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3. Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study

Author

Tan, Vanessa Y, Bull, Caroline J, Biernacka, Kalina M, Teumer, Alexander, Richardson, Tom G, Sanderson, Eleanor, Corbin, Laura J, Dudding, Tom, Qi, Qibin, Kaplan, Robert C, Rotter, Jerome I, Friedrich, Nele, Völker, Uwe, Mayerle, Julia, Perks, Claire M, Holly, Jeff MP, and Timpson, Nicholas J

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Breast Cancer, Cardiovascular, Atherosclerosis, Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Causality, Cholesterol, HDL, Cholesterol, LDL, Cross-Sectional Studies, Female, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor I, Mendelian Randomization Analysis, Triglycerides, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundCirculating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer. Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to breast cancer overlap is unclear.MethodsMendelian randomization (MR) was conducted to estimate the relationship between lipids or IGF-I and breast cancer risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol, LDL-C; high-density lipoprotein cholesterol, HDL-C; triglycerides, TGs), IGF-I and breast cancer from GLGC/UKBB (N = 239,119), CHARGE/UKBB (N = 252,547), and Breast Cancer Association Consortium (N = 247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N = 3,812) and UKBB (N = 422,389), and using genetic summary statistics from GLGC (N = 188,577) and CHARGE/UKBB (N = 469,872).ResultsIn multivariable MR (MVMR) analyses, the OR for breast cancer per 1-SD increase in HDL-C and TG was 1.08 [95% confidence interval (CI), 1.04-1.13] and 0.94 (95% CI, 0.89-0.98), respectively. The OR for breast cancer per 1-SD increase in IGF-I was 1.09 (95% CI, 1.04-1.15). MR analyses suggested a bi-directional TG-IGF-I relationship (TG-IGF-I β per 1-SD: -0.13; 95% CI, -0.23 to -0.04; and IGF-I-TG β per 1-SD: -0.11; 95% CI, -0.18 to -0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with breast cancer were robust to adjustment for IGF-I or TG, respectively.ConclusionsOur findings suggest a causal role of HDL-C, TG, and IGF-I in breast cancer. Observational and MR analyses support an interplay between IGF-I and TG; however, MVMR estimates suggest that TG and IGF-I may act independently to influence breast cancer.ImpactOur findings should be considered in the development of prevention strategies for breast cancer, where interventions are known to modify circulating lipids and IGF-I.

Published
2021

4. Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes

Author

Bull, Caroline J., Hazelwood, Emma, Legge, Danny N., Corbin, Laura J., Richardson, Tom G., Lee, Matthew, Yarmolinsky, James, Smith-Byrne, Karl, Hughes, David A., Johansson, Mattias, Peters, Ulrike, Berndt, Sonja I., Brenner, Hermann, Burnett-Hartman, Andrea, Cheng, Iona, Kweon, Sun-Seog, Le Marchand, Loic, Li, Li, Newcomb, Polly A., Pearlman, Rachel, McConnachie, Alex, Welsh, Paul, Taylor, Roy, Lean, Mike E.J., Sattar, Naveed, Murphy, Neil, Gunter, Marc J., Timpson, Nicholas J., and Vincent, Emma E.

Published
2024
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7. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

Author

Wade, Kaitlin H., Lam, Brian Y. H., Melvin, Audrey, Pan, Warren, Corbin, Laura J., Hughes, David A., and Rainbow, Kara

Subjects
Gene mutations -- Health aspects, Obesity -- Genetic aspects -- Risk factors, Biological sciences, Health
Abstract

Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m.sup.-2 (95% CI 2.19, 7.49) and 14.78 kg (95% CI 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity. Analysis of mutations in MC4R and associated anthropometric phenotypes in the ALSPAC birth cohort reveals a prevalence of heterozygous loss of function of 0.30% and provides evidence that these mutations are associated with substantial excess adiposity in early life., Author(s): Kaitlin H. Wade [sup.1] [sup.2] , Brian Y. H. Lam [sup.3] , Audrey Melvin [sup.3] , Warren Pan [sup.3] , Laura J. Corbin [sup.1] [sup.2] , David A. Hughes [...]

Published
2021
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8. Epigenetic Regulation of F2RL3 Associates with Myocardial Infarction and Platelet Function

Author

Corbin, Laura J., White, Stephen J., Taylor, Amy E., Williams, Christopher M., Taylor, Kurt, van den Bosch, Marion T., Teasdale, Jack E., Jones, Matthew, Bond, Mark, Harper, Matthew T., Falk, Louise, Groom, Alix, Hazell, Georgina G J, Paternoster, Lavinia, Munafò, Marcus R., Nordestgaard, Børge G., Tybjærg-Hansen, Anne, Bojesen, Stig E., Relton, Caroline, Min, Josine L., Smith, George Davey, Mumford, Andrew D., Poole, Alastair W., and Timpson, Nicholas J.

Published
2022
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9. Inflammation proteomics datasets in the ALSPAC cohort

Author

Goulding, Neil, primary, Goudswaard, Lucy J., additional, Hughes, David A., additional, Corbin, Laura J., additional, Groom, Alix, additional, Ring, Susan, additional, Timpson, Nicholas J., additional, Fraser, Abigail, additional, Northstone, Kate, additional, and Suderman, Matthew, additional

Published
2024
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10. SMIM1 absence is associated with reduced energy expenditure and excess weight

Author

Banasik, Karina, Bay, Jakob, Boldsen, Jens Kjærgaard, Brodersen, Thorsten, Brunak, Søren, Burgdorf, Kristoffer, Chalmer, Mona Ameri, Didriksen, Maria, Dinh, Khoa Manh, Dowsett, Joseph, Erikstrup, Christian, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hansen, Thomas Folkmann, Hindhede, Lotte, Hjalgrim, Henrik, Jacobsen, Rikke Louise, Jemec, Gregor, Jensen, Bitten Aagaard, Kaspersen, Katrine, Kjerulff, Bertram Dalskov, Kogelman, Lisette, Hørup Larsen, Margit Anita, Louloudis, Ioannis, Lundgaard, Agnete, Susan, Mikkelsen, Christina, Nissen, Ioanna, Nyegaard, Mette, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Henriksen, Alexander Pil, Rohde, Palle Duun, Rostgaard, Klaus, Schwinn, Michael, Stefansson, Kari, Stefánsson, Hreinn, Sørensen, Erik, þorsteinsdóttir, Unnur, Thørner, Lise Wegner, Bruun, Mie Topholm, Ullum, Henrik, Werge, Thomas, Westergaard, David, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian’an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Katie Chan, Kei Hang, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Loz, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V.R., Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P., Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Southam, Lorraine, Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J.L., Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J.C., Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M. Arfan, Johnson, W. Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R.H.J., Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, Van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Goncalo R., Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Ida Chen, Yii-Der, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, Janaka de Silva, H., Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J. Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L.R., Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J.F., Magnusson, Patrik K.E., Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N.A., Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P. Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I.A., Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E. Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G.M., Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C.J., Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., Barroso, Inês, Stefanucci, Luca, Moslemi, Camous, Tomé, Ana R., Virtue, Samuel, Bidault, Guillaume, Gleadall, Nicholas S., Watson, Laura P.E., Kwa, Jing E., Burden, Frances, Farrow, Samantha, Võsa, Urmo, Burling, Keith, Walker, Lindsay, Ord, John, Barker, Peter, Warner, James, Frary, Amy, Renhstrom, Karola, Ashford, Sofie E., Piper, Jo, Biggs, Gail, Erber, Wendy N., Hoffman, Gary J., Schoenmakers, Nadia, Rieneck, Klaus, Dziegiel, Morten H., Azzu, Vian, Vacca, Michele, Aparicio, Hugo Javier, Hui, Qin, Cho, Kelly, Sun, Yan V., Wilson, Peter W., Bayraktar, Omer A., Vidal-Puig, Antonio, Ostrowski, Sisse R., Astle, William J., Olsson, Martin L., Storry, Jill R., Pedersen, Ole B., Ouwehand, Willem H., Chatterjee, Krishna, Vuckovic, Dragana, and Frontini, Mattia

Published
2024
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12. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

Author

Duckett, Katie, Williamson, Alice, Kincaid, John WR, Rainbow, Kara, Corbin, Laura J, Martin, Hilary C, Eberhardt, Ruth Y, Huang, Qin Qin, Hurles, Matthew E, He, Wen, Brauner, Raja, Delaney, Angela, Dunkel, Leo, Grinspon, Romina P, Hall, Janet E, Hirschhorn, Joel N, Howard, Sasha R, Latronico, Ana C, Jorge, Alexander AL, McElreavey, Ken, Mericq, Verónica, Merino, Paulina M, Palmert, Mark R, Plummer, Lacey, Rey, Rodolfo A, Rezende, Raíssa C, Seminara, Stephanie B, Salnikov, Kathryn, Banerjee, Indraneel, Lam, Brian YH, Perry, John RB, Timpson, Nicholas J, Clayton, Peter, Chan, Yee-Ming, Ong, Ken K, O'Rahilly, Stephen, Duckett, Katie [0000-0002-0222-1689], Williamson, Alice [0000-0002-7599-9301], Kincaid, John WR [0000-0003-0660-9813], Rainbow, Kara [0000-0002-8089-0693], Corbin, Laura J [0000-0002-4032-9500], Martin, Hilary C [0000-0002-4454-9084], Eberhardt, Ruth Y [0000-0001-6152-1369], Huang, Qin Qin [0000-0003-3073-717X], Hurles, Matthew E [0000-0002-2333-7015], Brauner, Raja [0000-0002-4456-4508], Delaney, Angela [0000-0002-0632-6365], Grinspon, Romina P [0000-0002-6291-1518], Hall, Janet E [0000-0003-4644-3061], Hirschhorn, Joel N [0000-0002-1650-7901], Palmert, Mark R [0000-0002-4096-0685], Lam, Brian YH [0000-0002-3638-9025], Timpson, Nicholas J [0000-0002-7141-9189], Clayton, Peter [0000-0003-1225-4537], Chan, Yee-Ming [0000-0003-0554-8502], Ong, Ken K [0000-0003-4689-7530], O'Rahilly, Stephen [0000-0003-2199-4449], and Apollo - University of Cambridge Repository

Subjects
UK Biobank, constitutional delay, MC3R, ALSPAC, delayed puberty
Abstract

ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Published
2023
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14. Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty

Author

Duckett, Katie, primary, Williamson, Alice, additional, Kincaid, John W R, additional, Rainbow, Kara, additional, Corbin, Laura J, additional, Martin, Hilary C, additional, Eberhardt, Ruth Y, additional, Huang, Qin Qin, additional, Hurles, Matthew E, additional, He, Wen, additional, Brauner, Raja, additional, Delaney, Angela, additional, Dunkel, Leo, additional, Grinspon, Romina P, additional, Hall, Janet E, additional, Hirschhorn, Joel N, additional, Howard, Sasha R, additional, Latronico, Ana C, additional, Jorge, Alexander A L, additional, McElreavey, Ken, additional, Mericq, Verónica, additional, Merino, Paulina M, additional, Palmert, Mark R, additional, Plummer, Lacey, additional, Rey, Rodolfo A, additional, Rezende, Raíssa C, additional, Seminara, Stephanie B, additional, Salnikov, Kathryn, additional, Banerjee, Indraneel, additional, Lam, Brian Y H, additional, Perry, John R B, additional, Timpson, Nicholas J, additional, Clayton, Peter, additional, Chan, Yee-Ming, additional, Ong, Ken K, additional, and O’Rahilly, Stephen, additional

Published
2023
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16. The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium

Author

Guida, Florence, Tan, Vanessa Y., Corbin, Laura J., Smith-Byrne, Karl, Alcala, Karine, Langenberg, Claudia, Stewart, Isobel D., Butterworth, Adam S., Surendran, Praveen, Achaintre, David, Adamski, Jerzy, Amiano Exezarreta, Pilar, Bergmann, Manuela M., Bull, Caroline J., Dahm, Christina C., Gicquiau, Audrey, Giles, Graham G., Gunter, Marc J., Haller, Toomas, Langhammer, Arnulf, Larose, Tricia L., Ljungberg, Börje, Metspalu, Andres, Milne, Roger L., Muller, David C., Nøst, Therese H., Pettersen Sørgjerd, Elin, Prehn, Cornelia, Riboli, Elio, Rinaldi, Sabina, Rothwell, Joseph A., Scalbert, Augustin, Schmidt, Julie A., Severi, Gianluca, Sieri, Sabina, Vermeulen, Roel, Vincent, Emma E., Waldenberger, Melanie, Timpson, Nicholas J., and Johansson, Mattias

Subjects
Kidney cancer -- Risk factors -- Development and progression -- Physiological aspects, Metabolites -- Health aspects -- Measurement, Body mass index, Biological sciences
Abstract

Background Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). Methods and findings We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 x 10.sup.-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 x 10.sup.-5 ), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ß.sub.BMI ] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 x 10.sup.-5). BMI was also associated with increased levels of glutamate (ß.sub.BMI : 0.12, p = 1.5 x 10.sup.-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. Conclusions This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer., Author(s): Florence Guida 1, Vanessa Y. Tan 2,3, Laura J. Corbin 2,3, Karl Smith-Byrne 1, Karine Alcala 1, Claudia Langenberg 4, Isobel D. Stewart 4, Adam S. Butterworth 5,6,7,8, Praveen [...]

Published
2021
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17. Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Author

Broadaway, K Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A, Wilson, Emma P, Moxley, Anne H, Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U, Ahuja, Vasudha, Bornstein, Stefan R, Corbin, Laura J, Delgado, Graciela E, Dwivedi, Om P, Silva, Lilian Fernandes, Frayling, Timothy M, Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A, Kleber, Marcus E, Lindgren, Cecilia M, Liu, Ching-Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P, Morris, Andrew P, Perakakis, Nikolaos, Peters, Annette, Petrie, John R, Roden, Michael, Schwarz, Peter E H, Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J, Tuomi, Tiinamaija, Wood, Andrew R, Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G, Fall, Tove, Florez, Jose C, Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A, Lind, Lars, März, Winfried, Meigs, James B, Sundström, Johan, Timpson, Nicholas J, Wagner, Robert, Walker, Mark, Wareham, Nicholas J, Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, Mohlke, Karen L, Broadaway, K Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A, Wilson, Emma P, Moxley, Anne H, Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U, Ahuja, Vasudha, Bornstein, Stefan R, Corbin, Laura J, Delgado, Graciela E, Dwivedi, Om P, Silva, Lilian Fernandes, Frayling, Timothy M, Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A, Kleber, Marcus E, Lindgren, Cecilia M, Liu, Ching-Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P, Morris, Andrew P, Perakakis, Nikolaos, Peters, Annette, Petrie, John R, Roden, Michael, Schwarz, Peter E H, Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J, Tuomi, Tiinamaija, Wood, Andrew R, Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G, Fall, Tove, Florez, Jose C, Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A, Lind, Lars, März, Winfried, Meigs, James B, Sundström, Johan, Timpson, Nicholas J, Wagner, Robert, Walker, Mark, Wareham, Nicholas J, Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, and Mohlke, Karen L

Abstract

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Published
2023
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18. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author

Broadaway, K. Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A., Wilson, Emma P., Moxley, Anne H., Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U., Ahuja, Vasudha, Bornstein, Stefan R., Corbin, Laura J., Delgado, Graciela E., Dwivedi, Om P., Silva, Lilian Fernandes, Frayling, Timothy M., Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A., Kleber, Marcus E., Lindgren, Cecilia M., Liu, Ching Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P., Morris, Andrew P., Perakakis, Nikolaos, Peters, Annette, Petrie, John R., Roden, Michael, Schwarz, Peter E.H., Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J., Tuomi, Tiinamaija, Wood, Andrew R., Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G., Fall, Tove, Florez, Jose C., Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A., Lind, Lars, März, Winfried, Meigs, James B., Sundström, Johan, Timpson, Nicholas J., Wagner, Robert, Walker, Mark, Wareham, Nicholas J., Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, Mohlke, Karen L., Broadaway, K. Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A., Wilson, Emma P., Moxley, Anne H., Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U., Ahuja, Vasudha, Bornstein, Stefan R., Corbin, Laura J., Delgado, Graciela E., Dwivedi, Om P., Silva, Lilian Fernandes, Frayling, Timothy M., Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A., Kleber, Marcus E., Lindgren, Cecilia M., Liu, Ching Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P., Morris, Andrew P., Perakakis, Nikolaos, Peters, Annette, Petrie, John R., Roden, Michael, Schwarz, Peter E.H., Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J., Tuomi, Tiinamaija, Wood, Andrew R., Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G., Fall, Tove, Florez, Jose C., Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A., Lind, Lars, März, Winfried, Meigs, James B., Sundström, Johan, Timpson, Nicholas J., Wagner, Robert, Walker, Mark, Wareham, Nicholas J., Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, and Mohlke, Karen L.

Abstract

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Published
2023

19. Prevalence of Deleterious Variants in MC3Rin Patients With Constitutional Delay of Growth and Puberty

Author

Duckett, Katie, Williamson, Alice, Kincaid, John W R, Rainbow, Kara, Corbin, Laura J, Martin, Hilary C, Eberhardt, Ruth Y, Huang, Qin Qin, Hurles, Matthew E, He, Wen, Brauner, Raja, Delaney, Angela, Dunkel, Leo, Grinspon, Romina P, Hall, Janet E, Hirschhorn, Joel N, Howard, Sasha R, Latronico, Ana C, Jorge, Alexander A L, McElreavey, Ken, Mericq, Verónica, Merino, Paulina M, Palmert, Mark R, Plummer, Lacey, Rey, Rodolfo A, Rezende, Raíssa C, Seminara, Stephanie B, Salnikov, Kathryn, Banerjee, Indraneel, Lam, Brian Y H, Perry, John R B, Timpson, Nicholas J, Clayton, Peter, Chan, Yee-Ming, Ong, Ken K, and O’Rahilly, Stephen

Published
2023
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20. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author

Broadaway, K. Alaine, primary, Yin, Xianyong, additional, Williamson, Alice, additional, Parsons, Victoria A., additional, Wilson, Emma P., additional, Moxley, Anne H., additional, Vadlamudi, Swarooparani, additional, Varshney, Arushi, additional, Jackson, Anne U., additional, Ahuja, Vasudha, additional, Bornstein, Stefan R., additional, Corbin, Laura J., additional, Delgado, Graciela E., additional, Dwivedi, Om P., additional, Fernandes Silva, Lilian, additional, Frayling, Timothy M., additional, Grallert, Harald, additional, Gustafsson, Stefan, additional, Hakaste, Liisa, additional, Hammar, Ulf, additional, Herder, Christian, additional, Herrmann, Sandra, additional, Højlund, Kurt, additional, Hughes, David A., additional, Kleber, Marcus E., additional, Lindgren, Cecilia M., additional, Liu, Ching-Ti, additional, Luan, Jian’an, additional, Malmberg, Anni, additional, Moissl, Angela P., additional, Morris, Andrew P., additional, Perakakis, Nikolaos, additional, Peters, Annette, additional, Petrie, John R., additional, Roden, Michael, additional, Schwarz, Peter E.H., additional, Sharma, Sapna, additional, Silveira, Angela, additional, Strawbridge, Rona J., additional, Tuomi, Tiinamaija, additional, Wood, Andrew R., additional, Wu, Peitao, additional, Zethelius, Björn, additional, Baldassarre, Damiano, additional, Eriksson, Johan G., additional, Fall, Tove, additional, Florez, Jose C., additional, Fritsche, Andreas, additional, Gigante, Bruna, additional, Hamsten, Anders, additional, Kajantie, Eero, additional, Laakso, Markku, additional, Lahti, Jari, additional, Lawlor, Deborah A., additional, Lind, Lars, additional, März, Winfried, additional, Meigs, James B., additional, Sundström, Johan, additional, Timpson, Nicholas J., additional, Wagner, Robert, additional, Walker, Mark, additional, Wareham, Nicholas J., additional, Watkins, Hugh, additional, Barroso, Inês, additional, O’Rahilly, Stephen, additional, Grarup, Niels, additional, Parker, Stephen CJ., additional, Boehnke, Michael, additional, Langenberg, Claudia, additional, Wheeler, Eleanor, additional, and Mohlke, Karen L., additional

Published
2023
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22. Inflammation proteomics datasets in the ALSPAC cohort

Author

Goulding, Neil, primary, Goudswaard, Lucy J., additional, Hughes, David A., additional, Corbin, Laura J., additional, Groom, Alix, additional, Ring, Susan, additional, Timpson, Nicholas J., additional, Fraser, Abigail, additional, Northstone, Kate, additional, and Suderman, Matthew, additional

Published
2022
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23. Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH.

Author

Li, Josephine H., Brenner, Laura N., Kaur, Varinderpal, Figueroa, Katherine, Schroeder, Philip, Huerta-Chagoya, Alicia, MAGIC Investigators, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian'an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, and Waage, Johannes

Abstract

Aims/hypothesis: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. Methods: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. Results: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10−9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10−8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10−3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10−5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology. Conclusions/interpretation: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene–drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Data availability: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal (https://hugeamp.org) and the GWAS Catalog (www.ebi.ac.uk/gwas/, accession IDs: GCST90269867 to GCST90269899). [ABSTRACT FROM AUTHOR]

Published
2023
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24. The metabolomic signature of weight loss in the Diabetes Remission Clinical Trial (DiRECT)

Author

Corbin, Laura J, primary, Hughes, David A, additional, Bull, Caroline J, additional, Vincent, Emma E, additional, Smith, Madeleine L, additional, McConnachie, Alex, additional, Messow, Claudia-Martina, additional, Welsh, Paul I, additional, Taylor, Roy, additional, Lean, Michael E J, additional, Sattar, Naveed J, additional, and Timpson, Nicholas J, additional

Published
2022
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25. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

Author

Wade, Kaitlin H, Lam, Brian YH, Melvin, Audrey, Pan, Warren, Corbin, Laura J, Hughes, David A, Rainbow, Kara, Chen, Jian-Hua, Duckett, Katie, Liu, Xiaoming, Mokrosiński, Jacek, Mörseburg, Alexander, Neaves, Sam, Williamson, Alice, Zhang, Chen, Farooqi, I Sadaf, Yeo, Giles SH, Timpson, Nicholas J, O'Rahilly, Stephen, Lam, Brian YH [0000-0002-3638-9025], Corbin, Laura J [0000-0002-4032-9500], Hughes, David A [0000-0002-9644-8998], Mokrosiński, Jacek [0000-0001-5008-0457], Yeo, Giles SH [0000-0001-8823-3615], Timpson, Nicholas J [0000-0002-7141-9189], O'Rahilly, Stephen [0000-0003-2199-4449], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Heterozygote, Adolescent, Body Weight, Infant, Newborn, Infant, United Kingdom, Young Adult, Phenotype, Loss of Function Mutation, Child, Preschool, Humans, Receptor, Melanocortin, Type 4, Genetic Predisposition to Disease, Obesity, Child
Abstract

Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m-2 (95% CI 2.19, 7.49) and 14.78 kg (95% CI 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.

Published
2021

29. Higher body mass index raises immature platelet count: potential contribution to obesity-related thrombosis

Author

Goudswaard, Lucy J., primary, Corbin, Laura J., additional, Burley, Kate L., additional, Mumford, Andrew, additional, Akbari, Parsa, additional, Soranzo, Nicole, additional, Butterworth, Adam S., additional, Watkins, Nicholas A., additional, Pournaras, Dimitri J., additional, Harris, Jessica, additional, Timpson, Nicholas J., additional, and Hers, Ingeborg, additional

Published
2022
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30. The trans-ancestral genomic architecture of glycemic traits

Author

Chen, Ji, Spracklen, Cassandra N, Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J, et al, Bornstein, Stefan R, and University of Zurich

Subjects
1311 Genetics, 10265 Clinic for Endocrinology and Diabetology, 610 Medicine & health
Published
2021

35. Higher body mass index raises immature platelet count: evidence from Mendelian randomization analyses

Author

Goudswaard, Lucy J., primary, Corbin, Laura J., additional, Burley, Kate L., additional, Mumford, Andrew, additional, Akbari, Parsa, additional, Soranzo, Nicole, additional, Butterworth, Adam S., additional, Watkins, Nicholas A., additional, Pournaras, Dimitri J., additional, Harris, Jessica, additional, Timpson, Nicholas J., additional, and Hers, Ingeborg, additional

Published
2021
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36. SMIM1absence is associated with reduced energy expenditure and excess weight

Author

Stefanucci, Luca, Moslemi, Camous, Tomé, Ana R., Virtue, Samuel, Bidault, Guillaume, Gleadall, Nicholas S., Watson, Laura P.E., Kwa, Jing E., Burden, Frances, Farrow, Samantha, Banasik, Karina, Bay, Jakob, Boldsen, Jens Kjærgaard, Brodersen, Thorsten, Brunak, Søren, Burgdorf, Kristoffer, Chalmer, Mona Ameri, Didriksen, Maria, Dinh, Khoa Manh, Dowsett, Joseph, Erikstrup, Christian, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hansen, Thomas Folkmann, Hindhede, Lotte, Hjalgrim, Henrik, Jacobsen, Rikke Louise, Jemec, Gregor, Jensen, Bitten Aagaard, Kaspersen, Katrine, Kjerulff, Bertram Dalskov, Kogelman, Lisette, Hørup Larsen, Margit Anita, Louloudis, Ioannis, Lundgaard, Agnete, Susan, Mikkelsen, Christina, Nissen, Ioanna, Nyegaard, Mette, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Henriksen, Alexander Pil, Rohde, Palle Duun, Rostgaard, Klaus, Schwinn, Michael, Stefansson, Kari, Stefánsson, Hreinn, Sørensen, Erik, þorsteinsdóttir, Unnur, Thørner, Lise Wegner, Bruun, Mie Topholm, Ullum, Henrik, Werge, Thomas, Westergaard, David, Chen, Ji, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian’an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Katie Chan, Kei Hang, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Loz, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V.R., Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P., Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Southam, Lorraine, Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J.L., Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J.C., Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M. Arfan, Johnson, W. Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R.H.J., Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, Van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Goncalo R., Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Ida Chen, Yii-Der, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, Janaka de Silva, H., Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J. Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L.R., Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J.F., Magnusson, Patrik K.E., Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N.A., Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P. Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I.A., Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E. Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G.M., Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C.J., Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., Barroso, Inês, Võsa, Urmo, Burling, Keith, Walker, Lindsay, Ord, John, Barker, Peter, Warner, James, Frary, Amy, Renhstrom, Karola, Ashford, Sofie E., Piper, Jo, Biggs, Gail, Erber, Wendy N., Hoffman, Gary J., Schoenmakers, Nadia, Erikstrup, Christian, Rieneck, Klaus, Dziegiel, Morten H., Ullum, Henrik, Azzu, Vian, Vacca, Michele, Aparicio, Hugo Javier, Hui, Qin, Cho, Kelly, Sun, Yan V., Wilson, Peter W., Bayraktar, Omer A., Vidal-Puig, Antonio, Ostrowski, Sisse R., Astle, William J., Olsson, Martin L., Storry, Jill R., Pedersen, Ole B., Ouwehand, Willem H., Chatterjee, Krishna, Vuckovic, Dragana, and Frontini, Mattia

Abstract

Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.

Published
2024
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37. Narrow-sense heritability estimation of complex traits using identity-by-descent information

Author

Evans, Luke M., Tahmasbi, Rasool, Jones, Matthew, Vrieze, Scott I., Abecasis, Gonçalo R., Das, Sayantan, Bjelland, Doug W., deCandia, Teresa R., Abecasis, Gonçalo, Altshuler, David, Anderson, Carl A, Angius, Andrea, Barrett, Jeffrey C, Berndt, Sonja, Boehnke, Michael, Boomsma, Dorrett, Branham, Kari, Breen, Gerome, Brummett, Chad M, Busonero, Fabio, Campbell, Harry, Campbell, Peter, Chan, Andrew, Chen, Sai, Chew, Emily, Cocca, Massimiliano, Collins, Francis S, Corbin, Laura J, Cucca, Francesco, Danecek, Petr, de Bakker, Paul I W, Dedoussis, George, Dekker, Annelot, Delaneau, Olivier, Dorr, Marcus, Durbin, Richard, Farmaki, Aliki-Eleni, Ferrucci, Luigi, Forer, Lukas, Fraser, Ross M, Frayling, Timothy, Fuchsberger, Christian, Gabriel, Stacey, Gandin, Ilaria, Gasparini, Paolo, Gillies, Christopher E, Gilly, Arthur, Groop, Leif, Harrison, Tabitha, Hattersley, Andrew, Holmen, Oddgeir L, Hveem, Kristian, Iacono, William, Joshi, Amit, Kang, Hyun Min, Khalili, Hamed, Kooperberg, Charles, Koskinen, Seppo, Kretzler, Matthias, Kretzschmar, Warren, Kwong, Alan, Lee, James C, Levy, Shawn, Luo, Yang, Mahajan, Anubha, Marchini, Jonathan, McCarroll, Steven, McCarthy, Mark I, McCarthy, Shane, McGue, Matt, McInnis, Melvin, Meitinger, Thomas, Melzer, David, Mezzavilla, Massimo, Min, Josine L, Mohlke, Karen L, Myers, Richard M, Nauck, Matthias, Nickerson, Deborah, Palotie, Aarno, Pato, Carlos, Pato, Michele, Peters, Ulrike, Pirastu, Nicola, Rheenen, Wouter Van, Richards, J Brent, Ripatti, Samuli, Sala, Cinzia, Salomaa, Veikko, Sampson, Matthew G, Schlessinger, David, Schoen, Robert E, Schoenherr, Sebastian, Scott, Laura J, Sharp, Kevin, Sidore, Carlo, Slagboom, P Eline, Small, Kerrin, Smith, George Davey, Soranzo, Nicole, Spector, Timothy, Stambolian, Dwight, Swaroop, Anand, Swertz, Morris A, Teumer, Alexander, Timpson, Nicholas, Toniolo, Daniela, Traglia, Michela, Tuke, Marcus, Tuomilehto, Jaakko, den Berg, Leonard H Van, van Duijn, Cornelia M, Veldink, Jan, Vincent, John B, Volker, Uwe, Vrieze, Scott, Walter, Klaudia, Wijmenga, Cisca, Willer, Cristen, Wilson, James F, Wood, Andrew R, Zeggini, Eleftheria, Zhang, He, Yang, Jian, Goddard, Michael E., Visscher, Peter M., and Keller, Matthew C.

Subjects
0301 basic medicine, Genome-wide association study, Biology, Population stratification, Genetic correlation, Polymorphism, Single Nucleotide, Identity by descent, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Missing heritability problem, Genetic variation, Genetics, Chromosomes, Human, Humans, Human height, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Genome, Human, Heritability, Twin study, Minor allele frequency, Phenotype, 030104 developmental biology, Haplotypes, Evolutionary biology, Trait, 030217 neurology & neurosurgery
Abstract

Heritability is a fundamental parameter in genetics. Traditional estimates based on family or twin studies can be biased due to shared environmental or non-additive genetic variance. Alternatively, those based on genotyped or imputed variants typically underestimate narrow-sense heritability contributed by rare or otherwise poorly tagged causal variants. Identical-by-descent (IBD) segments of the genome share all variants between pairs of chromosomes except new mutations that have arisen since the last common ancestor. Therefore, relating phenotypic similarity to degree of IBD sharing among classically unrelated individuals is an appealing approach to estimating the near full additive genetic variance while possibly avoiding biases that can occur when modeling close relatives. We applied an IBD-based approach (GREML-IBD) to estimate heritability in unrelated individuals using phenotypic simulation with thousands of whole-genome sequences across a range of stratification, polygenicity levels, and the minor allele frequencies of causal variants (CVs). In simulations, the IBD-based approach produced unbiased heritability estimates, even when CVs were extremely rare, although precision was low. However, population stratification and non-genetic familial environmental effects shared across generations led to strong biases in IBD-based heritability. We used data on two traits in ~120,000 people from the UK Biobank to demonstrate that, depending on the trait and possible confounding environmental effects, GREML-IBD can be applied to very large genetic datasets to infer the contribution of very rare variants lost using other methods. However, we observed apparent biases in these real data, suggesting that more work may be required to understand and mitigate factors that influence IBD-based heritability estimates.

Published
2018

38. The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease

Author

Kalaoja, Marita, primary, Corbin, Laura J., additional, Tan, Vanessa Y., additional, Ahola‐Olli, Ari V., additional, Havulinna, Aki S., additional, Santalahti, Kristiina, additional, Pitkänen, Niina, additional, Lehtimäki, Terho, additional, Lyytikäinen, Leo‐Pekka, additional, Raitoharju, Emma, additional, Seppälä, Ilkka, additional, Kähönen, Mika, additional, Ripatti, Samuli, additional, Palotie, Aarno, additional, Perola, Markus, additional, Viikari, Jorma S., additional, Jalkanen, Sirpa, additional, Maksimow, Mikael, additional, Salomaa, Veikko, additional, Salmi, Marko, additional, Raitakari, Olli T., additional, Kettunen, Johannes, additional, and Timpson, Nicholas J., additional

Published
2021
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39. The Trans-Ancestral Genomic Architecture of Glycaemic Traits

Author

Chen, Ji, primary, Spracklen, Cassandra N., additional, Marenne, Gaëlle, additional, Varshney, Arushi, additional, Corbin, Laura J, additional, Luan, Jian’an, additional, Willems, Sara, additional, Wu, Ying, additional, Zhang, Xiaoshuai, additional, Horikoshi, Momoko, additional, Boutin, Thibaud S, additional, Mägi, Reedik, additional, Waage, Johannes, additional, Pitsilides, Achilleas, additional, Li-Gao, Ruifang, additional, Hang, Kei, additional, Yao, Jie, additional, Anasanti, Mila D, additional, Chu, Audrey Y, additional, Claringbould, Annique, additional, Heikkinen, Jani, additional, Hong, Jaeyoung, additional, Hottenga, Jouke-Jan, additional, Huo, Shaofeng, additional, Kaakinen, Marika A., additional, Louie, Tin, additional, März, Winfried, additional, Moreno-Macias, Hortensia, additional, Ndungu, Anne, additional, Nelson, Sarah C., additional, Nolte, Ilja M., additional, North, Kari, additional, Raulerson, Chelsea K., additional, Ray, Debashree, additional, Rohde, Rebecca, additional, Rybin, Denis, additional, Schurmann, Claudia, additional, Sim, Xueling, additional, Southam, Loz, additional, Stewart, Isobel, additional, Wang, Carol A., additional, Wang, Yujie, additional, Wu, Peitao, additional, Zhang, Weihua, additional, Ahluwalia, Tarunveer S., additional, Appel, Emil VR, additional, Bielak, Lawrence F., additional, Brody, Jennifer A., additional, Burtt, Noel P, additional, Cabrera, Claudia P, additional, Cade, Brian E, additional, Chai, Jin Fang, additional, Chai, Xiaoran, additional, Chang, Li-Ching, additional, Chen, Chien-Hsiun, additional, Chen, Brian H, additional, Chitrala, Kumaraswamy N, additional, Chiu, Yen-Feng, additional, de Haan, Hugoline G., additional, Delgado, Graciela E, additional, Demirkan, Ayse, additional, Duan, Qing, additional, Engmann, Jorgen, additional, Fatumo, Segun A, additional, Gayán, Javier, additional, Giulianini, Franco, additional, Gong, Jung Ho, additional, Gustafsson, Stefan, additional, Hai, Yang, additional, Hartwig, Fernando P, additional, He, Jing, additional, Heianza, Yoriko, additional, Huang, Tao, additional, Huerta-Chagoya, Alicia, additional, Hwang, Mi Yeong, additional, Jensen, Richard A., additional, Kawaguchi, Takahisa, additional, Kentistou, Katherine A, additional, Kim, Young Jin, additional, Kleber, Marcus E, additional, Kooner, Ishminder K, additional, Lai, Shuiqing, additional, Lange, Leslie A, additional, Langefeld, Carl D, additional, Lauzon, Marie, additional, Li, Man, additional, Ligthart, Symen, additional, Liu, Jun, additional, Loh, Marie, additional, Long, Jirong, additional, Lyssenko, Valeriya, additional, Mangino, Massimo, additional, Marzi, Carola, additional, Montasser, May E, additional, Nag, Abhishek, additional, Nakatochi, Masahiro, additional, Noce, Damia, additional, Noordam, Raymond, additional, Pistis, Giorgio, additional, Preuss, Michael, additional, Raffield, Laura, additional, Rasmussen-Torvik, Laura J., additional, Rich, Stephen S, additional, Robertson, Neil R, additional, Rueedi, Rico, additional, Ryan, Kathleen, additional, Sanna, Serena, additional, Saxena, Richa, additional, Schraut, Katharina E, additional, Sennblad, Bengt, additional, Setoh, Kazuya, additional, Smith, Albert V, additional, Southam, Lorraine, additional, Sparsø, Thomas, additional, Strawbridge, Rona J, additional, Takeuchi, Fumihiko, additional, Tan, Jingyi, additional, Trompet, Stella, additional, van den Akker, Erik, additional, Van der Most, Peter J, additional, Verweij, Niek, additional, Vogel, Mandy, additional, Wang, Heming, additional, Wang, Chaolong, additional, Wang, Nan, additional, Warren, Helen R, additional, Wen, Wanqing, additional, Wilsgaard, Tom, additional, Wong, Andrew, additional, Wood, Andrew R, additional, Xie, Tian, additional, Zafarmand, Mohammad Hadi, additional, Zhao, Jing-Hua, additional, Zhao, Wei, additional, Amin, Najaf, additional, Arzumanyan, Zorayr, additional, Astrup, Arne, additional, Bakker, Stephan JL, additional, Baldassarre, Damiano, additional, Beekman, Marian, additional, Bergman, Richard N, additional, Bertoni, Alain, additional, Blüher, Matthias, additional, Bonnycastle, Lori L., additional, Bornstein, Stefan R, additional, Bowden, Donald W, additional, Cai, Qiuyin, additional, Campbell, Archie, additional, Campbell, Harry, additional, Chang, Yi Cheng, additional, de Geus, Eco J.C., additional, Dehghan, Abbas, additional, Du, Shufa, additional, Eiriksdottir, Gudny, additional, Farmaki, Aliki Eleni, additional, Frånberg, Mattias, additional, Fuchsberger, Christian, additional, Gao, Yutang, additional, Gjesing, Anette P, additional, Goel, Anuj, additional, Han, Sohee, additional, Hartman, Catharina A, additional, Herder, Christian, additional, Hicks, Andrew A., additional, Hsieh, Chang-Hsun, additional, Hsueh, Willa A., additional, Ichihara, Sahoko, additional, Igase, Michiya, additional, Ikram, M. Arfan, additional, Johnson, W. Craig, additional, Jørgensen, Marit E, additional, Joshi, Peter K, additional, Kalyani, Rita R, additional, Kandeel, Fouad R., additional, Katsuya, Tomohiro, additional, Khor, Chiea Chuen, additional, Kiess, Wieland, additional, Kolcic, Ivana, additional, Kuulasmaa, Teemu, additional, Kuusisto, Johanna, additional, Läll, Kristi, additional, Lam, Kelvin, additional, Lawlor, Deborah A, additional, Lee, Nanette R., additional, Lemaitre, Rozenn N., additional, Li, Honglan, additional, Study, Lifelines Cohort, additional, Lin, Shih-Yi, additional, Lindström, Jaana, additional, Linneberg, Allan, additional, Liu, Jianjun, additional, Lorenzo, Carlos, additional, Matsubara, Tatsuaki, additional, Matsuda, Fumihiko, additional, Mingrone, Geltrude, additional, Mooijaart, Simon, additional, Moon, Sanghoon, additional, Nabika, Toru, additional, Nadkarni, Girish N., additional, Nadler, Jerry L., additional, Nelis, Mari, additional, Neville, Matthew J, additional, Norris, Jill M, additional, Ohyagi, Yasumasa, additional, Peters, Annette, additional, Peyser, Patricia A., additional, Polasek, Ozren, additional, Qi, Qibin, additional, Raven, Dennis, additional, Reilly, Dermot F, additional, Reiner, Alex, additional, Rivideneira, Fernando, additional, Roll, Kathryn, additional, Rudan, Igor, additional, Sabanayagam, Charumathi, additional, Sandow, Kevin, additional, Sattar, Naveed, additional, Schürmann, Annette, additional, Shi, Jinxiu, additional, Stringham, Heather M, additional, Taylor, Kent D., additional, Teslovich, Tanya M., additional, Thuesen, Betina, additional, Timmers, Paul RHJ, additional, Tremoli, Elena, additional, Tsai, Michael Y, additional, Uitterlinden, Andre, additional, van Dam, Rob M, additional, van Heemst, Diana, additional, van Hylckama Vlieg, Astrid, additional, Van Vliet-Ostaptchouk, Jana V, additional, Vangipurapu, Jagadish, additional, Vestergaard, Henrik, additional, Wang, Tao, additional, van Dijk, Ko Willems, additional, Xiang, Yongbing, additional, Zemunik, Tatijana, additional, Abecasis, Goncalo R, additional, Adair, Linda S., additional, Aguilar-Salinas, Carlos Alberto, additional, Alarcón-Riquelme, Marta E, additional, An, Ping, additional, Aviles-Santa, Larissa, additional, Becker, Diane M, additional, Beilin, Lawrence J, additional, Bergmann, Sven, additional, Bisgaard, Hans, additional, Black, Corri, additional, Boehnke, Michael, additional, Boerwinkle, Eric, additional, Böhm, Bernhard O, additional, Bønnelykke, Klaus, additional, Boomsma, D I., additional, Bottinger, Erwin P., additional, Buchanan, Thomas A, additional, Canouil, Mickaël, additional, Caulfield, Mark J, additional, Chambers, John C., additional, Chasman, Daniel I., additional, Chen, Yii-Der Ida, additional, Cheng, Ching-Yu, additional, Collins, Francis S., additional, Correa, Adolfo, additional, Cucca, Francesco, additional, de Silva, H. Janaka, additional, Dedoussis, George, additional, Elmståhl, Sölve, additional, Evans, Michele K., additional, Ferranni, Ele, additional, Ferruci, Luigi, additional, Florez, Jose C, additional, Franks, Paul, additional, Frayling, Timothy M, additional, Froguel, Philippe, additional, Gigante, Bruna, additional, Goodarzi, Mark O., additional, Gordon-Larsen, Penny, additional, Grallert, Harald, additional, Grarup, Niels, additional, Grimsgaard, Sameline, additional, Groop, Leif, additional, Gudnason, Vilmundur, additional, Guo, Xiuqing, additional, Hamsten, Anders, additional, Hansen, Torben, additional, Hayward, Caroline, additional, Heckbert, Susan R., additional, Horta, Bernardo L, additional, Huang, Wei, additional, Ingelsson, Erik, additional, James, Pankow S, additional, Jonas, Jost B, additional, Jukema, J. Wouter, additional, Kaleebu, Pontiano, additional, Kaplan, Robert, additional, Kardia, Sharon L.R., additional, Kato, Norihiro, additional, Keinanen-Kiukaanniemi, Sirkka M., additional, Kim, Bong-Jo, additional, Kivimaki, Mika, additional, Koistinen, Heikki A., additional, Kooner, Jaspal S., additional, Körner, Antje, additional, Kovacs, Peter, additional, Kuh, Diana, additional, Kumari, Meena, additional, Kutalik, Zoltan, additional, Laakso, Markku, additional, Lakka, Timo A., additional, Launer, Lenore J, additional, Leander, Karin, additional, Li, Huaixing, additional, Lin, Xu, additional, Lind, Lars, additional, Lindgren, Cecilia, additional, Liu, Simin, additional, Loos, Ruth J.F., additional, Magnusson, Patrik, additional, Mahajan, Anubha, additional, Metspalu, Andres, additional, Mook-Kanamori, Dennis O, additional, Mori, Trevor A, additional, Munroe, Patricia B, additional, Njølstad, Inger, additional, O’Connell, Jeffrey R, additional, Oldehinkel, Albertine J, additional, Ong, Ken K, additional, Padmanabhan, Sandosh, additional, Palmer, Colin N.A., additional, Palmer, Nicholette D, additional, Pedersen, Oluf, additional, Pennell, Craig E, additional, Porteous, David J, additional, Pramstaller, Peter P., additional, Province, Michael A., additional, Psaty, Bruce M., additional, Qi, Lu, additional, Raffel, Leslie J., additional, Rauramaa, Rainer, additional, Redline, Susan, additional, Ridker, Paul M, additional, Rosendaal, Frits R., additional, Saaristo, Timo E., additional, Sandhu, Manjinder, additional, Saramies, Jouko, additional, Schneiderman, Neil, additional, Schwarz, Peter, additional, Scott, Laura J., additional, Selvin, Elizabeth, additional, Sever, Peter, additional, Shu, Xiao-ou, additional, Slagboom, P Eline, additional, Small, Kerrin S, additional, Smith, Blair H, additional, Snieder, Harold, additional, Sofer, Tamar, additional, Sørensen, Thorkild I.A., additional, Spector, Tim D, additional, Stanton, Alice, additional, Steves, Claire J, additional, Stumvoll, Michael, additional, Sun, Liang, additional, Tabara, Yasuharu, additional, Tai, E Shyong, additional, Timpson, Nicholas J, additional, Tönjes, Anke, additional, Tuomilehto, Jaakko, additional, Tusie, Teresa, additional, Uusitupa, Matti, additional, van der Harst, Pim, additional, van Duijn, Cornelia, additional, Vitart, Veronique, additional, Vollenweider, Peter, additional, Vrijkotte, Tanja GM, additional, Wagenknecht, Lynne E, additional, Walker, Mark, additional, Wang, Ya X, additional, Wareham, Nick J, additional, Watanabe, Richard M, additional, Watkins, Hugh, additional, Wei, Wen B, additional, Wickremasinghe, Ananda R, additional, Willemsen, Gonneke, additional, Wilson, James F, additional, Wong, Tien-Yin, additional, Wu, Jer-Yuarn, additional, Xiang, Anny H, additional, Yanek, Lisa R, additional, Yengo, Loïc, additional, Yokota, Mitsuhiro, additional, Zeggini, Eleftheria, additional, Zheng, Wei, additional, Zonderman, Alan B, additional, Rotter, Jerome I, additional, Gloyn, Anna L, additional, McCarthy, Mark I., additional, Dupuis, Josée, additional, Meigs, James B, additional, Scott, Robert, additional, Prokopenko, Inga, additional, Leong, Aaron, additional, Liu, Ching-Ti, additional, Parker, Stephen CJ, additional, Mohlke, Karen L., additional, Langenberg, Claudia, additional, Wheeler, Eleanor, additional, Morris, Andrew P., additional, and Barroso, Inês, additional

Published
2020
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40. Effects of adiposity on the human plasma proteome: Observational and Mendelian randomization estimates

Author

Goudswaard, Lucy J., primary, Bell, Joshua A., additional, Hughes, David A., additional, Corbin, Laura J., additional, Walter, Klaudia, additional, Smith, George Davey, additional, Soranzo, Nicole, additional, Danesh, John, additional, Di Angelantonio, Emanuele, additional, Ouwehand, Willem H., additional, Watkins, Nicholas A., additional, Roberts, David J., additional, Butterworth, Adam S., additional, Hers, Ingeborg, additional, and Timpson, Nicholas J., additional

Published
2020
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45. Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Author

Corbin, Laura J., Tan, Vanessa Y., Hughes, David A., Wade, Kaitlin H., Paul, Dirk S., Tansey, Katherine E., Butcher, Frances, Dudbridge, Frank, Howson, Joanna M., Jallow, Momodou W., John, Catherine, Kingston, Nathalie, Lindgren, Cecilia M., O'Donavan, Michael, O'Rahilly, Stephen, Owen, Michael J., Palmer, Colin N. A., Pearson, Ewan R., Scott, Robert A., van Heel, David A., Whittaker, John, Frayling, Tim, Tobin, Martin D., Wain, Louise V., Smith, George Davey, Evans, David M., Karpe, Fredrik, McCarthy, Mark I., Danesh, John, Franks, Paul W., Timpson, Nicholas J., Corbin, Laura J., Tan, Vanessa Y., Hughes, David A., Wade, Kaitlin H., Paul, Dirk S., Tansey, Katherine E., Butcher, Frances, Dudbridge, Frank, Howson, Joanna M., Jallow, Momodou W., John, Catherine, Kingston, Nathalie, Lindgren, Cecilia M., O'Donavan, Michael, O'Rahilly, Stephen, Owen, Michael J., Palmer, Colin N. A., Pearson, Ewan R., Scott, Robert A., van Heel, David A., Whittaker, John, Frayling, Tim, Tobin, Martin D., Wain, Louise V., Smith, George Davey, Evans, David M., Karpe, Fredrik, McCarthy, Mark I., Danesh, John, Franks, Paul W., and Timpson, Nicholas J.

Abstract

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

Published
2018
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46. Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Author

Corbin, Laura J., primary, Tan, Vanessa Y., additional, Hughes, David A., additional, Wade, Kaitlin H., additional, Paul, Dirk S., additional, Tansey, Katherine E., additional, Butcher, Frances, additional, Dudbridge, Frank, additional, Howson, Joanna M., additional, Jallow, Momodou W., additional, John, Catherine, additional, Kingston, Nathalie, additional, Lindgren, Cecilia M., additional, O’Donavan, Michael, additional, O’Rahilly, Stephen, additional, Owen, Michael J., additional, Palmer, Colin N. A., additional, Pearson, Ewan R., additional, Scott, Robert A., additional, van Heel, David A., additional, Whittaker, John, additional, Frayling, Tim, additional, Tobin, Martin D., additional, Wain, Louise V., additional, Smith, George Davey, additional, Evans, David M., additional, Karpe, Fredrik, additional, McCarthy, Mark I., additional, Danesh, John, additional, Franks, Paul W., additional, and Timpson, Nicholas J., additional

Published
2018
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47. A reference panel of 64,976 haplotypes for genotype imputation

Author

McCarthy, Shane, Das, Sayantan, Kretzschmar, Warren, Delaneau, Olivier, Wood, Andrew R, Teumer, Alexander, Kang, Hyun Min, Fuchsberger, Christian, Danecek, Petr, Sharp, Kevin, Luo, Yang, Sidore, Carlo, Kwong, Alan, Timpson, Nicholas, Koskinen, Seppo, Vrieze, Scott, Scott, Laura J, Zhang, He, Mahajan, Anubha, Veldink, Jan, Peters, Ulrike, Pato, Carlos, van Duijn, Cornelia M, Gillies, Christopher E, Gandin, Ilaria, Mezzavilla, Massimo, Gilly, Arthur, Cocca, Massimiliano, Traglia, Michela, Angius, Andrea, Barrett, Jeffrey C, Boomsma, Dorrett, Branham, Kari, Breen, Gerome, Brummett, Chad M, Busonero, Fabio, Campbell, Harry, Chan, Andrew, Chen, Sai, Chew, Emily, Collins, Francis S, Corbin, Laura J, Smith, George Davey, Dedoussis, George, Dorr, Marcus, Farmaki, Aliki-Eleni, Van den Berg, Leonard H, Van Rheenen, Wouter, de Bakker, Paul I W, Dekker, Annelot, and Haplotype Reference Consortium

Subjects
Journal Article
Abstract

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

Published
2016

48. Body mass index:Has epidemiology started to break down causal contributions to health and disease?

Author

Corbin, Laura J and Timpson, Nicholas John

Subjects
obesity, causal analyses, Mendelian randomization, body mass index, epidemiology
Abstract

ObjectivesTo review progress in understanding the methods and results concerning the causal contribution of body mass index (BMI) to health and disease.MethodsIn the context of conventional evidence focused on the relationship between BMI and health, this review considers current literature on the common, population-based, genetic contribution to BMI and how this has fed into the developing field of applied epidemiology.ResultsTechnological and analytical developments have driven considerable success in identifying genetic variants relevant to BMI. This has enabled the implementation of Mendelian randomization to address questions of causality. The product of this work has been the implication of BMI as a causal agent in a host of health outcomes. Further breakdown of causal pathways by integration with other “omics” technologies promises to deliver additional benefit.ConclusionsGaps remain in our understanding of BMI as a risk factor for health and disease, and while promising, applied genetic epidemiology should be considered alongside alternative methods for assessing the impact of BMI on health. Potential limitations, relating to inappropriate or nonspecific measures of obesity and the improper use of genetic instruments, will need to be explored and incorporated into future research aiming to dissect BMI as a risk factor.

Published
2016

49. Causal analyses, statistical efficiency and phenotypic precision through Recall-by-Genotype study design

Author

Corbin, Laura J., primary, Tan, Vanessa Y., additional, Hughes, David A., additional, Wade, Kaitlin H., additional, Paul, Dirk S., additional, Tansey, Katherine E., additional, Butcher, Frances, additional, Dudbridge, Frank, additional, Howson, Joanna M., additional, Jallow, Momodou W., additional, John, Catherine, additional, Kingston, Nathalie, additional, Lindgren, Cecilia M., additional, O’Donavan, Michael, additional, O’Rahilly, Steve, additional, Owen, Michael J., additional, Palmer, Colin N.A., additional, Pearson, Ewan R., additional, Scott, Robert A., additional, Heel, David A. van, additional, Whittaker, John, additional, Frayling, Tim, additional, Tobin, Martin D., additional, Wain, Louise V., additional, Evans, David M., additional, Karpe, Fredrik, additional, McCarthy, Mark I., additional, Danesh, John, additional, Franks, Paul W., additional, and Timpson, Nicholas J., additional

Published
2017
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50. Genetics, sleep and memory:a recall-by-genotype study of ZNF804A variants and sleep neurophysiology

Author

Hellmich, Charlotte, Durant, Claire, Jones, Matthew W., Timpson, Nicholas J., Bartsch, Ullrich, and Corbin, Laura J.

Subjects
Adult, Male, Polysomnography, Kruppel-Like Transcription Factors, Pilot Projects, Motor Activity, Polymorphism, Single Nucleotide, CRICBristol, Young Adult, Memory, Surveys and Questionnaires, Genetics, Humans, Genetics(clinical), Longitudinal Studies, Memory Consolidation, Genetics & Heredity, 0604 Genetics, Recall-by-genotype, Brain, 1103 Clinical Sciences, ALSPAC, Healthy Volunteers, rs1344706, Schizophrenia, Spindles, Sleep, ZNF804A
Abstract

Background Schizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis. However, the biological mechanisms underpinning the different symptom clusters remain undefined. The rs1344706 single nucleotide polymorphism within ZNF804A was among the first genetic variants found to be associated with schizophrenia. Previously, neuroimaging and cognitive studies have revealed several associations between rs1344706 and brain structure and function. The aim of this study is to use a recall-by-genotype (RBG) design to investigate the biological basis for the association of ZNF804A variants with schizophrenia. A RBG study, implemented in a population cohort, will be used to evaluate the impact of genetic variation at rs1344706 on sleep neurophysiology and procedural memory consolidation in healthy participants. Methods/Design Participants will be recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) on the basis of genotype at rs1344706 (n = 24). Each participant will be asked to take part in two nights of in-depth sleep monitoring (polysomnography) allowing collection of neurophysiological sleep data in a manner not amenable to large-scale study. Sleep questionnaires will be used to assess general sleep quality and subjective sleep experience after each in-house recording. A motor sequencing task (MST) will be performed before and after the second night of polysomnography. In order to gather additional data about habitual sleep behaviour participants will be asked to wear a wrist worn activity monitor (actiwatch) and complete a sleep diary for two weeks. Discussion This study will explore the biological function of ZNF804A genotype (rs1344706) in healthy volunteers by examining detailed features of sleep architecture and physiology in relation to motor learning. Using a RBG approach will enable us to collect precise and detailed phenotypic data whilst achieving an informative biological gradient. It would not be feasible to collect such data in the large sample sizes that would be required under a random sampling scheme. By dissecting the role of individual variants associated with schizophrenia in this way, we can begin to unravel the complex genetic mechanisms of psychiatric disorders and pave the way for future development of novel therapeutic approaches.

Published
2015

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