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1. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Samuli Olli Ripatti / Principal Investigator, University of Helsinki, Department of Public Health, University of Helsinki, Haartman Institute, University of Helsinki, Clinicum, University of Helsinki, Diabetes and Obesity Research Program, University of Helsinki, Department of Public Health (-2009), Randall, Joshua C., Winkler, Thomas W., Kutalik, Zoltan, Berndt, Sonja I., Jackson, Anne U., Monda, Keri L., Kilpelaeinen, Tuomas O., Esko, Tonu, Maegi, Reedik, Li, Shengxu, Workalemahu, Tsegaselassie, Feitosa, Mary F., Croteau-Chonka, Damien C., Day, Felix R., Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Locke, Adam E., Mathieson, Iain, Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Liang, Liming, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Dermitzakis, Emmanouil T., Dimas, Antigone S., Karpe, Fredrik, Min, Josine L., Nicholson, George, Clegg, Deborah J., Person, Thomas, Krohn, Jon P., Bauer, Sabrina, Buechler, Christa, Eisinger, Kristina, Bonnefond, Amelie, Froguel, Philippe, Hottenga, Jouke-Jan, Prokopenko, Inga, Waite, Lindsay L., Harris, Tamara B., Smith, Albert Vernon, Shuldiner, Alan R., McArdle, Wendy L., Caulfield, Mark J., Munroe, Patricia B., Gronberg, Henrik, Chen, Yii-Der Ida, Li, Guo, Beckmann, Jacques S., Johnson, Toby, Thorsteinsdottir, Unnur, Teder-Laving, Maris, Khaw, Kay-Tee, Wareham, Nicholas J., Zhao, Jing Hua, Amin, Najaf, Oostra, Ben A., Kraja, Aldi T., Province, Michael A., Cupples, L. Adrienne, Heard-Costa, Nancy L., Kaprio, Jaakko, Ripatti, Samuli, Surakka, Ida, Collins, Francis S., Saramies, Jouko, Tuomilehto, Jaakko, Jula, Antti, Salomaa, Veikko, Erdmann, Jeanette, Hengstenberg, Christian, Loley, Christina, Schunkert, Heribert, Lamina, Claudia, Wichmann, H. Erich, Albrecht, Eva, Gieger, Christian, Hicks, Andrew A., Johansson, Asa, Pramstaller, Peter P., Kathiresan, Sekar, Speliotes, Elizabeth K., Penninx, Brenda, Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Gyllensten, Ulf, Boomsma, Dorret I., Campbell, Harry, Wilson, James F., Chanock, Stephen J., Farrall, Martin, Goel, Anuj, Medina-Gomez, Carolina, Rivadeneira, Fernando, Estrada, Karol, Uitterlinden, Andre G., Hofman, Albert, Zillikens, M. Carola, den Heijer, Martin, Kiemeney, Lambertus A., Maschio, Andrea, Hall, Per, Tyrer, Jonathan, Teumer, Alexander, Voelzke, Henry, Kovacs, Peter, Toenjes, Anke, Mangino, Massimo, Spector, Tim D., Hayward, Caroline, Rudan, Igor, Hall, Alistair S., Samani, Nilesh J., Attwood, Antony Paul, Sambrook, Jennifer G., Hung, Joseph, Palmer, Lyle J., Lokki, Marja-Liisa, Sinisalo, Juha-Pekka, Boucher, Gabrielle, Huikuri, Heikki, Lorentzon, Mattias, Ohlsson, Claes, Eklund, Niina, Eriksson, Johan G., Barlassina, Cristina, Rivolta, Carlo, Nolte, Ilja M., Snieder, Harold, Van der Klauw, Melanie M., Van Vliet-Ostaptchouk, Jana V., Gejman, Pablo V., Shi, Jianxin, Jacobs, Kevin B., Wang, Zhaoming, Bakker, Stephan J. L., Leach, Irene Mateo, Navis, Gerjan, van der Harst, Pim, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Yang, Jian, Chasman, Daniel I., Ridker, Paul M., Rose, Lynda M., Lehtimaki, Terho, Raitakari, Olli, Absher, Devin, Iribarren, Carlos, Basart, Hanneke, Hovingh, Kees G., Hyppoenen, Elina, Power, Chris, Anderson, Denise, Beilby, John P., Hui, Jennie, Jolley, Jennifer, Sager, Hendrik, Bornstein, Stefan R., Schwarz, Peter E. H., Kristiansson, Kati, Perola, Markus, Lindstrom, Jaana, Swift, Amy J., Uusitupa, Matti, Atalay, Mustafa, Lakka, Timo A., Rauramaa, Rainer, Bolton, Jennifer L., Fowkes, Gerry, Fraser, Ross M., Price, Jackie F., Fischer, Krista, KrjutAikov, Kaarel, Metspalu, Andres, Mihailov, Evelin, Langenberg, Claudia, Luan, Jian'an, Ong, Ken K., Chines, Peter S., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Edkins, Sarah, Franks, Paul W., Hallmans, Goran, Shungin, Dmitry, Morris, Andrew David, Palmer, Colin N. A., Erbel, Raimund, Moebus, Susanne, Noethen, Markus M., Pechlivanis, Sonali, Hveem, Kristian, Narisu, Narisu, Hamsten, Anders, Humphries, Steve E., Strawbridge, Rona J., Tremoli, Elena, Grallert, Harald, Thorand, Barbara, Illig, Thomas, Koenig, Wolfgang, Mueller-Nurasyid, Martina, Peters, Annette, Boehm, Bernhard O., Kleber, Marcus E., Maerz, Winfried, Winkelmann, Bernhard R., Kuusisto, Johanna, Laakso, Markku, Arveiler, Dominique, Cesana, Giancarlo, Kuulasmaa, Kari, Virtamo, Jarmo, Yarnell, John W. G., Kuh, Diana, Wong, Andrew, Lind, Lars, de Faire, Ulf, Gigante, Bruna, Magnusson, Patrik K. E., Pedersen, Nancy L., Dedoussis, George, Dimitriou, Maria, Kolovou, Genovefa, Kanoni, Stavroula, Stirrups, Kathleen, Bonnycastle, Lori L., Njolstad, Inger, Wilsgaard, Tom, Ganna, Andrea, Rehnberg, Emil, Hingorani, Aroon, Kivimäki, Mika, Kumari, Meena, Assimes, Themistocles L., Barroso, Ine S., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Frayling, Timothy, Groop, Leif C., Haritunians, Talin, Hunter, David, Ingelsson, Erik, Kaplan, Robert, Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Abecasis, Goncalo R., McCarthy, Mark I., Hirschhorn, Joel N., Qi, Lu, Loos, Ruth J. F., Lindgren, Cecilia M., North, Kari E., Heid, Iris M., Consortium, DIAGRAM, Investigators, MAGIC, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Samuli Olli Ripatti / Principal Investigator, University of Helsinki, Department of Public Health, University of Helsinki, Haartman Institute, University of Helsinki, Clinicum, University of Helsinki, Diabetes and Obesity Research Program, University of Helsinki, Department of Public Health (-2009), Randall, Joshua C., Winkler, Thomas W., Kutalik, Zoltan, Berndt, Sonja I., Jackson, Anne U., Monda, Keri L., Kilpelaeinen, Tuomas O., Esko, Tonu, Maegi, Reedik, Li, Shengxu, Workalemahu, Tsegaselassie, Feitosa, Mary F., Croteau-Chonka, Damien C., Day, Felix R., Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Locke, Adam E., Mathieson, Iain, Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Liang, Liming, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Dermitzakis, Emmanouil T., Dimas, Antigone S., Karpe, Fredrik, Min, Josine L., Nicholson, George, Clegg, Deborah J., Person, Thomas, Krohn, Jon P., Bauer, Sabrina, Buechler, Christa, Eisinger, Kristina, Bonnefond, Amelie, Froguel, Philippe, Hottenga, Jouke-Jan, Prokopenko, Inga, Waite, Lindsay L., Harris, Tamara B., Smith, Albert Vernon, Shuldiner, Alan R., McArdle, Wendy L., Caulfield, Mark J., Munroe, Patricia B., Gronberg, Henrik, Chen, Yii-Der Ida, Li, Guo, Beckmann, Jacques S., Johnson, Toby, Thorsteinsdottir, Unnur, Teder-Laving, Maris, Khaw, Kay-Tee, Wareham, Nicholas J., Zhao, Jing Hua, Amin, Najaf, Oostra, Ben A., Kraja, Aldi T., Province, Michael A., Cupples, L. Adrienne, Heard-Costa, Nancy L., Kaprio, Jaakko, Ripatti, Samuli, Surakka, Ida, Collins, Francis S., Saramies, Jouko, Tuomilehto, Jaakko, Jula, Antti, Salomaa, Veikko, Erdmann, Jeanette, Hengstenberg, Christian, Loley, Christina, Schunkert, Heribert, Lamina, Claudia, Wichmann, H. Erich, Albrecht, Eva, Gieger, Christian, Hicks, Andrew A., Johansson, Asa, Pramstaller, Peter P., Kathiresan, Sekar, Speliotes, Elizabeth K., Penninx, Brenda, Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Gyllensten, Ulf, Boomsma, Dorret I., Campbell, Harry, Wilson, James F., Chanock, Stephen J., Farrall, Martin, Goel, Anuj, Medina-Gomez, Carolina, Rivadeneira, Fernando, Estrada, Karol, Uitterlinden, Andre G., Hofman, Albert, Zillikens, M. Carola, den Heijer, Martin, Kiemeney, Lambertus A., Maschio, Andrea, Hall, Per, Tyrer, Jonathan, Teumer, Alexander, Voelzke, Henry, Kovacs, Peter, Toenjes, Anke, Mangino, Massimo, Spector, Tim D., Hayward, Caroline, Rudan, Igor, Hall, Alistair S., Samani, Nilesh J., Attwood, Antony Paul, Sambrook, Jennifer G., Hung, Joseph, Palmer, Lyle J., Lokki, Marja-Liisa, Sinisalo, Juha-Pekka, Boucher, Gabrielle, Huikuri, Heikki, Lorentzon, Mattias, Ohlsson, Claes, Eklund, Niina, Eriksson, Johan G., Barlassina, Cristina, Rivolta, Carlo, Nolte, Ilja M., Snieder, Harold, Van der Klauw, Melanie M., Van Vliet-Ostaptchouk, Jana V., Gejman, Pablo V., Shi, Jianxin, Jacobs, Kevin B., Wang, Zhaoming, Bakker, Stephan J. L., Leach, Irene Mateo, Navis, Gerjan, van der Harst, Pim, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Yang, Jian, Chasman, Daniel I., Ridker, Paul M., Rose, Lynda M., Lehtimaki, Terho, Raitakari, Olli, Absher, Devin, Iribarren, Carlos, Basart, Hanneke, Hovingh, Kees G., Hyppoenen, Elina, Power, Chris, Anderson, Denise, Beilby, John P., Hui, Jennie, Jolley, Jennifer, Sager, Hendrik, Bornstein, Stefan R., Schwarz, Peter E. H., Kristiansson, Kati, Perola, Markus, Lindstrom, Jaana, Swift, Amy J., Uusitupa, Matti, Atalay, Mustafa, Lakka, Timo A., Rauramaa, Rainer, Bolton, Jennifer L., Fowkes, Gerry, Fraser, Ross M., Price, Jackie F., Fischer, Krista, KrjutAikov, Kaarel, Metspalu, Andres, Mihailov, Evelin, Langenberg, Claudia, Luan, Jian'an, Ong, Ken K., Chines, Peter S., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Edkins, Sarah, Franks, Paul W., Hallmans, Goran, Shungin, Dmitry, Morris, Andrew David, Palmer, Colin N. A., Erbel, Raimund, Moebus, Susanne, Noethen, Markus M., Pechlivanis, Sonali, Hveem, Kristian, Narisu, Narisu, Hamsten, Anders, Humphries, Steve E., Strawbridge, Rona J., Tremoli, Elena, Grallert, Harald, Thorand, Barbara, Illig, Thomas, Koenig, Wolfgang, Mueller-Nurasyid, Martina, Peters, Annette, Boehm, Bernhard O., Kleber, Marcus E., Maerz, Winfried, Winkelmann, Bernhard R., Kuusisto, Johanna, Laakso, Markku, Arveiler, Dominique, Cesana, Giancarlo, Kuulasmaa, Kari, Virtamo, Jarmo, Yarnell, John W. G., Kuh, Diana, Wong, Andrew, Lind, Lars, de Faire, Ulf, Gigante, Bruna, Magnusson, Patrik K. E., Pedersen, Nancy L., Dedoussis, George, Dimitriou, Maria, Kolovou, Genovefa, Kanoni, Stavroula, Stirrups, Kathleen, Bonnycastle, Lori L., Njolstad, Inger, Wilsgaard, Tom, Ganna, Andrea, Rehnberg, Emil, Hingorani, Aroon, Kivimäki, Mika, Kumari, Meena, Assimes, Themistocles L., Barroso, Ine S., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Frayling, Timothy, Groop, Leif C., Haritunians, Talin, Hunter, David, Ingelsson, Erik, Kaplan, Robert, Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Abecasis, Goncalo R., McCarthy, Mark I., Hirschhorn, Joel N., Qi, Lu, Loos, Ruth J. F., Lindgren, Cecilia M., North, Kari E., Heid, Iris M., Consortium, DIAGRAM, and Investigators, MAGIC

Published
2013

2. The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants.

Author

Lawlor, Debbie A., Harbord, Roger M., Timpson, Nic J., Lowe, Gordon D. O., Rumley, Ann, Gaunt, Tom R., Baker, Ian, Yarnell, John W. G., Mika Kivimäki, Kumari, Meena, Norman, Paul E., Jamrozik, Konrad, Hankey, Graeme J., Almeida, Osvaldo P., Flicker, Leon, Warrington, Nicole, Marmot, Michael G., Ben-Shlomo, Yoav, Palmer, Lyle J., and Day, Ian N. M.

Subjects
CORONARY heart disease complications, GEOMETRIC analysis, C-reactive protein, GENOTYPE-environment interaction, ESTIMATION theory, HUMAN genetic variation, GENETIC regulation, GENETIC research
Abstract

Background: It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C.T (rs1130864) and CHD risk in the largest study to date of this association. Methods and Results: We estimated the association of CRP genetic variant +1444C.T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N= 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95%CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I2 = 0%, p.0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I2,7.5%, p.0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80). Conclusions: We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out. [ABSTRACT FROM AUTHOR]

Published
2008
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3. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Author

Randall, Joshua C., Winkler, Thomas W., Kutalik, Zoltán, Berndt, Sonja I., Jackson, Anne U., Monda, Keri L., Kilpeläinen, Tuomas O., Esko, Tõnu, Mägi, Reedik, Li, Shengxu, Workalemahu, Tsegaselassie, Feitosa, Mary F., Croteau-Chonka, Damien C., Day, Felix R., Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Locke, Adam E., Mathieson, Iain, Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Liang, Liming, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Dermitzakis, Emmanouil T., Dimas, Antigone S., Karpe, Fredrik, Min, Josine L., Nicholson, George, Clegg, Deborah J., Person, Thomas, Krohn, Jon P., Bauer, Sabrina, Buechler, Christa, Eisinger, Kristina, Bonnefond, Amélie, Froguel, Philippe, Hottenga, Jouke-Jan, Prokopenko, Inga, Waite, Lindsay L., Harris, Tamara B., Smith, Albert Vernon, Shuldiner, Alan R., McArdle, Wendy L., Caulfield, Mark J., Munroe, Patricia B., Grönberg, Henrik, Chen, Yii-Der Ida, Li, Guo, Beckmann, Jacques S., Johnson, Toby, Thorsteinsdottir, Unnur, Teder-Laving, Maris, Khaw, Kay-Tee, Wareham, Nicholas J., Zhao, Jing Hua, Amin, Najaf, Oostra, Ben A., Kraja, Aldi T., Province, Michael A., Cupples, L. Adrienne, Heard-Costa, Nancy L., Kaprio, Jaakko, Ripatti, Samuli, Surakka, Ida, Collins, Francis S., Saramies, Jouko, Tuomilehto, Jaakko, Jula, Antti, Salomaa, Veikko, Erdmann, Jeanette, Hengstenberg, Christian, Loley, Christina, Schunkert, Heribert, Lamina, Claudia, Wichmann, H. Erich, Albrecht, Eva, Gieger, Christian, Hicks, Andrew A., Johansson, Åsa, Pramstaller, Peter P., Kathiresan, Sekar, Speliotes, Elizabeth K., Penninx, Brenda, Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Gyllensten, Ulf, Boomsma, Dorret I., Campbell, Harry, Wilson, James F., Chanock, Stephen J., Farrall, Martin, Goel, Anuj, Medina-Gomez, Carolina, Rivadeneira, Fernando, Estrada, Karol, Uitterlinden, André G., Hofman, Albert, Zillikens, M. Carola, den Heijer, Martin, Kiemeney, Lambertus A., Maschio, Andrea, Hall, Per, Tyrer, Jonathan, Teumer, Alexander, Völzke, Henry, Kovacs, Peter, Tönjes, Anke, Mangino, Massimo, Spector, Tim D., Hayward, Caroline, Rudan, Igor, Hall, Alistair S., Samani, Nilesh J., Attwood, Antony Paul, Sambrook, Jennifer G., Hung, Joseph, Palmer, Lyle J., Lokki, Marja-Liisa, Sinisalo, Juha, Boucher, Gabrielle, Huikuri, Heikki, Lorentzon, Mattias, Ohlsson, Claes, Eklund, Niina, Eriksson, Johan G., Barlassina, Cristina, Rivolta, Carlo, Nolte, Ilja M., Snieder, Harold, Van der Klauw, Melanie M., Van Vliet-Ostaptchouk, Jana V., Gejman, Pablo V., Shi, Jianxin, Jacobs, Kevin B., Wang, Zhaoming, Bakker, Stephan J. L., Mateo Leach, Irene, Navis, Gerjan, van der Harst, Pim, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Yang, Jian, Chasman, Daniel I., Ridker, Paul M., Rose, Lynda M., Lehtimäki, Terho, Raitakari, Olli, Absher, Devin, Iribarren, Carlos, Basart, Hanneke, Hovingh, Kees G., Hyppönen, Elina, Power, Chris, Anderson, Denise, Beilby, John P., Hui, Jennie, Jolley, Jennifer, Sager, Hendrik, Bornstein, Stefan R., Schwarz, Peter E. H., Kristiansson, Kati, Perola, Markus, Lindström, Jaana, Swift, Amy J., Uusitupa, Matti, Atalay, Mustafa, Lakka, Timo A., Rauramaa, Rainer, Bolton, Jennifer L., Fowkes, Gerry, Fraser, Ross M., Price, Jackie F., Fischer, Krista, KrjutÅ¡kov, Kaarel, Metspalu, Andres, Mihailov, Evelin, Langenberg, Claudia, Luan, Jian'an, Ong, Ken K., Chines, Peter S., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Edkins, Sarah, Franks, Paul W., Hallmans, Göran, Shungin, Dmitry, Morris, Andrew David, Palmer, Colin N. A., Erbel, Raimund, Moebus, Susanne, Nöthen, Markus M., Pechlivanis, Sonali, Hveem, Kristian, Narisu, Narisu, Hamsten, Anders, Humphries, Steve E., Strawbridge, Rona J., Tremoli, Elena, Grallert, Harald, Thorand, Barbara, Illig, Thomas, Koenig, Wolfgang, Müller-Nurasyid, Martina, Peters, Annette, Boehm, Bernhard O., Kleber, Marcus E., März, Winfried, Winkelmann, Bernhard R., Kuusisto, Johanna, Laakso, Markku, Arveiler, Dominique, Cesana, Giancarlo, Kuulasmaa, Kari, Virtamo, Jarmo, Yarnell, John W. G., Kuh, Diana, Wong, Andrew, Lind, Lars, de Faire, Ulf, Gigante, Bruna, Magnusson, Patrik K. E., Pedersen, Nancy L., Dedoussis, George, Dimitriou, Maria, Kolovou, Genovefa, Kanoni, Stavroula, Stirrups, Kathleen, Bonnycastle, Lori L., Njølstad, Inger, Wilsgaard, Tom, Ganna, Andrea, Rehnberg, Emil, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Assimes, Themistocles L., Barroso, Inês, Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Frayling, Timothy, Groop, Leif C., Haritunians, Talin, Hunter, David, Ingelsson, Erik, Kaplan, Robert, Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Abecasis, Gonçalo R., McCarthy, Mark I., Hirschhorn, Joel N., Qi, Lu, Loos, Ruth J. F., Lindgren, Cecilia M., North, Kari E., and Heid, Iris M.

Subjects
Medicine, Epidemiology, Genetic Epidemiology
Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Published
2013
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4. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits

Author

Randall, Joshua C., Winkler, Thomas W., Kutalik, Zoltán, Berndt, Sonja I., Jackson, Anne U., Monda, Keri L., Kilpeläinen, Tuomas O., Esko, Tõnu, Mägi, Reedik, Li, Shengxu, Workalemahu, Tsegaselassie, Feitosa, Mary F., Croteau-Chonka, Damien C., Day, Felix R., Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Locke, Adam E., Mathieson, Iain, Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Liang, Liming, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Dermitzakis, Emmanouil T., Dimas, Antigone S., Karpe, Fredrik, Min, Josine L., Nicholson, George, Clegg, Deborah J., Person, Thomas, Krohn, Jon P., Bauer, Sabrina, Buechler, Christa, Eisinger, Kristina, Diagram Consortium, Bonnefond, Amélie, Froguel, Philippe, Magic Investigators, Hottenga, Jouke-Jan, Prokopenko, Inga, Waite, Lindsay L., Harris, Tamara B., Smith, Albert Vernon, Shuldiner, Alan R., McArdle, Wendy L., Caulfield, Mark J., Munroe, Patricia B., Grönberg, Henrik, Chen, Yii-Der Ida, Li, Guo, Beckmann, Jacques S., Johnson, Toby, Thorsteinsdottir, Unnur, Teder-Laving, Maris, Khaw, Kay-Tee, Wareham, Nicholas J., Zhao, Jing Hua, Amin, Najaf, Oostra, Ben A., Kraja, Aldi T., Province, Michael A., Cupples, L. Adrienne, Heard-Costa, Nancy L., Kaprio, Jaakko, Ripatti, Samuli, Surakka, Ida, Collins, Francis S., Saramies, Jouko, Tuomilehto, Jaakko, Jula, Antti, Salomaa, Veikko, Erdmann, Jeanette, Hengstenberg, Christian, Loley, Christina, Schunkert, Heribert, Lamina, Claudia, Wichmann, H. Erich, Albrecht, Eva, Gieger, Christian, Hicks, Andrew A., Johansson, Asa, Pramstaller, Peter P., Kathiresan, Sekar, Speliotes, Elizabeth K., Penninx, Brenda, Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Gyllensten, Ulf, Boomsma, Dorret I., Campbell, Harry, Wilson, James F., Chanock, Stephen J., Farrall, Martin, Goel, Anuj, Medina-Gomez, Carolina, Rivadeneira, Fernando, Estrada, Karol, Uitterlinden, André G., Hofman, Albert, Zillikens, M. Carola, den Heijer, Martin, Kiemeney, Lambertus A., Maschio, Andrea, Hall, Per, Tyrer, Jonathan, Teumer, Alexander, Völzke, Henry, Kovacs, Peter, Tönjes, Anke, Mangino, Massimo, Spector, Tim D., Hayward, Caroline, Rudan, Igor, Hall, Alistair S., Samani, Nilesh J., Attwood, Antony Paul, Sambrook, Jennifer G., Hung, Joseph, Palmer, Lyle J., Lokki, Marja-Liisa, Sinisalo, Juha, Boucher, Gabrielle, Huikuri, Heikki, Lorentzon, Mattias, Ohlsson, Claes, Eklund, Niina, Eriksson, Johan G., Barlassina, Cristina, Rivolta, Carlo, Nolte, Ilja M., Snieder, Harold, Van der Klauw, Melanie M., Van Vliet-Ostaptchouk, Jana V., Gejman, Pablo V., Shi, Jianxin, Jacobs, Kevin B., Wang, Zhaoming, Bakker, Stephan J. L., Mateo Leach, Irene, Navis, Gerjan, van der Harst, Pim, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Yang, Jian, Chasman, Daniel I., Ridker, Paul M., Rose, Lynda M., Lehtimäki, Terho, Raitakari, Olli, Absher, Devin, Iribarren, Carlos, Basart, Hanneke, Hovingh, Kees G., Hyppönen, Elina, Power, Chris, Anderson, Denise, Beilby, John P., Hui, Jennie, Jolley, Jennifer, Sager, Hendrik, Bornstein, Stefan R., Schwarz, Peter E. H., Kristiansson, Kati, Perola, Markus, Lindström, Jaana, Swift, Amy J., Uusitupa, Matti, Atalay, Mustafa, Lakka, Timo A., Rauramaa, Rainer, Bolton, Jennifer L., Fowkes, Gerry, Fraser, Ross M., Price, Jackie F., Fischer, Krista, Krjutå Kov, Kaarel, Metspalu, Andres, Mihailov, Evelin, Langenberg, Claudia, Luan, Jian'an, Ong, Ken K., Chines, Peter S., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Edkins, Sarah, Franks, Paul W., Hallmans, Göran, Shungin, Dmitry, Morris, Andrew David, Palmer, Colin N. A., Erbel, Raimund, Moebus, Susanne, Nöthen, Markus M., Pechlivanis, Sonali, Hveem, Kristian, Narisu, Narisu, Hamsten, Anders, Humphries, Steve E., Strawbridge, Rona J., Tremoli, Elena, Grallert, Harald, Thorand, Barbara, Illig, Thomas, Koenig, Wolfgang, Müller-Nurasyid, Martina, Peters, Annette, Boehm, Bernhard O., Kleber, Marcus E., März, Winfried, Winkelmann, Bernhard R., Kuusisto, Johanna, Laakso, Markku, Arveiler, Dominique, Cesana, Giancarlo, Kuulasmaa, Kari, Virtamo, Jarmo, Yarnell, John W. G., Kuh, Diana, Wong, Andrew, Lind, Lars, de Faire, Ulf, Gigante, Bruna, Magnusson, Patrik K. E., Pedersen, Nancy L., Dedoussis, George, Dimitriou, Maria, Kolovou, Genovefa, Kanoni, Stavroula, Stirrups, Kathleen, Bonnycastle, Lori L., Njølstad, Inger, Wilsgaard, Tom, Ganna, Andrea, Rehnberg, Emil, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Assimes, Themistocles L., Barroso, Inês, Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Frayling, Timothy, Groop, Leif C., Haritunians, Talin, Hunter, David, Ingelsson, Erik, Kaplan, Robert, Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Abecasis, Gonçalo R., McCarthy, Mark I., Hirschhorn, Joel N., Qi, Lu, Loos, Ruth J. F., Lindgren, Cecilia M., North, Kari E., and Heid, Iris M.

Subjects
2. Zero hunger

5. A genome-wide association search for type 2 diabetes genes in African Americans.

Author

Palmer ND, McDonough CW, Hicks PJ, Roh BH, Wing MR, An SS, Hester JM, Cooke JN, Bostrom MA, Rudock ME, Talbert ME, Lewis JP, Ferrara A, Lu L, Ziegler JT, Sale MM, Divers J, Shriner D, Adeyemo A, Rotimi CN, Ng MC, Langefeld CD, Freedman BI, Bowden DW, Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI, Soranzo N, Wheeler E, Glazer NL, Bouatia-Naji N, Mägi R, Randall J, Johnson T, Elliott P, Rybin D, Henneman P, Dehghan A, Hottenga JJ, Song K, Goel A, Egan JM, Lajunen T, Doney A, Kanoni S, Cavalcanti-Proença C, Kumari M, Timpson NJ, Zabena C, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Roccasecca RM, Pattou F, Sethupathy P, Ariyurek Y, Barter P, Beilby JP, Ben-Shlomo Y, Bergmann S, Bochud M, Bonnefond A, Borch-Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Crisponi L, Day IN, de Geus EJ, Delplanque J, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Grundy S, Gwilliam R, Hallmans G, Hammond N, Han X, Hartikainen AL, Hayward C, Heath SC, Hercberg S, Hicks AA, Hillman DR, Hingorani AD, Hui J, Hung J, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Mahley R, Mangino M, Manning AK, Martínez-Larrad MT, McAteer JB, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Mukherjee S, Naitza S, Neville MJ, Oostra BA, Orrù M, Pakyz R, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Seedorf U, Sharp SJ, Shields B, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Tönjes A, Uitterlinden AG, van Dijk KW, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Ward KL, Watkins H, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Ríos M, Lind L, Palmer LJ, Franks PW, Ebrahim S, Marmot M, Kao WH, Pramstaller PP, Wright AF, Stumvoll M, Hamsten A, Buchanan TA, Valle TT, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Ferrucci L, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, and Sladek R

Subjects
Adult, Aged, Case-Control Studies, Cohort Studies, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Validation Studies as Topic, Black or African American genetics, Diabetes Mellitus, Type 2 ethnology, Diabetes Mellitus, Type 2 genetics, Genome-Wide Association Study
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Published
2012
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6. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

Dastani Z, Hivert MF, Timpson N, Perry JR, Yuan X, Scott RA, Henneman P, Heid IM, Kizer JR, Lyytikäinen LP, Fuchsberger C, Tanaka T, Morris AP, Small K, Isaacs A, Beekman M, Coassin S, Lohman K, Qi L, Kanoni S, Pankow JS, Uh HW, Wu Y, Bidulescu A, Rasmussen-Torvik LJ, Greenwood CM, Ladouceur M, Grimsby J, Manning AK, Liu CT, Kooner J, Mooser VE, Vollenweider P, Kapur KA, Chambers J, Wareham NJ, Langenberg C, Frants R, Willems-Vandijk K, Oostra BA, Willems SM, Lamina C, Winkler TW, Psaty BM, Tracy RP, Brody J, Chen I, Viikari J, Kähönen M, Pramstaller PP, Evans DM, St Pourcain B, Sattar N, Wood AR, Bandinelli S, Carlson OD, Egan JM, Böhringer S, van Heemst D, Kedenko L, Kristiansson K, Nuotio ML, Loo BM, Harris T, Garcia M, Kanaya A, Haun M, Klopp N, Wichmann HE, Deloukas P, Katsareli E, Couper DJ, Duncan BB, Kloppenburg M, Adair LS, Borja JB, Wilson JG, Musani S, Guo X, Johnson T, Semple R, Teslovich TM, Allison MA, Redline S, Buxbaum SG, Mohlke KL, Meulenbelt I, Ballantyne CM, Dedoussis GV, Hu FB, Liu Y, Paulweber B, Spector TD, Slagboom PE, Ferrucci L, Jula A, Perola M, Raitakari O, Florez JC, Salomaa V, Eriksson JG, Frayling TM, Hicks AA, Lehtimäki T, Smith GD, Siscovick DS, Kronenberg F, van Duijn C, Loos RJ, Waterworth DM, Meigs JB, Dupuis J, Richards JB, Voight BF, Scott LJ, Steinthorsdottir V, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Hofmann OM, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Morris AD, Palmer CN, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Pedersen O, Barroso I, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI, Soranzo N, Wheeler E, Glazer NL, Bouatia-Naji N, Mägi R, Randall J, Elliott P, Rybin D, Dehghan A, Hottenga JJ, Song K, Goel A, Lajunen T, Doney A, Cavalcanti-Proença C, Kumari M, Timpson NJ, Zabena C, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Roccasecca RM, Pattou F, Sethupathy P, Ariyurek Y, Barter P, Beilby JP, Ben-Shlomo Y, Bergmann S, Bochud M, Bonnefond A, Borch-Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Crisponi L, Day IN, de Geus EJ, Delplanque J, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Grundy S, Gwilliam R, Hallmans G, Hammond N, Han X, Hartikainen AL, Hayward C, Heath SC, Hercberg S, Hillman DR, Hingorani AD, Hui J, Hung J, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Mahley R, Mangino M, Martínez-Larrad MT, McAteer JB, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Mukherjee S, Naitza S, Neville MJ, Orrù M, Pakyz R, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Seedorf U, Sharp SJ, Shields B, Sigurðsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tönjes A, Uitterlinden AG, van Dijk KW, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Ward KL, Watkins H, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Meneton P, Magnusson PK, Nathan DM, Williams GH, Silander K, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Serrano-Ríos M, Lind L, Palmer LJ, Hu FB 1st, Franks PW, Ebrahim S, Marmot M, Kao WH, Pramstaller PP, Wright AF, Stumvoll M, Hamsten A, Buchanan TA, Valle TT, Rotter JI, Penninx BW, Boomsma DI, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Peltonen L, Mooser V, Sladek R, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Chasman DI, Johansen CT, Fouchier SW, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Feitosa MF, Orho-Melander M, Melander O, Li X, Li M, Cho YS, Go MJ, Kim YJ, Lee JY, Park T, Kim K, Sim X, Ong RT, Croteau-Chonka DC, Lange LA, Smith JD, Ziegler A, Zhang W, Zee RY, Whitfield JB, Thompson JR, Surakka I, Spector TD, Smit JH, Sinisalo J, Scott J, Saharinen J, Sabatti C, Rose LM, Roberts R, Rieder M, Parker AN, Pare G, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, McArdle W, Masson D, Martin NG, Marroni F, Lucas G, Luben R, Lokki ML, Lettre G, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, König IR, Khaw KT, Kaplan LM, Johansson Å, Janssens AC, Igl W, Hovingh GK, Hengstenberg C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Groop LC, Gonzalez E, Freimer NB, Erdmann J, Ejebe KG, Döring A, Dominiczak AF, Demissie S, Deloukas P, de Faire U, Crawford G, Chen YD, Caulfield MJ, Boekholdt SM, Assimes TL, Quertermous T, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Taylor HA Jr, Gabriel SB, Holm H, Gudnason V, Krauss RM, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Strachan DP, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, and Kathiresan S

Subjects
Adiponectin genetics, Black or African American, Asian People, Cholesterol, HDL genetics, Female, Gene Expression, Genetic Predisposition to Disease, Glucose Tolerance Test, Humans, Insulin Resistance genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, White People, Adiponectin blood, Diabetes Mellitus, Type 2 genetics, Genome-Wide Association Study
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance., Competing Interests: DM Waterworth, X Yuan, and VE Mooser are full-time employees of GlaxoSmithKline. P Vollenweider received grant money from GlaxoSmithKline to fund the CoLaus study. The other authors declare no competing financial interests.

Published
2012
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