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1. The impact of low-frequency and rare variants on lipid levels

Author

Surakka, Ida, Horikoshi, Momoko, Magi, Reedik, Sarin, Antti-Pekka, Mahajan, Anubha, Lagou, Vasiliki, Marullo, Letizia, Ferreira, Teresa, Miraglio, Benjamin, Timonen, Sanna, Kettunen, Johannes, Pirinen, Matti, Karjalainen, Julia, Thorleifsson, Gudmar, Hägg, Sara, Hottenga, Jouke-Jan, Isaacs, Aaron, Ladenvall, Claes, Beekman, Marian, Esko, Tonu, Ried, Janina S., Nelson, Christopher P., Willenborg, Christina, Gustafsson, Stefan, Westra, Harm-Jan, Blades, Matthew, de Craen, Anton J. M., de Geus, Eco J., Deelen, Joris, Grallert, Harald, Hamsten, Anders, Havulinna, Aki S., Hengstenberg, Christian, Houwing-Duistermaat, Jeanine J., Hypponen, Elina, Karssen, Lennart C., Lehtimaki, Terho, Lyssenko, Valeriya, Magnusson, Patrik K. E., Mihailov, Evelin, Muller-Nurasyid, Martina, Mpindi, John-Patrick, Pedersen, Nancy L., Penninx, Brenda W. J. H., Perola, Markus, Pers, Tune H., Peters, Annette, Rung, Johan, Smit, Johannes H., Steinthorsdottir, Valgerdur, Tobin, Martin D., Tsernikova, Natalia, van Leeuwen, Elisabeth M., Viikari, Jorma S., Willems, Sara M., Willemsen, Gonneke, Schunkert, Heribert, Erdmann, Jeanette, Samani, Nilesh J., Kaprio, Jaakko, Lind, Lars, Gieger, Christian, Metspalu, Andres, Slagboom, P. Eline, Groop, Leif, van Duijn, Cornelia M., Eriksson, Johan G., Jula, Antti, Salomaa, Veikko, Boomsma, Dorret I., Power, Christine, Raitakari, Olli T., Ingelsson, Erik, Jarvelin, Marjo-Riitta, Thorsteinsdottir, Unnur, Franke, Lude, Ikonen, Elina, Kallioniemi, Olli, Pietiainen, Vilja, Lindgren, Cecilia M., Stefansson, Kari, Palotie, Aarno, McCarthy, Mark I., Morris, Andrew P., Prokopenko, Inga, Ripatti, Samuli, Surakka, Ida, Horikoshi, Momoko, Magi, Reedik, Sarin, Antti-Pekka, Mahajan, Anubha, Lagou, Vasiliki, Marullo, Letizia, Ferreira, Teresa, Miraglio, Benjamin, Timonen, Sanna, Kettunen, Johannes, Pirinen, Matti, Karjalainen, Julia, Thorleifsson, Gudmar, Hägg, Sara, Hottenga, Jouke-Jan, Isaacs, Aaron, Ladenvall, Claes, Beekman, Marian, Esko, Tonu, Ried, Janina S., Nelson, Christopher P., Willenborg, Christina, Gustafsson, Stefan, Westra, Harm-Jan, Blades, Matthew, de Craen, Anton J. M., de Geus, Eco J., Deelen, Joris, Grallert, Harald, Hamsten, Anders, Havulinna, Aki S., Hengstenberg, Christian, Houwing-Duistermaat, Jeanine J., Hypponen, Elina, Karssen, Lennart C., Lehtimaki, Terho, Lyssenko, Valeriya, Magnusson, Patrik K. E., Mihailov, Evelin, Muller-Nurasyid, Martina, Mpindi, John-Patrick, Pedersen, Nancy L., Penninx, Brenda W. J. H., Perola, Markus, Pers, Tune H., Peters, Annette, Rung, Johan, Smit, Johannes H., Steinthorsdottir, Valgerdur, Tobin, Martin D., Tsernikova, Natalia, van Leeuwen, Elisabeth M., Viikari, Jorma S., Willems, Sara M., Willemsen, Gonneke, Schunkert, Heribert, Erdmann, Jeanette, Samani, Nilesh J., Kaprio, Jaakko, Lind, Lars, Gieger, Christian, Metspalu, Andres, Slagboom, P. Eline, Groop, Leif, van Duijn, Cornelia M., Eriksson, Johan G., Jula, Antti, Salomaa, Veikko, Boomsma, Dorret I., Power, Christine, Raitakari, Olli T., Ingelsson, Erik, Jarvelin, Marjo-Riitta, Thorsteinsdottir, Unnur, Franke, Lude, Ikonen, Elina, Kallioniemi, Olli, Pietiainen, Vilja, Lindgren, Cecilia M., Stefansson, Kari, Palotie, Aarno, McCarthy, Mark I., Morris, Andrew P., Prokopenko, Inga, and Ripatti, Samuli

Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

Published
2015
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2. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Horikoshi, Momoko, Maegi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Haegg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S., Winkler, Thomas W., Willems, Sara M., Tsernikova, Natalia, Esko, Tonu, Beekman, Marian, Nelson, Christopher P., Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J., Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K. E., Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R., Groves, Christopher J., Bennett, Amanda J., Lehtimaeki, Terho, Viikari, Jorma S., Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M., Herder, Christian, Grallert, Harald, Mueller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M., Karssen, Lennart C., Mihailov, Evelin, Houwing-Duistermaat, Jeanine J., de Craen, Anton J. M., Deelen, Joris, Havulinna, Aki S., Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D., Samani, Nilesh J., Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M., Slagboom, P. Eline, Metspalu, Andres, van Duijn, Cornelia M., Eriksson, Johan G., Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T., Power, Chris, Penninx, Brenda W. J. H., de Geus, Eco, Smit, Johannes H., Boomsma, Dorret I., Pedersen, Nancy L., Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I., Morris, Andrew P., Engage Consortium, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Horikoshi, Momoko, Maegi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Haegg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S., Winkler, Thomas W., Willems, Sara M., Tsernikova, Natalia, Esko, Tonu, Beekman, Marian, Nelson, Christopher P., Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J., Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K. E., Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R., Groves, Christopher J., Bennett, Amanda J., Lehtimaeki, Terho, Viikari, Jorma S., Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M., Herder, Christian, Grallert, Harald, Mueller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M., Karssen, Lennart C., Mihailov, Evelin, Houwing-Duistermaat, Jeanine J., de Craen, Anton J. M., Deelen, Joris, Havulinna, Aki S., Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D., Samani, Nilesh J., Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M., Slagboom, P. Eline, Metspalu, Andres, van Duijn, Cornelia M., Eriksson, Johan G., Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T., Power, Chris, Penninx, Brenda W. J. H., de Geus, Eco, Smit, Johannes H., Boomsma, Dorret I., Pedersen, Nancy L., Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I., Morris, Andrew P., and Engage Consortium

Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency >= 0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Published
2015

3. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Perry, John R. B., Day, Felix, Elks, Cathy E., Sulem, Patrick, Thompson, Deborah J., Ferreira, Teresa, He, Chunyan, Chasman, Daniel I., Esko, Toenu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q., Corre, Tanguy, Cousminer, Diana L., Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D., Kjellqvist, Sanela, Lunetta, Kathryn L., McMahon, George, Nolte, Ilja M., Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Tsernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K., Amin, Najaf, Bierut, Laura J., Byrne, Enda M., Hottenga, Jouke-Jan, Koller, Daniel L., Mangino, Massimo, Pers, Tune H., Yerges-Armstrong, Laura M., Zhao, Jing Hua, Andrulis, Irene L., Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E., Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collee, J. Margriet, Couch, Fergus J., Couper, David, Coviello, Andrea D., Cox, Angela, Czene, Kamila, D'adamo, Adamo Pio, Smith, George Davey, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K., Dunning, Alison M., Eiriksdottir, Gudny, Eriksson, Johan G., Fasching, Peter A., Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E., Garcia-Closas, Montserrat, Geller, Frank, de Geus, Eco E. J., Giles, Graham G., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guenel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A., Heath, AndrewC., Hofman, Albert, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Hunter, David J., Karasik, David, Kiel, Douglas P., Knight, Julia A., Kosma, Veli-Matti, Kutalik, Zoltan, Lai, Sandra, Lambrechts, Diether, Lindblom, Annika, Maegi, Reedik, Magnusson, Patrik K., Mannermaa, Arto, Martin, Nicholas G., Masson, Gisli, McArdle, Patrick F., McArdle, Wendy L., Melbye, Mads, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Nevanlinna, Heli, Neven, Patrick, Nohr, Ellen A., Oldehinkel, Albertine J., Oostra, Ben A., Palotie, Aarno, Peacock, Munro, Pedersen, Nancy L., Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Postma, Dirkje S., Pouta, Anneli, Pylkaes, Katri, Radice, Paolo, Ring, Susan, Rivadeneira, Fernando, Robino, Antonietta, Rose, Lynda M., Rudolph, Anja, Salomaa, Veikko, Sanna, Serena, Schlessinger, David, Schmidt, Marjanka K., Southey, Mellissa C., Sovio, Ulla, Stampfer, Meir J., Stoeckl, Doris, Storniolo, Anna M., Timpson, Nicholas J., Tyrer, Jonathan, Visser, Jenny A., Vollenweider, Peter, Voelzke, Henry, Waeber, Gerard, Waldenberger, Melanie, Wallaschofski, Henri, Wang, Qin, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Wright, Margaret J., Boomsma, Dorret I., Econs, Michael J., Khaw, Kay-Tee, Loos, Ruth J. F., McCarthy, Mark I., Montgomery, Grant W., Rice, John P., Streeten, Elizabeth A., Thorsteinsdottir, Unnur, van Duijn, Cornelia M., Alizadeh, Behrooz Z., Bergmann, Sven, Boerwinkle, Eric, Boyd, Heather A., Crisponi, Laura, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B., Ingelsson, Erik, Jaervelin, Marjo-Riitta, Kraft, Peter, Lawlor, Debbie, Metspalu, Andres, Pennell, Craig E., Ridker, Paul M., Snieder, Harold, Sorensen, Thorkild I. A., Spector, Tim D., Strachan, David P., Uitterlinden, Andre G., Wareham, Nicholas J., Widen, Elisabeth, Zygmunt, Marek, Murray, Anna, Easton, Douglas F., Stefansson, Kari, Murabito, Joanne M., Ong, Ken K., Perry, John R. B., Day, Felix, Elks, Cathy E., Sulem, Patrick, Thompson, Deborah J., Ferreira, Teresa, He, Chunyan, Chasman, Daniel I., Esko, Toenu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q., Corre, Tanguy, Cousminer, Diana L., Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D., Kjellqvist, Sanela, Lunetta, Kathryn L., McMahon, George, Nolte, Ilja M., Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Tsernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K., Amin, Najaf, Bierut, Laura J., Byrne, Enda M., Hottenga, Jouke-Jan, Koller, Daniel L., Mangino, Massimo, Pers, Tune H., Yerges-Armstrong, Laura M., Zhao, Jing Hua, Andrulis, Irene L., Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E., Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collee, J. Margriet, Couch, Fergus J., Couper, David, Coviello, Andrea D., Cox, Angela, Czene, Kamila, D'adamo, Adamo Pio, Smith, George Davey, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K., Dunning, Alison M., Eiriksdottir, Gudny, Eriksson, Johan G., Fasching, Peter A., Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E., Garcia-Closas, Montserrat, Geller, Frank, de Geus, Eco E. J., Giles, Graham G., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guenel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A., Heath, AndrewC., Hofman, Albert, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Hunter, David J., Karasik, David, Kiel, Douglas P., Knight, Julia A., Kosma, Veli-Matti, Kutalik, Zoltan, Lai, Sandra, Lambrechts, Diether, Lindblom, Annika, Maegi, Reedik, Magnusson, Patrik K., Mannermaa, Arto, Martin, Nicholas G., Masson, Gisli, McArdle, Patrick F., McArdle, Wendy L., Melbye, Mads, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Nevanlinna, Heli, Neven, Patrick, Nohr, Ellen A., Oldehinkel, Albertine J., Oostra, Ben A., Palotie, Aarno, Peacock, Munro, Pedersen, Nancy L., Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Postma, Dirkje S., Pouta, Anneli, Pylkaes, Katri, Radice, Paolo, Ring, Susan, Rivadeneira, Fernando, Robino, Antonietta, Rose, Lynda M., Rudolph, Anja, Salomaa, Veikko, Sanna, Serena, Schlessinger, David, Schmidt, Marjanka K., Southey, Mellissa C., Sovio, Ulla, Stampfer, Meir J., Stoeckl, Doris, Storniolo, Anna M., Timpson, Nicholas J., Tyrer, Jonathan, Visser, Jenny A., Vollenweider, Peter, Voelzke, Henry, Waeber, Gerard, Waldenberger, Melanie, Wallaschofski, Henri, Wang, Qin, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Wright, Margaret J., Boomsma, Dorret I., Econs, Michael J., Khaw, Kay-Tee, Loos, Ruth J. F., McCarthy, Mark I., Montgomery, Grant W., Rice, John P., Streeten, Elizabeth A., Thorsteinsdottir, Unnur, van Duijn, Cornelia M., Alizadeh, Behrooz Z., Bergmann, Sven, Boerwinkle, Eric, Boyd, Heather A., Crisponi, Laura, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B., Ingelsson, Erik, Jaervelin, Marjo-Riitta, Kraft, Peter, Lawlor, Debbie, Metspalu, Andres, Pennell, Craig E., Ridker, Paul M., Snieder, Harold, Sorensen, Thorkild I. A., Spector, Tim D., Strachan, David P., Uitterlinden, Andre G., Wareham, Nicholas J., Widen, Elisabeth, Zygmunt, Marek, Murray, Anna, Easton, Douglas F., Stefansson, Kari, Murabito, Joanne M., and Ong, Ken K.

Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Published
2014
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4. Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

Author

University of Helsinki, Haartman Institute, Hoggart, Clive J., Venturini, Giulia, Mangino, Massimo, Gomez, Felicia, Ascari, Giulia, Zhao, Jing Hua, Teumer, Alexander, Winkler, Thomas W., Tsernikova, Natalia, Luan, Jian'an, Mihailov, Evelin, Ehret, Georg B., Zhang, Weihua, Lamparter, David, Esko, Tonu, Mace, Aurelien, Rueeger, Sina, Bochud, Pierre-Yves, Barcella, Matteo, Dauvilliers, Yves, Benyamin, Beben, Evans, David M., Hayward, Caroline, Lopez, Mary F., Franke, Lude, Russo, Alessia, Heid, Iris M., Salvi, Erika, Vendantam, Sailaja, Arking, Dan E., Boerwinkle, Eric, Chambers, John C., Fiorito, Giovanni, Grallert, Harald, Guarrera, Simonetta, Homuth, Georg, Huffman, Jennifer E., Porteous, David, Moradpour, Darius, Iranzo, Alex, Hebebrand, Johannes, Kemp, John P., Lammers, Gert J., Aubert, Vincent, Heim, Markus H., Martin, Nicholas G., Montgomery, Grant W., Peraita-Adrados, Rosa, Santamaria, Joan, Negro, Francesco, Schmidt, Carsten O., Scott, Robert A., Spector, Tim D., Strauch, Konstantin, Voelzke, Henry, Wareham, Nicholas J., Yuan, Wei, Bell, Jordana T., Chakravarti, Aravinda, Kooner, Jaspal S., Peters, Annette, Matullo, Giuseppe, Wallaschofski, Henri, Whitfield, John B., Paccaud, Fred, Vollenweider, Peter, Bergmann, Sven, Beckmann, Jacques S., Tafti, Mehdi, Hastie, Nicholas D., Cusi, Daniele, Bochud, Murielle, Frayling, Timothy M., Metspalu, Andres, Jarvelin, Marjo-Riitta, Scherag, Andre, Smith, George Davey, Borecki, Ingrid B., Rousson, Valentin, Hirschhorn, Joel N., Rivolta, Carlo, Loos, Ruth J. F., Kutalik, Zoltan, Generation Scotland Consortium, LifeLines Cohort Study, GIANT Consortium, Lokki, Marja-Liisa, University of Helsinki, Haartman Institute, Hoggart, Clive J., Venturini, Giulia, Mangino, Massimo, Gomez, Felicia, Ascari, Giulia, Zhao, Jing Hua, Teumer, Alexander, Winkler, Thomas W., Tsernikova, Natalia, Luan, Jian'an, Mihailov, Evelin, Ehret, Georg B., Zhang, Weihua, Lamparter, David, Esko, Tonu, Mace, Aurelien, Rueeger, Sina, Bochud, Pierre-Yves, Barcella, Matteo, Dauvilliers, Yves, Benyamin, Beben, Evans, David M., Hayward, Caroline, Lopez, Mary F., Franke, Lude, Russo, Alessia, Heid, Iris M., Salvi, Erika, Vendantam, Sailaja, Arking, Dan E., Boerwinkle, Eric, Chambers, John C., Fiorito, Giovanni, Grallert, Harald, Guarrera, Simonetta, Homuth, Georg, Huffman, Jennifer E., Porteous, David, Moradpour, Darius, Iranzo, Alex, Hebebrand, Johannes, Kemp, John P., Lammers, Gert J., Aubert, Vincent, Heim, Markus H., Martin, Nicholas G., Montgomery, Grant W., Peraita-Adrados, Rosa, Santamaria, Joan, Negro, Francesco, Schmidt, Carsten O., Scott, Robert A., Spector, Tim D., Strauch, Konstantin, Voelzke, Henry, Wareham, Nicholas J., Yuan, Wei, Bell, Jordana T., Chakravarti, Aravinda, Kooner, Jaspal S., Peters, Annette, Matullo, Giuseppe, Wallaschofski, Henri, Whitfield, John B., Paccaud, Fred, Vollenweider, Peter, Bergmann, Sven, Beckmann, Jacques S., Tafti, Mehdi, Hastie, Nicholas D., Cusi, Daniele, Bochud, Murielle, Frayling, Timothy M., Metspalu, Andres, Jarvelin, Marjo-Riitta, Scherag, Andre, Smith, George Davey, Borecki, Ingrid B., Rousson, Valentin, Hirschhorn, Joel N., Rivolta, Carlo, Loos, Ruth J. F., Kutalik, Zoltan, Generation Scotland Consortium, LifeLines Cohort Study, GIANT Consortium, and Lokki, Marja-Liisa

Published
2014

5. Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression

Author

Tammiste, Anu, Jiang, Tao, Fischer, Krista, Mägi, Reedik, Krjutskov, Kaarel, Pettai, Kristi, Esko, Tonu, Li, Yingrui, Tansey, Katherine E., Carroll, Liam S., Uher, Rudolf, McGuffin, Peter, Vosa, Urmo, Tsernikova, Natalia, Saria, Alois, Ng, Pauline C., Eller, Triin, Vasar, Veiko, Nutt, David J., Maron, Eduard, Wang, Jun, Metspalu, Andres, Tammiste, Anu, Jiang, Tao, Fischer, Krista, Mägi, Reedik, Krjutskov, Kaarel, Pettai, Kristi, Esko, Tonu, Li, Yingrui, Tansey, Katherine E., Carroll, Liam S., Uher, Rudolf, McGuffin, Peter, Vosa, Urmo, Tsernikova, Natalia, Saria, Alois, Ng, Pauline C., Eller, Triin, Vasar, Veiko, Nutt, David J., Maron, Eduard, Wang, Jun, and Metspalu, Andres

Published
2013

6. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, Peter K., Esko, Tonu, Mattsson, Hannele, Eklund, Niina, Gandin, Ilaria, Nutile, Teresa, Jackson, Anne U., Schurmann, Claudia, Smith, Albert V., Zhang, Weihua, Okada, Yukinori, Stančáková, Alena, Faul, Jessica D., Zhao, Wei, Bartz, Traci M., Concas, Maria Pina, Franceschini, Nora, Enroth, Stefan, Vitart, Veronique, Trompet, Stella, Guo, Xiuqing, Chasman, Daniel I., O’Connel, Jeffery R., Corre, Tanguy, Nongmaithem, Suraj S., Chen, Yuning, Mangino, Massimo, Ruggiero, Daniela, Traglia, Michela, Farmaki, Aliki-Eleni, Kacprowski, Tim, Bjonnes, Andrew, van der Spek, Ashley, Wu, Ying, Giri, Anil K., Yanek, Lisa R., Wang, Lihua, Hofer, Edith, Rietveld, Cornelius A., McLeod, Olga, Cornelis, Marilyn C., Pattaro, Cristian, Verweij, Niek, Baumbach, Clemens, Abdellaoui, Abdel, Warren, Helen R., Vuckovic, Dragana, Mei, Hao, Bouchard, Claude, Perry, John R.B., Cappellani, Stefania, Mirza, Saira S., Benton, Miles C., Broeckel, Ulrich, Medland, Sarah E., Lind, Penelope A., Malerba, Giovanni, Drong, Alexander, Yengo, Loic, Bielak, Lawrence F., Zhi, Degui, van der Most, Peter J., Shriner, Daniel, Mägi, Reedik, Hemani, Gibran, Karaderi, Tugce, Wang, Zhaoming, Liu, Tian, Demuth, Ilja, Zhao, Jing Hua, Meng, Weihua, Lataniotis, Lazaros, van der Laan, Sander W., Bradfield, Jonathan P., Wood, Andrew R., Bonnefond, Amelie, Ahluwalia, Tarunveer S., Hall, Leanne M., Salvi, Erika, Yazar, Seyhan, Carstensen, Lisbeth, de Haan, Hugoline G., Abney, Mark, Afzal, Uzma, Allison, Matthew A., Amin, Najaf, Asselbergs, Folkert W., Bakker, Stephan J.L., Barr, R. Graham, Baumeister, Sebastian E., Benjamin, Daniel J., Bergmann, Sven, Boerwinkle, Eric, Bottinger, Erwin P., Campbell, Archie, Chakravarti, Aravinda, Chan, Yingleong, Chanock, Stephen J., Chen, Constance, Chen, Y.-D. Ida, Collins, Francis S., Connell, John, Correa, Adolfo, Cupples, L. Adrienne, Smith, George Davey, Davies, Gail, Dörr, Marcus, Ehret, Georg, Ellis, Stephen B., Feenstra, Bjarke, Feitosa, Mary F., Ford, Ian, Fox, Caroline S., Frayling, Timothy M., Friedrich, Nele, Geller, Frank, Scotland, Generation, Gillham-Nasenya, Irina, Gottesman, Omri, Graff, Misa, Grodstein, Francine, Gu, Charles, Haley, Chris, Hammond, Christopher J., Harris, Sarah E., Harris, Tamara B., Hastie, Nicholas D., Heard-Costa, Nancy L., Heikkilä, Kauko, Hocking, Lynne J., Homuth, Georg, Hottenga, Jouke-Jan, Huang, Jinyan, Huffman, Jennifer E., Hysi, Pirro G., Ikram, M. Arfan, Ingelsson, Erik, Joensuu, Anni, Johansson, Åsa, Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kanoni, Stavroula, Kerr, Shona M., Khan, Nazir M., Koellinger, Philipp, Koistinen, Heikki A., Kooner, Manraj K., Kubo, Michiaki, Kuusisto, Johanna, Lahti, Jari, Launer, Lenore J., Lea, Rodney A., Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C.M., Lind, Lars, Loh, Marie, Lokki, Marja-Liisa, London, Stephanie J., Loomis, Stephanie J., Loukola, Anu, Lu, Yingchang, Lumley, Thomas, Lundqvist, Annamari, Männistö, Satu, Marques-Vidal, Pedro, Masciullo, Corrado, Matchan, Angela, Mathias, Rasika A., Matsuda, Koichi, Meigs, James B., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Mentch, Frank D., Mihailov, Evelin, Milani, Lili, Montasser, May E., Montgomery, Grant W., Morrison, Alanna, Myers, Richard H., Nadukuru, Rajiv, Navarro, Pau, Nelis, Mari, Nieminen, Markku S., Nolte, Ilja M., O’Connor, George T., Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Pankow, James S., Patarcic, Inga, Pavani, Francesca, Peyser, Patricia A., Pietilainen, Kirsi, Poulter, Neil, Prokopenko, Inga, Ralhan, Sarju, Redmond, Paul, Rich, Stephen S., Rissanen, Harri, Robino, Antonietta, Rose, Lynda M., Rose, Richard, Sala, Cinzia, Salako, Babatunde, Salomaa, Veikko, Sarin, Antti-Pekka, Saxena, Richa, Schmidt, Helena, Scott, Laura J., Scott, William R., Sennblad, Bengt, Seshadri, Sudha, Sever, Peter, Shrestha, Smeeta, Smith, Blair H., Smith, Jennifer A., Soranzo, Nicole, Sotoodehnia, Nona, Southam, Lorraine, Stanton, Alice V., Stathopoulou, Maria G., Strauch, Konstantin, Strawbridge, Rona J., Suderman, Matthew J., Tandon, Nikhil, Tang, Sian-Tsun, Taylor, Kent D., Tayo, Bamidele O., Töglhofer, Anna Maria, Tomaszewski, Maciej, Tšernikova, Natalia, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vaidya, Dhananjay, van Hylckama Vlieg, Astrid, van Setten, Jessica, Vasankari, Tuula, Vedantam, Sailaja, Vlachopoulou, Efthymia, Vozzi, Diego, Vuoksimaa, Eero, Waldenberger, Melanie, Ware, Erin B., Wentworth-Shields, William, Whitfield, John B., Wild, Sarah, Willemsen, Gonneke, Yajnik, Chittaranjan S., Yao, Jie, Zaza, Gianluigi, Zhu, Xiaofeng, Project, The BioBank Japan, Salem, Rany M., Melbye, Mads, Bisgaard, Hans, Samani, Nilesh J., Cusi, Daniele, Mackey, David A., Cooper, Richard S., Froguel, Philippe, Pasterkamp, Gerard, Grant, Struan F.A., Hakonarson, Hakon, Ferrucci, Luigi, Scott, Robert A., Morris, Andrew D., Palmer, Colin N.A., Dedoussis, George, Deloukas, Panos, Bertram, Lars, Lindenberger, Ulman, Berndt, Sonja I., Lindgren, Cecilia M., Timpson, Nicholas J., Tönjes, Anke, Munroe, Patricia B., Sørensen, Thorkild I.A., Rotimi, Charles N., Arnett, Donna K., Oldehinkel, Albertine J., Kardia, Sharon L.R., Balkau, Beverley, Gambaro, Giovanni, Morris, Andrew P., Eriksson, Johan G., Wright, Margie J., Martin, Nicholas G., Hunt, Steven C., Starr, John M., Deary, Ian J., Griffiths, Lyn R., Tiemeier, Henning, Pirastu, Nicola, Kaprio, Jaakko, Wareham, Nicholas J., Pérusse, Louis, Wilson, James G., Girotto, Giorgia, Caulfield, Mark J., Raitakari, Olli, Boomsma, Dorret I., Gieger, Christian, van der Harst, Pim, Hicks, Andrew A., Kraft, Peter, Sinisalo, Juha, Knekt, Paul, Johannesson, Magnus, Magnusson, Patrik K.E., Hamsten, Anders, Schmidt, Reinhold, Borecki, Ingrid B., Vartiainen, Erkki, Becker, Diane M., Bharadwaj, Dwaipayan, Mohlke, Karen L., Boehnke, Michael, van Duijn, Cornelia M., Sanghera, Dharambir K., Teumer, Alexander, Zeggini, Eleftheria, Metspalu, Andres, Gasparini, Paolo, Ulivi, Sheila, Ober, Carole, Toniolo, Daniela, Rudan, Igor, Porteous, David J., Ciullo, Marina, Spector, Tim D., Hayward, Caroline, Dupuis, Josée, Loos, Ruth J.F., Wright, Alan F., Chandak, Giriraj R., Vollenweider, Peter, Shuldiner, Alan, Ridker, Paul M., Rotter, Jerome I., Sattar, Naveed, Gyllensten, Ulf, North, Kari E., Pirastu, Mario, Psaty, Bruce M., Weir, David R., Laakso, Markku, Gudnason, Vilmundur, Takahashi, Atsushi, Chambers, John C., Kooner, Jaspal S., Strachan, David P., Campbell, Harry, Hirschhorn, Joel N., Perola, Markus, Polašek, Ozren, and Wilson, James F.

Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Published
2015
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7. Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche

Author

Perry, John RB, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, McMahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke-Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges-Armstrong, Laura M, Zhao, Jing Hua, Andrulis, Irene L, Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collée, J. Margriet, Couch, Fergus J, Couper, David, Coveillo, Andrea D, Cox, Angela, Czene, Kamila, D’adamo, Adamo Pio, Smith, George Davey, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García-Closas, Montserrat, Geller, Frank, de Geus, Eco EJ, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, Kiel, Douglas P, Knight, Julia A, Kosma, Veli-Matti, Kutalik, Zoltan, Lai, Sandra, Lambrechts, Diether, Lindblom, Annika, Mägi, Reedik, Magnusson, Patrik K, Mannermaa, Arto, Martin, Nicholas G, Masson, Gisli, McArdle, Patrick F, McArdle, Wendy L, Melbye, Mads, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Nevanlinna, Heli, Neven, Patrick, Nohr, Ellen A, Oldehinkel, Albertine J, Oostra, Ben A, Palotie, Aarno, Peacock, Munro, Pedersen, Nancy L, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Postma, Dirkje S, Pouta, Anneli, Pylkäs, Katri, Radice, Paolo, Ring, Susan, Rivadeneira, Fernando, Robino, Antonietta, Rose, Lynda M, Rudolph, Anja, Salomaa, Veikko, Sanna, Serena, Schlessinger, David, Schmidt, Marjanka K, Southey, Mellissa C, Sovio, Ulla, Stampfer, Meir J, Stöckl, Doris, Storniolo, Anna M, Timpson, Nicholas J, Tyrer, Jonathan, Visser, Jenny A, Vollenweider, Peter, Völzke, Henry, Waeber, Gerard, Waldenberger, Melanie, Wallaschofski, Henri, Wang, Qin, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce HR, Wright, Margaret J, Boomsma, Dorret I, Econs, Michael J, Khaw, Kay-Tee, Loos, Ruth JF, McCarthy, Mark I, Montgomery, Grant W, Rice, John P, Streeten, Elizabeth A, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Bergmann, Sven, Boerwinkle, Eric, Boyd, Heather A, Crisponi, Laura, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kraft, Peter, Lawlor, Debbie, Metspalu, Andres, Pennell, Craig E, Ridker, Paul M, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Strachan, David P, Uitterlinden, André G, Wareham, Nicholas J, Widen, Elisabeth, Zygmunt, Marek, Murray, Anna, Easton, Douglas F, Stefansson, Kari, Murabito, Joanne M, and Ong, Ken K

Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Published
2014
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8. Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

Author

Hoggart, Clive J., Venturini, Giulia, Mangino, Massimo, Gomez, Felicia, Ascari, Giulia, Zhao, Jing Hua, Teumer, Alexander, Winkler, Thomas W., Tšernikova, Natalia, Luan, Jian'an, Mihailov, Evelin, Ehret, Georg B., Zhang, Weihua, Lamparter, David, Esko, Tõnu, Macé, Aurelien, Rüeger, Sina, Bochud, Pierre-Yves, Barcella, Matteo, Dauvilliers, Yves, Benyamin, Beben, Evans, David M., Hayward, Caroline, Lopez, Mary F., Franke, Lude, Russo, Alessia, Heid, Iris M., Salvi, Erika, Vendantam, Sailaja, Arking, Dan E., Boerwinkle, Eric, Chambers, John C., Fiorito, Giovanni, Grallert, Harald, Guarrera, Simonetta, Homuth, Georg, Huffman, Jennifer E., Porteous, David, Moradpour, Darius, Iranzo, Alex, Hebebrand, Johannes, Kemp, John P., Lammers, Gert J., Aubert, Vincent, Heim, Markus H., Martin, Nicholas G., Montgomery, Grant W., Peraita-Adrados, Rosa, Santamaria, Joan, Negro, Francesco, Schmidt, Carsten O., Scott, Robert A., Spector, Tim D., Strauch, Konstantin, Völzke, Henry, Wareham, Nicholas J., Yuan, Wei, Bell, Jordana T., Chakravarti, Aravinda, Kooner, Jaspal S., Peters, Annette, Matullo, Giuseppe, Wallaschofski, Henri, Whitfield, John B., Paccaud, Fred, Vollenweider, Peter, Bergmann, Sven, Beckmann, Jacques S., Tafti, Mehdi, Hastie, Nicholas D., Cusi, Daniele, Bochud, Murielle, Frayling, Timothy M., Metspalu, Andres, Jarvelin, Marjo-Riitta, Scherag, André, Smith, George Davey, Borecki, Ingrid B., Rousson, Valentin, Hirschhorn, Joel N., Rivolta, Carlo, Loos, Ruth J. F., and Kutalik, Zoltán

Subjects
Physical Sciences, Mathematics, Statistics (Mathematics), Biostatistics, Statistical Methods, Biology and Life Sciences, Computational Biology, Genome Analysis, Genome-Wide Association Studies, Epigenomics, Developmental Biology, Genomic Imprinting, Genetics, Epigenetics, Genomics
Abstract

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.

Published
2014
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9. The impact of low-frequency and rare variants on lipid levels.

Author

Surakka I, Horikoshi M, Mägi R, Sarin AP, Mahajan A, Lagou V, Marullo L, Ferreira T, Miraglio B, Timonen S, Kettunen J, Pirinen M, Karjalainen J, Thorleifsson G, Hägg S, Hottenga JJ, Isaacs A, Ladenvall C, Beekman M, Esko T, Ried JS, Nelson CP, Willenborg C, Gustafsson S, Westra HJ, Blades M, de Craen AJ, de Geus EJ, Deelen J, Grallert H, Hamsten A, Havulinna AS, Hengstenberg C, Houwing-Duistermaat JJ, Hyppönen E, Karssen LC, Lehtimäki T, Lyssenko V, Magnusson PK, Mihailov E, Müller-Nurasyid M, Mpindi JP, Pedersen NL, Penninx BW, Perola M, Pers TH, Peters A, Rung J, Smit JH, Steinthorsdottir V, Tobin MD, Tsernikova N, van Leeuwen EM, Viikari JS, Willems SM, Willemsen G, Schunkert H, Erdmann J, Samani NJ, Kaprio J, Lind L, Gieger C, Metspalu A, Slagboom PE, Groop L, van Duijn CM, Eriksson JG, Jula A, Salomaa V, Boomsma DI, Power C, Raitakari OT, Ingelsson E, Järvelin MR, Thorsteinsdottir U, Franke L, Ikonen E, Kallioniemi O, Pietiäinen V, Lindgren CM, Stefansson K, Palotie A, McCarthy MI, Morris AP, Prokopenko I, and Ripatti S

Subjects
Dyslipidemias genetics, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Mutation, Missense, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Lipid Metabolism genetics
Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

Published
2015
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