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2. 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

3. Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Author

Zillikens, M Carola, Demissie, Serkalem, Hsu, Yi-Hsiang, Yerges-Armstrong, Laura M, Chou, Wen-Chi, Stolk, Lisette, Livshits, Gregory, Broer, Linda, Johnson, Toby, Koller, Daniel L, Kutalik, Zoltán, Luan, Jian'an, Malkin, Ida, Ried, Janina S, Smith, Albert V, Thorleifsson, Gudmar, Vandenput, Liesbeth, Hua Zhao, Jing, Zhang, Weihua, Aghdassi, Ali, Åkesson, Kristina, Amin, Najaf, Baier, Leslie J, Barroso, Inês, Bennett, David A, Bertram, Lars, Biffar, Rainer, Bochud, Murielle, Boehnke, Michael, Borecki, Ingrid B, Buchman, Aron S, Byberg, Liisa, Campbell, Harry, Campos Obanda, Natalia, Cauley, Jane A, Cawthon, Peggy M, Cederberg, Henna, Chen, Zhao, Cho, Nam H, Jin Choi, Hyung, Claussnitzer, Melina, Collins, Francis, Cummings, Steven R, De Jager, Philip L, Demuth, Ilja, Dhonukshe-Rutten, Rosalie AM, Diatchenko, Luda, Eiriksdottir, Gudny, Enneman, Anke W, Erdos, Mike, Eriksson, Johan G, Eriksson, Joel, Estrada, Karol, Evans, Daniel S, Feitosa, Mary F, Fu, Mao, Garcia, Melissa, Gieger, Christian, Girke, Thomas, Glazer, Nicole L, Grallert, Harald, Grewal, Jagvir, Han, Bok-Ghee, Hanson, Robert L, Hayward, Caroline, Hofman, Albert, Hoffman, Eric P, Homuth, Georg, Hsueh, Wen-Chi, Hubal, Monica J, Hubbard, Alan, Huffman, Kim M, Husted, Lise B, Illig, Thomas, Ingelsson, Erik, Ittermann, Till, Jansson, John-Olov, Jordan, Joanne M, Jula, Antti, Karlsson, Magnus, Khaw, Kay-Tee, Kilpeläinen, Tuomas O, Klopp, Norman, Kloth, Jacqueline SL, Koistinen, Heikki A, Kraus, William E, Kritchevsky, Stephen, Kuulasmaa, Teemu, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Lang, Thomas, Langdahl, Bente L, Launer, Lenore J, Lee, Jong-Young, Lerch, Markus M, Lewis, Joshua R, Lind, Lars, Lindgren, Cecilia, and Liu, Yongmei

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics
Abstract

A correction to this article has been published and is linked from the HTML version of this article.

Published
2017

4. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Author

Zillikens, M Carola, Demissie, Serkalem, Hsu, Yi-Hsiang, Yerges-Armstrong, Laura M, Chou, Wen-Chi, Stolk, Lisette, Livshits, Gregory, Broer, Linda, Johnson, Toby, Koller, Daniel L, Kutalik, Zoltán, Luan, Jian'an, Malkin, Ida, Ried, Janina S, Smith, Albert V, Thorleifsson, Gudmar, Vandenput, Liesbeth, Hua Zhao, Jing, Zhang, Weihua, Aghdassi, Ali, Åkesson, Kristina, Amin, Najaf, Baier, Leslie J, Barroso, Inês, Bennett, David A, Bertram, Lars, Biffar, Rainer, Bochud, Murielle, Boehnke, Michael, Borecki, Ingrid B, Buchman, Aron S, Byberg, Liisa, Campbell, Harry, Campos Obanda, Natalia, Cauley, Jane A, Cawthon, Peggy M, Cederberg, Henna, Chen, Zhao, Cho, Nam H, Jin Choi, Hyung, Claussnitzer, Melina, Collins, Francis, Cummings, Steven R, De Jager, Philip L, Demuth, Ilja, Dhonukshe-Rutten, Rosalie AM, Diatchenko, Luda, Eiriksdottir, Gudny, Enneman, Anke W, Erdos, Mike, Eriksson, Johan G, Eriksson, Joel, Estrada, Karol, Evans, Daniel S, Feitosa, Mary F, Fu, Mao, Garcia, Melissa, Gieger, Christian, Girke, Thomas, Glazer, Nicole L, Grallert, Harald, Grewal, Jagvir, Han, Bok-Ghee, Hanson, Robert L, Hayward, Caroline, Hofman, Albert, Hoffman, Eric P, Homuth, Georg, Hsueh, Wen-Chi, Hubal, Monica J, Hubbard, Alan, Huffman, Kim M, Husted, Lise B, Illig, Thomas, Ingelsson, Erik, Ittermann, Till, Jansson, John-Olov, Jordan, Joanne M, Jula, Antti, Karlsson, Magnus, Khaw, Kay-Tee, Kilpeläinen, Tuomas O, Klopp, Norman, Kloth, Jacqueline SL, Koistinen, Heikki A, Kraus, William E, Kritchevsky, Stephen, Kuulasmaa, Teemu, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Lang, Thomas, Langdahl, Bente L, Launer, Lenore J, Lee, Jong-Young, Lerch, Markus M, Lewis, Joshua R, Lind, Lars, Lindgren, Cecilia, and Liu, Yongmei

Subjects
Humans, Thinness, 17-Hydroxysteroid Dehydrogenases, Aldehyde Oxidoreductases, Extracellular Matrix Proteins, Body Composition, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Elements, Transcriptional, Versicans, Genome-Wide Association Study, Insulin Receptor Substrate Proteins, ADAMTS Proteins, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Human Genome, Genetics, 1.1 Normal biological development and functioning
Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p

Published
2017

6. Genomewide meta‐analysis identifies loci associated with IGF‐I and IGFBP‐3 levels with impact on age‐related traits

Author

Teumer, Alexander, Qi, Qibin, Nethander, Maria, Aschard, Hugues, Bandinelli, Stefania, Beekman, Marian, Berndt, Sonja I, Bidlingmaier, Martin, Broer, Linda, Group, CHARGE Longevity Working, Cappola, Anne, Ceda, Gian Paolo, Chanock, Stephen, Chen, Ming‐Huei, Chen, Tai C, Chen, Yii‐Der Ida, Chung, Jonathan, Del Greco Miglianico, Fabiola, Eriksson, Joel, Ferrucci, Luigi, Friedrich, Nele, Gnewuch, Carsten, Goodarzi, Mark O, Grarup, Niels, Guo, Tingwei, Hammer, Elke, Hayes, Richard B, Hicks, Andrew A, Hofman, Albert, Houwing‐Duistermaat, Jeanine J, Hu, Frank, Hunter, David J, Husemoen, Lise L, Isaacs, Aaron, Jacobs, Kevin B, Janssen, Joop AMJL, Jansson, John‐Olov, Jehmlich, Nico, Johnson, Simon, Juul, Anders, Karlsson, Magnus, Kilpelainen, Tuomas O, Kovacs, Peter, Kraft, Peter, Li, Chao, Linneberg, Allan, Liu, Yongmei, Loos, Ruth JF, Consortium, Body Composition Genetics, Lorentzon, Mattias, Lu, Yingchang, Maggio, Marcello, Magi, Reedik, Meigs, James, Mellström, Dan, Nauck, Matthias, Newman, Anne B, Pollak, Michael N, Pramstaller, Peter P, Prokopenko, Inga, Psaty, Bruce M, Reincke, Martin, Rimm, Eric B, Rotter, Jerome I, Pierre, Aude Saint, Schurmann, Claudia, Seshadri, Sudha, Sjögren, Klara, Slagboom, P Eline, Strickler, Howard D, Stumvoll, Michael, Suh, Yousin, Sun, Qi, Zhang, Cuilin, Svensson, Johan, Tanaka, Toshiko, Tare, Archana, Tönjes, Anke, Uh, Hae‐Won, van Duijn, Cornelia M, van Heemst, Diana, Vandenput, Liesbeth, Vasan, Ramachandran S, Völker, Uwe, Willems, Sara M, Ohlsson, Claes, Wallaschofski, Henri, and Kaplan, Robert C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Aging, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Cardiovascular, Adult, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Metabolome, Quantitative Trait Loci, Quantitative Trait, Heritable, Regulatory Sequences, Nucleic Acid, aging, genomewide association study, growth hormone axis, IGF-I, IGFBP-3, longevity, CHARGE Longevity Working Group, Body Composition Genetics Consortium, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

Published
2016

7. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Author

Kilpeläinen, Tuomas O, Carli, Jayne F Martin, Skowronski, Alicja A, Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F, Hedman, Åsa K, Drong, Alexander W, Hayes, James E, Zhao, Jinghua, Pers, Tune H, Schick, Ursula, Grarup, Niels, Kutalik, Zoltán, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikäinen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renström, Frida, Willems, Sara M, Mahajan, Anubha, Rose, Lynda M, Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E, Pérusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S, Ju Sung, Yun, Ramos, Yolande F, Amin, Najaf, Amuzu, Antoinette, Barroso, Inês, Bellis, Claire, Blangero, John, Buckley, Brendan M, Böhringer, Stefan, I Chen, Yii-Der, de Craen, Anton JN, Crosslin, David R, Dale, Caroline E, Dastani, Zari, Day, Felix R, Deelen, Joris, Delgado, Graciela E, Demirkan, Ayse, Finucane, Francis M, Ford, Ian, Garcia, Melissa E, Gieger, Christian, Gustafsson, Stefan, Hallmans, Göran, Hankinson, Susan E, Havulinna, Aki S, Herder, Christian, Hernandez, Dena, Hicks, Andrew A, Hunter, David J, Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S, Jørgensen, Marit E, Jørgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A, Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P, Myers, Richard H, Männistö, Satu, Nalls, Mike A, Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D, Rankinen, Tuomo, Rasmussen-Torvik, Laura J, Rathmann, Wolfgang, Rice, Treva K, Brent Richards, J, Ridker, Paul M, Sattar, Naveed, and Savage, David B

Subjects
Adipose Tissue, Animals, Mice, Leptin, RNA, Messenger, Tissue Culture Techniques, Gene Expression Regulation, Male, Genome-Wide Association Study, Gene Knockdown Techniques, RNA, Messenger
Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P

Published
2016

8. Reduction of body weight by increased loading is associated with activation of norepinephrine neurones in the medial nucleus of the solitary tract

Author

Zlatkovic, Jovana, primary, Dalmau Gasull, Adrià, additional, Hägg, Daniel, additional, Font‐Gironès, Ferran, additional, Bellman, Jakob, additional, Meister, Björn, additional, Palsdottir, Vilborg, additional, Ruud, Johan, additional, Ohlsson, Claes, additional, Dickson, Suzanne L., additional, Anesten, Fredrik, additional, and Jansson, John‐Olov, additional

Published
2023
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11. Body weight homeostat that regulates fat mass independently of leptin in rats and mice

Author

Jansson, John-Olov, Palsdottir, Vilborg, Hägg, Daniel A., Schéle, Erik, Dickson, Suzanne L., Anesten, Fredrik, Bake, Tina, Montelius, Mikael, Bellman, Jakob, Johansson, Maria E., Cone, Roger D., Drucker, Daniel J., Wu, Jianyao, Aleksic, Biljana, Törnqvist, Anna E., Sjögren, Klara, Gustafsson, Jan-Åke, Windahl, Sara H., and Ohlsson, Claes

Published
2018

12. A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Author

Coviello, Andrea D, Haring, Robin, Wellons, Melissa, Vaidya, Dhananjay, Lehtimäki, Terho, Keildson, Sarah, Lunetta, Kathryn L, He, Chunyan, Fornage, Myriam, Lagou, Vasiliki, Mangino, Massimo, Onland-Moret, N Charlotte, Chen, Brian, Eriksson, Joel, Garcia, Melissa, Liu, Yong Mei, Koster, Annemarie, Lohman, Kurt, Lyytikäinen, Leo-Pekka, Petersen, Ann-Kristin, Prescott, Jennifer, Stolk, Lisette, Vandenput, Liesbeth, Wood, Andrew R, Zhuang, Wei Vivian, Ruokonen, Aimo, Hartikainen, Anna-Liisa, Pouta, Anneli, Bandinelli, Stefania, Biffar, Reiner, Brabant, Georg, Cox, David G, Chen, Yuhui, Cummings, Steven, Ferrucci, Luigi, Gunter, Marc J, Hankinson, Susan E, Martikainen, Hannu, Hofman, Albert, Homuth, Georg, Illig, Thomas, Jansson, John-Olov, Johnson, Andrew D, Karasik, David, Karlsson, Magnus, Kettunen, Johannes, Kiel, Douglas P, Kraft, Peter, Liu, Jingmin, Ljunggren, Östen, Lorentzon, Mattias, Maggio, Marcello, Markus, Marcello RP, Mellström, Dan, Miljkovic, Iva, Mirel, Daniel, Nelson, Sarah, Papunen, Laure Morin, Peeters, Petra HM, Prokopenko, Inga, Raffel, Leslie, Reincke, Martin, Reiner, Alex P, Rexrode, Kathryn, Rivadeneira, Fernando, Schwartz, Stephen M, Siscovick, David, Soranzo, Nicole, Stöckl, Doris, Tworoger, Shelley, Uitterlinden, André G, van Gils, Carla H, Vasan, Ramachandran S, Wichmann, H-Erich, Zhai, Guangju, Bhasin, Shalender, Bidlingmaier, Martin, Chanock, Stephen J, De Vivo, Immaculata, Harris, Tamara B, Hunter, David J, Kähönen, Mika, Liu, Simin, Ouyang, Pamela, Spector, Tim D, van der Schouw, Yvonne T, Viikari, Jorma, Wallaschofski, Henri, McCarthy, Mark I, Frayling, Timothy M, Murray, Anna, Franks, Steve, Järvelin, Marjo-Riitta, de Jong, Frank H, Raitakari, Olli, Teumer, Alexander, Ohlsson, Claes, Murabito, Joanne M, and Perry, John RB

Subjects
Biological Sciences, Genetics, Breast Cancer, Aging, Estrogen, Cancer Genomics, Urologic Diseases, Cancer, Prostate Cancer, Human Genome, Women's Health, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Alleles, Female, Genetic Heterogeneity, Genome-Wide Association Study, Gonadal Steroid Hormones, Humans, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Sex Characteristics, Sex Hormone-Binding Globulin, Developmental Biology
Abstract

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Published
2012

13. Genetic determinants of serum testosterone concentrations in men.

Author

Ohlsson, Claes, Wallaschofski, Henri, Lunetta, Kathryn L, Stolk, Lisette, Perry, John RB, Koster, Annemarie, Petersen, Ann-Kristin, Eriksson, Joel, Lehtimäki, Terho, Huhtaniemi, Ilpo T, Hammond, Geoffrey L, Maggio, Marcello, Coviello, Andrea D, EMAS Study Group, Ferrucci, Luigi, Heier, Margit, Hofman, Albert, Holliday, Kate L, Jansson, John-Olov, Kähönen, Mika, Karasik, David, Karlsson, Magnus K, Kiel, Douglas P, Liu, Yongmei, Ljunggren, Osten, Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Meitinger, Thomas, Mellström, Dan, Melzer, David, Miljkovic, Iva, Nauck, Matthias, Nilsson, Maria, Penninx, Brenda, Pye, Stephen R, Vasan, Ramachandran S, Reincke, Martin, Rivadeneira, Fernando, Tajar, Abdelouahid, Teumer, Alexander, Uitterlinden, André G, Ulloor, Jagadish, Viikari, Jorma, Völker, Uwe, Völzke, Henry, Wichmann, H Erich, Wu, Tsung-Sheng, Zhuang, Wei Vivian, Ziv, Elad, Wu, Frederick CW, Raitakari, Olli, Eriksson, Anna, Bidlingmaier, Martin, Harris, Tamara B, Murray, Anna, de Jong, Frank H, Murabito, Joanne M, Bhasin, Shalender, Vandenput, Liesbeth, and Haring, Robin

Subjects
EMAS Study Group, Chromosomes, Human, X, Humans, Testosterone, Sex Hormone-Binding Globulin, Nuclear Proteins, Body Mass Index, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, 80 and over, Middle Aged, Male, Genome-Wide Association Study, Aged, and over, Chromosomes, Human, X, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as

Published
2011

15. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Author

Speliotes, Elizabeth K, Willer, Cristen J, Berndt, Sonja I, Monda, Keri L, Thorleifsson, Gudmar, Jackson, Anne U, Allen, Hana Lango, Lindgren, Cecilia M, Luan, Jian'an, Mägi, Reedik, Randall, Joshua C, Vedantam, Sailaja, Winkler, Thomas W, Qi, Lu, Workalemahu, Tsegaselassie, Heid, Iris M, Steinthorsdottir, Valgerdur, Stringham, Heather M, Weedon, Michael N, Wheeler, Eleanor, Wood, Andrew R, Ferreira, Teresa, Weyant, Robert J, Segrè, Ayellet V, Estrada, Karol, Liang, Liming, Nemesh, James, Park, Ju-Hyun, Gustafsson, Stefan, Kilpeläinen, Tuomas O, Yang, Jian, Bouatia-Naji, Nabila, Esko, Tõnu, Feitosa, Mary F, Kutalik, Zoltán, Mangino, Massimo, Raychaudhuri, Soumya, Scherag, Andre, Smith, Albert Vernon, Welch, Ryan, Zhao, Jing Hua, Aben, Katja K, Absher, Devin M, Amin, Najaf, Dixon, Anna L, Fisher, Eva, Glazer, Nicole L, Goddard, Michael E, Heard-Costa, Nancy L, Hoesel, Volker, Hottenga, Jouke-Jan, Johansson, Åsa, Johnson, Toby, Ketkar, Shamika, Lamina, Claudia, Li, Shengxu, Moffatt, Miriam F, Myers, Richard H, Narisu, Narisu, Perry, John RB, Peters, Marjolein J, Preuss, Michael, Ripatti, Samuli, Rivadeneira, Fernando, Sandholt, Camilla, Scott, Laura J, Timpson, Nicholas J, Tyrer, Jonathan P, van Wingerden, Sophie, Watanabe, Richard M, White, Charles C, Wiklund, Fredrik, Barlassina, Christina, Chasman, Daniel I, Cooper, Matthew N, Jansson, John-Olov, Lawrence, Robert W, Pellikka, Niina, Prokopenko, Inga, Shi, Jianxin, Thiering, Elisabeth, Alavere, Helene, Alibrandi, Maria TS, Almgren, Peter, Arnold, Alice M, Aspelund, Thor, Atwood, Larry D, Balkau, Beverley, Balmforth, Anthony J, Bennett, Amanda J, Ben-Shlomo, Yoav, Bergman, Richard N, Bergmann, Sven, Biebermann, Heike, Blakemore, Alexandra IF, Boes, Tanja, Bonnycastle, Lori L, Bornstein, Stefan R, Brown, Morris J, and Buchanan, Thomas A

Subjects
Biological Sciences, Genetics, Prevention, Human Genome, Body Height, Body Mass Index, Body Size, Body Weight, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide, White People, MAGIC, Procardis Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Published
2010

21. Common genetic determinants of vitamin D insufficiency: a genome-wide association study

Author

Wang, Thomas J, Zhang, Feng, Richards, J Brent, Kestenbaum, Bryan, van Meurs, Joyce B, Berry, Diane, Kiel, Douglas P, Streeten, Elizabeth A, Ohlsson, Claes, Koller, Daniel L, Peltonen, Leena, Cooper, Jason D, O'Reilly, Paul F, Houston, Denise K, Glazer, Nicole L, Vandenput, Liesbeth, Peacock, Munro, Shi, Julia, Rivadeneira, Fernando, McCarthy, Mark I, Anneli, Pouta, de Boer, Ian H, Mangino, Massimo, Kato, Bernet, Smyth, Deborah J, Booth, Sarah L, Jacques, Paul F, Burke, Greg L, Goodarzi, Mark, Cheung, Ching-Lung, Wolf, Myles, Rice, Kenneth, Goltzman, David, Hidiroglou, Nick, Ladouceur, Martin, Wareham, Nicholas J, Hocking, Lynne J, Hart, Deborah, Arden, Nigel K, Cooper, Cyrus, Malik, Suneil, Fraser, William D, Hartikainen, Anna-Liisa, Zhai, Guangju, Macdonald, Helen M, Forouhi, Nita G, Loos, Ruth JF, Reid, David M, Hakim, Alan, Dennison, Elaine, Liu, Yongmei, Power, Chris, Stevens, Helen E, Jaana, Laitinen, Vasan, Ramachandran S, Soranzo, Nicole, Bojunga, Jörg, Psaty, Bruce M, Lorentzon, Mattias, Foroud, Tatiana, Harris, Tamara B, Hofman, Albert, Jansson, John-Olov, Cauley, Jane A, Uitterlinden, Andre G, Gibson, Quince, Järvelin, Marjo-Riitta, Karasik, David, Siscovick, David S, Econs, Michael J, Kritchevsky, Stephen B, Florez, Jose C, Todd, John A, Dupuis, Josee, Hyppönen, Elina, and Spector, Timothy D

Published
2010
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22. Testosterone reduces metabolic brown fat activity in male mice

Author

Lantero Rodriguez, Marta, primary, Schilperoort, Maaike, additional, Johansson, Inger, additional, Svedlund Eriksson, Elin, additional, Palsdottir, Vilborg, additional, Kroon, Jan, additional, Henricsson, Marcus, additional, Kooijman, Sander, additional, Ericson, Mia, additional, Borén, Jan, additional, Ohlsson, Claes, additional, Jansson, John-Olov, additional, Levin, Malin C, additional, Rensen, Patrick C N, additional, and Tivesten, Åsa, additional

Published
2021
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23. Interactions Between the Gravitostat and the Fibroblast Growth Factor System for the Regulation of Body Weight

Author

Palsdottir, Vilborg, Windahl, Sara H, Hägg, Daniel A, Keantar, Hanna, Bellman, Jakob, Buchanan, Andrew, Vaughan, Tristan J, Lindén, Daniel, Jansson, John-Olov, and Ohlsson, Claes

Subjects
Leptin, Mice, Knockout, Obesity and Adipocyte Biology, Brief Report, Body Weight, Antibodies, Monoclonal, Gene Expression, Mice, Transgenic, Fibroblast Growth Factors, Mice, Inbred C57BL, Adipose Tissue, Liver, Animals, Obesity, Receptor, Fibroblast Growth Factor, Type 1
Abstract

Both fibroblast growth factors (FGFs), by binding to FGF receptors (FGFRs), and activation of the gravitostat, by artificial loading, decrease the body weight (BW). Previous studies demonstrate that both the FGF system and loading have the capacity to regulate BW independently of leptin. The aim of the current study was to determine the possible interactions between the effect of increased loading and the FGF system for the regulation of BW. We observed that the BW-reducing effect of increased loading was abolished in mice treated with a monoclonal antibody directed against FGFR1c, suggesting interactions between the two systems. As serum levels of endocrine FGF21 and hepatic FGF21 mRNA were increased in the loaded mice compared with the control mice, we first evaluated the loading response in FGF21 over expressing mice with constant high FGF21 levels. Leptin treatment, but not increased loading, decreased the BW in the FGF21-overexpressing mice, demonstrating that specifically the loading effect is attenuated in the presence of high activity in the FGF system. However, as FGF21 knockout mice displayed a normal loading response on BW, FGF21 is neither mediating nor essential for the loading response. In conclusion, the BW-reducing effect of increased loading but not of leptin treatment is blocked by high activity in the FGF system. We propose that both the gravitostat and the FGF system regulate BW independently of leptin and that pharmacologically enhanced activity in the FGF system reduces the sensitivity of the gravitostat.

Published
2019

28. Downregulation of cilia-localized Il-6R[alpha] by 17[beta]-estradiol in mouse and human fallopian tubes

Author

Shao, Ruijin, Nutu, Magdalena, Karlsson-Lindahl, Linda, Benrick, Anna, Weijdegard, Birgitta, Lager, Susanne, Egecioglu, Emil, Fernandez-Rodriguez, Julia, Gemzell-Danielsson, Kristina, Ohlsson, Claes, Jansson, John-Olov, and Billig, Hakan

Subjects
Estradiol -- Physiological aspects, Fallopian tubes -- Properties, Interleukin-6 -- Physiological aspects, Biological sciences
Abstract

The action of interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6R[alpha] and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6R[alpha] is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17[beta]-estradiol ([E.sub.2]), but not progesterone ([P.sub.4]), causes a time-dependent decrease in IL-6R[alpha] expression, which is blocked by the estrogen receptor (ER) antagonist ICI-182,780. Exposure of different ER-selective agonists propyl-(1H)-pyrazole-1,3,5-triyl-trisphenol or 2,3-bis-(4-hydroxyphenyl)-propionitrile demonstrated an ER subtype-specific regulation of IL-6R[alpha] in mouse fallopian tubes. In contrast to IL-6R[alpha], gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6R[alpha] and gp130 in IL-6 knockout mice was found to be normal; however, [E.sub.2] treatment increased IL-6R[alpha], but not gp130, in IL-6 knockout mice when compared with wild-type mice. Furthermore, expression levels of IL-6R[alpha], but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings open the posibility that cilia-specific IL-6R[alpha] may play a role in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6R[alpha] in the fallopian tube. estrogen; oocyte-cumulus complex transport

Published
2009

31. Reduced stress- and cold-induced increase in energy expenditure in interleukin-6-deficient mice

Author

Wernstedt, Ingrid, Edgley, Amanda, Berndtsson, Anna, Faldt, Jenny, Bergstrom, Goran, Wallenius, Ville, and Jansson, John-Olov

Subjects
Interleukin-6 -- Health aspects, Bioenergetics -- Research, Energy metabolism -- Research, Biological sciences
Abstract

Interleukin-6 (IL-6) deficient (-/-) mice develop mature onset obesity. Pharmacological studies have shown that IL-6 has direct lipolytic effects and when administered centrally increases sympathetic outflow. However, the metabolic functions of endogenous IL-6 are not fully elucidated. We aimed to investigate the effect of IL-6 deficiency with respect to cold exposure and cage-switch stress, that is, situations that normally increase sympathetic outflow. Energy metabolism, core temperature, heart rate, and activity were investigated in young preobese IL-6-/- mice by indirect calorimetry together with telemetry. Baseline measurements and the effect of cage-switch stress were investigated at thermoneutrality (30[degrees]C) and at room temperature (20[degrees]C). The effect of cold exposure was investigated at 4[degrees]C. At 30[degrees]C, the basal core temperature was 0.6 [+ or -] 0.24[degrees]C lower in IL-6-/- compared with wild-type mice, whereas the oxygen consumption did not differ significantly. The respiratory exchange ratio at 20[degrees]C was significantly higher and the calculated fat utilization rate was lower in IL-6-/- mice. In response to cage-switch stress, the increase in oxygen consumption at both 30 and 20[degrees]C was lower in IL-6-/- than in wild-type mice. The increase in heart rate was lower in IL-6-/- mice at 30[degrees]C. At 4[degrees]C, both the oxygen consumption and core temperature were lower in IL-6-/- compared with wild-type mice, suggesting a lower cold-induced thermogenesis in IL-6-/- mice. The present results indicate that endogenous IL-6 is of importance for stress- and cold-induced energy expenditure in mice. obesity; telemetry; indirect calorimetry; cytokine doi:10.1152/ajpregu.00514.2005.

Published
2006

32. Body weight homeostat that regulates fat mass independently of leptin in rats and mice

Author

Jansson, John-Olov, Palsdottir, Vilborg, Hägg, Daniel A., Schéle, Erik, Dickson, Suzanne L., Anesten, Fredrik, Bake, Tina, Montelius, Mikael, Bellman, Jakob, Johansson, Maria E., Cone, Roger D., Drucker, Daniel J., Wu, Jianyao, Aleksic, Biljana, Törnqvist, Anna E., Sjögren, Klara, Gustafsson, Jan-Åke, Windahl, Sara H., and Ohlsson, Claes

Subjects
Leptin, Mice, Knockout, diet-induced obesity, Physiology, glucose metabolism, Body Weight, Mice, Obese, Biological Sciences, Diet, High-Fat, Mice, Inbred C57BL, Rats, Sprague-Dawley, Adipose Tissue, Gene Expression Regulation, Animals, Homeostasis, Obesity, Letters, weight loss, Energy Intake, Energy Metabolism, osteocytes
Abstract

Significance The only known homeostatic regulator of fat mass is the leptin system. We hypothesized that there is a second homeostat regulating body weight with an impact on fat mass. In this study we have added and removed weight loads from experimental animals and measured the effects on the biological body weight. The results demonstrate that there is a body weight homeostat that regulates fat mass independently of leptin. As the body weight-reducing effect of increased loading was dependent on osteocytes, we propose that there is a sensor for body weight in the long bones of the lower extremities acting as “body scales.” This is part of a body weight homeostat, “gravitostat,” that keeps body weight and body fat mass constant., Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat (“gravitostat”) that regulates fat mass.

Published
2017

39. Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity

Author

Jiao, Hong, Arner, Peter, Dickson, Suzanne L., Vidal, Hubert, Mejhert, Niklas, Henegar, Corneliu, Taube, Magdalena, Hansson, Caroline, Hinney, Anke, Galan, Pilar, Simon, Chantal, Silveira, Angela, Benrick, Anna, Jansson, John-Olov, Bouloumié, Anne, Langin, Dominique, Laville, Martine, Debard, Cyrille, Axelsson, Tomas, Rydén, Mikael, Kere, Juha, Dahlman-Wright, Karin, Hamsten, Anders, Clement, Karine, and Dahlman, Ingrid

Published
2011

47. Testosterone reduces metabolic brown fat activity in male mice.

Author

Rodriguez, Marta Lantero, Schilperoort, Maaike, Johansson, Inger, Eriksson, Elin Svedlund, Palsdottir, Vilborg, Kroon, Jan, Henricsson, Marcus, Kooijman, Sander, Ericson, Mia, Borén, Jan, Ohlsson, Claes, Jansson, John-Olov, Levin, Malin C., Rensen, Patrick C. N., and Tivesten, Åsa

Subjects
BROWN adipose tissue, ANDROGEN receptors, HYPOTHERMIA, BODY temperature, TESTOSTERONE
Abstract

Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expre ssion of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceridederived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic a ctions of testosterone. [ABSTRACT FROM AUTHOR]

Published
2021
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