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1. Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Author

Kentistou, Katherine A., Kaisinger, Lena R., Stankovic, Stasa, Vaudel, Marc, Mendes de Oliveira, Edson, Messina, Andrea, Walters, Robin G., Liu, Xiaoxi, Busch, Alexander S., Helgason, Hannes, Thompson, Deborah J., Santoni, Federico, Petricek, Konstantin M., Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, Daniel F., Bratland, Eirik, Lin, Kuang, Gardner, Eugene J., Zhao, Yajie, Jia, Raina Y., Terao, Chikashi, Riggan, Marjorie J., Bolla, Manjeet K., Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan P., Broer, Linda, Campbell, Archie, Chasman, Daniel I., Cousminer, Diana L., Franceschini, Nora, Franke, Lude H., Girotto, Giorgia, He, Chunyan, Järvelin, Marjo-Riitta, Joshi, Peter K., Kamatani, Yoichiro, Karlsson, Robert, Luan, Jian’an, Lunetta, Kathryn L., Mägi, Reedik, Mangino, Massimo, Medland, Sarah E., Meisinger, Christa, Noordam, Raymond, Nutile, Teresa, Concas, Maria Pina, Polašek, Ozren, Porcu, Eleonora, Ring, Susan M., Sala, Cinzia, Smith, Albert V., Tanaka, Toshiko, van der Most, Peter J., Vitart, Veronique, Wang, Carol A., Willemsen, Gonneke, Zygmunt, Marek, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Auer, Paul L., Barnes, Catriona L. K., Beckmann, Matthias W., Berrington de Gonzalez, Amy, Bogdanova, Natalia V., Bojesen, Stig E., Brenner, Hermann, Buring, Julie E., Canzian, Federico, Chang-Claude, Jenny, Couch, Fergus J., Cox, Angela, Crisponi, Laura, Czene, Kamila, Daly, Mary B., Demerath, Ellen W., Dennis, Joe, Devilee, Peter, De Vivo, Immaculata, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eriksson, Johan G., Fasching, Peter A., Fernandez-Rhodes, Lindsay, Ferreli, Liana, Fletcher, Olivia, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., González-Neira, Anna, Grallert, Harald, Guénel, Pascal, Haiman, Christopher A., Hall, Per, Hamann, Ute, Hakonarson, Hakon, Hart, Roger J., Hickey, Martha, Hooning, Maartje J., Hoppe, Reiner, Hopper, John L., Hottenga, Jouke-Jan, Hu, Frank B., Huebner, Hanna, Hunter, David J., Jernström, Helena, John, Esther M., Karasik, David, Khusnutdinova, Elza K., Kristensen, Vessela N., Lacey, James V., Lambrechts, Diether, Launer, Lenore J., Lind, Penelope A., Lindblom, Annika, Magnusson, Patrik K. E., Mannermaa, Arto, McCarthy, Mark I., Meitinger, Thomas, Menni, Cristina, Michailidou, Kyriaki, Millwood, Iona Y., Milne, Roger L., Montgomery, Grant W., Nevanlinna, Heli, Nolte, Ilja M., Nyholt, Dale R., Obi, Nadia, O’Brien, Katie M., Offit, Kenneth, Oldehinkel, Albertine J., Ostrowski, Sisse R., Palotie, Aarno, Pedersen, Ole B., Peters, Annette, Pianigiani, Giulia, Plaseska-Karanfilska, Dijana, Pouta, Anneli, Pozarickij, Alfred, Radice, Paolo, Rennert, Gad, Rosendaal, Frits R., Ruggiero, Daniela, Saloustros, Emmanouil, Sandler, Dale P., Schipf, Sabine, Schmidt, Carsten O., Schmidt, Marjanka K., Small, Kerrin, Spedicati, Beatrice, Stampfer, Meir, Stone, Jennifer, Tamimi, Rulla M., Teras, Lauren R., Tikkanen, Emmi, Turman, Constance, Vachon, Celine M., Wang, Qin, Winqvist, Robert, Wolk, Alicja, Zemel, Babette S., Zheng, Wei, van Dijk, Ko W., Alizadeh, Behrooz Z., Bandinelli, Stefania, Boerwinkle, Eric, Boomsma, Dorret I., Ciullo, Marina, Chenevix-Trench, Georgia, Cucca, Francesco, Esko, Tõnu, Gieger, Christian, Grant, Struan F. A., Gudnason, Vilmundur, Hayward, Caroline, Kolčić, Ivana, Kraft, Peter, Lawlor, Deborah A., Martin, Nicholas G., Nøhr, Ellen A., Pedersen, Nancy L., Pennell, Craig E., Ridker, Paul M., Robino, Antonietta, Snieder, Harold, Sovio, Ulla, Spector, Tim D., Stöckl, Doris, Sudlow, Cathie, Timpson, Nic J., Toniolo, Daniela, Uitterlinden, André, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J., Widen, Elisabeth, Wilson, James F., Pharoah, Paul D. P., Li, Liming, Easton, Douglas F., Njølstad, Pål R., Sulem, Patrick, Murabito, Joanne M., Murray, Anna, Manousaki, Despoina, Juul, Anders, Erikstrup, Christian, Stefansson, Kari, Horikoshi, Momoko, Chen, Zhengming, Farooqi, I. Sadaf, Pitteloud, Nelly, Johansson, Stefan, Day, Felix R., Perry, John R. B., and Ong, Ken K.

Published
2024
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3. Publisher Correction: Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Author

Kentistou, Katherine A., Kaisinger, Lena R., Stankovic, Stasa, Vaudel, Marc, Mendes de Oliveira, Edson, Messina, Andrea, Walters, Robin G., Liu, Xiaoxi, Busch, Alexander S., Helgason, Hannes, Thompson, Deborah J., Santoni, Federico, Petricek, Konstantin M., Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, Daniel F., Bratland, Eirik, Lin, Kuang, Gardner, Eugene J., Zhao, Yajie, Jia, Raina Y., Terao, Chikashi, Riggan, Marjorie J., Bolla, Manjeet K., Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan P., Broer, Linda, Campbell, Archie, Chasman, Daniel I., Cousminer, Diana L., Franceschini, Nora, Franke, Lude H., Girotto, Giorgia, He, Chunyan, Järvelin, Marjo-Riitta, Joshi, Peter K., Kamatani, Yoichiro, Karlsson, Robert, Luan, Jian’an, Lunetta, Kathryn L., Mägi, Reedik, Mangino, Massimo, Medland, Sarah E., Meisinger, Christa, Noordam, Raymond, Nutile, Teresa, Concas, Maria Pina, Polašek, Ozren, Porcu, Eleonora, Ring, Susan M., Sala, Cinzia, Smith, Albert V., Tanaka, Toshiko, van der Most, Peter J., Vitart, Veronique, Wang, Carol A., Willemsen, Gonneke, Zygmunt, Marek, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Auer, Paul L., Barnes, Catriona L. K., Beckmann, Matthias W., Berrington de Gonzalez, Amy, Bogdanova, Natalia V., Bojesen, Stig E., Brenner, Hermann, Buring, Julie E., Canzian, Federico, Chang-Claude, Jenny, Couch, Fergus J., Cox, Angela, Crisponi, Laura, Czene, Kamila, Daly, Mary B., Demerath, Ellen W., Dennis, Joe, Devilee, Peter, De Vivo, Immaculata, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eriksson, Johan G., Fasching, Peter A., Fernandez-Rhodes, Lindsay, Ferreli, Liana, Fletcher, Olivia, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., González-Neira, Anna, Grallert, Harald, Guénel, Pascal, Haiman, Christopher A., Hall, Per, Hamann, Ute, Hakonarson, Hakon, Hart, Roger J., Hickey, Martha, Hooning, Maartje J., Hoppe, Reiner, Hopper, John L., Hottenga, Jouke-Jan, Hu, Frank B., Huebner, Hanna, Hunter, David J., Jernström, Helena, John, Esther M., Karasik, David, Khusnutdinova, Elza K., Kristensen, Vessela N., Lacey, James V., Lambrechts, Diether, Launer, Lenore J., Lind, Penelope A., Lindblom, Annika, Magnusson, Patrik K. E., Mannermaa, Arto, McCarthy, Mark I., Meitinger, Thomas, Menni, Cristina, Michailidou, Kyriaki, Millwood, Iona Y., Milne, Roger L., Montgomery, Grant W., Nevanlinna, Heli, Nolte, Ilja M., Nyholt, Dale R., Obi, Nadia, O’Brien, Katie M., Offit, Kenneth, Oldehinkel, Albertine J., Ostrowski, Sisse R., Palotie, Aarno, Pedersen, Ole B., Peters, Annette, Pianigiani, Giulia, Plaseska-Karanfilska, Dijana, Pouta, Anneli, Pozarickij, Alfred, Radice, Paolo, Rennert, Gad, Rosendaal, Frits R., Ruggiero, Daniela, Saloustros, Emmanouil, Sandler, Dale P., Schipf, Sabine, Schmidt, Carsten O., Schmidt, Marjanka K., Small, Kerrin, Spedicati, Beatrice, Stampfer, Meir, Stone, Jennifer, Tamimi, Rulla M., Teras, Lauren R., Tikkanen, Emmi, Turman, Constance, Vachon, Celine M., Wang, Qin, Winqvist, Robert, Wolk, Alicja, Zemel, Babette S., Zheng, Wei, van Dijk, Ko W., Alizadeh, Behrooz Z., Bandinelli, Stefania, Boerwinkle, Eric, Boomsma, Dorret I., Ciullo, Marina, Chenevix-Trench, Georgia, Cucca, Francesco, Esko, Tõnu, Gieger, Christian, Grant, Struan F. A., Gudnason, Vilmundur, Hayward, Caroline, Kolčić, Ivana, Kraft, Peter, Lawlor, Deborah A., Martin, Nicholas G., Nøhr, Ellen A., Pedersen, Nancy L., Pennell, Craig E., Ridker, Paul M., Robino, Antonietta, Snieder, Harold, Sovio, Ulla, Spector, Tim D., Stöckl, Doris, Sudlow, Cathie, Timpson, Nic J., Toniolo, Daniela, Uitterlinden, André, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J., Widen, Elisabeth, Wilson, James F., Pharoah, Paul D. P., Li, Liming, Easton, Douglas F., Njølstad, Pål R., Sulem, Patrick, Murabito, Joanne M., Murray, Anna, Manousaki, Despoina, Juul, Anders, Erikstrup, Christian, Stefansson, Kari, Horikoshi, Momoko, Chen, Zhengming, Farooqi, I. Sadaf, Pitteloud, Nelly, Johansson, Stefan, Day, Felix R., Perry, John R. B., and Ong, Ken K.

Published
2024
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5. A perspective on muscle phenotyping in musculoskeletal research

Author

Foessl, Ines, Ackert-Bicknell, Cheryl L., Kague, Erika, Laskou, Faidra, Jakob, Franz, Karasik, David, Obermayer-Pietsch, Barbara, Alonso, Nerea, Bjørnerem, Åshild, Brandi, Maria Luisa, Busse, Björn, Calado, Ângelo, Cebi, Alper Han, Christou, Maria, Curran, Kathleen M., Hald, Jannie Dahl, Semeraro, Maria Donatella, Douni, Eleni, Duncan, Emma L., Duran, Ivan, Formosa, Melissa M., Gabet, Yankel, Ghatan, Samuel, Gkitakou, Artemis, Hassler, Eva Maria, Högler, Wolfgang, Heino, Terhi J., Hendrickx, Gretl, Khashayar, Patricia, Kiel, Douglas P., Koromani, Fjorda, Langdahl, Bente, Lopes, Philippe, Mäkitie, Outi, Maurizi, Antonio, Medina-Gomez, Carolina, Ntzani, Evangelia, Ohlsson, Claes, Prijatelj, Vid, Rabionet, Raquel, Reppe, Sjur, Rivadeneira, Fernando, Roshchupkin, Gennady, Sharma, Neha, Søe, Kent, Styrkarsdottir, Unnur, Szulc, Pavel, Teti, Anna, Tobias, Jon, Valjevac, Amina, van de Peppel, Jeroen, van der Eerden, Bram, van Rietbergen, Bert, Zekic, Tatjana, and Zillikens, M. Carola

Published
2024
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7. Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits

Author

Nicoletti, Paola, Zafer, Samreen, Matok, Lital, Irron, Inbar, Patrick, Meidva, Haklai, Rotem, Evangelista, John Erol, Marino, Giacomo B., Ma’ayan, Avi, Sewda, Anshuman, Holmes, Greg, Britton, Sierra R., Lee, Won Jun, Wu, Meng, Ru, Ying, Arnaud, Eric, Botto, Lorenzo, Brody, Lawrence C., Byren, Jo C., Caggana, Michele, Carmichael, Suzan L., Cilliers, Deirdre, Conway, Kristin, Crawford, Karen, Cuellar, Araceli, Di Rocco, Federico, Engel, Michael, Fearon, Jeffrey, Feldkamp, Marcia L., Finnell, Richard, Fisher, Sarah, Freudlsperger, Christian, Garcia-Fructuoso, Gemma, Hagge, Rhinda, Heuzé, Yann, Harshbarger, Raymond J., Hobbs, Charlotte, Howley, Meredith, Jenkins, Mary M., Johnson, David, Justice, Cristina M., Kane, Alex, Kay, Denise, Gosain, Arun Kumar, Langlois, Peter, Legal-Mallet, Laurence, Lin, Angela E., Mills, James L., Morton, Jenny E.V., Noons, Peter, Olshan, Andrew, Persing, John, Phipps, Julie M., Redett, Richard, Reefhuis, Jennita, Rizk, Elias, Samson, Thomas D., Shaw, Gary M., Sicko, Robert, Smith, Nataliya, Staffenberg, David, Stoler, Joan, Sweeney, Elizabeth, Taub, Peter J., Timberlake, Andrew T., Topczewska, Jolanta, Wall, Steven A., Wilson, Alexander F., Wilson, Louise C., Boyadjiev, Simeon A., Wilkie, Andrew O.M., Richtsmeier, Joan T., Jabs, Ethylin Wang, Romitti, Paul A., Karasik, David, Birnbaum, Ramon Y., and Peter, Inga

Published
2024
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9. The influence of adult hip shape genetic variants on adolescent hip shape: Findings from a population-based DXA study

Author

Frysz, Monika, Baird, Denis, Gregory, Jenny S, Aspden, Richard M, Lane, Nancy E, Ohlsson, Claes, Pettersson-Kymmer, Ulrika, Karasik, David, Tobias, Jonathan H, and Paternoster, Lavinia

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Osteoporosis, Genetics, Physical Injury - Accidents and Adverse Effects, Pediatric, Prevention, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Absorptiometry, Photon, Adolescent, Adult, Bone Density, Child, Femur, Femur Head, Hip, Humans, Longitudinal Studies, Osteoarthritis, Hip, ALSPAC, DXA, Hip shape, Osteoarthritis, Hip fracture risk, Genetic association, Biological Sciences, Engineering, Medical and Health Sciences, Endocrinology & Metabolism, Clinical sciences
Abstract

ObjectiveHip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape.MethodsHip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2.ResultsComplete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta -0.05, p = 9.9 × 10-8; age 18: -0.05, p = 3.3 × 10-6) and HSM5 (age 14: beta -0.07, p = 1.6 × 10-4; age 18: -0.1, p = 2.7 × 10-6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10-5; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: -0.06, p = 0.001; age 18: -0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture.ConclusionIn conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.

Published
2021

11. A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Author

Deelen, Joris, Evans, Daniel S, Arking, Dan E, Tesi, Niccolò, Nygaard, Marianne, Liu, Xiaomin, Wojczynski, Mary K, Biggs, Mary L, van der Spek, Ashley, Atzmon, Gil, Ware, Erin B, Sarnowski, Chloé, Smith, Albert V, Seppälä, Ilkka, Cordell, Heather J, Dose, Janina, Amin, Najaf, Arnold, Alice M, Ayers, Kristin L, Barzilai, Nir, Becker, Elizabeth J, Beekman, Marian, Blanché, Hélène, Christensen, Kaare, Christiansen, Lene, Collerton, Joanna C, Cubaynes, Sarah, Cummings, Steven R, Davies, Karen, Debrabant, Birgit, Deleuze, Jean-François, Duncan, Rachel, Faul, Jessica D, Franceschi, Claudio, Galan, Pilar, Gudnason, Vilmundur, Harris, Tamara B, Huisman, Martijn, Hurme, Mikko A, Jagger, Carol, Jansen, Iris, Jylhä, Marja, Kähönen, Mika, Karasik, David, Kardia, Sharon LR, Kingston, Andrew, Kirkwood, Thomas BL, Launer, Lenore J, Lehtimäki, Terho, Lieb, Wolfgang, Lyytikäinen, Leo-Pekka, Martin-Ruiz, Carmen, Min, Junxia, Nebel, Almut, Newman, Anne B, Nie, Chao, Nohr, Ellen A, Orwoll, Eric S, Perls, Thomas T, Province, Michael A, Psaty, Bruce M, Raitakari, Olli T, Reinders, Marcel JT, Robine, Jean-Marie, Rotter, Jerome I, Sebastiani, Paola, Smith, Jennifer, Sørensen, Thorkild IA, Taylor, Kent D, Uitterlinden, André G, van der Flier, Wiesje, van der Lee, Sven J, van Duijn, Cornelia M, van Heemst, Diana, Vaupel, James W, Weir, David, Ye, Kenny, Zeng, Yi, Zheng, Wanlin, Holstege, Henne, Kiel, Douglas P, Lunetta, Kathryn L, Slagboom, P Eline, and Murabito, Joanne M

Subjects
Humans, Heat-Shock Proteins, Longevity, Apolipoprotein E2, Apolipoprotein E4, Genome-Wide Association Study
Abstract

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

Published
2019

12. Disentangling the genetics of lean mass.

Author

Karasik, David, Zillikens, M, Hsu, Yi-Hsiang, Aghdassi, Ali, Akesson, Kristina, Amin, Najaf, Barroso, Inês, Bennett, David, Bertram, Lars, Bochud, Murielle, Borecki, Ingrid, Broer, Linda, Buchman, Aron, Byberg, Liisa, Campbell, Harry, Campos-Obando, Natalia, Cauley, Jane, Cawthon, Peggy, Chambers, John, Chen, Zhao, Cho, Nam, Choi, Hyung, Chou, Wen-Chi, Cummings, Steven, de Groot, Lisette, De Jager, Phillip, Demuth, Ilja, Diatchenko, Luda, Econs, Michael, Eiriksdottir, Gudny, Enneman, Anke, Eriksson, Joel, Eriksson, Johan, Estrada, Karol, Evans, Daniel, Feitosa, Mary, Fu, Mao, Gieger, Christian, Grallert, Harald, Gudnason, Vilmundur, Lenore, Launer, Hayward, Caroline, Hofman, Albert, Homuth, Georg, Huffman, Kim, Husted, Lise, Illig, Thomas, Ingelsson, Erik, Ittermann, Till, Jansson, John-Olov, Johnson, Toby, Biffar, Reiner, Jordan, Joanne, Jula, Antti, Karlsson, Magnus, Khaw, Kay-Tee, Kilpeläinen, Tuomas, Klopp, Norman, Kloth, Jacqueline, Koller, Daniel, Kooner, Jaspal, Kraus, William, Kritchevsky, Stephen, Kutalik, Zoltán, Kuulasmaa, Teemu, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Langdahl, Bente, Lerch, Markus, Lewis, Joshua, Lill, Christina, Lind, Lars, Lindgren, Cecilia, Liu, Yongmei, Livshits, Gregory, Ljunggren, Östen, Loos, Ruth, Lorentzon, Mattias, Luan, Jianan, Luben, Robert, Malkin, Ida, McGuigan, Fiona, Medina-Gomez, Carolina, Meitinger, Thomas, Melhus, Håkan, Mellström, Dan, Michaëlsson, Karl, Mitchell, Braxton, Morris, Andrew, Mosekilde, Leif, Nethander, Maria, Newman, Anne, OConnell, Jeffery, Oostra, Ben, Orwoll, Eric, Palotie, Aarno, Peacock, Munro, Perola, Markus, and Peters, Annette

Subjects
ADAMTS Proteins, Absorptiometry, Photon, Adipose Tissue, Adolescent, Adult, Aged, Aged, 80 and over, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Composition, Body Fluid Compartments, Electric Impedance, Extracellular Matrix Proteins, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Muscle, Skeletal, Phenotype, Polymorphism, Single Nucleotide, RNA-Binding Proteins, Receptor, Melanocortin, Type 4, Versicans, White People, Young Adult
Abstract

BACKGROUND: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. OBJECTIVES: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. METHODS: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). RESULTS: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as sumo wrestler loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed body builder loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in body builder loci were associated with metabolic protection. CONCLUSIONS: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Published
2019

13. Identification of Novel Loci Associated With Hip Shape: A Meta‐Analysis of Genomewide Association Studies

Author

Baird, Denis A, Evans, Daniel S, Kamanu, Frederick K, Gregory, Jennifer S, Saunders, Fiona R, Giuraniuc, Claudiu V, Barr, Rebecca J, Aspden, Richard M, Jenkins, Deborah, Kiel, Douglas P, Orwoll, Eric S, Cummings, Steven R, Lane, Nancy E, Mullin, Benjamin H, Williams, Frances MK, Richards, J Brent, Wilson, Scott G, Spector, Tim D, Faber, Benjamin G, Lawlor, Deborah A, Grundberg, Elin, Ohlsson, Claes, Pettersson‐Kymmer, Ulrika, Capellini, Terence D, Richard, Daniel, Beck, Thomas J, Evans, David M, Paternoster, Lavinia, Karasik, David, and Tobias, Jonathan H

Subjects
Prevention, Genetics, Osteoporosis, Arthritis, Aging, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Animals, Bone Density, Femur Head, Genetic Loci, Genome-Wide Association Study, Hip Fractures, Humans, Linkage Disequilibrium, Longitudinal Studies, Mice, Osteoporotic Fractures, Polymorphism, Single Nucleotide, HIP SHAPE, OSTEOARTHRITIS, HIP FRACTURE RISK, DXA, GWAS, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology
Abstract

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p  0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Published
2019

16. Genetic Control of Aging

Author

Baghdadi, Maarouf, Karasik, David, Deelen, Joris, Govindaraju, Diddahally R., Section editor, Gu, Danan, editor, and Dupre, Matthew E., editor

Published
2021
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17. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, Danesh, John, and Spector, Timothy

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Amidohydrolases, Autoimmune Diseases, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D, White People
Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018

18. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Author

Medina-Gomez, Carolina, Kemp, John P, Trajanoska, Katerina, Luan, Jian’an, Chesi, Alessandra, Ahluwalia, Tarunveer S, Mook-Kanamori, Dennis O, Ham, Annelies, Hartwig, Fernando P, Evans, Daniel S, Joro, Raimo, Nedeljkovic, Ivana, Zheng, Hou-Feng, Zhu, Kun, Atalay, Mustafa, Liu, Ching-Ti, Nethander, Maria, Broer, Linda, Porleifsson, Gudmar, Mullin, Benjamin H, Handelman, Samuel K, Nalls, Mike A, Jessen, Leon E, Heppe, Denise HM, Richards, J Brent, Wang, Carol, Chawes, Bo, Schraut, Katharina E, Amin, Najaf, Wareham, Nick, Karasik, David, Van der Velde, Nathalie, Ikram, M Arfan, Zemel, Babette S, Zhou, Yanhua, Carlsson, Christian J, Liu, Yongmei, McGuigan, Fiona E, Boer, Cindy G, Bønnelykke, Klaus, Ralston, Stuart H, Robbins, John A, Walsh, John P, Zillikens, M Carola, Langenberg, Claudia, Li-Gao, Ruifang, Williams, Frances MK, Harris, Tamara B, Akesson, Kristina, Jackson, Rebecca D, Sigurdsson, Gunnar, Heijer, Martin den, van der Eerden, Bram CJ, van de Peppel, Jeroen, Spector, Timothy D, Pennell, Craig, Horta, Bernardo L, Felix, Janine F, Zhao, Jing Hua, Wilson, Scott G, de Mutsert, Renée, Bisgaard, Hans, Styrkársdóttir, Unnur, Jaddoe, Vincent W, Orwoll, Eric, Lakka, Timo A, Scott, Robert, Grant, Struan FA, Lorentzon, Mattias, van Duijn, Cornelia M, Wilson, James F, Stefansson, Kari, Psaty, Bruce M, Kiel, Douglas P, Ohlsson, Claes, Ntzani, Evangelia, van Wijnen, Andre J, Forgetta, Vincenzo, Ghanbari, Mohsen, Logan, John G, Williams, Graham R, Bassett, JH Duncan, Croucher, Peter I, Evangelou, Evangelos, Uitterlinden, Andre G, Ackert-Bicknell, Cheryl L, Tobias, Jonathan H, Evans, David M, and Rivadeneira, Fernando

Subjects
Rare Diseases, Aging, Human Genome, Osteoporosis, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Good Health and Well Being, Adolescent, Age Factors, Animals, Bone Density, Child, Child, Preschool, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Regression Analysis, BMD, CREB3L1, ESR1, GWASs, RANKL, age-dependent effects, bone mineral density, fracture, genetic correlation, genome-wide association studies, meta-regression, total-body DXA, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Published
2018

19. Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk

Author

Zhao, Pianpian, primary, Ying, Zhimin, additional, Yuan, Chengda, additional, Zhang, Haisheng, additional, Dong, Ao, additional, Tao, Jianguo, additional, Yi, Xiangjiao, additional, Yang, Mengyuan, additional, Jin, Wen, additional, Tian, Weiliang, additional, Karasik, David, additional, Tian, Geng, additional, and Zheng, Houfeng, additional

Published
2024
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20. Deciphering the complex relationship between type 2 diabetes and fracture risk with both genetic and observational evidence

Author

Zhao, Pianpian, primary, Sheng, Zhifeng, primary, Xu, Lin, primary, Li, Peng, additional, Xiao, Wenjin, additional, Yuan, Chengda, additional, Xu, Zhanwei, additional, Yang, Mengyuan, additional, Qian, Yu, additional, Zhong, Jiadong, additional, Gu, Jiaxuan, additional, Karasik, David, additional, and Zheng, Hou-Feng, additional

Published
2024
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21. Author response: Deciphering the complex relationship between type 2 diabetes and fracture risk with both genetic and observational evidence

Author

Zhao, Pianpian, primary, Sheng, Zhi-Feng, additional, Xu, Lin, additional, Li, Peng, additional, Xiao, Wen-Jin, additional, Yuan, Cheng-Da, additional, Xu, Zhanwei, additional, Yang, Meng-Yuan, additional, Qian, Yu, additional, Zhong, Jia-Dong, additional, Zhong, Jiaxuan, additional, Karasik, David, additional, and Zheng, Hou-Feng, additional

Published
2024
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22. Author Response: Type 2 diabetes and fracture risk: deciphering the complex relationship with both genetic and observational evidence

Author

Zhao, Pianpian, primary, Sheng, Zhifeng, additional, Xu, Lin, additional, Li, Peng, additional, Xiao, Wenjin, additional, Yuan, Chengda, additional, Xu, Zhanwei, additional, Yang, Mengyuan, additional, Qian, Yu, additional, Zhong, Jiadong, additional, Gu, Jiaxuan, additional, Karasik, David, additional, and Zheng, Hou-Feng, additional

Published
2024
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23. Type 2 diabetes and fracture risk: deciphering the complex relationship with both genetic and observational evidence

Author

Zhao, Pianpian, primary, Sheng, Zhifeng, additional, Xu, Lin, additional, Li, Peng, additional, Xiao, Wenjin, additional, Yuan, Chengda, additional, Xu, Zhanwei, additional, Yang, Mengyuan, additional, Qian, Yu, additional, Zhong, Jiadong, additional, Gu, Jiaxuan, additional, Karasik, David, additional, and Zheng, Hou-Feng, additional

Published
2024
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25. Contributors

Author

Anderson, Kate, primary, Barmanray, Rahul D., additional, Beauchamp, Alison, additional, Boschiero, Dario, additional, Brennan-Olsen, Sharon L., additional, Colón-Emeric, Cathleen, additional, Cordero, Natanael Perez, additional, Cvijetic, Selma, additional, Darling, Andrea L., additional, Dian, Larry, additional, Duckham, Rachel L., additional, Duque, Gustavo, additional, Farr, Joshua N., additional, Feehan, Jack, additional, Fulzele, Sadanand, additional, Ghasem-Zadeh, Ali, additional, Gilman, Jennifer C., additional, Hassan, Ebrahim Bani, additional, Hill, William D., additional, Hiruma, Eisuke, additional, Huang, Yushu, additional, Ilich, Jasminka Z., additional, Imani, Mahdi, additional, Karasik, David, additional, Kaur, Japneet, additional, Kelly, Owen J., additional, Khrystoforova, Iryna, additional, Lee, Peter, additional, Leng, Sean X., additional, Li, Yukang, additional, Liu, Ching-Ti, additional, MacDonald, Brian Alexander, additional, Malekipour, Fatemeh, additional, Mokhtarzadeh, Hossein, additional, Negm, Ahmed M., additional, O’Connor, Jordan, additional, Papaioannou, Alexandra, additional, Parmar, Naaz, additional, Schoenlein, Patricia V., additional, Seldeen, Kenneth Ladd, additional, Sharda, Neema, additional, Stefanaki, Charikleia, additional, Troen, Bruce Robert, additional, Waters, Debra L., additional, and Yates, Christopher J., additional

Published
2022
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27. A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

Author

Sinnott-Armstrong, Nasa, Sousa, Isabel S., Laber, Samantha, Rendina-Ruedy, Elizabeth, Nitter Dankel, Simon E., Ferreira, Teresa, Mellgren, Gunnar, Karasik, David, Rivas, Manuel, Pritchard, Jonathan, Guntur, Anyonya R., Cox, Roger D., Lindgren, Cecilia M., Hauner, Hans, Sallari, Richard, Rosen, Clifford J., Hsu, Yi-Hsiang, Lander, Eric S., Kiel, Douglas P., and Claussnitzer, Melina

Published
2021
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28. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Author

Manousaki, Despoina, Dudding, Tom, Haworth, Simon, Hsu, Yi-Hsiang, Liu, Ching-Ti, Medina-Gómez, Carolina, Voortman, Trudy, van der Velde, Nathalie, Melhus, Håkan, Robinson-Cohen, Cassianne, Cousminer, Diana L, Nethander, Maria, Vandenput, Liesbeth, Noordam, Raymond, Forgetta, Vincenzo, Greenwood, Celia MT, Biggs, Mary L, Psaty, Bruce M, Rotter, Jerome I, Zemel, Babette S, Mitchell, Jonathan A, Taylor, Bruce, Lorentzon, Mattias, Karlsson, Magnus, Jaddoe, Vincent VW, Tiemeier, Henning, Campos-Obando, Natalia, Franco, Oscar H, Utterlinden, Andre G, Broer, Linda, van Schoor, Natasja M, Ham, Annelies C, Ikram, M Arfan, Karasik, David, de Mutsert, Renée, Rosendaal, Frits R, Heijer, Martin den, Wang, Thomas J, Lind, Lars, Orwoll, Eric S, Mook-Kanamori, Dennis O, Michaëlsson, Karl, Kestenbaum, Bryan, Ohlsson, Claes, Mellström, Dan, de Groot, Lisette CPGM, Grant, Struan FA, Kiel, Douglas P, Zillikens, M Carola, Rivadeneira, Fernando, Sawcer, Stephen, Timpson, Nicholas J, and Richards, J Brent

Subjects
Biological Sciences, Health Sciences, Genetics, Prevention, Multiple Sclerosis, Nutrition, Autoimmune Disease, Neurodegenerative, Human Genome, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Cholestanetriol 26-Monooxygenase, Cytochrome P450 Family 2, Gene Frequency, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors, Vitamin D, Vitamin D Deficiency, GWAS, low-frequency genetic variants, multiple sclerosis, vitamin D, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Published
2017

29. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Author

Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brüning, Thomas, Buring, Julie E, Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J, Cousminer, Diana L, Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eriksson, Johan G, Fasching, Peter A, Fernández-Rhodes, Lindsay, Ferrucci, Luigi, Flesch-Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Guénel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B, Hartman, Catharina A, Heiss, Gerardo, Hooning, Maartje J, Hopper, John L, Hu, Frank, Hunter, David J, Ikram, M Arfan, Im, Hae Kyung, Järvelin, Marjo-Riitta, Joshi, Peter K, Karasik, David, and Kellis, Manolis

Subjects
LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Humans, Neoplasms, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Ribonucleoproteins, Membrane Proteins, Body Mass Index, Risk Factors, Age Factors, Genomic Imprinting, Puberty, Menarche, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Databases, Genetic, Adolescent, Female, Male, Genome-Wide Association Study, Aging, Breast Cancer, Biotechnology, Cancer, Human Genome, Genetics, Prostate Cancer, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017

30. Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2

Author

Nielson, Carrie M, Liu, Ching‐Ti, Smith, Albert V, Ackert‐Bicknell, Cheryl L, Reppe, Sjur, Jakobsdottir, Johanna, Wassel, Christina, Register, Thomas C, Oei, Ling, Alonso, Nerea, Oei, Edwin H, Parimi, Neeta, Samelson, Elizabeth J, Nalls, Mike A, Zmuda, Joseph, Lang, Thomas, Bouxsein, Mary, Latourelle, Jeanne, Claussnitzer, Melina, Siggeirsdottir, Kristin, Srikanth, Priya, Lorentzen, Erik, Vandenput, Liesbeth, Langefeld, Carl, Raffield, Laura, Terry, Greg, Cox, Amanda J, Allison, Matthew A, Criqui, Michael H, Bowden, Don, Ikram, M Arfan, Mellström, Dan, Karlsson, Magnus K, Carr, John, Budoff, Matthew, Phillips, Caroline, Cupples, L Adrienne, Chou, Wen‐Chi, Myers, Richard H, Ralston, Stuart H, Gautvik, Kaare M, Cawthon, Peggy M, Cummings, Steven, Karasik, David, Rivadeneira, Fernando, Gudnason, Vilmundur, Orwoll, Eric S, Harris, Tamara B, Ohlsson, Claes, Kiel, Douglas P, and Hsu, Yi‐Hsiang

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Human Genome, Aging, Osteoporosis, Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Animals, Biopsy, Bone Density, Cancellous Bone, Excitatory Amino Acid Transporter 1, Gene Expression Regulation, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Lumbar Vertebrae, Mice, Molecular Sequence Annotation, Organ Size, Osteoblasts, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptor, EphB2, Risk Factors, Spinal Fractures, Spine, BONE QCT, CT, ANALYSIS, QUANTITATION OF BONE, OSTEOPOROSIS, DISEASES AND DISORDERS OF, RELATED TO BONE, GENERAL POPULATION STUDIES, EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES, GENETIC RESEARCH, FRACTURE RISK ASSESSMENT, ANALYSIS/QUANTITATION OF BONE, BONE QCT/μCT, DISEASES AND DISORDERS OF/RELATED TO BONE, EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES, Engineering, Medical and Health Sciences, Anatomy & Morphology, Biological sciences, Biomedical and clinical sciences
Abstract

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

Published
2016

31. Targeted sequencing of genome wide significant loci associated with bone mineral density (BMD) reveals significant novel and rare variants: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study.

Author

Hsu, Yi-Hsiang, Li, Guo, Liu, Ching-Ti, Brody, Jennifer A, Karasik, David, Chou, Wen-Chi, Demissie, Serkalem, Nandakumar, Kannabiran, Zhou, Yanhua, Cheng, Chia-Ho, Gill, Richard, Gibbs, Richard A, Muzny, Donna, Santibanez, Jireh, Estrada, Karol, Rivadeneira, Fernando, Harris, Tamara, Gudnason, Vilmundur, Uitterlinden, Andre, Psaty, Bruce M, Robbins, John A, Adrienne Cupples, L, and Kiel, Douglas P

Subjects
Biological Sciences, Genetics, Human Genome, Osteoporosis, 2.1 Biological and endogenous factors, Aetiology, Aging, Bone Density, Cardiovascular Diseases, Cohort Studies, Epidemiologic Studies, Female, Femur Neck, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, MEF2 Transcription Factors, Male, Middle Aged, Polymorphism, Single Nucleotide, Medical and Health Sciences, Genetics & Heredity
Abstract

BackgroundBone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis. Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study ( n =  925) and Cardiovascular Health Study ( n =  366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80% were rare with MAF

Published
2016

32. Septin 7 Interacts With Numb To Preserve Sarcomere Structural Organization And Muscle Contractile Function

Author

Gasperi, Rita De, primary, Csernoch, Laszlo, additional, Dienes, Beatrix, additional, Gonczi, Monika, additional, Chakrabarty, Jayanta K., additional, Goeta, Shahar, additional, Aslan, Abdurrahman, additional, Toro, Carlos A., additional, Karasik, David, additional, Brown, Lewis M., additional, Brotto, Marco, additional, and Cardozo, Christopher P., additional

Published
2024
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33. GWAS of ∼30,000 samples with bone mineral density at multiple skeletal sites and its clinical relevance on fracture prediction, genetic correlations and prioritization of drug targets

Author

Qian, Yu, primary, Xia, Jiangwei, additional, Wang, Pingyu, additional, Xie, Chao, additional, Lin, Hong-Li, additional, Li, Gloria Hoi-Yee, additional, Yuan, Cheng-Da, additional, Qiu, Mo-Chang, additional, Fang, Yi-Hu, additional, Yu, Chun-Fu, additional, Cai, Xiang-Chun, additional, Khederzadeh, Saber, additional, Zhao, Pian-Pian, additional, Yang, Meng-Yuan, additional, Zhong, Jia-Dong, additional, Li, Xin, additional, Guan, Peng-Lin, additional, Gu, Jia-Xuan, additional, Gai, Si-Rui, additional, Yi, Xiang-Jiao, additional, Tao, Jian-Guo, additional, Chen, Xiang, additional, Miao, Mao-Mao, additional, Jin, Wen, additional, Xu, Lin, additional, Xie, Shu-Yang, additional, Tian, Geng, additional, Yue, Hua, additional, Li, Guangfei, additional, Xiao, Wenjin, additional, Karasik, David, additional, Xu, Youjia, additional, Yang, Liu, additional, Huang, Fei, additional, Cheung, Ching-Lung, additional, Zhang, Zhenlin, additional, and Zheng, Hou-Feng, additional

Published
2024
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34. GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.

Author

Matteini, Amy M, Tanaka, Toshiko, Karasik, David, Atzmon, Gil, Chou, Wen-Chi, Eicher, John D, Johnson, Andrew D, Arnold, Alice M, Callisaya, Michele L, Davies, Gail, Evans, Daniel S, Holtfreter, Birte, Lohman, Kurt, Lunetta, Kathryn L, Mangino, Massimo, Smith, Albert V, Smith, Jennifer A, Teumer, Alexander, Yu, Lei, Arking, Dan E, Buchman, Aron S, Chibinik, Lori B, De Jager, Philip L, Evans, Denis A, Faul, Jessica D, Garcia, Melissa E, Gillham-Nasenya, Irina, Gudnason, Vilmundur, Hofman, Albert, Hsu, Yi-Hsiang, Ittermann, Till, Lahousse, Lies, Liewald, David C, Liu, Yongmei, Lopez, Lorna, Rivadeneira, Fernando, Rotter, Jerome I, Siggeirsdottir, Kristin, Starr, John M, Thomson, Russell, Tranah, Gregory J, Uitterlinden, André G, Völker, Uwe, Völzke, Henry, Weir, David R, Yaffe, Kristine, Zhao, Wei, Zhuang, Wei Vivian, Zmuda, Joseph M, Bennett, David A, Cummings, Steven R, Deary, Ian J, Ferrucci, Luigi, Harris, Tamara B, Kardia, Sharon LR, Kocher, Thomas, Kritchevsky, Stephen B, Psaty, Bruce M, Seshadri, Sudha, Spector, Timothy D, Srikanth, Velandai K, Windham, B Gwen, Zillikens, M Carola, Newman, Anne B, Walston, Jeremy D, Kiel, Douglas P, and Murabito, Joanne M

Subjects
Humans, Hand Strength, Cohort Studies, Reproducibility of Results, Chromatin Immunoprecipitation, Epigenesis, Genetic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Adult, Aged, Muscle Strength, Genome-Wide Association Study, Molecular Sequence Annotation, SNP, aging, genomewide association, meta-analysis, muscle strength, older adults, Epigenesis, Genetic, Polymorphism, Single Nucleotide, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

Published
2016

35. SEAD: an augmented reference panel with 22,134 haplotypes boosts the rare variants imputation and GWAS analysis in Asian population

Author

Yang, Meng-Yuan, primary, Zhong, Jia-Dong, additional, Li, Xin, additional, Bai, Wei-Yang, additional, Yuan, Cheng-Da, additional, Qiu, Mo-Chang, additional, Liu, Ke-Qi, additional, Yu, Chun-Fu, additional, Li, Nan, additional, Yang, Ji-Jian, additional, Liu, Yu-Heng, additional, Yu, Shi-Hui, additional, Zhao, Wei-Wei, additional, Liu, Jun-Quan, additional, Sun, Yi, additional, Cong, Pei-Kuan, additional, Khederzadeh, Saber, additional, Zhao, Pian-Pian, additional, Qian, Yu, additional, Guan, Peng-Lin, additional, Gu, Jia-Xuan, additional, Gai, Si-Rui, additional, Yi, Xiang-Jiao, additional, Tao, Jian-Guo, additional, Chen, Xiang, additional, Miao, Mao-Mao, additional, Lei, Lan-Xin, additional, Xu, Lin, additional, Xie, Shu-Yang, additional, Tian, Geng, additional, Li, Jin-Chen, additional, Guo, Ji-Feng, additional, Karasik, David, additional, Yang, Liu, additional, Tang, Bei-Sha, additional, Huang, Fei, additional, and Zheng, Hou-Feng, additional

Published
2023
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36. Septin 7 Interacts With Numb To Preserve Sarcomere Structural Organization And Muscle Contractile Function

Author

De Gasperi, Rita, primary, Csernoch, Laszlo, additional, Dienes, Beatrix, additional, Gonczi, Monika, additional, Chakrabarty, Jayanta K., additional, Goeta, Shahar, additional, Aslan, Abdurrahman, additional, Toro, Carlos A., additional, Karasik, David, additional, Brown, Lewis M., additional, Brotto, Marco, additional, and Cardozo, Christopher P., additional

Published
2023
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38. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Author

Jones, Garan, Trajanoska, Katerina, Santanasto, Adam J., Stringa, Najada, Kuo, Chia-Ling, Atkins, Janice L., Lewis, Joshua R., Duong, ThuyVy, Hong, Shengjun, Biggs, Mary L., Luan, Jian’an, Sarnowski, Chloe, Lunetta, Kathryn L., Tanaka, Toshiko, Wojczynski, Mary K., Cvejkus, Ryan, Nethander, Maria, Ghasemi, Sahar, Yang, Jingyun, Zillikens, M. Carola, Walter, Stefan, Sicinski, Kamil, Kague, Erika, Ackert-Bicknell, Cheryl L., Arking, Dan E., Windham, B. Gwen, Boerwinkle, Eric, Grove, Megan L., Graff, Misa, Spira, Dominik, Demuth, Ilja, van der Velde, Nathalie, de Groot, Lisette C. P. G. M., Psaty, Bruce M., Odden, Michelle C., Fohner, Alison E., Langenberg, Claudia, Wareham, Nicholas J., Bandinelli, Stefania, van Schoor, Natasja M., Huisman, Martijn, Tan, Qihua, Zmuda, Joseph, Mellström, Dan, Karlsson, Magnus, Bennett, David A., Buchman, Aron S., De Jager, Philip L., Uitterlinden, Andre G., Völker, Uwe, Kocher, Thomas, Teumer, Alexander, Rodriguéz-Mañas, Leocadio, García, Francisco J., Carnicero, José A., Herd, Pamela, Bertram, Lars, Ohlsson, Claes, Murabito, Joanne M., Melzer, David, Kuchel, George A., Ferrucci, Luigi, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P., and Pilling, Luke C.

Published
2021
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39. Publisher Correction: A meta-analysis of genome-wide association studies identifies multiple longevity genes

Author

Deelen, Joris, Evans, Daniel S., Arking, Dan E., Tesi, Niccolò, Nygaard, Marianne, Liu, Xiaomin, Wojczynski, Mary K., Biggs, Mary L., van der Spek, Ashley, Atzmon, Gil, Ware, Erin B., Sarnowski, Chloé, Smith, Albert V., Seppälä, Ilkka, Cordell, Heather J., Dose, Janina, Amin, Najaf, Arnold, Alice M., Ayers, Kristin L., Barzilai, Nir, Becker, Elizabeth J., Beekman, Marian, Blanché, Hélène, Christensen, Kaare, Christiansen, Lene, Collerton, Joanna C., Cubaynes, Sarah, Cummings, Steven R., Davies, Karen, Debrabant, Birgit, Deleuze, Jean-François, Duncan, Rachel, Faul, Jessica D., Franceschi, Claudio, Galan, Pilar, Gudnason, Vilmundur, Harris, Tamara B., Huisman, Martijn, Hurme, Mikko A., Jagger, Carol, Jansen, Iris, Jylhä, Marja, Kähönen, Mika, Karasik, David, Kardia, Sharon L. R., Kingston, Andrew, Kirkwood, Thomas B. L., Launer, Lenore J., Lehtimäki, Terho, Lieb, Wolfgang, Lyytikäinen, Leo-Pekka, Martin-Ruiz, Carmen, Min, Junxia, Nebel, Almut, Newman, Anne B., Nie, Chao, Nohr, Ellen A., Orwoll, Eric S., Perls, Thomas T., Province, Michael A., Psaty, Bruce M., Raitakari, Olli T., Reinders, Marcel J. T., Robine, Jean-Marie, Rotter, Jerome I., Sebastiani, Paola, Smith, Jennifer, Sørensen, Thorkild I. A., Taylor, Kent D., Uitterlinden, André G., van der Flier, Wiesje, van der Lee, Sven J., van Duijn, Cornelia M., van Heemst, Diana, Vaupel, James W., Weir, David, Ye, Kenny, Zeng, Yi, Zheng, Wanlin, Holstege, Henne, Kiel, Douglas P., Lunetta, Kathryn L., Slagboom, P. Eline, and Murabito, Joanne M.

Published
2021
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41. GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.

Author

Broer, Linda, Buchman, Aron S, Deelen, Joris, Evans, Daniel S, Faul, Jessica D, Lunetta, Kathryn L, Sebastiani, Paola, Smith, Jennifer A, Smith, Albert V, Tanaka, Toshiko, Yu, Lei, Arnold, Alice M, Aspelund, Thor, Benjamin, Emelia J, De Jager, Philip L, Eirkisdottir, Gudny, Evans, Denis A, Garcia, Melissa E, Hofman, Albert, Kaplan, Robert C, Kardia, Sharon LR, Kiel, Douglas P, Oostra, Ben A, Orwoll, Eric S, Parimi, Neeta, Psaty, Bruce M, Rivadeneira, Fernando, Rotter, Jerome I, Seshadri, Sudha, Singleton, Andrew, Tiemeier, Henning, Uitterlinden, André G, Zhao, Wei, Bandinelli, Stefania, Bennett, David A, Ferrucci, Luigi, Gudnason, Vilmundur, Harris, Tamara B, Karasik, David, Launer, Lenore J, Perls, Thomas T, Slagboom, P Eline, Tranah, Gregory J, Weir, David R, Newman, Anne B, van Duijn, Cornelia M, and Murabito, Joanne M

Subjects
Humans, Apolipoproteins E, Cell Adhesion Molecules, Receptors, Kainic Acid, Cohort Studies, Longevity, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Forkhead Transcription Factors, Genome-Wide Association Study, Forkhead Box Protein O3, APOE., FOXO3, GWAS, APOE, Receptors, Kainic Acid, Polymorphism, Single Nucleotide, and over, Gerontology, Clinical Sciences
Abstract

BackgroundThe genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.MethodsWe conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.ResultsIn our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).ConclusionsWe did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

Published
2015

42. Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels

Author

Kwan, Johnny SH, Hsu, Yi-Hsiang, Cheung, Ching-Lung, Dupuis, Josée, Saint-Pierre, Aude, Eriksson, Joel, Handelman, Samuel K, Aragaki, Aaron, Karasik, David, Pramstaller, Peter P, Kooperberg, Charles, Lacroix, Andrea Z, Larson, Martin G, Lau, Kam-Shing, Lorentzon, Mattias, Pichler, Irene, Sham, Pak C, Taliun, Daniel, Vandenput, Liesbeth, Kiel, Douglas P, Hicks, Andrew A, Jackson, Rebecca D, Ohlsson, Claes, Benjamin, Emelia J, and Kung, Annie WC

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Atherosclerosis, Asian People, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 17, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Male, Osteoprotegerin, Polymorphism, Genetic, Quantitative Trait, Heritable, White People, Medical and Health Sciences, Genetics & Heredity
Abstract

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

Published
2014

44. 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, Hua Zhao, Jing, 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, Coviello, Andrea D, Cox, Angela, Czene, Kamila, D’adamo, Adamo Pio, Davey Smith, George, 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, and Kiel, Douglas P

Subjects
Paediatrics, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Contraception/Reproduction, Pediatric, Biotechnology, Human Genome, Clinical Research, Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Calcium-Binding Proteins, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins, Ubiquitin-Protein Ligases, Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, General Science & Technology
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 mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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

Published
2014

45. Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Author

Moayyeri, Alireza, Hsu, Yi-Hsiang, Karasik, David, Estrada, Karol, Xiao, Su-Mei, Nielson, Carrie, Srikanth, Priya, Giroux, Sylvie, Wilson, Scott G, Zheng, Hou-Feng, Smith, Albert V, Pye, Stephen R, Leo, Paul J, Teumer, Alexander, Hwang, Joo-Yeon, Ohlsson, Claes, McGuigan, Fiona, Minster, Ryan L, Hayward, Caroline, Olmos, José M, Lyytikäinen, Leo-Pekka, Lewis, Joshua R, Swart, Karin MA, Masi, Laura, Oldmeadow, Chris, Holliday, Elizabeth G, Cheng, Sulin, van Schoor, Natasja M, Harvey, Nicholas C, Kruk, Marcin, del Greco M, Fabiola, Igl, Wilmar, Trummer, Olivia, Grigoriou, Efi, Luben, Robert, Liu, Ching-Ti, Zhou, Yanhua, Oei, Ling, Medina-Gomez, Carolina, Zmuda, Joseph, Tranah, Greg, Brown, Suzanne J, Williams, Frances M, Soranzo, Nicole, Jakobsdottir, Johanna, Siggeirsdottir, Kristin, Holliday, Kate L, Hannemann, Anke, Go, Min Jin, Garcia, Melissa, Polasek, Ozren, Laaksonen, Marika, Zhu, Kun, Enneman, Anke W, McEvoy, Mark, Peel, Roseanne, Sham, Pak Chung, Jaworski, Maciej, Johansson, Åsa, Hicks, Andrew A, Pludowski, Pawel, Scott, Rodney, Dhonukshe-Rutten, Rosalie AM, van der Velde, Nathalie, Kähönen, Mika, Viikari, Jorma S, Sievänen, Harri, Raitakari, Olli T, González-Macías, Jesús, Hernández, Jose L, Mellström, Dan, Ljunggren, Osten, Cho, Yoon Shin, Völker, Uwe, Nauck, Matthias, Homuth, Georg, Völzke, Henry, Haring, Robin, Brown, Matthew A, McCloskey, Eugene, Nicholson, Geoffrey C, Eastell, Richard, Eisman, John A, Jones, Graeme, Reid, Ian R, Dennison, Elaine M, Wark, John, Boonen, Steven, Vanderschueren, Dirk, Wu, Frederick CW, Aspelund, Thor, Richards, J Brent, Bauer, Doug, Hofman, Albert, Khaw, Kay-Tee, Dedoussis, George, Obermayer-Pietsch, Barbara, Gyllensten, Ulf, Pramstaller, Peter P, and Lorenc, Roman S

Subjects
Calcaneus, Humans, Osteoporosis, Genetic Predisposition to Disease, Ultrasonography, Cohort Studies, Bone Density, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Fractures, Bone, Genome-Wide Association Study, Young Adult, Human Genome, Genetics, Aging, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Published
2014

48. Geodesic Nucleation and Evolution of a de Sitter Brane

Author

Davidson, Aharon, Karasik, David, and Lederer, Yoav

Subjects
General Relativity and Quantum Cosmology
Abstract

Within the framework of Geodesic Brane Gravity, the deviation from General Relativity is parameterized by the conserved bulk energy. The corresponding geodesic evolution/nucleation of a de-Sitter brane is shown to be exclusively driven by a double-well Higgs potential, rather than by a plain cosmological constant. The (hairy) horizon serves then as the locus of unbroken $Z_{2}$ symmetry. The quartic structure of the scalar potential, singled out on finiteness grounds of the total (including the dark component) energy density, chooses the Hartle-Hawking no-boundary proposal., Comment: 5 PRD pages, 4 eps figures

Published
2005
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