19 results on '"Gasparini, Paolo"'
Search Results
2. The p.Cys169Tyr variant of connexin 26 is not a polymorphism
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Zonta, Francesco, Girotto, Giorgia, Buratto, Damiano, Crispino, Giulia, Morgan, Anna, Abdulhadi, Khalid, Alkowari, Moza, Badii, Ramin, Gasparini, Paolo, and Mammano, Fabio
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- 2015
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3. Salt-inducible kinase 3, SIK3, is a new gene associated with hearing
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Wolber, Lisa E., Girotto, Giorgia, Buniello, Annalisa, Vuckovic, Dragana, Pirastu, Nicola, Lorente-Cánovas, Beatriz, Rudan, Igor, Hayward, Caroline, Polasek, Ozren, Ciullo, Marina, Mangino, Massimo, Steves, Claire, Concas, Maria Pina, Cocca, Massilimiliano, Spector, Tim D., Gasparini, Paolo, Steel, Karen P., and Williams, Frances M.K.
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- 2014
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4. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause
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Perry, John R.B., Hsu, Yi-Hsiang, Chasman, Daniel I., Johnson, Andrew D., Elks, Cathy, Albrecht, Eva, Andrulis, Irene L., Beesley, Jonathan, Berenson, Gerald S., Bergmann, Sven, Bojesen, Stig E., Bolla, Manjeet K., Brown, Judith, Buring, Julie E., Campbell, Harry, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cox, Angela, Czene, Kamila, Dʼadamo, Adamo Pio, Davies, Gail, Deary, Ian J., Dennis, Joe, Easton, Douglas F., Engelhardt, Ellen G., Eriksson, Johan G., Esko, Tõnu, Fasching, Peter A., Figueroa, Jonine D., Flyger, Henrik, Fraser, Abigail, Garcia-Closas, Montse, Gasparini, Paolo, Gieger, Christian, Giles, Graham, Guenel, Pascal, Hägg, Sara, Hall, Per, Hayward, Caroline, Hopper, John, Ingelsson, Erik, Kardia, Sharon L.R., Kasiman, Katherine, Knight, Julia A., Lahti, Jari, Lawlor, Debbie A., Magnusson, Patrik K.E., Margolin, Sara, Marsh, Julie A., Metspalu, Andres, Olson, Janet E., Pennell, Craig E., Polasek, Ozren, Rahman, Iffat, Ridker, Paul M., Robino, Antonietta, Rudan, Igor, Rudolph, Anja, Salumets, Andres, Schmidt, Marjanka K., Schoemaker, Minouk J., Smith, Erin N., Smith, Jennifer A., Southey, Melissa, Stöckl, Doris, Swerdlow, Anthony J., Thompson, Deborah J., Truong, Therese, Ulivi, Sheila, Waldenberger, Melanie, Wang, Qin, Wild, Sarah, Wilson, James F, Wright, Alan F., Zgaga, Lina, Ong, Ken K., Murabito, Joanne M., Karasik, David, and Murray, Anna
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- 2014
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5. Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss
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Bassani, Sissy, primary, van Beelen, Edward, additional, Rossel, Mireille, additional, Voisin, Norine, additional, Morgan, Anna, additional, Arribat, Yoan, additional, Chatron, Nicolas, additional, Chrast, Jacqueline, additional, Cocca, Massimiliano, additional, Delprat, Benjamin, additional, Faletra, Flavio, additional, Giannuzzi, Giuliana, additional, Guex, Nicolas, additional, Machavoine, Roxane, additional, Pradervand, Sylvain, additional, Smits, Jeroen J, additional, van de Kamp, Jiddeke M, additional, Ziegler, Alban, additional, Amati, Francesca, additional, Marlin, Sandrine, additional, Kremer, Hannie, additional, Locher, Heiko, additional, Maurice, Tangui, additional, Gasparini, Paolo, additional, Girotto, Giorgia, additional, and Reymond, Alexandre, additional
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- 2021
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6. Runs of homozygosity are associated with staging of periodontitis in isolated populations
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Mezzavilla, Massimo, primary, Navarra, Chiara Ottavia, additional, Di Lenarda, Roberto, additional, Gasparini, Paolo, additional, Bevilacqua, Lorenzo, additional, and Robino, Antonietta, additional
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- 2021
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7. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
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Chasman, Daniel I., Fuchsberger, Christian, Pattaro, Cristian, Teumer, Alexander, Böger, Carsten A., Endlich, Karlhans, Olden, Matthias, Chen, Ming-Huei, Tin, Adrienne, Taliun, Daniel, Li, Man, Gao, Xiaoyi, Gorski, Mathias, Yang, Qiong, Hundertmark, Claudia, Foster, Meredith C., OʼSeaghdha, Conall M., Glazer, Nicole, Isaacs, Aaron, Liu, Ching-Ti, Smith, Albert V., OʼConnell, Jeffrey R., Struchalin, Maksim, Tanaka, Toshiko, Li, Guo, Johnson, Andrew D., Gierman, Hinco J., Feitosa, Mary F., Hwang, Shih-Jen, Atkinson, Elizabeth J., Lohman, Kurt, Cornelis, Marilyn C., Johansson, Åsa, Tönjes, Anke, Dehghan, Abbas, Lambert, Jean-Charles, Holliday, Elizabeth G., Sorice, Rossella, Kutalik, Zoltan, Lehtimäki, Terho, Esko, Tõnu, Deshmukh, Harshal, Ulivi, Sheila, Chu, Audrey Y., Murgia, Federico, Trompet, Stella, Imboden, Medea, Coassin, Stefan, Pistis, Giorgio, Harris, Tamara B., Launer, Lenore J., Aspelund, Thor, Eiriksdottir, Gudny, Mitchell, Braxton D., Boerwinkle, Eric, Schmidt, Helena, Cavalieri, Margherita, Rao, Madhumathi, Hu, Frank, Demirkan, Ayse, Oostra, Ben A., de Andrade, Mariza, Turner, Stephen T., Ding, Jingzhong, Andrews, Jeanette S., Freedman, Barry I., Giulianini, Franco, Koenig, Wolfgang, Illig, Thomas, Meisinger, Christa, Gieger, Christian, Zgaga, Lina, Zemunik, Tatijana, Boban, Mladen, Minelli, Cosetta, Wheeler, Heather E., Igl, Wilmar, Zaboli, Ghazal, Wild, Sarah H., Wright, Alan F., Campbell, Harry, Ellinghaus, David, Nöthlings, Ute, Jacobs, Gunnar, Biffar, Reiner, Ernst, Florian, Homuth, Georg, Kroemer, Heyo K., Nauck, Matthias, Stracke, Sylvia, Völker, Uwe, Völzke, Henry, Kovacs, Peter, Stumvoll, Michael, Mägi, Reedik, Hofman, Albert, Uitterlinden, Andre G., Rivadeneira, Fernando, Aulchenko, Yurii S., Polasek, Ozren, Hastie, Nick, Vitart, Veronique, Helmer, Catherine, Wang, Jie Jin, Stengel, Bénédicte, Ruggiero, Daniela, Bergmann, Sven, Kähönen, Mika, Viikari, Jorma, Nikopensius, Tiit, Province, Michael, Ketkar, Shamika, Colhoun, Helen, Doney, Alex, Robino, Antonietta, Krämer, Bernhard K., Portas, Laura, Ford, Ian, Buckley, Brendan M., Adam, Martin, Thun, Gian-Andri, Paulweber, Bernhard, Haun, Margot, Sala, Cinzia, Mitchell, Paul, Ciullo, Marina, Kim, Stuart K., Vollenweider, Peter, Raitakari, Olli, Metspalu, Andres, Palmer, Colin, Gasparini, Paolo, Pirastu, Mario, Jukema, J. Wouter, Probst-Hensch, Nicole M., Kronenberg, Florian, Toniolo, Daniela, Gudnason, Vilmundur, Shuldiner, Alan R., Coresh, Josef, Schmidt, Reinhold, Ferrucci, Luigi, Siscovick, David S., van Duijn, Cornelia M., Borecki, Ingrid B., Kardia, Sharon L.R., Liu, Yongmei, Curhan, Gary C., Rudan, Igor, Gyllensten, Ulf, Wilson, James F., Franke, Andre, Pramstaller, Peter P., Rettig, Rainer, Prokopenko, Inga, Witteman, Jacqueline, Hayward, Caroline, Ridker, Paul M, Parsa, Afshin, Bochud, Murielle, Heid, Iris M., Kao, W.H. Linda, Fox, Caroline S., and Köttgen, Anna
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- 2012
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8. Trans-ethnic meta-analysis of white blood cell phenotypes
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Keller, Margaux F, Reiner, Alexander P, Okada, Yukinori, van Rooij, Frank J. A, Johnson, Andrew D, Chen, Ming Huei, Smith, Albert V, Morris, Andrew P, Tanaka, Toshiko, Ferrucci, Luigi, Zonderman, Alan B, Lettre, Guillaume, Harris, Tamara, Garcia, Melissa, Bandinelli, Stefania, Qayyum, Rehan, Yanek, Lisa R, Becker, Diane M, Becker, Lewis C, Kooperberg, Charles, Keating, Brendan, Reis, Jared, Tang, Hua, Boerwinkle, Eric, Kamatani, Yoichiro, Matsuda, Koichi, Kamatani, Naoyuki, Nakamura, Yusuke, Kubo, Michiaki, Liu, Simin, Dehghan, Abbas, Felix, Janine F, Hofman, Albert, Uitterlinden, André G, van Duijn, Cornelia M, Franco, Oscar H, Longo, Dan L, Singleton, Andrew B, Psaty, Bruce M, Evans, Michelle K, Cupples, L. Adrienne, Rotter, Jerome I, O'Donnell, Christopher J, Takahashi, Atsushi, Wilson, James G, Ganesh, Santhi K, Nalls, Mike A, Arepalli, S, Bandinelli, S, Biffi, A, Bis, Jc, Boerwinkle, E, Chakravarti, A, Chen, Mh, Chong, S, Coresh, J, Couper, Dj, Cupples, L, Dehghan, A, Do'Ring, A, Eiriksdottir, G, Felix, Jf, Ferrucci, L, Folsom, Ar, Fox, Cs, Frayling, Tm, Ganesh, Sk, Garcia, M, Garner, Sf, Gasparini, Paolo, Gieger, C, Glazer, Nl, Gouskova, Na, Greinacher, A, Gudnason, V, Harris, Tb, Hernandez, Dg, Hofman, A, Illig, T, Kamatani, Y, Kamatani, N, Kubo, M, Kuhnel, B, Lagou, V, Lettre, G, Levi, D, Lin, J, Liu, Y, Longo, Dl, Lumley, T, Mangino, M, Matsuda, K, Meisinger, C, Melzer, D, Menzel, S, Moore, M, Nakamura, Y, Nalls, Ma, Nauck, M, O'Donnell, Cj, Okada, Y, Oostra, Ba, Ouwehand, Wh, Patel, Kv, Pirastu, Nicola, Pistis, Giorgio, Prokisch, H, Prokopenko, I, Psaty, Bm, Reiner, Ap, Rendon, A, Sambrook, J, Singleton, Ab, Smith, Av, Soranzo, N, Spector, Td, Stephens, J, Stumvoll, M, Takahashi, A, Tanaka, T, Taylor, K, Teumer, A, Thein, Sl, To'Njes, A, Toniolo, D, Tsunoda, T, Uitterlinden, Ag, van Duijn CM, van Rooij FJ, Vo'Lker, U, Vo'Lzke, H, Wichmann, H., Wiggins, Kl, Wilson, Jg, Witteman, Jc, Wood, Ar, Yamamoto, K, Yang, Q, Zakai, Na, Austin, Ma, Becker, Dm, Britton, A, Chen, Z, Couper, D, Curb, J, Dean, E, Eaton, Cb, Evans, Mk, Fornage, M, Grant, Sf, Hernandez, D, Kamatini, N, Keating, Bj, Lacroix, A, Lange, La, Liu, S, Lohman, K, Mathias, R, Meng, Y, Mohler ER 3rd, Musani, S, Palmer, Cd, Papanicolaou, Gj, Snively, Bm, Tang, H, Taylor HA Jr, Thomson, C, Yanek, Lr, Yang, L, Ziv, E, Zonderman, Ab, Higasa, K, Hirota, T, Hosono, N, Kumasaka, N, Ohmiya, H, Tamari, M, Yamaguchi Kabata, Y, Yamamoto, K., Epidemiology, Medical Informatics, Urology, Erasmus MC other, Internal Medicine, Keller, Margaux F, Reiner, Alexander P, Okada, Yukinori, van Rooij, Frank J. A, Johnson, Andrew D, Chen, Ming Huei, Smith, Albert V, Morris, Andrew P, Tanaka, Toshiko, Ferrucci, Luigi, Zonderman, Alan B, Lettre, Guillaume, Harris, Tamara, Garcia, Melissa, Bandinelli, Stefania, Qayyum, Rehan, Yanek, Lisa R, Becker, Diane M, Becker, Lewis C, Kooperberg, Charle, Keating, Brendan, Reis, Jared, Tang, Hua, Boerwinkle, Eric, Kamatani, Yoichiro, Matsuda, Koichi, Kamatani, Naoyuki, Nakamura, Yusuke, Kubo, Michiaki, Liu, Simin, Dehghan, Abba, Felix, Janine F, Hofman, Albert, Uitterlinden, André G, van Duijn, Cornelia M, Franco, Oscar H, Longo, Dan L, Singleton, Andrew B, Psaty, Bruce M, Evans, Michelle K, Cupples, L. Adrienne, Rotter, Jerome I, O'Donnell, Christopher J, Takahashi, Atsushi, Wilson, James G, Ganesh, Santhi K, Nalls, Mike A, Arepalli, S, Bandinelli, S, Biffi, A, Bis, Jc, Boerwinkle, E, Chakravarti, A, Chen, Mh, Chong, S, Coresh, J, Couper, Dj, Cupples, L, Dehghan, A, Do'Ring, A, Eiriksdottir, G, Felix, Jf, Ferrucci, L, Folsom, Ar, Fox, C, Frayling, Tm, Ganesh, Sk, Garcia, M, Garner, Sf, Gasparini, Paolo, Gieger, C, Glazer, Nl, Gouskova, Na, Greinacher, A, Gudnason, V, Harris, Tb, Hernandez, Dg, Hofman, A, Illig, T, Kamatani, Y, Kamatani, N, Kubo, M, Kuhnel, B, Lagou, V, Lettre, G, Levi, D, Lin, J, Liu, Y, Longo, Dl, Lumley, T, Mangino, M, Matsuda, K, Meisinger, C, Melzer, D, Menzel, S, Moore, M, Nakamura, Y, Nalls, Ma, Nauck, M, O'Donnell, Cj, Okada, Y, Oostra, Ba, Ouwehand, Wh, Patel, Kv, Pirastu, Nicola, Pistis, Giorgio, Prokisch, H, Prokopenko, I, Psaty, Bm, Reiner, Ap, Rendon, A, Sambrook, J, Singleton, Ab, Smith, Av, Soranzo, N, Spector, Td, Stephens, J, Stumvoll, M, Takahashi, A, Tanaka, T, Taylor, K, Teumer, A, Thein, Sl, To'Njes, A, Toniolo, D, Tsunoda, T, Uitterlinden, Ag, van Duijn, Cm, van Rooij, Fj, Vo'Lker, U, Vo'Lzke, H, Wichmann, H., Wiggins, Kl, Wilson, Jg, Witteman, Jc, Wood, Ar, Yamamoto, K, Yang, Q, Zakai, Na, Austin, Ma, Becker, Dm, Britton, A, Chen, Z, Couper, D, Curb, J, Dean, E, Eaton, Cb, Evans, Mk, Fornage, M, Grant, Sf, Hernandez, D, Kamatini, N, Keating, Bj, Lacroix, A, Lange, La, Liu, S, Lohman, K, Mathias, R, Meng, Y, Mohler ER, 3rd, Musani, S, Palmer, Cd, Papanicolaou, Gj, Snively, Bm, Tang, H, Taylor HA, Jr, Thomson, C, Yanek, Lr, Yang, L, Ziv, E, Zonderman, Ab, Higasa, K, Hirota, T, Hosono, N, Kumasaka, N, Ohmiya, H, Tamari, M, Yamaguchi Kabata, Y, and Yamamoto, K.
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Linkage disequilibrium ,Genotype ,Quantitative Trait Loci ,White blood cell count ,Single-nucleotide polymorphism ,Genome-wide association study ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,White People ,white blood cell phenotypes ,Leukocyte Count ,SDG 3 - Good Health and Well-being ,Asian People ,Polymorphism (computer science) ,Genetics ,Leukocytes ,Humans ,Allele ,Molecular Biology ,Genetics (clinical) ,White blood cell count, Trans-ethnic meta-analysis, white blood cell phenotypes ,Genome, Human ,Association Studies Articles ,Bayes Theorem ,General Medicine ,Heritability ,Black or African American ,Phenotype ,Trans-ethnic meta-analysis ,Genome-Wide Association Study - Abstract
White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.
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- 2014
9. Genome-wide association analysis on normal hearing function identifiesPCDH20andSLC28A3as candidates for hearing function and loss
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Vuckovic, Dragana, primary, Dawson, Sally, additional, Scheffer, Deborah I., additional, Rantanen, Taina, additional, Morgan, Anna, additional, Di Stazio, Mariateresa, additional, Vozzi, Diego, additional, Nutile, Teresa, additional, Concas, Maria P., additional, Biino, Ginevra, additional, Nolan, Lisa, additional, Bahl, Aileen, additional, Loukola, Anu, additional, Viljanen, Anne, additional, Davis, Adrian, additional, Ciullo, Marina, additional, Corey, David P., additional, Pirastu, Mario, additional, Gasparini, Paolo, additional, and Girotto, Giorgia, additional
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- 2015
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10. Functional analysis of mutations in SLC7A9, and genotype–phenotype correlation in non-Type I cystinuria
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Font, Mariona, primary, Feliubadaló, Lídia, additional, Estivill, Xavier, additional, Nunes, Virginia, additional, Golomb, Eliahu, additional, Kreiss, Yitshak, additional, Pras, Elon, additional, Bisceglia, Luigi, additional, d’Adamo, Adamo P., additional, Zelante, Leopoldo, additional, Gasparini, Paolo, additional, Bassi, Maria Teresa, additional, George Jr, Alfred L., additional, Manzoni, Marta, additional, Riboni, Mirko, additional, Ballabio, Andrea, additional, Borsani, Giuseppe, additional, Reig, Núria, additional, Fernández, Esperanza, additional, Zorzano, Antonio, additional, Bertran, Joan, additional, and Palacín, Manuel, additional
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- 2001
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11. Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F
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Gasparini, Paolo, primary, Borgato, Lorena, additional, Piperno, Alberto, additional, Girelli, Domenico, additional, Olivieri, Oliviero, additional, Gottardi, Enrico, additional, Roetto, Antonella, additional, Dianzani, Irma, additional, Fargion, Siliva, additional, Schinaia, Giuseppe, additional, Cappellini, Maria D., additional, Gandini, Giorgio, additional, Pignatti, PierFranco, additional, Fiorelli, Gemino, additional, De Sandre, Giorgio, additional, and Camaschella, Clara, additional
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- 1993
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12. Haplotype analysis to determine the position of a mutation among closely linked DNA markers
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Ramsay, Michele, primary, Williamson, Robert, additional, Estivill, Xavier, additional, Wainwright, Brandon J., additional, Ho, Meng-Falt, additional, Halford, Stephanie, additional, Kere, Juha, additional, Savilahti, Erkki, additional, Chapelle, Albert de la, additional, Schwartz, Marianne, additional, Schwartz, Martin, additional, Super, Maurice, additional, Farndon, Peter, additional, Hardlng, Carol, additional, Meredith, Linda, additional, Al-Jader, Layla, additional, Ferec, Claude, additional, Claustres, Mirellle, additional, Casals, Teresa, additional, Nunes, Virginia, additional, Gasparini, Paolo, additional, Savoia, Anna, additional, Pignatti, Pier Franco, additional, Novelli, Giuseppe, additional, Bennarelli, Massimo, additional, Dallapiccola, Bruno, additional, Kalaydjieva, Luba, additional, and Scambler, Peter J., additional
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- 1993
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13. Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.
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López-Bigas, Núria, Olivé, Montserrat, Rabionet, Raquel, Ben-David, Orit, Martínez-Matos, Juan Antonio, Bravo, Olga, Banchs, Isabel, Volpini, Victor, Gasparini, Paolo, Avraham, Karen B., Ferrer, Isidre, Arbonés, Maria Lourdes, and Estivill, Xavier
- Abstract
Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders. [ABSTRACT FROM PUBLISHER]
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- 2001
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14. Connexin26 Mutations Associated with the Most Common Form of Non-Syndromic Neurosensory Autosomal Recessive Deafness (DFNB1) in Mediterraneans.
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Zelante, Leopoldo, Gasparini, Paolo, Estivill, Xavier, Melchionda, Salvatore, D'Agruma, Leonardo, Govea, Nancy, Milá, Monserrat, Della Monica, Matteo, Lutfi, Jaber, Shohat, Mordechai, Mansfield, Elaine, Delgrosso, Kathleen, Rappaport, Eric, Surrey, Saul, and Fortina, Paolo
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- 1997
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15. Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss
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Alexandre Reymond, Paolo Gasparini, Jacqueline Chrast, Hannie Kremer, Sissy Bassani, Giorgia Girotto, Jiddeke M. van de Kamp, Massimiliano Cocca, Nicolas Guex, Benjamin Delprat, Mireille Rossel, Francesca Amati, Flavio Faletra, Heiko Locher, Yoan Arribat, Sylvain Pradervand, Alban Ziegler, Jeroen Smits, Sandrine Marlin, Norine Voisin, Giuliana Giannuzzi, Tangui Maurice, Anna Morgan, Roxane Machavoine, Edward S A van Beelen, Nicolas Chatron, Clinical genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Bassani, Sissy, van Beelen, Edward, Rossel, Mireille, Voisin, Norine, Morgan, Anna, Arribat, Yoan, Chatron, Nicola, Chrast, Jacqueline, Cocca, Massimiliano, Delprat, Benjamin, Faletra, Flavio, Giannuzzi, Giuliana, Guex, Nicola, Machavoine, Roxane, Pradervand, Sylvain, Smits, Jeroen J, van de Kamp, Jiddeke M, Ziegler, Alban, Amati, Francesca, Marlin, Sandrine, Kremer, Hannie, Locher, Heiko, Maurice, Tangui, Gasparini, Paolo, Girotto, Giorgia, and Reymond, Alexandre
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0301 basic medicine ,Reflex, Startle ,Hydrolases ,Hearing loss ,Spiral limbus ,ubiquitin hydrolase ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Hereditary hearing loss ,USP48 ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,otorhinolaryngologic diseases ,Animals ,Humans ,Missense mutation ,Inner ear ,Hearing Loss ,Molecular Biology ,Zebrafish ,Genetics (clinical) ,Exome sequencing ,Spiral ganglion ,biology ,Ubiquitin ,Cochlear nerve ,Hereditary hearing lo ,General Medicine ,biology.organism_classification ,030104 developmental biology ,medicine.anatomical_structure ,Ubiquitin-Specific Proteases ,sense organs ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays. influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner’s membrane and in the transient Kolliker’s organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays.
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- 2021
16. The p.Cys169Tyr variant of connexin 26 is not a polymorphism
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Fabio Mammano, Ramin Badii, Francesco Zonta, Khalid Abdulhadi, Giulia Crispino, Moza Khalifa Alkowari, Damiano Buratto, Anna Morgan, Giorgia Girotto, Paolo Gasparini, Zonta, Francesco, Girotto, Giorgia, Buratto, Damiano, Crispino, Giulia, Morgan, Anna, Abdulhadi, Khalid, Alkowari, Moza, Badii, Ramin, Gasparini, Paolo, and Mammano, Fabio
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Male ,Models, Molecular ,Genotype ,Protein Conformation ,Mutation, Missense ,Gene Expression ,Connexin ,connexin 26 ,Biology ,Molecular Dynamics ,Transfection ,Connexins ,Hereditary hearing loss ,Cell Line ,Protein structure ,Mutant protein ,deafness ,genetic deafness ,Gene expression ,otorhinolaryngologic diseases ,Genetics ,Humans ,Missense mutation ,Protein Interaction Domains and Motifs ,Hearing Loss ,Molecular Biology ,Gene ,Alleles ,Genetics (clinical) ,Polymorphism, Genetic ,Gap junction ,Hereditary hearing lo ,Gap Junctions ,Articles ,General Medicine ,Immunohistochemistry ,Molecular biology ,Pedigree ,Connexin 26 ,Amino Acid Substitution ,Female - Abstract
Mutations in the GJB2 gene, which encodes the gap junction protein connexin 26 (Cx26), are the primary cause of hereditary prelingual hearing impairment. Here, the p.Cys169Tyr missense mutation of Cx26 (Cx26C169Y), previously classified as a polymorphism, has been identified as causative of severe hearing loss in two Qatari families. We have analyzed the effect of this mutation using a combination of confocal immunofluorescence microscopy and molecular dynamics simulations. At the cellular level, our results show that the mutant protein fails to form junctional channels in HeLa transfectants despite being correctly targeted to the plasma membrane. At the molecular level, this effect can be accounted for by disruption of the disulfide bridge that Cys169 forms with Cys64 in the wild-type structure (Cx26WT). The lack of the disulfide bridge in the Cx26C169Y protein causes a spatial rearrangement of two important residues, Asn176 and Thr177. In the Cx26WT protein, these residues play a crucial role in the intra-molecular interactions that permit the formation of an intercellular channel by the head-to-head docking of two opposing hemichannels resident in the plasma membrane of adjacent cells. Our results elucidate the molecular pathogenesis of hereditary hearing loss due to the connexin mutation and facilitate the understanding of its role in both healthy and affected individuals.
- Published
- 2015
17. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause
- Author
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Jr, Perry, Yh, Hsu, Di, Chasman, Ad, Johnson, Elks C, Albrecht E, Il, Andrulis, Beesley J, Gs, Berenson, Bergmann S, Se, Bojesen, Mk, Bolla, Brown J, Je, Buring, Campbell H, Chang-Claude J, Chenevix-Trench G, Corre T, Fj, Couch, Cox A, Czene K, Adamo Ap, D., Davies G, Ij, Deary, Dennis J, Df, Easton, Eg, Engelhardt, Jg, Eriksson, Esko T, Fasching P, Jd, Figueroa, Flyger H, Fraser A, Garcia-Closas M, Gasparini P, Gieger C, Giles G, Guenel P, Hägg S, Hall P, Hayward C, Hopper J, Ingelsson E, kConFab investigators, Sl, Kardia, Kasiman K, Ja, Knight, Jari Lahti, Da, Lawlor, Pk, Magnusson, Margolin S, Ja, Marsh, Metspalu A, Je, Olson, Ce, Pennell, Polasek O, Rahman I, Pm, Ridker, Robino A, Rudan I, Rudolph A, Salumets A, Mk, Schmidt, Mj, Schoemaker, En, Smith, Ja, Smith, Southey M, Stöckl D, Aj, Swerdlow, Dj, Thompson, Truong T, Ulivi S, Waldenberger M, Wang Q, Wild S, Jf, Wilson, Af, Wright, Zgaga L, ReproGen Consortium, Kk, Ong, Jm, Murabito, Karasik D, Murray A, kConFab investigators, ReproGen Consortium, Perry, Jr, Hsu, Yh, Chasman, Di, Johnson, Ad, Elks, C, Albrecht, E, Andrulis, Il, Beesley, J, Berenson, G, Bergmann, S, Bojesen, Se, Bolla, Mk, Brown, J, Buring, Je, Campbell, H, Chang Claude, J, Chenevix Trench, G, Corre, T, Couch, Fj, Cox, A, Czene, K, D'Adamo, ADAMO PIO, Davies, G, Deary, Ij, Dennis, J, Easton, Df, Engelhardt, Eg, Eriksson, Jg, Esko, T, Fasching, Pa, Figueroa, Jd, Flyger, H, Fraser, A, Garcia Closas, M, Gasparini, Paolo, Gieger, C, Giles, G, Guenel, P, Hägg, S, Hall, P, Hayward, C, Hopper, J, Ingelsson, E, Kconfab, Investigator, Kardia, Sl, Kasiman, K, Knight, Ja, Lahti, J, Lawlor, Da, Magnusson, Pk, Margolin, S, Marsh, Ja, Metspalu, A, Olson, Je, Pennell, Ce, Polasek, O, Rahman, I, Ridker, Pm, Robino, Antonietta, Rudan, I, Rudolph, A, Salumets, A, Schmidt, Mk, Schoemaker, Mj, Smith, En, Smith, Ja, Southey, M, Stöckl, D, Swerdlow, Aj, Thompson, Dj, Truong, T, Ulivi, S, Waldenberger, M, Wang, Q, Wild, S, Wilson, Jf, Wright, Af, Zgaga, L, Consortium, R, Ong, Kk, Murabito, Jm, Karasik, D, and Murray, A.
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Association Studies Articles ,Age Factors ,Polymorphism, Single Nucleotide ,age at menopause ,GWAS ,MSH6 gene ,DNA-Binding Proteins ,Medizinische Fakultät ,Humans ,Female ,ddc:610 ,Menopause ,Genome-Wide Association Study - Abstract
The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain
- Published
- 2013
18. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- Author
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W. H. Linda Kao, Nicole Probst-Hensch, Florian Ernst, Paul Mitchell, Christa Meisinger, Florian Kronenberg, Sharon L.R. Kardia, Paul M. Ridker, Vilmundur Gudnason, Jeanette S. Andrews, Ming-Huei Chen, Frank B. Hu, Jean-Charles Lambert, Mario Pirastu, Ozren Polasek, Xiaoyi Gao, Sven Bergmann, Catherine Helmer, Wilmar Igl, Jie Jin Wang, Barry I. Freedman, Anke Tönjes, Jacqueline C. M. Witteman, Sheila Ulivi, Conall M. O'Seaghdha, Mika Kähönen, Mariza de Andrade, Daniel I. Chasman, Meredith C. Foster, Rossella Sorice, Mathias Gorski, Eric Boerwinkle, Karlhans Endlich, Maksim Struchalin, Bernhard K. Krämer, Bénédicte Stengel, Caroline Hayward, Giorgio Pistis, Andres Metspalu, Peter Kovacs, Jorma Viikari, Guo Li, Cristian Pattaro, Adrienne Tin, Igor Rudan, Christian Gieger, Mary F. Feitosa, Stephen T. Turner, Gary C. Curhan, Shamika Ketkar, Ian Ford, Peter Vollenweider, Wolfgang Koenig, Madhumathi Rao, Iris M. Heid, Stuart K. Kim, Heather E. Wheeler, Matthias Olden, Hinco J. Gierman, Alex S. F. Doney, Lenore J. Launer, Mladen Boban, Georg Homuth, Paolo Gasparini, Harshal Deshmukh, Henry Völzke, Daniela Ruggiero, Medea Imboden, Elizabeth J. Atkinson, Ben A. Oostra, Stefan Coassin, Ute Nöthlings, Marilyn C. Cornelis, David S. Siscovick, Yongmei Liu, Gian Andri Thun, Gunnar Jacobs, Franco Giulianini, Uwe Völker, Tõnu Esko, Alexander Teumer, Jeffrey R. O'Connell, Brendan M. Buckley, Heyo K. Kroemer, Albert V. Smith, Ulf Gyllensten, Federico Murgia, Man Li, Harry Campbell, Antonietta Robino, Abbas Dehghan, Inga Prokopenko, Shih-Jen Hwang, Sylvia Stracke, Michael Stumvoll, Alan R. Shuldiner, Christian Fuchsberger, Claudia Hundertmark, Luigi Ferrucci, David Ellinghaus, Laura Portas, Caroline S. Fox, Afshin Parsa, Carsten A. Böger, Toshiko Tanaka, Terho Lehtimäki, Ayse Demirkan, James F. Wilson, Elizabeth G. Holliday, Yurii S. Aulchenko, Murielle Bochud, Helen M. Colhoun, Jingzhong Ding, Nicole L. Glazer, Rainer Rettig, Bernhard Paulweber, Margherita Cavalieri, Andre Franke, Ingrid B. Borecki, Olli T. Raitakari, Josef Coresh, Tamara B. Harris, Sarah H. Wild, Reinhold Schmidt, Ching-Ti Liu, Zoltán Kutalik, André G. Uitterlinden, J. Wouter Jukema, Helena Schmidt, Martin Adam, Audrey Y. Chu, Fernando Rivadeneira, Cornelia M. van Duijn, Braxton D. Mitchell, Gudny Eiriksdottir, Tatijana Zemunik, Andrew D. Johnson, Ghazal Zaboli, Reiner Biffar, Thor Aspelund, Cinzia Sala, Peter P. Pramstaller, Veronique Vitart, Michael A. Province, Anna Köttgen, Nicholas D. Hastie, Daniel Taliun, Marina Ciullo, Cosetta Minelli, Kurt Lohman, Matthias Nauck, Thomas Illig, Alan F. Wright, Albert Hofman, Colin N. A. Palmer, Daniela Toniolo, Qiong Yang, Lina Zgaga, Åsa Johansson, Margot Haun, Stella Trompet, Aaron Isaacs, Reedik Mägi, Tiit Nikopensius, Epidemiology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Internal Medicine, Chasman, Di, Fuchsberger, C, Pattaro, C, Teumer, A, Böger, Ca, Endlich, K, Olden, M, Chen, Mh, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, Mc, O'Seaghdha, Cm, Glazer, N, Isaacs, A, Liu, Ct, Smith, Av, O'Connell, Jr, Struchalin, M, Tanaka, T, Li, G, Johnson, Ad, Gierman, Hj, Feitosa, Mf, Hwang, Sj, Atkinson, Ej, Lohman, K, Cornelis, Mc, Johansson, A, Tönjes, A, Dehghan, A, Lambert, Jc, Holliday, Eg, Sorice, R, Kutalik, Z, Lehtimäki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, Ay, Murgia, F, Trompet, S, Imboden, M, Coassin, S, Pistis, G, Cardiogram, Consortium, Icbp, Consortium, the CARe, Consortium, Wtccc2, Harris, Tb, Launer, Lj, Aspelund, T, Eiriksdottir, G, Mitchell, Bd, Boerwinkle, E, Schmidt, H, Cavalieri, M, Rao, M, Hu, F, Demirkan, A, Oostra, Ba, de Andrade, M, Turner, St, Ding, J, Andrews, J, Freedman, Bi, Giulianini, F, Koenig, W, Illig, T, Meisinger, C, Gieger, C, Zgaga, L, Zemunik, T, Boban, M, Minelli, C, Wheeler, He, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Ernst, F, Homuth, G, Kroemer, Hk, Nauck, M, Stracke, S, Völker, U, Völzke, H, Kovacs, P, Stumvoll, M, Mägi, R, Hofman, A, Uitterlinden, Ag, Rivadeneira, F, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, Jj, Stengel, B, Ruggiero, D, Bergmann, S, Kähönen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, Antonietta, Krämer, Bk, Portas, L, Ford, I, Buckley, Bm, Adam, M, Thun, Ga, Paulweber, B, Haun, M, Sala, C, Mitchell, P, Ciullo, M, Kim, Sk, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, Paolo, Pirastu, M, Jukema, Jw, Probst Hensch, Nm, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, D, van Duijn, Cm, Borecki, Ib, Kardia, Sl, Liu, Y, Curhan, Gc, Rudan, I, Gyllensten, U, Wilson, Jf, Franke, A, Pramstaller, Pp, Rettig, R, Prokopenko, I, Witteman, J, Hayward, C, Ridker, Pm, Parsa, A, Bochud, M, Heid, Im, Kao, Wl, Fox, C, and Köttgen, A.
- Subjects
Candidate gene ,Amino Acid Transport Systems ,Basic/genetics ,Genome-wide association study ,Gene ,Genome ,Inhibin-beta Subunits/genetics ,GWAS ,kidney ,eGFR ,Genetics (clinical) ,Inhibin-beta Subunits ,Glomerular Filtration Rate/genetics ,Genetics ,0303 health sciences ,Genetic Predisposition to Disease/genetics ,Association Studies Articles ,030305 genetics & heredity ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Low Density Lipoprotein Receptor-Related Protein-2/genetics ,Polymorphism, Single Nucleotide/genetics ,LRP2 ,3. Good health ,Low Density Lipoprotein Receptor-Related Protein-2 ,Genome-Wide Association Study/methods ,Single Nucleotide/genetics ,Glomerular Filtration Rate ,Fusion Regulatory Protein 1, Heavy Chain ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genome-Wide Association Studies ,Humans ,SNP ,Genetic Predisposition to Disease ,ddc:610 ,Membrane Proteins/genetics ,Polymorphism ,Molecular Biology ,030304 developmental biology ,Genetic association ,Fusion Regulatory Protein 1, Heavy Chain/genetics ,Fusion Regulatory Protein 1 ,Genes ,Kidney Function ,Membrane Proteins ,ta3121 ,Amino Acid Transport Systems, Basic ,Amino Acid Transport Systems, Basic/genetics ,Heavy Chain/genetics ,Intracellular Signaling Peptides and Proteins/genetics ,Candidate Disease Gene ,Genome-Wide Association Study - Abstract
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
- Published
- 2012
19. A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.
- Author
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Sung YJ, de las Fuentes L, Winkler TW, Chasman DI, Bentley AR, Kraja AT, Ntalla I, Warren HR, Guo X, Schwander K, Manning AK, Brown MR, Aschard H, Feitosa MF, Franceschini N, Lu Y, Cheng CY, Sim X, Vojinovic D, Marten J, Musani SK, Kilpeläinen TO, Richard MA, Aslibekyan S, Bartz TM, Dorajoo R, Li C, Liu Y, Rankinen T, Smith AV, Tajuddin SM, Tayo BO, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris SE, Hartwig FP, He M, Horimoto ARVR, Hsu FC, Jackson AU, Kammerer CM, Kasturiratne A, Komulainen P, Kühnel B, Leander K, Lee WJ, Lin KH, Luan J, Lyytikäinen LP, McKenzie CA, Nelson CP, Noordam R, Scott RA, Sheu WHH, Stančáková A, Takeuchi F, van der Most PJ, Varga TV, Waken RJ, Wang H, Wang Y, Ware EB, Weiss S, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking DE, Aung T, Barr RG, Bielak LF, Boerwinkle E, Bottinger EP, Braund PS, Brody JA, Broeckel U, Cade B, Campbell A, Canouil M, Chakravarti A, Cocca M, Collins FS, Connell JM, de Mutsert R, de Silva HJ, Dörr M, Duan Q, Eaton CB, Ehret G, Evangelou E, Faul JD, Forouhi NG, Franco OH, Friedlander Y, Gao H, Gigante B, Gu CC, Gupta P, Hagenaars SP, Harris TB, He J, Heikkinen S, Heng CK, Hofman A, Howard BV, Hunt SC, Irvin MR, Jia Y, Katsuya T, Kaufman J, Kerrison ND, Khor CC, Koh WP, Koistinen HA, Kooperberg CB, Krieger JE, Kubo M, Kutalik Z, Kuusisto J, Lakka TA, Langefeld CD, Langenberg C, Launer LJ, Lee JH, Lehne B, Levy D, Lewis CE, Li Y, Lim SH, Liu CT, Liu J, Liu J, Liu Y, Loh M, Lohman KK, Louie T, Mägi R, Matsuda K, Meitinger T, Metspalu A, Milani L, Momozawa Y, Mosley TH Jr, Nalls MA, Nasri U, O'Connell JR, Ogunniyi A, Palmas WR, Palmer ND, Pankow JS, Pedersen NL, Peters A, Peyser PA, Polasek O, Porteous D, Raitakari OT, Renström F, Rice TK, Ridker PM, Robino A, Robinson JG, Rose LM, Rudan I, Sabanayagam C, Salako BL, Sandow K, Schmidt CO, Schreiner PJ, Scott WR, Sever P, Sims M, Sitlani CM, Smith BH, Smith JA, Snieder H, Starr JM, Strauch K, Tang H, Taylor KD, Teo YY, Tham YC, Uitterlinden AG, Waldenberger M, Wang L, Wang YX, Wei WB, Wilson G, Wojczynski MK, Xiang YB, Yao J, Yuan JM, Zonderman AB, Becker DM, Boehnke M, Bowden DW, Chambers JC, Chen YI, Weir DR, de Faire U, Deary IJ, Esko T, Farrall M, Forrester T, Freedman BI, Froguel P, Gasparini P, Gieger C, Horta BL, Hung YJ, Jonas JB, Kato N, Kooner JS, Laakso M, Lehtimäki T, Liang KW, Magnusson PKE, Oldehinkel AJ, Pereira AC, Perls T, Rauramaa R, Redline S, Rettig R, Samani NJ, Scott J, Shu XO, van der Harst P, Wagenknecht LE, Wareham NJ, Watkins H, Wickremasinghe AR, Wu T, Kamatani Y, Laurie CC, Bouchard C, Cooper RS, Evans MK, Gudnason V, Hixson J, Kardia SLR, Kritchevsky SB, Psaty BM, van Dam RM, Arnett DK, Mook-Kanamori DO, Fornage M, Fox ER, Hayward C, van Duijn CM, Tai ES, Wong TY, Loos RJF, Reiner AP, Rotimi CN, Bierut LJ, Zhu X, Cupples LA, Province MA, Rotter JI, Franks PW, Rice K, Elliott P, Caulfield MJ, Gauderman WJ, Munroe PB, Rao DC, and Morrison AC
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antiporters genetics, Blood Pressure genetics, Caspase 9 genetics, Ethnicity genetics, Female, Genome-Wide Association Study, Humans, Hypertension etiology, Male, Membrane Proteins genetics, Middle Aged, Receptors, Vasopressin genetics, Sulfate Transporters genetics, Tumor Suppressor Proteins genetics, Young Adult, Arterial Pressure genetics, Gene-Environment Interaction, Hypertension genetics, Polymorphism, Genetic, Racial Groups genetics, Smoking adverse effects
- Abstract
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
- Full Text
- View/download PDF
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