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3. Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration

Author

Waksmunski, Andrea R., Grunin, Michelle, Kinzy, Tyler G., Igo, Robert P., Jr., Haines, Jonathan L., Bailey, Jessica N. Cooke, Fritsche, Lars G., Igl, Wilmar, Grassmann, Felix, Sengupta, Sebanti, Bragg-Gresham, Jennifer L., Burdon, Kathryn P., Hebbring, Scott J., Wen, Cindy, Gorski, Mathias, Kim, Ivana K., Cho, David, Zack, Donald, Souied, Eric, Scholl, Hendrik P. N., Bala, Elisa, Lee, Kristine E., Hunter, David J., Sardell, Rebecca J., Mitchell, Paul, Merriam, Joanna E., Cipriani, Valentina, Hoffman, Joshua D., Schick, Tina, Lechanteur, Yara T. E., Guymer, Robyn H., Johnson, Matthew P., Jiang, Yingda, Stanton, Chloe M., Buitendijk, Gabrielle H. S., Zhan, Xiaowei, Kwong, Alan M., Boleda, Alexis, Brooks, Matthew, Gieser, Linn, Ratnapriya, Rinki, Branham, Kari E., Foerster, Johanna R., Heckenlively, John R., Othman, Mohammad, I, Vote, Brendan J., Liang, Helena Hai, Souzeau, Emmanuelle, McAllister, Ian L., Isaacs, Timothy, Hall, Janette, Lake, Stewart, Mackey, David A., Constable, Ian J., Craig, Jamie E., Kitchner, Terrie E., Yang, Zhenglin, Su, Zhiguang, Luo, Hongrong, Chen, Daniel, Ouyang, Hong, Flagg, Ken, Lin, Danni, Mao, Guanping, Ferreyra, Henry, Stark, Klaus, von Strachwitz, Claudia N., Wolf, Armin, Brandl, Caroline, Rudolph, Guenther, Olden, Matthias, Morrison, Margaux A., Morgan, Denise J., Schu, Matthew, Ahn, Jeeyun, Silvestri, Giuliana, Tsironi, Evangelia E., Park, Kyu Hyung, Farrer, Lindsay A., Orlin, Anton, Brucker, Alexander, Li, Mingyao, Curcio, Christine A., Mohand-Said, Saddek, Sahel, Jose-Alain, Audo, Isabelle, Benchaboune, Mustapha, Cree, Angela J., Rennie, Christina A., Goverdhan, Srinivas, V, Hagbi-Levi, Shira, Campochiaro, Peter, Katsanis, Nicholas, Holz, Frank G., Blond, Frederic, Blanche, Helene, Deleuze, Jean-Francois, Truitt, Barbara, Peachey, Neal S., Meuer, Stacy M., Myers, Chelsea E., Moore, Emily L., Klein, Ronald, Hauser, Michael A., Postel, Eric A., Courtenay, Monique D., Schwartz, Stephen G., Kovach, Jaclyn L., Scott, William K., Liew, Gerald, Tan, Ava G., Gopinath, Bamini, Merriam, John C., Smith, R. Theodore, Khan, Jane C., Shahid, Humma, Moore, Anthony T., McGrath, J. Allie, Laux, Renee, Brantley, Milam A., Jr., Agarwal, Anita, Ersoy, Lebriz, Caramoy, Albert, Langmann, Thomas, Saksens, Nicole T. M., de Jong, Eiko K., Hoyng, Carel B., Cain, Melinda S., Richardson, Andrea J., Martin, Tammy M., Blangero, John, Weeks, Daniel E., Dhillon, Bal, van Duijn, Cornelia M., Doheny, Kimberly F., Romm, Jane, Klaver, Caroline C. W., Hayward, Caroline, Gorin, Michael B., Klein, Michael L., Baird, Paul N., den Hollander, Anneke, I, Fauser, Sascha, Yates, John R. W., Allikmets, Rando, Wang, Jie Jin, Schaumberg, Debra A., Klein, Barbara E. K., Hagstrom, Stephanie A., Chowers, Itay, Lotery, Andrew J., Leveillard, Thierry, Zhang, Kang, Brilliant, Murray H., Hewitt, Alex W., Swaroop, Anand, Chew, Emily Y., Pericak-Vance, Margaret A., DeAngelis, Margaret, Stambolian, Dwight, Iyengar, Sudha K., Weber, Bernhard H. F., Abecasis, Goncalo R., Heid, Iris M., Waksmunski, Andrea R., Grunin, Michelle, Kinzy, Tyler G., Igo, Robert P., Jr., Haines, Jonathan L., Bailey, Jessica N. Cooke, Fritsche, Lars G., Igl, Wilmar, Grassmann, Felix, Sengupta, Sebanti, Bragg-Gresham, Jennifer L., Burdon, Kathryn P., Hebbring, Scott J., Wen, Cindy, Gorski, Mathias, Kim, Ivana K., Cho, David, Zack, Donald, Souied, Eric, Scholl, Hendrik P. N., Bala, Elisa, Lee, Kristine E., Hunter, David J., Sardell, Rebecca J., Mitchell, Paul, Merriam, Joanna E., Cipriani, Valentina, Hoffman, Joshua D., Schick, Tina, Lechanteur, Yara T. E., Guymer, Robyn H., Johnson, Matthew P., Jiang, Yingda, Stanton, Chloe M., Buitendijk, Gabrielle H. S., Zhan, Xiaowei, Kwong, Alan M., Boleda, Alexis, Brooks, Matthew, Gieser, Linn, Ratnapriya, Rinki, Branham, Kari E., Foerster, Johanna R., Heckenlively, John R., Othman, Mohammad, I, Vote, Brendan J., Liang, Helena Hai, Souzeau, Emmanuelle, McAllister, Ian L., Isaacs, Timothy, Hall, Janette, Lake, Stewart, Mackey, David A., Constable, Ian J., Craig, Jamie E., Kitchner, Terrie E., Yang, Zhenglin, Su, Zhiguang, Luo, Hongrong, Chen, Daniel, Ouyang, Hong, Flagg, Ken, Lin, Danni, Mao, Guanping, Ferreyra, Henry, Stark, Klaus, von Strachwitz, Claudia N., Wolf, Armin, Brandl, Caroline, Rudolph, Guenther, Olden, Matthias, Morrison, Margaux A., Morgan, Denise J., Schu, Matthew, Ahn, Jeeyun, Silvestri, Giuliana, Tsironi, Evangelia E., Park, Kyu Hyung, Farrer, Lindsay A., Orlin, Anton, Brucker, Alexander, Li, Mingyao, Curcio, Christine A., Mohand-Said, Saddek, Sahel, Jose-Alain, Audo, Isabelle, Benchaboune, Mustapha, Cree, Angela J., Rennie, Christina A., Goverdhan, Srinivas, V, Hagbi-Levi, Shira, Campochiaro, Peter, Katsanis, Nicholas, Holz, Frank G., Blond, Frederic, Blanche, Helene, Deleuze, Jean-Francois, Truitt, Barbara, Peachey, Neal S., Meuer, Stacy M., Myers, Chelsea E., Moore, Emily L., Klein, Ronald, Hauser, Michael A., Postel, Eric A., Courtenay, Monique D., Schwartz, Stephen G., Kovach, Jaclyn L., Scott, William K., Liew, Gerald, Tan, Ava G., Gopinath, Bamini, Merriam, John C., Smith, R. Theodore, Khan, Jane C., Shahid, Humma, Moore, Anthony T., McGrath, J. Allie, Laux, Renee, Brantley, Milam A., Jr., Agarwal, Anita, Ersoy, Lebriz, Caramoy, Albert, Langmann, Thomas, Saksens, Nicole T. M., de Jong, Eiko K., Hoyng, Carel B., Cain, Melinda S., Richardson, Andrea J., Martin, Tammy M., Blangero, John, Weeks, Daniel E., Dhillon, Bal, van Duijn, Cornelia M., Doheny, Kimberly F., Romm, Jane, Klaver, Caroline C. W., Hayward, Caroline, Gorin, Michael B., Klein, Michael L., Baird, Paul N., den Hollander, Anneke, I, Fauser, Sascha, Yates, John R. W., Allikmets, Rando, Wang, Jie Jin, Schaumberg, Debra A., Klein, Barbara E. K., Hagstrom, Stephanie A., Chowers, Itay, Lotery, Andrew J., Leveillard, Thierry, Zhang, Kang, Brilliant, Murray H., Hewitt, Alex W., Swaroop, Anand, Chew, Emily Y., Pericak-Vance, Margaret A., DeAngelis, Margaret, Stambolian, Dwight, Iyengar, Sudha K., Weber, Bernhard H. F., Abecasis, Goncalo R., and Heid, Iris M.

Abstract

PURPOSE. Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. METHODS. We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. RESULTS. We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) drive'' the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. CONCLUSIONS. We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD.

Published
2019

4. Long-term cognitive outcomes in tuberous sclerosis complex.

Author

Tye, Charlotte, Mcewen, Fiona S, Liang, Holan, Underwood, Lisa, Woodhouse, Emma, Barker, Edward D, Sheerin, Fintan, Yates, John R W, Bolton, Patrick F, Higgins, N, Attard, V, Clarke, A, Elmslie, FV, Saggar, AK, Baines, D, Kerr, BA, Brayne, C, Carcani‐Rathwell, I, Connolly, C, and Clifford, M

Subjects
TUBEROUS sclerosis, INTELLECTUAL disabilities, SEIZURES (Medicine), INTELLECTUAL development, EPILEPSY, DISEASE risk factors, COGNITION, NEUROPSYCHOLOGICAL tests, RESEARCH funding, LONGITUDINAL method, DISEASE complications
Abstract

Aim: To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC).Method: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2.Results: Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence.Interpretation: Early-onset and severe epilepsy in the first 2 years of life are associated with increased risk of long-term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy.What This Paper Adds: Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC). Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings. Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability. Risk pathways through seizures in the first 2 years predict long-term cognitive outcomes in individuals with TSC. [ABSTRACT FROM AUTHOR]

Published
2020
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6. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, Lars G., Igl, Wilmar, Bailey, Jessica N. Cooke, Grassmann, Felix, Sengupta, Sebanti, Bragg-Gresham, Jennifer L., Burdon, Kathryn P., Hebbring, Scott J., Wen, Cindy, Gorski, Mathias, Kim, Ivana K., Cho, David, Zack, Donald, Souied, Eric, Scholl, Hendrik P. N., Bala, Elisa, Lee, Kristine E., Hunter, David J., Sardell, Rebecca J., Mitchell, Paul, Merriam, Joanna E., Cipriani, Valentina, Hoffman, Joshua D., Schick, Tina, Lechanteur, Yara T. E., Guymer, Robyn H., Johnson, Matthew P., Jiang, Yingda, Stanton, Chloe M., Buitendijk, Gabrielle H. S., Zhan, Xiaowei, Kwong, Alan M., Boleda, Alexis, Brooks, Matthew, Gieser, Linn, Ratnapriya, Rinki, Branham, Kari E., Foerster, Johanna R., Heckenlively, John R., Othman, Mohammad I., Vote, Brendan J., Liang, Helena Hai, Souzeau, Emmanuelle, McAllister, Ian L., Isaacs, Timothy, Hall, Janette, Lake, Stewart, Mackey, David A., Constable, Ian J., Craig, Jamie E., Kitchner, Terrie E., Yang, Zhenglin, Su, Zhiguang, Luo, Hongrong, Chen, Daniel, Flagg, Ken, Lin, Danni, Mao, Guanping, Ferreyra, Henry, Starke, Klaus, von Strachwitz, Claudia N., Wolf, Armin, Brandl, Caroline, Rudolph, Guenther, Olden, Matthias, Morrison, Margaux A., Morgan, Denise J., Schu, Matthew, Ahn, Jeeyun, Silvestri, Giuliana, Tsironi, Evangelia E., Park, Kyu Hyung, Farrer, Lindsay A., Orlin, Anton, Brucker, Alexander, Li, Mingyao, Curcio, Christine A., Mohand-Said, Saddek, Sahel, Jose-Main, Audo, Isabelle, Benchaboune, Mustapha, Cree, Angela J., Rennie, Christina A., Goverdhan, Srinivas V., Grunin, Michelle, Hagbi-Levi, Shira, Campochiaro, Peter, Katsanis, Nicholas, Holz, Frank G., Blond, Frederic, Blanche, Helene, Deleuze, Jean-Francois, Igo, Robert P., Jr., Truitt, Barbara, Peachey, Neal S., Meuer, Stacy M., Myers, Chelsea E., Moore, Emily L., Klein, Ronald, Hauser, Michael A., Postel, Eric A., Courtenay, Monique D., Schwartz, Stephen G., Kovach, Jaclyn L., Scott, William K., Liew, Gerald, Tan, Ava G., Gopinath, Bamini, Merriam, John C., Smith, R. Theodore, Khan, Jane C., Shahid, Humma, Moore, Anthony T., McGrath, J. Allie, Laux, Renee, Brantley, Milam A., Jr., Agarwal, Anita, Ersoy, Lebriz, Caramoy, Albert, Langmann, Thomas, Saksens, Nicole T. M., de Jong, Eiko K., Hoyng, Carel B., Cain, Melinda S., Richardson, Andrea J., Martin, Tammy M., Blangero, John, Weeks, Daniel E., Dhillon, Bal, van Duijn, Cornelia M., Doheny, Kimberly F., Romm, Jane, Klaver, Caroline C. W., Hayward, Caroline, Gorin, Michael B., Klein, Michael L., Baird, Paul N., den Hollander, Anneke I., Fauser, Sascha, Yates, John R. W., Allikmets, Rando, Wang, Jie Jin, Schaumberg, Debra A., Klein, Barbara E. K., Hagstrom, Stephanie A., Chowers, Itay, Lotery, Andrew J., Leveillard, Thierry, Zhang, Kang, Brilliant, Murray H., Hewitt, Alex W., Swaroop, Anand, Chew, Emily Y., Pericak-Vance, Margaret A., DeAngelis, Margaret, Stambolian, Dwight, Haines, Jonathan L., Iyengar, Sudha K., Weber, Bernhard H. F., Abecasis, Goncalo R., Heid, Iris M., Fritsche, Lars G., Igl, Wilmar, Bailey, Jessica N. Cooke, Grassmann, Felix, Sengupta, Sebanti, Bragg-Gresham, Jennifer L., Burdon, Kathryn P., Hebbring, Scott J., Wen, Cindy, Gorski, Mathias, Kim, Ivana K., Cho, David, Zack, Donald, Souied, Eric, Scholl, Hendrik P. N., Bala, Elisa, Lee, Kristine E., Hunter, David J., Sardell, Rebecca J., Mitchell, Paul, Merriam, Joanna E., Cipriani, Valentina, Hoffman, Joshua D., Schick, Tina, Lechanteur, Yara T. E., Guymer, Robyn H., Johnson, Matthew P., Jiang, Yingda, Stanton, Chloe M., Buitendijk, Gabrielle H. S., Zhan, Xiaowei, Kwong, Alan M., Boleda, Alexis, Brooks, Matthew, Gieser, Linn, Ratnapriya, Rinki, Branham, Kari E., Foerster, Johanna R., Heckenlively, John R., Othman, Mohammad I., Vote, Brendan J., Liang, Helena Hai, Souzeau, Emmanuelle, McAllister, Ian L., Isaacs, Timothy, Hall, Janette, Lake, Stewart, Mackey, David A., Constable, Ian J., Craig, Jamie E., Kitchner, Terrie E., Yang, Zhenglin, Su, Zhiguang, Luo, Hongrong, Chen, Daniel, Flagg, Ken, Lin, Danni, Mao, Guanping, Ferreyra, Henry, Starke, Klaus, von Strachwitz, Claudia N., Wolf, Armin, Brandl, Caroline, Rudolph, Guenther, Olden, Matthias, Morrison, Margaux A., Morgan, Denise J., Schu, Matthew, Ahn, Jeeyun, Silvestri, Giuliana, Tsironi, Evangelia E., Park, Kyu Hyung, Farrer, Lindsay A., Orlin, Anton, Brucker, Alexander, Li, Mingyao, Curcio, Christine A., Mohand-Said, Saddek, Sahel, Jose-Main, Audo, Isabelle, Benchaboune, Mustapha, Cree, Angela J., Rennie, Christina A., Goverdhan, Srinivas V., Grunin, Michelle, Hagbi-Levi, Shira, Campochiaro, Peter, Katsanis, Nicholas, Holz, Frank G., Blond, Frederic, Blanche, Helene, Deleuze, Jean-Francois, Igo, Robert P., Jr., Truitt, Barbara, Peachey, Neal S., Meuer, Stacy M., Myers, Chelsea E., Moore, Emily L., Klein, Ronald, Hauser, Michael A., Postel, Eric A., Courtenay, Monique D., Schwartz, Stephen G., Kovach, Jaclyn L., Scott, William K., Liew, Gerald, Tan, Ava G., Gopinath, Bamini, Merriam, John C., Smith, R. Theodore, Khan, Jane C., Shahid, Humma, Moore, Anthony T., McGrath, J. Allie, Laux, Renee, Brantley, Milam A., Jr., Agarwal, Anita, Ersoy, Lebriz, Caramoy, Albert, Langmann, Thomas, Saksens, Nicole T. M., de Jong, Eiko K., Hoyng, Carel B., Cain, Melinda S., Richardson, Andrea J., Martin, Tammy M., Blangero, John, Weeks, Daniel E., Dhillon, Bal, van Duijn, Cornelia M., Doheny, Kimberly F., Romm, Jane, Klaver, Caroline C. W., Hayward, Caroline, Gorin, Michael B., Klein, Michael L., Baird, Paul N., den Hollander, Anneke I., Fauser, Sascha, Yates, John R. W., Allikmets, Rando, Wang, Jie Jin, Schaumberg, Debra A., Klein, Barbara E. K., Hagstrom, Stephanie A., Chowers, Itay, Lotery, Andrew J., Leveillard, Thierry, Zhang, Kang, Brilliant, Murray H., Hewitt, Alex W., Swaroop, Anand, Chew, Emily Y., Pericak-Vance, Margaret A., DeAngelis, Margaret, Stambolian, Dwight, Haines, Jonathan L., Iyengar, Sudha K., Weber, Bernhard H. F., Abecasis, Goncalo R., and Heid, Iris M.

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 x 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 x 10(-10)). Very rare coding variants (frequency <0.1 %) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016

8. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, Lars G, primary, Igl, Wilmar, additional, Bailey, Jessica N Cooke, additional, Grassmann, Felix, additional, Sengupta, Sebanti, additional, Bragg-Gresham, Jennifer L, additional, Burdon, Kathryn P, additional, Hebbring, Scott J, additional, Wen, Cindy, additional, Gorski, Mathias, additional, Kim, Ivana K, additional, Cho, David, additional, Zack, Donald, additional, Souied, Eric, additional, Scholl, Hendrik P N, additional, Bala, Elisa, additional, Lee, Kristine E, additional, Hunter, David J, additional, Sardell, Rebecca J, additional, Mitchell, Paul, additional, Merriam, Joanna E, additional, Cipriani, Valentina, additional, Hoffman, Joshua D, additional, Schick, Tina, additional, Lechanteur, Yara T E, additional, Guymer, Robyn H, additional, Johnson, Matthew P, additional, Jiang, Yingda, additional, Stanton, Chloe M, additional, Buitendijk, Gabriëlle H S, additional, Zhan, Xiaowei, additional, Kwong, Alan M, additional, Boleda, Alexis, additional, Brooks, Matthew, additional, Gieser, Linn, additional, Ratnapriya, Rinki, additional, Branham, Kari E, additional, Foerster, Johanna R, additional, Heckenlively, John R, additional, Othman, Mohammad I, additional, Vote, Brendan J, additional, Liang, Helena Hai, additional, Souzeau, Emmanuelle, additional, McAllister, Ian L, additional, Isaacs, Timothy, additional, Hall, Janette, additional, Lake, Stewart, additional, Mackey, David A, additional, Constable, Ian J, additional, Craig, Jamie E, additional, Kitchner, Terrie E, additional, Yang, Zhenglin, additional, Su, Zhiguang, additional, Luo, Hongrong, additional, Chen, Daniel, additional, Ouyang, Hong, additional, Flagg, Ken, additional, Lin, Danni, additional, Mao, Guanping, additional, Ferreyra, Henry, additional, Stark, Klaus, additional, von Strachwitz, Claudia N, additional, Wolf, Armin, additional, Brandl, Caroline, additional, Rudolph, Guenther, additional, Olden, Matthias, additional, Morrison, Margaux A, additional, Morgan, Denise J, additional, Schu, Matthew, additional, Ahn, Jeeyun, additional, Silvestri, Giuliana, additional, Tsironi, Evangelia E, additional, Park, Kyu Hyung, additional, Farrer, Lindsay A, additional, Orlin, Anton, additional, Brucker, Alexander, additional, Li, Mingyao, additional, Curcio, Christine A, additional, Mohand-Saïd, Saddek, additional, Sahel, José-Alain, additional, Audo, Isabelle, additional, Benchaboune, Mustapha, additional, Cree, Angela J, additional, Rennie, Christina A, additional, Goverdhan, Srinivas V, additional, Grunin, Michelle, additional, Hagbi-Levi, Shira, additional, Campochiaro, Peter, additional, Katsanis, Nicholas, additional, Holz, Frank G, additional, Blond, Frédéric, additional, Blanché, Hélène, additional, Deleuze, Jean-François, additional, Igo, Robert P, additional, Truitt, Barbara, additional, Peachey, Neal S, additional, Meuer, Stacy M, additional, Myers, Chelsea E, additional, Moore, Emily L, additional, Klein, Ronald, additional, Hauser, Michael A, additional, Postel, Eric A, additional, Courtenay, Monique D, additional, Schwartz, Stephen G, additional, Kovach, Jaclyn L, additional, Scott, William K, additional, Liew, Gerald, additional, Tan, Ava G, additional, Gopinath, Bamini, additional, Merriam, John C, additional, Smith, R Theodore, additional, Khan, Jane C, additional, Shahid, Humma, additional, Moore, Anthony T, additional, McGrath, J Allie, additional, Laux, Reneé, additional, Brantley, Milam A, additional, Agarwal, Anita, additional, Ersoy, Lebriz, additional, Caramoy, Albert, additional, Langmann, Thomas, additional, Saksens, Nicole T M, additional, de Jong, Eiko K, additional, Hoyng, Carel B, additional, Cain, Melinda S, additional, Richardson, Andrea J, additional, Martin, Tammy M, additional, Blangero, John, additional, Weeks, Daniel E, additional, Dhillon, Bal, additional, van Duijn, Cornelia M, additional, Doheny, Kimberly F, additional, Romm, Jane, additional, Klaver, Caroline C W, additional, Hayward, Caroline, additional, Gorin, Michael B, additional, Klein, Michael L, additional, Baird, Paul N, additional, den Hollander, Anneke I, additional, Fauser, Sascha, additional, Yates, John R W, additional, Allikmets, Rando, additional, Wang, Jie Jin, additional, Schaumberg, Debra A, additional, Klein, Barbara E K, additional, Hagstrom, Stephanie A, additional, Chowers, Itay, additional, Lotery, Andrew J, additional, Léveillard, Thierry, additional, Zhang, Kang, additional, Brilliant, Murray H, additional, Hewitt, Alex W, additional, Swaroop, Anand, additional, Chew, Emily Y, additional, Pericak-Vance, Margaret A, additional, DeAngelis, Margaret, additional, Stambolian, Dwight, additional, Haines, Jonathan L, additional, Iyengar, Sudha K, additional, Weber, Bernhard H F, additional, Abecasis, Gonçalo R, additional, and Heid, Iris M, additional

Published
2015
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9. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, Lars G, Igl, Wilmar, Bailey, Jessica N Cooke, Grassmann, Felix, Sengupta, Sebanti, Bragg-Gresham, Jennifer L, Burdon, Kathryn P, Hebbring, Scott J, Wen, Cindy, Gorski, Mathias, Kim, Ivana K, Cho, David, Zack, Donald, Souied, Eric, Scholl, Hendrik P N, Bala, Elisa, Lee, Kristine E, Hunter, David J, Sardell, Rebecca J, Mitchell, Paul, Merriam, Joanna E, Cipriani, Valentina, Hoffman, Joshua D, Schick, Tina, Lechanteur, Yara T E, Guymer, Robyn H, Johnson, Matthew P, Jiang, Yingda, Stanton, Chloe M, Buitendijk, Gabriëlle H S, Zhan, Xiaowei, Kwong, Alan M, Boleda, Alexis, Brooks, Matthew, Gieser, Linn, Ratnapriya, Rinki, Branham, Kari E, Foerster, Johanna R, Heckenlively, John R, Othman, Mohammad I, Vote, Brendan J, Liang, Helena Hai, Souzeau, Emmanuelle, McAllister, Ian L, Isaacs, Timothy, Hall, Janette, Lake, Stewart, Mackey, David A, Constable, Ian J, Craig, Jamie E, Kitchner, Terrie E, Yang, Zhenglin, Su, Zhiguang, Luo, Hongrong, Chen, Daniel, Ouyang, Hong, Flagg, Ken, Lin, Danni, Mao, Guanping, Ferreyra, Henry, Stark, Klaus, von Strachwitz, Claudia N, Wolf, Armin, Brandl, Caroline, Rudolph, Guenther, Olden, Matthias, Morrison, Margaux A, Morgan, Denise J, Schu, Matthew, Ahn, Jeeyun, Silvestri, Giuliana, Tsironi, Evangelia E, Park, Kyu Hyung, Farrer, Lindsay A, Orlin, Anton, Brucker, Alexander, Li, Mingyao, Curcio, Christine A, Mohand-Saïd, Saddek, Sahel, José-Alain, Audo, Isabelle, Benchaboune, Mustapha, Cree, Angela J, Rennie, Christina A, Goverdhan, Srinivas V, Grunin, Michelle, Hagbi-Levi, Shira, Campochiaro, Peter, Katsanis, Nicholas, Holz, Frank G, Blond, Frédéric, Blanché, Hélène, Deleuze, Jean-François, Igo, Robert P, Truitt, Barbara, Peachey, Neal S, Meuer, Stacy M, Myers, Chelsea E, Moore, Emily L, Klein, Ronald, Hauser, Michael A, Postel, Eric A, Courtenay, Monique D, Schwartz, Stephen G, Kovach, Jaclyn L, Scott, William K, Liew, Gerald, Tan, Ava G, Gopinath, Bamini, Merriam, John C, Smith, R Theodore, Khan, Jane C, Shahid, Humma, Moore, Anthony T, McGrath, J Allie, Laux, Reneé, Brantley, Milam A, Agarwal, Anita, Ersoy, Lebriz, Caramoy, Albert, Langmann, Thomas, Saksens, Nicole T M, de Jong, Eiko K, Hoyng, Carel B, Cain, Melinda S, Richardson, Andrea J, Martin, Tammy M, Blangero, John, Weeks, Daniel E, Dhillon, Bal, van Duijn, Cornelia M, Doheny, Kimberly F, Romm, Jane, Klaver, Caroline C W, Hayward, Caroline, Gorin, Michael B, Klein, Michael L, Baird, Paul N, den Hollander, Anneke I, Fauser, Sascha, Yates, John R W, Allikmets, Rando, Wang, Jie Jin, Schaumberg, Debra A, Klein, Barbara E K, Hagstrom, Stephanie A, Chowers, Itay, Lotery, Andrew J, Léveillard, Thierry, Zhang, Kang, Brilliant, Murray H, Hewitt, Alex W, Swaroop, Anand, Chew, Emily Y, Pericak-Vance, Margaret A, DeAngelis, Margaret, Stambolian, Dwight, Haines, Jonathan L, Iyengar, Sudha K, Weber, Bernhard H F, Abecasis, Gonçalo R, and Heid, Iris M

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10−8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10−10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016
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10. Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.

Author

Cipriani V, Tierney A, Griffiths JR, Zuber V, Sergouniotis PI, Yates JRW, Moore AT, Bishop PN, Clark SJ, and Unwin RD

Subjects
Aged, Case-Control Studies, Complement C3b Inactivator Proteins genetics, Female, Humans, Macular Degeneration genetics, Macular Degeneration pathology, Male, Risk Factors, Complement C3b Inactivator Proteins metabolism, Complement Factor H genetics, Genetic Predisposition to Disease, Macular Degeneration blood, Polymorphism, Single Nucleotide
Abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p = 2.4 × 10 -10 ; FHR-2, p = 6.0 × 10 -10 ; FHR-3, p = 1.5 × 10 -5 ; FHR-4, p = 1.3 × 10 -3 ; FHR-5, p = 1.9 × 10 -4 ) and FHL-1 (p = 4.9 × 10 -4 ) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD., Competing Interests: Declaration of interests P.N.B., S.J.C., and R.D.U. are inventors named in patent applications that describe the use of complement inhibitors for therapeutic purposes and the use of circulating complement-protein measurement for patient stratification and are co-founders of and shareholders in Complement Therapeutics, a company that focuses on the development of complement-targeted therapeutics, including for AMD. The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2021
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