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3. Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease

Author

Wakeling, Matthew Neil, Laver, Thomas William, Wright, Caroline Fiona, De Franco, Elisa, Stals, Karen Lucy, Patch, Ann-Marie, Hattersley, Andrew Tym, Flanagan, Sarah Elizabeth, and Ellard, Sian

Subjects
Article
Abstract

PURPOSE: One of the greatest challenges currently facing those studying Mendelian disease is identifying the pathogenic variant from the long list produced by a next generation sequencing test. We investigate the predictive ability of homozygosity mapping for identifying the regions likely to contain the causative variant. METHODS: We use 179 homozygous pathogenic variants from three independent cohorts to investigate the predictive power of homozygosity mapping. RESULTS: We demonstrate that homozygous pathogenic variants in our cohorts are disproportionately likely to be found within one of the largest regions of homozygosity: 80% of pathogenic variants are found in a homozygous region that is in the 10 largest regions in a sample. The maximal predictive power is achieved in patients with 3Mb from a telomere, this gives an AUC of 0.735 and results in 92% of the causative variants being in one of the 10 largest homozygous regions. CONCLUSION: This predictive power can be used to prioritize the list of candidate variants in gene discovery studies. When classifying a homozygous variant the size and rank of the region of homozygosity in which the candidate variant is located can also be considered as supporting evidence for pathogenicity.

Published
2018

4. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Clinicum, University of Helsinki, Hjelt Institute, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg-Gresham, Jennifer L., van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tonu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltan, Lahti, Jari, Luan, Jian'an, Maegi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Perusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Stancakova, Alena, Sung, Yun Ju, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, van der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Alves, Alexessander Couto, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blueher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S., Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, de Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Doering, Angela, Eriksson, Johan G., Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Graessler, Juergen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S., Heliovaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jorgensen, Torben, Jousilahti, Pekka, Jula, Antti, Justesen, Johanne Marie, Justice, Anne E., Kahonen, Mika, Karaleftheri, Maria, Khaw, Kay Tee, Keinanen-Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindstrom, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Mannisto, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Mueller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polasek, Ozren, Pramstaller, Peter P., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel-Madsen, Rasmus, Rice, Treva K., Richards, Marcus, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparso, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Toenjes, Anke, Tsafantakis, Emmanouil, van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M., Waeber, Gerard, Widen, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges-Armstrong, Laura M., Zhao, Jing Hua, Zillikens, M. Carola, Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimaeki, Terho, Metspalu, Andres, Njolstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sorensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Matti, Voelker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., McCarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Mueller-Nurasyid, Martina, Loos, Ruth J. F., University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Clinicum, University of Helsinki, Hjelt Institute, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg-Gresham, Jennifer L., van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tonu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltan, Lahti, Jari, Luan, Jian'an, Maegi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Perusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Stancakova, Alena, Sung, Yun Ju, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, van der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Alves, Alexessander Couto, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blueher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S., Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, de Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Doering, Angela, Eriksson, Johan G., Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Graessler, Juergen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S., Heliovaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jorgensen, Torben, Jousilahti, Pekka, Jula, Antti, Justesen, Johanne Marie, Justice, Anne E., Kahonen, Mika, Karaleftheri, Maria, Khaw, Kay Tee, Keinanen-Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindstrom, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Mannisto, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Mueller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polasek, Ozren, Pramstaller, Peter P., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel-Madsen, Rasmus, Rice, Treva K., Richards, Marcus, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparso, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Toenjes, Anke, Tsafantakis, Emmanouil, van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M., Waeber, Gerard, Widen, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges-Armstrong, Laura M., Zhao, Jing Hua, Zillikens, M. Carola, Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimaeki, Terho, Metspalu, Andres, Njolstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sorensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Matti, Voelker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., McCarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Mueller-Nurasyid, Martina, and Loos, Ruth J. F.

Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Published
2016

5. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Ried, Janina S, Jeff M, Janina, Chu, Audrey Y, Bragg-Gresham, Jennifer L, van Dongen, Jenny, Huffman, Jennifer E, Ahluwalia, Tarun Veer Singh, Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tõnu, Feitosa, Mary F, Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L, Jackson, Anne U, Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'an, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L, Nolte, Ilja M, Pérusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M, Salvi, Erika, Smith, Megan T, Snieder, Harold, Stančáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, van der Harst, Pim, Walker, Ryan W, Wang, Sophie R, Wild, Sarah H, Willems, Sara M, Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J L, Barlassina, Cristina, Bartz, Traci M, Beilby, John, Bellis, Claire, Bergman, Richard N, Bergmann, Sven, Blangero, John, Blüher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L, Bornstein, Stefan R, Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston W K, Chines, Peter S, Collins, Francis S, Cucca, Fracensco, Cupples, L Adrienne, D'Avila, Francesca, de Geus, Eco J C, Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G, Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G, Friedrich, Nele, Gjesing, Anette Marianne Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S, Heliövaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G, Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L, Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E, Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen-Kiukaanniemi, Sirkka M, Kinnunen, Leena, Knekt, Paul B, Koistinen, Heikki A, Kolcic, Ivana, Kooner, Ishminder K, Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M, Lichtner, Peter, Lindgren, Cecilia M, Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L, Mcknight, Barbara, Mohlke, Karen L, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E, Morris, Andrew P, Müller, Gabriele, Musk, Arthur W, Narisu, Narisu, Ong, Ken K, Oostra, Ben A, Osmond, Clive, Palotie, Aarno, Pankow, James S, Paternoster, Lavinia, Penninx, Brenda W, Pichler, Irene, Pilia, Maria G, Polašek, Ozren, Pramstaller, Peter P, Raitakari, Olli T, Rankinen, Tuomo, Rao, D C, Rayner, Nigel W, Ribel-Madsen, Rasmus, Rice, Treva K, Richards, Marcus, Ridker, Paul M, Rivadeneira, Fernando, Ryan, Kathy A, Sanna, Serena, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P, Strauch, Konstantin, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Tönjes, Anke, Tsafantakis, Emmanouil, van der Most, Peter J, Van Vliet-Ostaptchouk, Jana V, Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S, Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M, Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W, Wright, Alan F, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Carola Zillikens, M, Boomsma, Dorret I, Bouchard, Claude, Chambers, John C, Chasman, Daniel I, Cusi, Daniele, Gansevoort, Ron T, Gieger, Christian, Hansen, Torben, Hicks, Andrew A, Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S, Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Metspalu, Andres, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Palmer, Lyle J, Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M, Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E H, Shudiner, Alan R, Smit, Jan H, Sørensen, Thorkild I A, Spector, Timothy D, Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J, Watkins, Hugh, Wilson, James F, Zeggini, Eleftheria, Abecasis, Goncalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, van Duijn, Cornelia M, Fox, Caroline, Groop, Leif C, Heid, Iris M, Hunter, David J, Kaplan, Robert C, McCarthy, Mark I, North, Kari E, O'Connell, Jeffrey R, Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P, Frayling, Timothy, Hirschhorn, Joel N, Müller-Nurasyid, Martina, Loos, Ruth J F, Ried, Janina S, Jeff M, Janina, Chu, Audrey Y, Bragg-Gresham, Jennifer L, van Dongen, Jenny, Huffman, Jennifer E, Ahluwalia, Tarun Veer Singh, Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tõnu, Feitosa, Mary F, Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L, Jackson, Anne U, Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'an, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L, Nolte, Ilja M, Pérusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M, Salvi, Erika, Smith, Megan T, Snieder, Harold, Stančáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, van der Harst, Pim, Walker, Ryan W, Wang, Sophie R, Wild, Sarah H, Willems, Sara M, Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J L, Barlassina, Cristina, Bartz, Traci M, Beilby, John, Bellis, Claire, Bergman, Richard N, Bergmann, Sven, Blangero, John, Blüher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L, Bornstein, Stefan R, Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston W K, Chines, Peter S, Collins, Francis S, Cucca, Fracensco, Cupples, L Adrienne, D'Avila, Francesca, de Geus, Eco J C, Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G, Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G, Friedrich, Nele, Gjesing, Anette Marianne Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S, Heliövaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G, Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L, Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E, Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen-Kiukaanniemi, Sirkka M, Kinnunen, Leena, Knekt, Paul B, Koistinen, Heikki A, Kolcic, Ivana, Kooner, Ishminder K, Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M, Lichtner, Peter, Lindgren, Cecilia M, Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L, Mcknight, Barbara, Mohlke, Karen L, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E, Morris, Andrew P, Müller, Gabriele, Musk, Arthur W, Narisu, Narisu, Ong, Ken K, Oostra, Ben A, Osmond, Clive, Palotie, Aarno, Pankow, James S, Paternoster, Lavinia, Penninx, Brenda W, Pichler, Irene, Pilia, Maria G, Polašek, Ozren, Pramstaller, Peter P, Raitakari, Olli T, Rankinen, Tuomo, Rao, D C, Rayner, Nigel W, Ribel-Madsen, Rasmus, Rice, Treva K, Richards, Marcus, Ridker, Paul M, Rivadeneira, Fernando, Ryan, Kathy A, Sanna, Serena, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P, Strauch, Konstantin, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Tönjes, Anke, Tsafantakis, Emmanouil, van der Most, Peter J, Van Vliet-Ostaptchouk, Jana V, Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S, Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M, Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W, Wright, Alan F, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Carola Zillikens, M, Boomsma, Dorret I, Bouchard, Claude, Chambers, John C, Chasman, Daniel I, Cusi, Daniele, Gansevoort, Ron T, Gieger, Christian, Hansen, Torben, Hicks, Andrew A, Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S, Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Metspalu, Andres, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Palmer, Lyle J, Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M, Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E H, Shudiner, Alan R, Smit, Jan H, Sørensen, Thorkild I A, Spector, Timothy D, Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J, Watkins, Hugh, Wilson, James F, Zeggini, Eleftheria, Abecasis, Goncalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, van Duijn, Cornelia M, Fox, Caroline, Groop, Leif C, Heid, Iris M, Hunter, David J, Kaplan, Robert C, McCarthy, Mark I, North, Kari E, O'Connell, Jeffrey R, Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P, Frayling, Timothy, Hirschhorn, Joel N, Müller-Nurasyid, Martina, and Loos, Ruth J F

Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Published
2016

6. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Ried, Janina S., primary, Jeff M., Janina, additional, Chu, Audrey Y., additional, Bragg-Gresham, Jennifer L., additional, van Dongen, Jenny, additional, Huffman, Jennifer E., additional, Ahluwalia, Tarunveer S., additional, Cadby, Gemma, additional, Eklund, Niina, additional, Eriksson, Joel, additional, Esko, Tõnu, additional, Feitosa, Mary F., additional, Goel, Anuj, additional, Gorski, Mathias, additional, Hayward, Caroline, additional, Heard-Costa, Nancy L., additional, Jackson, Anne U., additional, Jokinen, Eero, additional, Kanoni, Stavroula, additional, Kristiansson, Kati, additional, Kutalik, Zoltán, additional, Lahti, Jari, additional, Luan, Jian'an, additional, Mägi, Reedik, additional, Mahajan, Anubha, additional, Mangino, Massimo, additional, Medina-Gomez, Carolina, additional, Monda, Keri L., additional, Nolte, Ilja M., additional, Pérusse, Louis, additional, Prokopenko, Inga, additional, Qi, Lu, additional, Rose, Lynda M., additional, Salvi, Erika, additional, Smith, Megan T., additional, Snieder, Harold, additional, Stančáková, Alena, additional, Ju Sung, Yun, additional, Tachmazidou, Ioanna, additional, Teumer, Alexander, additional, Thorleifsson, Gudmar, additional, van der Harst, Pim, additional, Walker, Ryan W., additional, Wang, Sophie R., additional, Wild, Sarah H., additional, Willems, Sara M., additional, Wong, Andrew, additional, Zhang, Weihua, additional, Albrecht, Eva, additional, Couto Alves, Alexessander, additional, Bakker, Stephan J. L., additional, Barlassina, Cristina, additional, Bartz, Traci M., additional, Beilby, John, additional, Bellis, Claire, additional, Bergman, Richard N., additional, Bergmann, Sven, additional, Blangero, John, additional, Blüher, Matthias, additional, Boerwinkle, Eric, additional, Bonnycastle, Lori L., additional, Bornstein, Stefan R., additional, Bruinenberg, Marcel, additional, Campbell, Harry, additional, Chen, Yii-Der Ida, additional, Chiang, Charleston W. K., additional, Chines, Peter S., additional, Collins, Francis S, additional, Cucca, Fracensco, additional, Cupples, L Adrienne, additional, D’Avila, Francesca, additional, de Geus, Eco J .C., additional, Dedoussis, George, additional, Dimitriou, Maria, additional, Döring, Angela, additional, Eriksson, Johan G., additional, Farmaki, Aliki-Eleni, additional, Farrall, Martin, additional, Ferreira, Teresa, additional, Fischer, Krista, additional, Forouhi, Nita G., additional, Friedrich, Nele, additional, Gjesing, Anette Prior, additional, Glorioso, Nicola, additional, Graff, Mariaelisa, additional, Grallert, Harald, additional, Grarup, Niels, additional, Gräßler, Jürgen, additional, Grewal, Jagvir, additional, Hamsten, Anders, additional, Harder, Marie Neergaard, additional, Hartman, Catharina A., additional, Hassinen, Maija, additional, Hastie, Nicholas, additional, Hattersley, Andrew Tym, additional, Havulinna, Aki S., additional, Heliövaara, Markku, additional, Hillege, Hans, additional, Hofman, Albert, additional, Holmen, Oddgeir, additional, Homuth, Georg, additional, Hottenga, Jouke-Jan, additional, Hui, Jennie, additional, Husemoen, Lise Lotte, additional, Hysi, Pirro G., additional, Isaacs, Aaron, additional, Ittermann, Till, additional, Jalilzadeh, Shapour, additional, James, Alan L., additional, Jørgensen, Torben, additional, Jousilahti, Pekka, additional, Jula, Antti, additional, Marie Justesen, Johanne, additional, Justice, Anne E., additional, Kähönen, Mika, additional, Karaleftheri, Maria, additional, Tee Khaw, Kay, additional, Keinanen-Kiukaanniemi, Sirkka M., additional, Kinnunen, Leena, additional, Knekt, Paul B., additional, Koistinen, Heikki A., additional, Kolcic, Ivana, additional, Kooner, Ishminder K., additional, Koskinen, Seppo, additional, Kovacs, Peter, additional, Kyriakou, Theodosios, additional, Laitinen, Tomi, additional, Langenberg, Claudia, additional, Lewin, Alexandra M., additional, Lichtner, Peter, additional, Lindgren, Cecilia M., additional, Lindström, Jaana, additional, Linneberg, Allan, additional, Lorbeer, Roberto, additional, Lorentzon, Mattias, additional, Luben, Robert, additional, Lyssenko, Valeriya, additional, Männistö, Satu, additional, Manunta, Paolo, additional, Leach, Irene Mateo, additional, McArdle, Wendy L., additional, Mcknight, Barbara, additional, Mohlke, Karen L., additional, Mihailov, Evelin, additional, Milani, Lili, additional, Mills, Rebecca, additional, Montasser, May E., additional, Morris, Andrew P., additional, Müller, Gabriele, additional, Musk, Arthur W., additional, Narisu, Narisu, additional, Ong, Ken K., additional, Oostra, Ben A., additional, Osmond, Clive, additional, Palotie, Aarno, additional, Pankow, James S., additional, Paternoster, Lavinia, additional, Penninx, Brenda W., additional, Pichler, Irene, additional, Pilia, Maria G., additional, Polašek, Ozren, additional, Pramstaller, Peter P., additional, Raitakari, Olli T, additional, Rankinen, Tuomo, additional, Rao, D. C., additional, Rayner, Nigel W., additional, Ribel-Madsen, Rasmus, additional, Rice, Treva K., additional, Richards, Marcus, additional, Ridker, Paul M., additional, Rivadeneira, Fernando, additional, Ryan, Kathy A., additional, Sanna, Serena, additional, Sarzynski, Mark A., additional, Scholtens, Salome, additional, Scott, Robert A., additional, Sebert, Sylvain, additional, Southam, Lorraine, additional, Sparsø, Thomas Hempel, additional, Steinthorsdottir, Valgerdur, additional, Stirrups, Kathleen, additional, Stolk, Ronald P., additional, Strauch, Konstantin, additional, Stringham, Heather M., additional, Swertz, Morris A., additional, Swift, Amy J., additional, Tönjes, Anke, additional, Tsafantakis, Emmanouil, additional, van der Most, Peter J., additional, Van Vliet-Ostaptchouk, Jana V., additional, Vandenput, Liesbeth, additional, Vartiainen, Erkki, additional, Venturini, Cristina, additional, Verweij, Niek, additional, Viikari, Jorma S., additional, Vitart, Veronique, additional, Vohl, Marie-Claude, additional, Vonk, Judith M., additional, Waeber, Gérard, additional, Widén, Elisabeth, additional, Willemsen, Gonneke, additional, Wilsgaard, Tom, additional, Winkler, Thomas W., additional, Wright, Alan F., additional, Yerges-Armstrong, Laura M., additional, Hua Zhao, Jing, additional, Carola Zillikens, M., additional, Boomsma, Dorret I., additional, Bouchard, Claude, additional, Chambers, John C., additional, Chasman, Daniel I., additional, Cusi, Daniele, additional, Gansevoort, Ron T., additional, Gieger, Christian, additional, Hansen, Torben, additional, Hicks, Andrew A., additional, Hu, Frank, additional, Hveem, Kristian, additional, Jarvelin, Marjo-Riitta, additional, Kajantie, Eero, additional, Kooner, Jaspal S., additional, Kuh, Diana, additional, Kuusisto, Johanna, additional, Laakso, Markku, additional, Lakka, Timo A., additional, Lehtimäki, Terho, additional, Metspalu, Andres, additional, Njølstad, Inger, additional, Ohlsson, Claes, additional, Oldehinkel, Albertine J., additional, Palmer, Lyle J., additional, Pedersen, Oluf, additional, Perola, Markus, additional, Peters, Annette, additional, Psaty, Bruce M., additional, Puolijoki, Hannu, additional, Rauramaa, Rainer, additional, Rudan, Igor, additional, Salomaa, Veikko, additional, Schwarz, Peter E. H., additional, Shudiner, Alan R., additional, Smit, Jan H., additional, Sørensen, Thorkild I. A., additional, Spector, Timothy D., additional, Stefansson, Kari, additional, Stumvoll, Michael, additional, Tremblay, Angelo, additional, Tuomilehto, Jaakko, additional, Uitterlinden, André G., additional, Uusitupa, Matti, additional, Völker, Uwe, additional, Vollenweider, Peter, additional, Wareham, Nicholas J., additional, Watkins, Hugh, additional, Wilson, James F., additional, Zeggini, Eleftheria, additional, Abecasis, Goncalo R., additional, Boehnke, Michael, additional, Borecki, Ingrid B., additional, Deloukas, Panos, additional, van Duijn, Cornelia M., additional, Fox, Caroline, additional, Groop, Leif C., additional, Heid, Iris M., additional, Hunter, David J., additional, Kaplan, Robert C., additional, McCarthy, Mark I., additional, North, Kari E., additional, O'Connell, Jeffrey R., additional, Schlessinger, David, additional, Thorsteinsdottir, Unnur, additional, Strachan, David P., additional, Frayling, Timothy, additional, Hirschhorn, Joel N., additional, Müller-Nurasyid, Martina, additional, and Loos, Ruth J. F., additional

Published
2016
Full Text
View/download PDF

7. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Farmaki, Aliki-Eleni, Hui, Jennie, Gräßler, Jürgen, Van Der Most, Peter J., Walker, Ryan W., Cupples, L Adrienne, Holmen, Oddgeir, Hassinen, Maija, Pedersen, Oluf, Lichtner, Peter, Tachmazidou, Ioanna, Hillege, Hans, Tremblay, Angelo, Musk, Arthur W., Heard-Costa, Nancy L., Sørensen, Thorkild I. A., Völker, Uwe, Sebert, Sylvain, Eriksson, Joel, Bellis, Claire, Willemsen, Gonneke, Chen, Yii-Der Ida, Hofman, Albert, Pankow, James S., Huffman, Jennifer E., Boehnke, Michael, Jeff, Janina M., Qi, Lu, Thorsteinsdottir, Unnur, Hunter, David J., Ried, Janina S., Monda, Keri L., Hirschhorn, Joel N., Uusitupa, Matti, Grarup, Niels, Salvi, Erika, Mccarthy, Mark I., Laakso, Markku, Wright, Alan F., Feitosa, Mary F., Stefansson, Kari, Widén, Elisabeth, Friedrich, Nele, O'connell, Jeffrey R., Kyriakou, Theodosios, Lyssenko, Valeriya, Zeggini, Eleftheria, Teumer, Alexander, Justice, Anne E., Cadby, Gemma, Hu, Frank, Lindström, Jaana, Tee Khaw, Kay, Kovacs, Peter, Marie Justesen, Johanne, Mcardle, Wendy L., Willems, Sara M., Stringham, Heather M., Montasser, May E., Kuh, Diana, Isaacs, Aaron, Karaleftheri, Maria, Scott, Robert A., Rauramaa, Rainer, Jokinen, Eero, Schlessinger, David, Pilia, Maria G., North, Kari E., Ong, Ken K., Ittermann, Till, Lorbeer, Roberto, Couto Alves, Alexessander, Salomaa, Veikko, Luben, Robert, Hartman, Catharina A., Bouchard, Claude, Rayner, Nigel W., Hayward, Caroline, Rao, Ridker, Paul M., Peters, Annette, Hveem, Kristian, Vohl, Marie-Claude, Ribel-Madsen, Rasmus, Albrecht, Eva, Wilsgaard, Tom, Lorentzon, Mattias, Fox, Caroline, Palmer, Lyle J., Stolk, Ronald P., Carola Zillikens, Stirrups, Kathleen, Southam, Lorraine, Chasman, Daniel I., Forouhi, Nita G., Ryan, Kathy A., Esko, Toñu, Linneberg, Allan, Hastie, Nicholas, Wild, Sarah H., Palotie, Aarno, Mohlke, Karen L., Wareham, Nicholas J., Lakka, Timo A., Koistinen, Heikki A., Paternoster, Lavinia, Prokopenko, Inga, Osmond, Clive, Oostra, Ben A., Borecki, Ingrid B., Tuomilehto, Jaakko, Van Dongen, Jenny, Collins, Francis S, Grallert, Harald, Bragg-Gresham, Jennifer L., Smith, Megan T., Medina-Gomez, Carolina, Boerwinkle, Eric, Müller, Gabriele, Bornstein, Stefan R., Heliövaara, Markku, Jousilahti, Pekka, Kinnunen, Leena, Kooner, Jaspal S., Swift, Amy J., Kuusisto, Johanna, Loos, Ruth J. F., Zhao, Jing Hua, Ju Sung, Yun, Rankinen, Tuomo, Grewal, Jagvir, Bartz, Traci M., Hamsten, Anders, Döring, Angela, Hicks, Andrew A., Mägi, Reedik, Njølstad, Inger, Rudan, Igor, Rice, Treva K., Strachan, David P., De Geus, Eco J.C., Chiang, Charleston W. K., Watkins, Hugh, Kaplan, Robert C., Blüher, Matthias, Standáková, Alena, Luan, Jian'an, Cusi, Daniele, Homuth, Georg, Sarzynski, Mark A., Jarvelin, Marjo-Riitta, Ohlsson, Claes, Stumvoll, Michael, Groop, Leif C., Chambers, John C., Gjesing, Anette Prior, Penninx, Brenda W., Bruinenberg, Marcel, Strauch, Konstantin, Waeber, Gérard, Knekt, Paul B., Kolcic, Ivana, Husemoen, Lise Lotte, Dedoussis, George, Mahajan, Anubha, Fischer, Krista, Chu, Audrey Y., Lahti, Jari, Lehtimäki, Terho, Morris, Andrew P., Nolte, Ilja M., Havulinna, Aki S., Spector, Timothy D., Vitart, Veronique, Keinanen-Kiukaanniemi, Sirkka M., Gieger, Christian, Abecasis, Goncalo R., Metspalu, Andres, Sanna, Serena, Psaty, Bruce M., Goel, Anuj, Thorleifsson, Gudmar, Scholtens, Salome, Ferreira, Teresa, Viikari, Jorma S., Lewin, Alexandra M., Glorioso, Nicola, Mcknight, Barbara, Richards, Marcus, Winkler, Thomas W., Snieder, Harold, Männistö, Satu, Kähönen, Mika, Harder, Marie Neergaard, Laitinen, Tomi, Bergmann, Sven, Oldehinkel, Albertine J., Langenberg, Claudia, Wilson, James F., Pérusse, Louis, Kutalik, Zoltán, Dimitriou, Maria, Farrall, Martin, Zhang, Weihua, Tönjes, Anke, Wang, Sophie R., Verweij, Niek, Jackson, Anne U., Lindgren, Cecilia M., Bonnycastle, Lori L., Narisu, Narisu, Eklund, Niina, Müller-Nurasyid, Martina, Polašek, Ozren, Kooner, Ishminder K., Pichler, Irene, Pramstaller, Peter P., Smit, Jan H., Perola, Markus, Tsafantakis, Emmanouil, Beilby, John, Rivadeneira, Fernando, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Graff, Mariaelisa, Manunta, Paolo, Wong, Andrew, Hottenga, Jouke-Jan, Raitakari, Olli T, Leach, Irene Mateo, Milani, Lili, Swertz, Morris A., Boomsma, Dorret I., Yerges-Armstrong, Laura M., James, Alan L., Ahluwalia, Tarunveer S., Vartiainen, Erkki, Blangero, John, Campbell, Harry, Uitterlinden, André G., Puolijoki, Hannu, Frayling, Timothy, Jula, Antti, Kristiansson, Kati, Eriksson, Johan G., Gansevoort, Ron T., Heid, Iris M., Kajantie, Eero, Bakker, Stephan J. L., Rose, Lynda M., Gorski, Mathias, Mangino, Massimo, Vollenweider, Peter, Van Der Harst, Pim, Van Duijn, Cornelia M., Koskinen, Seppo, Venturini, Cristina, Van Vliet-Ostaptchouk, Jana V., Mills, Rebecca, Jørgensen, Torben, Mihailov, Evelin, Vandenput, Liesbeth, Shudiner, Alan R., Barlassina, Cristina, Hattersley, Andrew Tym, Chines, Peter S., Hansen, Torben, D'avila, Francesca, Deloukas, Panos, Cucca, Fracensco, Vonk, Judith M., Hysi, Pirro G., Kanoni, Stavroula, Schwarz, Peter E. H., Jalilzadeh, Shapour, and Bergman, Richard N.

Subjects
2. Zero hunger
Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

8. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Ried, Janina S, Jeff M, Janina, Chu, Audrey Y, Bragg-Gresham, Jennifer L, Van Dongen, Jenny, Huffman, Jennifer E, Ahluwalia, Tarunveer S, Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tõnu, Feitosa, Mary F, Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L, Jackson, Anne U, Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'an, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L, Nolte, Ilja M, Pérusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M, Salvi, Erika, Smith, Megan T, Snieder, Harold, Stančáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W, Wang, Sophie R, Wild, Sarah H, Willems, Sara M, Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan JL, Barlassina, Cristina, Bartz, Traci M, Beilby, John, Bellis, Claire, Bergman, Richard N, Bergmann, Sven, Blangero, John, Blüher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L, Bornstein, Stefan R, Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston WK, Chines, Peter S, Collins, Francis S, Cucca, Fracensco, Cupples, L Adrienne, D'Avila, Francesca, De Geus, Eco JC, Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G, Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G, Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S, Heliövaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G, Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L, Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E, Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen-Kiukaanniemi, Sirkka M, Kinnunen, Leena, Knekt, Paul B, Koistinen, Heikki A, Kolcic, Ivana, Kooner, Ishminder K, Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M, Lichtner, Peter, Lindgren, Cecilia M, Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L, Mcknight, Barbara, Mohlke, Karen L, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E, Morris, Andrew P, Müller, Gabriele, Musk, Arthur W, Narisu, Narisu, Ong, Ken K, Oostra, Ben A, Osmond, Clive, Palotie, Aarno, Pankow, James S, Paternoster, Lavinia, Penninx, Brenda W, Pichler, Irene, Pilia, Maria G, Polašek, Ozren, Pramstaller, Peter P, Raitakari, Olli T, Rankinen, Tuomo, Rao, DC, Rayner, Nigel W, Ribel-Madsen, Rasmus, Rice, Treva K, Richards, Marcus, Ridker, Paul M, Rivadeneira, Fernando, Ryan, Kathy A, Sanna, Serena, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P, Strauch, Konstantin, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J, Van Vliet-Ostaptchouk, Jana V, Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S, Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M, Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W, Wright, Alan F, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Zillikens, M Carola, Boomsma, Dorret I, Bouchard, Claude, Chambers, John C, Chasman, Daniel I, Cusi, Daniele, Gansevoort, Ron T, Gieger, Christian, Hansen, Torben, Hicks, Andrew A, Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S, Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Metspalu, Andres, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Palmer, Lyle J, Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M, Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter EH, Shudiner, Alan R, Smit, Jan H, Sørensen, Thorkild IA, Spector, Timothy D, Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J, Watkins, Hugh, Wilson, James F, Zeggini, Eleftheria, Abecasis, Goncalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Van Duijn, Cornelia M, Fox, Caroline, Groop, Leif C, Heid, Iris M, Hunter, David J, Kaplan, Robert C, McCarthy, Mark I, North, Kari E, O'Connell, Jeffrey R, Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P, Frayling, Timothy, Hirschhorn, Joel N, Müller-Nurasyid, Martina, and Loos, Ruth JF

Subjects
2. Zero hunger, Principal Component Analysis, Anthropometry, Genotype, Models, Genetic, Body Size, Humans, Genome-Wide Association Study
Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

9. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Niina Eklund, Robert C. Kaplan, Niek Verweij, Marcus Richards, Nancy L. Heard-Costa, Angelo Tremblay, Lu Qi, Andres Metspalu, Mark A. Sarzynski, Charleston W. K. Chiang, Tõnu Esko, Jaana Lindström, Pirro G. Hysi, Torben Hansen, James F. Wilson, Serena Sanna, Marie-Claude Vohl, Lynda M. Rose, Daniele Cusi, Megan T. Smith, Anne U. Jackson, Jing Hua Zhao, Anubha Mahajan, Nele Friedrich, Marcel Bruinenberg, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Weihua Zhang, Lavinia Paternoster, Jenny van Dongen, Torben Jørgensen, Aarno Palotie, Jana V. van Vliet-Ostaptchouk, Martin Farrall, Konstantin Strauch, Jan Smit, Zoltán Kutalik, Anne E. Justice, Elisabeth Widen, Tuomo Rankinen, Timo A. Lakka, Maria Dimitriou, Louis Pérusse, Peter J. van der Most, Yun Ju Sung, George Dedoussis, Caroline Hayward, Tom Wilsgaard, Peter P. Pramstaller, Maria Karaleftheri, Seppo Koskinen, Clive Osmond, Panos Deloukas, David J. Hunter, Kathleen Stirrups, Nicola Glorioso, Andrew T. Hattersley, Hugh Watkins, Sven Bergmann, Eric Boerwinkle, Catharina A. Hartman, Anke Tönjes, Daniel I. Chasman, May E. Montasser, Alan James, Ben A. Oostra, Nigel W. Rayner, Massimo Mangino, Ron T. Gansevoort, Cristina Barlassina, Johanna Kuusisto, Andrew A. Hicks, Roberto Lorbeer, Tomi Laitinen, Narisu Narisu, Stefan R. Bornstein, Gemma Cadby, Johan G. Eriksson, Gudmar Thorleifsson, Erika Salvi, Jari Lahti, Cornelia M. van Duijn, Janina M. Jeff, Heather M. Stringham, Bruce M. Psaty, Thomas W. Winkler, Paul M. Ridker, Unnur Thorsteinsdottir, Lyle J. Palmer, Alexander Teumer, Jürgen Gräßler, Allan Linneberg, Francesca D'Avila, Markku Heliövaara, Harald Grallert, Ivana Kolcic, Kari E. North, Eleftheria Zeggini, James S. Pankow, Alena Standáková, Marjo-Riitta Järvelin, Ozren Polasek, Krista Fischer, Valeriya Lyssenko, Thorkild I. A. Sørensen, André G. Uitterlinden, Stavroula Kanoni, Caroline S. Fox, Sophie R. Wang, Treva Rice, Maria Grazia Pilia, Olli T. Raitakari, Claudia Langenberg, Thomas Sparsø, Emmanouil Tsafantakis, Irene Pichler, Kathy Ryan, Eero Jokinen, Mika Kähönen, Leif Groop, Irene Mateo Leach, Gabriele Müller, Annette Peters, Peter Vollenweider, Oddgeir L. Holmen, David Schlessinger, Paul Knekt, M. Carola Zillikens, Evelin Mihailov, Erkki Vartiainen, Nicholas J. Wareham, Francis S. Collins, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Janina S. Ried, Valgerdur Steinthorsdottir, Shapour Jalilzadeh, Peter Kovacs, Anuj Goel, Pim van der Harst, Peter Schwarz, Mathias Gorski, Jorma Viikari, Uwe Völker, Cecilia M. Lindgren, Theodosios Kyriakou, Morris A. Swertz, Inga Prokopenko, Ken K. Ong, Leena Kinnunen, Markus Perola, Kristian Hveem, Matthias Blüher, Rebecca Mills, Albertine J. Oldehinkel, Anders Hamsten, Mattias Lorentzon, Joel Eriksson, Karen L. Mohlke, Rasmus Ribel-Madsen, Pekka Jousilahti, Paolo Manunta, Eva Albrecht, Jeffrey R. O'Connell, Wendy L. McArdle, Amy J. Swift, Dorret I. Boomsma, Harry Campbell, Fracensco Cucca, Aaron Isaacs, Andrew Wong, Georg Homuth, Laura M. Yerges-Armstrong, Carolina Medina-Gomez, Kay-Tee Khaw, Claes Ohlsson, Claude Bouchard, John Blangero, Aliki-Eleni Farmaki, Lorraine Southam, Anette P. Gjesing, Traci M. Bartz, Dabeeru C. Rao, Andrew P. Morris, David P. Strachan, Nita G. Forouhi, Eco J. C. de Geus, Jaakko Tuomilehto, Antti Jula, Ryan W. Walker, Mary F. Feitosa, Reedik Mägi, Aki S. Havulinna, Inger Njølstad, Alan R. Shudiner, Jennifer E. Huffman, Peter Lichtner, Richard N. Bergman, Mariaelisa Graff, Diana Kuh, Tim D. Spector, Robert Luben, Veikko Salomaa, Christian Gieger, Jaspal S. Kooner, Teresa Ferreira, Jennifer L. Bragg-Gresham, Sylvain Sebert, Terho Lehtimäki, Heikki A. Koistinen, Alexandra M. Lewin, Alexessander Couto Alves, Peter S. Chines, Lise Lotte N. Husemoen, Salome Scholtens, Yii-Der Ida Chen, Kati Kristiansson, Barbara McKnight, Sara M. Willems, Rainer Rauramaa, Satu Männistö, Stephan J. L. Bakker, Angela Döring, Audrey Y. Chu, Niels Grarup, Matti Uusitupa, Hannu Puolijoki, L. Adrienne Cupples, Veronique Vitart, Marie Neergaard Harder, Jouke-Jan Hottenga, Kari Stefansson, Alan F. Wright, Igor Rudan, Keri L. Monda, Jian'an Luan, Robert A. Scott, Albert Hofman, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Maija Hassinen, Sarah H. Wild, Iris M. Heid, Brenda W.J.H. Penninx, John C. Chambers, Claire Bellis, Nicholas D. Hastie, Ruth J. F. Loos, Martina Müller-Nurasyid, Johanne Marie Justesen, Gérard Waeber, Jennie Hui, Gonçalo R. Abecasis, Ishminder K. Kooner, Harold Snieder, Judith M. Vonk, Ioanna Tachmazidou, Ronald P. Stolk, Michael Stumvoll, Till Ittermann, Oluf Pedersen, Ingrid B. Borecki, Gonneke Willemsen, Jagvir Grewal, Markku Laakso, Arthur W. Musk, Eero Kajantie, Hans L. Hillege, Michael Boehnke, Cristina Venturini, Lili Milani, John Beilby, Fernando Rivadeneira, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Goel, Anuj [0000-0003-2307-4021], Jackson, Anne U [0000-0002-9672-2547], Kristiansson, Kati [0000-0003-4688-107X], Medina-Gomez, Carolina [0000-0001-7999-5538], Nolte, Ilja M [0000-0001-5047-4077], Prokopenko, Inga [0000-0003-1624-7457], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Beilby, John [0000-0002-4915-2254], Bergmann, Sven [0000-0002-6785-9034], Strachan, David P [0000-0001-7854-1366], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Energy & Sustainability Programme, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Children's Hospital, Lastentautien yksikkö, Clinicum, Institute for Molecular Medicine Finland, Behavioural Sciences, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Department of Medicine, Endokrinologian yksikkö, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Leif Groop Research Group, Quantitative Genetics, HUS Children and Adolescents, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Clinical Medicine, School of Medicine / Biomedicine,School of Medicine / Clinical Nutrition, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg Gresham, Jennifer L., Van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Toñu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathia, Hayward, Caroline, Heard Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'An, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Pérusse, Loui, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Standáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blüher, Matthia, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S, Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, De Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G., Farmaki, Aliki Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niel, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Ander, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nichola, Hattersley, Andrew Tym, Havulinna, Aki S., Heliövaara, Markku, Hillege, Han, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E., Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosio, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattia, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, Mcardle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Müller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polašek, Ozren, Pramstaller, Peter P., Raitakari, Olli T, Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel Madsen, Rasmu, Rice, Treva K., Richards, Marcu, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J., Van Vliet Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie Claude, Vonk, Judith M., Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges Armstrong, Laura M., Zhao, Jing Hua, Carola Zillikens, M., Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Metspalu, Andre, Njølstad, Inger, Ohlsson, Clae, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Marku, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sørensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Pano, Van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., Mccarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Müller Nurasyid, Martina, Loos, Ruth J. F., Internal medicine, Psychiatry, EMGO - Mental health, Public Health, Epidemiology, Surgery, Internal Medicine, Erasmus MC other, and Child and Adolescent Psychiatry / Psychology

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Mice, HEIGHT, Body Size, Mass index, 2. Zero hunger, Genetics, Principal Component Analysis, Multidisciplinary, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, Chemistry (all), Phenotype, Common, gene, body, shape, Multidisciplinary Sciences, Principal component analysis, Trait, Science & Technology - Other Topics, DIET-INDUCED OBESITY, Waist, Genotype, 515 Psychology, Science, EARLY-ONSET, Snp, BIOLOGY, HIP RATIO, Genome-wide association studies Statistical methods, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), MASS INDEX, DISEASE ASSOCIATIONS, RESOURCE, MD Multidisciplinary, Humans, GENOME-WIDE ASSOCIATION, Biochemistry, Genetics and Molecular Biology (all), Science & Technology, Models, Genetic, ta1184, FAT DISTRIBUTION, General Chemistry, ta3121, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Body mass index, Genome-Wide Association Study
Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed

Published
2016
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