Chan-Yeung, Jim Gauderman, Frank Geller, Sailaja Vedantam, Rajesh Kumar, Kian Fan Chung, Jon Genuneit, John Henderson, David B. Kantor, Carole Ober, Alexessander Couto Alves, Craig E. Pennell, Inge M. Wouters, Catherine Laprise, Terho Lehtimäki, Colin F. Robertson, Emmanuelle Bouzigon, Maxim B. Freidin, William O.C.M. Cookson, Bruno H. Stricker, John A. Curtin, Albert Hofman, Muhammad T. Salam, Blanca E. Del-Rio-Navarro, Young-Ae Lee, Liesbeth Duijts, Klaus Bønnelykke, Vincent W. V. Jaddoe, Göran Pershagen, Dirkje S. Postma, Pekka Jousilahti, Hans Bisgaard, Dorret I. Boomsma, Amaury Vaysse, Deborah Jarvis, Maria Solodilova, Gudmar Thorleifsson, James J. Yang, V. P. Puzyrev, Manuel A. R. Ferreira, Maartje A.E. Nieuwenhuis, Jouke J. Hottenga, Ingileif Jonsdottir, Graham Jones, Myriam Brossard, Jennie Hui, Judith M. Vonk, Allan B. Becker, Elza Khusnutdinova, Wendy L. McArdle, Benjamin A. Raby, Olli T. Raitakari, Wendy B. White, Mark Lathrop, Adnan Custovic, Ingo Marenholz, Joel N. Hirschhorn, Fernando J. Martinez, Mikko Kuokkanen, Michiaki Kubo, Patrick G. Holt, Torben Sigsgaard, Eskil Kreiner, Stephanie J. London, Daniel F. Gudbjartsson, Mika Kähönen, Guy Brusselle, Blanca E. Himes, R. Graham Barr, Scott T. Weiss, David P. Strachan, Hamdi Mbarek, Wei Ang, A. S. Karunas, Marie Standl, Angela Simpson, Dick Heederik, Zofia K. Z. Gajdos, Raquel Granell, Ani Manichaikul, Fondation Jean-Dausset-CEPH, INSERM U946, Institut National de la Santé et de la Recherche Médicale (INSERM), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], National Heart and Lung Institute (NHLI), Imperial College London, Cologne Center for Genomics (CCG), Cologne Center for Genomics-University of Cologne, Johns Hopkins University (JHU), Pediatrics and Child Health, University of Manitoba [Winnipeg], University of Arizona, King‘s College London, Méthodologie statistique et épidémiologie génétique de maladies multifactorielles, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Respiratory Medicine and Thoracic Surgery, University of Leicester-Institute for Lung Health, Ghent University Hospital, Department of Paediatric Respiratory Medicine, Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute [UK], Airway Disease Section, National Heart and Lung Institute, The Generation R Study group, Erasmus University Medical Centre, Medstar Research Institute, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Université Paris-Sorbonne - Paris 4 - École supérieure du professorat et de l'éducation - Académie de Paris (ESPE Paris), Université Paris-Sorbonne (UP4), Population Genetics Laboratory [Tomsk, Russia], Research Institute for Medical Genetics [Tomsk, Russia], University of Southern California (USC), Utrecht University [Utrecht], Institute of Epidemiology, Universität Ulm - Ulm University [Ulm, Allemagne], MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni] (MRC IEU), University of Bristol [Bristol], Arizona Respiratory Center, Helsinki University Hospital, Division of Occupational and Environmental Health, Institute for Risk Assessment (IRAS), Ludwig Maximilian University [Munich] (LMU), National Institute of Health and Welfare, MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Sir Charles Gairdner Hospital, Swiss Tropical and Public Health Institute [Basel], The Generation R Study, Pediatrics, Epidemiology, Uppsala University, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Tampere University Hospital, Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, National Center for Atmospheric Research [Boulder] (NCAR), Epidemiology & Public Health, Swiss Tropical and Public Health Institute [Basel]-Medical School University of Basel, Department of Respiratory Medicine, Departments of Pulmonary Medicine and Medical Genetics, Université du Québec à Chicoutimi (UQAC), McGill University and Genome Quebec Innovation Centre, Department of Pediatric Pneumology and Immunology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), China Agricultural University (CAU), Harvard School of Public Health, Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, National Institute for Environmental Health Sciences Research Triangle Park, National Institute for Materials Science (NIMS), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], Institute of Environmental Medicine [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Astrid Lindgren Children's Hospital, Center for Human Genomics, Wake Forest University, Université de Tsukuba = University of Tsukuba, Head of Medical Sequencing, Institute of environmental medicine, Karolinska Institute, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centre International de Recherche contre le Cancer (CIRC), Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Aarhus University [Aarhus], Institute of Metabolic Science, MRC, Section of Environment Occupation & Health, University of Manchester [Manchester], Epidémiologie et Biostatistique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), deCODE Genetics, deCODE genetics [Reykjavik], Population Health Sciences and Education, St George's University of London, Drug Safety Unit, Inspectorate for Health Care, Tohoku University [Sendai], Department of Oceanography, University of Hawai‘i [Mānoa] (UHM), University of California [San Francisco] (UCSF), University of California, Asthma and Allergy Department, University Children's Hospital-Ludwig Maximilians University, IT University of Copenhagen, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge [UK] (CAM), Sachs’ Children and Youth Hospital [Stockholm, Sweden], Genetic Epidemiology Unit, Addenbrooke's Hospital, University of Illinois [Chicago] (UIC), University of Illinois System, Titu Maiorescu University Bucharest, Titu Maiorescu University = Universitatea Titu Maiorescu [Buchares] (UTM), Pulmonary Medicine, Erasmus MC other, Internal Medicine, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Vaysse, Amaury, University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), University Children's Hospital-Ludwig-Maximilians University [Munich] (LMU), IT University of Copenhagen (ITU), Groningen Research Institute for Asthma and COPD (GRIAC), Medical Research Council (MRC), National Institute for Health Research, Wellcome Trust, Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, HAY-FEVER, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, VARIANTS, Australian Asthma Genetics Consortium (AAGC) collaborators, Epigenesis, Genetic, 0302 clinical medicine, Pleiotropy, immune system diseases, Leukocytes, Promoter Regions, Genetic, AUTOIMMUNE-DISEASE, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, Genetics & Heredity, 3. Good health, Histone Code, [SDV] Life Sciences [q-bio], Enhancer Elements, Genetic, Phenotype, TWINS, Hay fever, POPULATIONS, Life Sciences & Biomedicine, Risk, EXPRESSION, Coronacrisis-Taverne, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Immune system, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Alleles, METAANALYSIS, Genetic association, Asthma, Autoimmune disease, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Rhinitis, Allergic, Seasonal, 06 Biological Sciences, medicine.disease, GENE, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Immunology, Developmental Biology, Genome-Wide Association Study
Abstract

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

Published
2018

41. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.

Author

Shi J, Yang XR, Ballew B, Rotunno M, Calista D, Fargnoli MC, Ghiorzo P, Bressac-de Paillerets B, Nagore E, Avril MF, Caporaso NE, McMaster ML, Cullen M, Wang Z, Zhang X, Bruno W, Pastorino L, Queirolo P, Banuls-Roca J, Garcia-Casado Z, Vaysse A, Mohamdi H, Riazalhosseini Y, Foglio M, Jouenne F, Hua X, Hyland PL, Yin J, Vallabhaneni H, Chai W, Minghetti P, Pellegrini C, Ravichandran S, Eggermont A, Lathrop M, Peris K, Scarra GB, Landi G, Savage SA, Sampson JN, He J, Yeager M, Goldin LR, Demenais F, Chanock SJ, Tucker MA, Goldstein AM, Liu Y, and Landi MT

Subjects
Amino Acid Sequence, Base Sequence, Computational Biology, Exome genetics, France, Humans, In Situ Hybridization, Fluorescence, Italy, Molecular Sequence Data, Pedigree, Sequence Alignment, Sequence Analysis, DNA, Shelterin Complex, Skin Neoplasms, Telomere-Binding Proteins chemistry, United States, Melanoma, Cutaneous Malignant, Genetic Predisposition to Disease genetics, Melanoma genetics, Models, Molecular, Mutation, Missense genetics, Neoplasms, Connective Tissue genetics, Telomere Homeostasis genetics, Telomere-Binding Proteins genetics
Abstract

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Published
2014
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42. Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

Author

Vaysse A, Ratnakumar A, Derrien T, Axelsson E, Rosengren Pielberg G, Sigurdsson S, Fall T, Seppälä EH, Hansen MS, Lawley CT, Karlsson EK, Bannasch D, Vilà C, Lohi H, Galibert F, Fredholm M, Häggström J, Hedhammar A, André C, Lindblad-Toh K, Hitte C, and Webster MT

Subjects
Animals, Body Size genetics, Dogs anatomy & histology, Ear anatomy & histology, Genome-Wide Association Study, Genotyping Techniques, Haplotypes, Heterozygote, Homozygote, Phenotype, Phylogeny, Polymorphism, Single Nucleotide, Behavior, Animal, Breeding, Dogs genetics, Genetic Variation genetics, Selection, Genetic
Abstract

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease., Competing Interests: The authors have declared that no competing interests exist.

Published
2011
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