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1. Risk thresholds for alcohol consumption:combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Wood, A. M. (Angela M.), Kaptoge, S. (Stephen), Butterworth, A. S. (Adam S.), Willeit, P. (Peter), Warnakula, S. (Samantha), Bolton, T. (Thomas), Paige, E. (Ellie), Paul, D. S. (Dirk S.), Sweeting, M. (Michael), Burgess, S. (Stephen), Bell, S. (Steven), Astle, W. (William), Stevens, D. (David), Koulman, A. (Albert), Selmer, R. M. (Randi M.), Verschuren, W. M. (W. M. Monique), Sato, S. (Shinichi), Njolstad, I. (Inger), Woodward, M. (Mark), Salomaa, V. (Veikko), Nordestgaard, B. G. (Borge G.), Yeap, B. B. (Bu B.), Fletcher, A. (Astrid), Melander, O. (Olle), Kuller, L. H. (Lewis H.), Balkau, B. (Beverley), Marmot, M. (Michael), Koenig, W. (Wolfgang), Casiglia, E. (Edoardo), Cooper, C. (Cyrus), Arndt, V. (Volker), Franco, O. H. (Oscar H.), Wennberg, P. (Patrik), Gallacher, J. (John), de la Camara, A. G. (Agustin Gomez), Volzke, H. (Henry), Dahm, C. C. (Christina C.), Dale, C. E. (Caroline E.), Bergmann, M. M. (Manuela M.), Crespo, C. J. (Carlos J.), van der Schouw, Y. T. (Yvonne T.), Kaaks, R. (Rudolf), Simons, L. A. (Leon A.), Lagiou, P. (Pagona), Schoufour, J. D. (Josje D.), Boer, J. M. (Jolanda M. A.), Key, T. J. (Timothy J.), Rodriguez, B. (Beatriz), Moreno-Iribas, C. (Conchi), Davidson, K. W. (Karina W.), Taylor, J. O. (James O.), Sacerdote, C. (Carlotta), Wallace, R. B. (Robert B.), Quiros, J. R. (J. Ramon), Tumino, R. (Rosario), Blazer, D. G. (Dan G., II), Linneberg, A. (Allan), Daimon, M. (Makoto), Panico, S. (Salvatore), Howard, B. (Barbara), Skeie, G. (Guri), Strandberg, T. (Timo), Weiderpass, E. (Elisabete), Nietert, P. J. (Paul J.), Psaty, B. M. (Bruce M.), Kromhout, D. (Daan), Salamanca-Fernandez, E. (Elena), Kiechl, S. (Stefan), Krumholz, H. M. (Harlan M.), Grioni, S. (Sara), Palli, D. (Domenico), Huerta, J. M. (Jose M.), Price, J. (Jackie), Sundstrom, J. (Johan), Arriola, L. (Larraitz), Arima, H. (Hisatomi), Travis, R. C. (Ruth C.), Panagiotakos, D. B. (Demosthenes B.), Karakatsani, A. (Anna), Trichopoulou, A. (Antonia), Kuhn, T. (Tilman), Grobbee, D. E. (Diederick E.), Barrett-Connor, E. (Elizabeth), van Schoor, N. (Natasja), Boeing, H. (Heiner), Overvad, K. (Kim), Kauhanen, J. (Jussi), Wareham, N. (Nick), Langenberg, C. (Claudia), Forouhi, N. (Nita), Wennberg, M. (Maria), Despres, J.-P. (Jean-Pierre), Cushman, M. (Mary), Cooper, J. A. (Jackie A.), Rodriguez, C. J. (Carlos J.), Sakurai, M. (Masaru), Shaw, J. E. (Jonathan E.), Knuiman, M. (Matthew), Voortman, T. (Trudy), Meisinger, C. (Christa), Tjonneland, A. (Anne), Brenner, H. (Hermann), Palmieri, L. (Luigi), Dallongeville, J. (Jean), Brunner, E. J. (Eric J.), Assmann, G. (Gerd), Trevisan, M. (Maurizio), Gillum, R. F. (Richard F.), Ford, I. (Ian), Sattar, N. (Naveed), Lazo, M. (Mariana), Thompson, S. G. (Simon G.), Ferrari, P. (Pietro), Leon, D. A. (David A.), Smith, G. D. (George Davey), Peto, R. (Richard), Jackson, R. (Rod), Banks, E. (Emily), Di Angelantonio, E. (Emanuele), Danesh, J. (John), Wood, A. M. (Angela M.), Kaptoge, S. (Stephen), Butterworth, A. S. (Adam S.), Willeit, P. (Peter), Warnakula, S. (Samantha), Bolton, T. (Thomas), Paige, E. (Ellie), Paul, D. S. (Dirk S.), Sweeting, M. (Michael), Burgess, S. (Stephen), Bell, S. (Steven), Astle, W. (William), Stevens, D. (David), Koulman, A. (Albert), Selmer, R. M. (Randi M.), Verschuren, W. M. (W. M. Monique), Sato, S. (Shinichi), Njolstad, I. (Inger), Woodward, M. (Mark), Salomaa, V. (Veikko), Nordestgaard, B. G. (Borge G.), Yeap, B. B. (Bu B.), Fletcher, A. (Astrid), Melander, O. (Olle), Kuller, L. H. (Lewis H.), Balkau, B. (Beverley), Marmot, M. (Michael), Koenig, W. (Wolfgang), Casiglia, E. (Edoardo), Cooper, C. (Cyrus), Arndt, V. (Volker), Franco, O. H. (Oscar H.), Wennberg, P. (Patrik), Gallacher, J. (John), de la Camara, A. G. (Agustin Gomez), Volzke, H. (Henry), Dahm, C. C. (Christina C.), Dale, C. E. (Caroline E.), Bergmann, M. M. (Manuela M.), Crespo, C. J. (Carlos J.), van der Schouw, Y. T. (Yvonne T.), Kaaks, R. (Rudolf), Simons, L. A. (Leon A.), Lagiou, P. (Pagona), Schoufour, J. D. (Josje D.), Boer, J. M. (Jolanda M. A.), Key, T. J. (Timothy J.), Rodriguez, B. (Beatriz), Moreno-Iribas, C. (Conchi), Davidson, K. W. (Karina W.), Taylor, J. O. (James O.), Sacerdote, C. (Carlotta), Wallace, R. B. (Robert B.), Quiros, J. R. (J. Ramon), Tumino, R. (Rosario), Blazer, D. G. (Dan G., II), Linneberg, A. (Allan), Daimon, M. (Makoto), Panico, S. (Salvatore), Howard, B. (Barbara), Skeie, G. (Guri), Strandberg, T. (Timo), Weiderpass, E. (Elisabete), Nietert, P. J. (Paul J.), Psaty, B. M. (Bruce M.), Kromhout, D. (Daan), Salamanca-Fernandez, E. (Elena), Kiechl, S. (Stefan), Krumholz, H. M. (Harlan M.), Grioni, S. (Sara), Palli, D. (Domenico), Huerta, J. M. (Jose M.), Price, J. (Jackie), Sundstrom, J. (Johan), Arriola, L. (Larraitz), Arima, H. (Hisatomi), Travis, R. C. (Ruth C.), Panagiotakos, D. B. (Demosthenes B.), Karakatsani, A. (Anna), Trichopoulou, A. (Antonia), Kuhn, T. (Tilman), Grobbee, D. E. (Diederick E.), Barrett-Connor, E. (Elizabeth), van Schoor, N. (Natasja), Boeing, H. (Heiner), Overvad, K. (Kim), Kauhanen, J. (Jussi), Wareham, N. (Nick), Langenberg, C. (Claudia), Forouhi, N. (Nita), Wennberg, M. (Maria), Despres, J.-P. (Jean-Pierre), Cushman, M. (Mary), Cooper, J. A. (Jackie A.), Rodriguez, C. J. (Carlos J.), Sakurai, M. (Masaru), Shaw, J. E. (Jonathan E.), Knuiman, M. (Matthew), Voortman, T. (Trudy), Meisinger, C. (Christa), Tjonneland, A. (Anne), Brenner, H. (Hermann), Palmieri, L. (Luigi), Dallongeville, J. (Jean), Brunner, E. J. (Eric J.), Assmann, G. (Gerd), Trevisan, M. (Maurizio), Gillum, R. F. (Richard F.), Ford, I. (Ian), Sattar, N. (Naveed), Lazo, M. (Mariana), Thompson, S. G. (Simon G.), Ferrari, P. (Pietro), Leon, D. A. (David A.), Smith, G. D. (George Davey), Peto, R. (Richard), Jackson, R. (Rod), Banks, E. (Emily), Di Angelantonio, E. (Emanuele), and Danesh, J. (John)

Abstract

Background: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. Findings: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality ris

Published
2018

2. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, R.A. (Robert), Freitag, C.M. (Christine), Li, L. (Li), Chu, A.Y. (Audrey), Surendran, P. (Praveen), Young, R. (Robin), Grarup, N. (Niels), Stancáková, A. (Alena), Chen, Y. (Yuning), Varga, T.V. (Tibor V.), Yaghootkar, H. (Hanieh), Luan, J. (Jian'An), Zhao, J.H. (Jing Hua), Willems, S.M. (Sara), Wessel, J. (Jennifer), Wang, S. (Shuai), Maruthur, N.M. (Nisa M), Michailidou, K. (Kyriaki), Pirie, A. (Ailith), Lee, S.J. (Sven) van der, Gillson, C.J. (Christopher), Al Olama, A.A. (Ali Amin), Amouyel, P. (Philippe), Arriola, L. (Larraitz), Arveiler, D. (Dominique), Aviles-Olmos, I. (Iciar), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Barroso, I.E. (Inês), Garcia, S.B. (Sara Benlloch), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boehnke, M. (Michael), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bork-Jensen, J. (Jette), Bowden, S. (Sarah), Caldas, C. (Carlos), Caslake, M. (Muriel), Cupples, L.A. (Adrienne), Cruchaga, C. (Carlos), Czajkowski, J. (Jacek), Hoed, M. (Marcel) den, Dunn, J.A. (Janet A.), Earl, H. (Helena), Ehret, G.B. (Georg), Ferrannini, E. (Ele), Ferrieres, J. (Jean), Foltynie, T. (Thomas), Ford, I. (Ian), Forouhi, N.G. (Nita), Gianfagna, F. (Francesco), Gonzalez, C. (Carlos), Grioni, S. (Sara), Hiller, L. (Louise), Jansson, J.H., Jørgensen, M.E. (Marit E.), Jukema, J.W. (Jan Wouter), Kaaks, R. (Rudolf), Kee, F. (Frank), Kerrison, N.D. (Nicola D.), Key, T. (Tim), Kontto, J. (Jukka), Kote-Jarai, Z., Kraja, A. (Aldi), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Linneberg, A. (Allan), Liu, C. (Chunyu), Marenne, G. (Gaëlle), Mohlke, K.L. (Karen), Morris, A.P. (Andrew), Muir, K.R. (K.), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Navarro, C. (Carmen), Nielsen, S.F. (Sune), Nilsson, P. (Peter), Nordestgaard, B.G. (Børge), Packard, C.J. (Chris J.), Palli, D. (Domenico), Panico, S. (Salvatore), Peloso, G.M. (Gina), Perola, M. (Markus), Peters, A. (Annette), Poole, C.J. (Christopher J.), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Salomaa, V. (Veikko), Sánchez, M.-J. (María-José), Sattar, N. (Naveed), Sharp, S.J. (Stephen), Sims, R. (Rebecca), Slimani, N. (Nadia), Smith, J.A. (Jennifer A), Thompson, D. (Deborah), Trompet, S. (Stella), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Virtamo, J. (Jarmo), Walker, M. (Mark), Walter, K. (Klaudia), Abraham, J.E. (Jean E.), Amundadottir, L.T. (Laufey T.), Butterworth, A.S. (Adam), Aponte, J.L. (Jennifer L), Dupuis, J. (Josée), Easton, D.F. (Douglas F.), Eeles, R. (Rosalind), Erdmann, J. (Jeanette), Franks, P.W. (Paul), Frayling, T.M. (Timothy), Hansen, T. (T.), Howson, J.M.M. (Joanna M.M.), Jorgensen, T. (Torben), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), McCarthy, M.I. (Mark), Pankow, J.S. (James), Pedersen, O. (Oluf), Riboli, E. (Elio), Rotter, J.I. (Jerome I.), Saleheen, D. (Danish), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Vollenweider, P. (Peter), O'Rahilly, S. (Stephen), Deloukas, P. (Panagiotis), Danesh, J. (John), Goodarzi, M. (Mark), Kathiresan, S. (Sekar), Meigs, J.B. (James), Ehm, M.G. (Margaret G), Wareham, N.J. (Nick), Waterworth, D. (Dawn), Scott, R.A. (Robert), Freitag, C.M. (Christine), Li, L. (Li), Chu, A.Y. (Audrey), Surendran, P. (Praveen), Young, R. (Robin), Grarup, N. (Niels), Stancáková, A. (Alena), Chen, Y. (Yuning), Varga, T.V. (Tibor V.), Yaghootkar, H. (Hanieh), Luan, J. (Jian'An), Zhao, J.H. (Jing Hua), Willems, S.M. (Sara), Wessel, J. (Jennifer), Wang, S. (Shuai), Maruthur, N.M. (Nisa M), Michailidou, K. (Kyriaki), Pirie, A. (Ailith), Lee, S.J. (Sven) van der, Gillson, C.J. (Christopher), Al Olama, A.A. (Ali Amin), Amouyel, P. (Philippe), Arriola, L. (Larraitz), Arveiler, D. (Dominique), Aviles-Olmos, I. (Iciar), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Barroso, I.E. (Inês), Garcia, S.B. (Sara Benlloch), Bis, J.C. (Joshua), Blankenberg, S. (Stefan), Boehnke, M. (Michael), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borecki, I.B. (Ingrid), Bork-Jensen, J. (Jette), Bowden, S. (Sarah), Caldas, C. (Carlos), Caslake, M. (Muriel), Cupples, L.A. (Adrienne), Cruchaga, C. (Carlos), Czajkowski, J. (Jacek), Hoed, M. (Marcel) den, Dunn, J.A. (Janet A.), Earl, H. (Helena), Ehret, G.B. (Georg), Ferrannini, E. (Ele), Ferrieres, J. (Jean), Foltynie, T. (Thomas), Ford, I. (Ian), Forouhi, N.G. (Nita), Gianfagna, F. (Francesco), Gonzalez, C. (Carlos), Grioni, S. (Sara), Hiller, L. (Louise), Jansson, J.H., Jørgensen, M.E. (Marit E.), Jukema, J.W. (Jan Wouter), Kaaks, R. (Rudolf), Kee, F. (Frank), Kerrison, N.D. (Nicola D.), Key, T. (Tim), Kontto, J. (Jukka), Kote-Jarai, Z., Kraja, A. (Aldi), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Linneberg, A. (Allan), Liu, C. (Chunyu), Marenne, G. (Gaëlle), Mohlke, K.L. (Karen), Morris, A.P. (Andrew), Muir, K.R. (K.), Müller-Nurasyid, M. (Martina), Munroe, P. (Patricia), Navarro, C. (Carmen), Nielsen, S.F. (Sune), Nilsson, P. (Peter), Nordestgaard, B.G. (Børge), Packard, C.J. (Chris J.), Palli, D. (Domenico), Panico, S. (Salvatore), Peloso, G.M. (Gina), Perola, M. (Markus), Peters, A. (Annette), Poole, C.J. (Christopher J.), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Salomaa, V. (Veikko), Sánchez, M.-J. (María-José), Sattar, N. (Naveed), Sharp, S.J. (Stephen), Sims, R. (Rebecca), Slimani, N. (Nadia), Smith, J.A. (Jennifer A), Thompson, D. (Deborah), Trompet, S. (Stella), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Virtamo, J. (Jarmo), Walker, M. (Mark), Walter, K. (Klaudia), Abraham, J.E. (Jean E.), Amundadottir, L.T. (Laufey T.), Butterworth, A.S. (Adam), Aponte, J.L. (Jennifer L), Dupuis, J. (Josée), Easton, D.F. (Douglas F.), Eeles, R. (Rosalind), Erdmann, J. (Jeanette), Franks, P.W. (Paul), Frayling, T.M. (Timothy), Hansen, T. (T.), Howson, J.M.M. (Joanna M.M.), Jorgensen, T. (Torben), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), McCarthy, M.I. (Mark), Pankow, J.S. (James), Pedersen, O. (Oluf), Riboli, E. (Elio), Rotter, J.I. (Jerome I.), Saleheen, D. (Danish), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Vollenweider, P. (Peter), O'Rahilly, S. (Stephen), Deloukas, P. (Panagiotis), Danesh, J. (John), Goodarzi, M. (Mark), Kathiresan, S. (Sekar), Meigs, J.B. (James), Ehm, M.G. (Margaret G), Wareham, N.J. (Nick), and Waterworth, D. (Dawn)

Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016
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3. Rare coding variants and X-linked loci associated with age at menarche

Author

Lunetta, K.L. (Kathryn), Day, F.R. (Felix), Sulem, P. (Patrick), Ruth, K.S. (Katherine S.), Tung, J.Y. (Joyce Y.), Hinds, D.A. (David A.), Esko, T. (Tõnu), Elks, C.E. (Cathy), Altmaier, E.L. (Elizabeth), He, C. (Chunyan), Huffman, J.E. (Jennifer), Mihailov, E. (Evelin), Porcu, E. (Eleonora), Robino, A. (Antonietta), Rose, L.M. (Lynda), Schick, U.M. (Ursula), Stolk, L. (Lisette), Teumer, A. (Alexander), Thompson, D. (Deborah), Traglia, M. (Michela), Wang, C.A. (Carol A.), Yerges-Armstrong, L.M. (Laura), Antoniou, A.C. (Antonis), Barbieri, C. (Caterina), Coviello, A.D. (Andrea), Cucca, F. (Francesco), Demerath, E.W. (Ellen), Dunning, A.M. (Alison), Gandin, I. (Ilaria), Grove, M.L. (Megan L.), Gudbjartsson, D.F. (Daniel), Hocking, L.J. (Lynne), Hofman, A. (Albert), Huang, J. (Jian), Jackson, R.D. (Rebecca), Karasik, D. (David), Kriebel, J. (Jennifer), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langenberg, C. (Claudia), Li, X. (Xin), Luan, J., Mägi, R. (Reedik), Morrison, A.C. (Alanna), Padmanabhan, S. (Sandosh), Pirie, A. (Ailith), Polasek, O. (Ozren), Porteous, D.J. (David J.), Reiner, A. (Alexander), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Sala, C. (Cinzia), Schlessinger, D. (David), Scott, R.A. (Robert), Stöckl, D. (Doris), Visser, J.A. (Jenny), Völker, U. (Uwe), Vozzi, D. (Diego), Wilson, J.G. (James), Zygmunt, M. (Marek), Boerwinkle, E.A. (Eric), Buring, J.E. (Julie), Crisponi, L. (Laura), Easton, D.F. (Douglas), Hayward, C. (Caroline), Hu, F.B. (Frank), Liu, S. (Simin), Metspalu, A. (Andres), Pennell, C.E. (Craig), Ridker, P.M. (Paul), Strauch, K. (Konstantin), Streeten, E.A. (Elizabeth), Toniolo, D. (Daniela), Uitterlinden, A.G. (André), Ulivi, S. (Shelia), Völzke, H. (Henry), Wareham, N.J. (Nick), Wellons, M. (Melissa), Franceschini, N. (Nora), Chasman, D.I. (Daniel), Thorsteinsdottir, U. (Unnur), Murray, A. (Anna), Zwart, J-A. (John-Anker), Murabito, J. (Joanne), Ong, K.K. (Ken), Perry, J.R.B. (John), Forouhi, N.G. (Nita G.), Kerrison, N.D. (Nicola D.), Sharp, S.J. (Stephen J.), Sims, M.A. (Matthew), Barroso, I.E. (Inês), Deloukas, P. (Panagiotis), McCarthy, M.I. (Mark), Arriola, L. (Larraitz), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Boeing, H. (Heiner), Franks, P.W., Gonzalez, C. (Carlos), Grioni, S. (Sara), Kaaks, R. (Rudolf), Key, T.J. (Timothy J.), Navarro, C. (Carmen), Nilsson, P.M. (Peter M.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Sánchez, M.-J. (María-José), Slimani, N. (Nadia), Tjonneland, A. (Anne), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Riboli, E. (Elio), Smith, B.H. (Blair), Campbell, A. (Archie), Deary, I.J. (Ian), McIntosh, A.M. (Andrew), Lunetta, K.L. (Kathryn), Day, F.R. (Felix), Sulem, P. (Patrick), Ruth, K.S. (Katherine S.), Tung, J.Y. (Joyce Y.), Hinds, D.A. (David A.), Esko, T. (Tõnu), Elks, C.E. (Cathy), Altmaier, E.L. (Elizabeth), He, C. (Chunyan), Huffman, J.E. (Jennifer), Mihailov, E. (Evelin), Porcu, E. (Eleonora), Robino, A. (Antonietta), Rose, L.M. (Lynda), Schick, U.M. (Ursula), Stolk, L. (Lisette), Teumer, A. (Alexander), Thompson, D. (Deborah), Traglia, M. (Michela), Wang, C.A. (Carol A.), Yerges-Armstrong, L.M. (Laura), Antoniou, A.C. (Antonis), Barbieri, C. (Caterina), Coviello, A.D. (Andrea), Cucca, F. (Francesco), Demerath, E.W. (Ellen), Dunning, A.M. (Alison), Gandin, I. (Ilaria), Grove, M.L. (Megan L.), Gudbjartsson, D.F. (Daniel), Hocking, L.J. (Lynne), Hofman, A. (Albert), Huang, J. (Jian), Jackson, R.D. (Rebecca), Karasik, D. (David), Kriebel, J. (Jennifer), Lange, E.M. (Ethan), Lange, L.A. (Leslie), Langenberg, C. (Claudia), Li, X. (Xin), Luan, J., Mägi, R. (Reedik), Morrison, A.C. (Alanna), Padmanabhan, S. (Sandosh), Pirie, A. (Ailith), Polasek, O. (Ozren), Porteous, D.J. (David J.), Reiner, A. (Alexander), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Sala, C. (Cinzia), Schlessinger, D. (David), Scott, R.A. (Robert), Stöckl, D. (Doris), Visser, J.A. (Jenny), Völker, U. (Uwe), Vozzi, D. (Diego), Wilson, J.G. (James), Zygmunt, M. (Marek), Boerwinkle, E.A. (Eric), Buring, J.E. (Julie), Crisponi, L. (Laura), Easton, D.F. (Douglas), Hayward, C. (Caroline), Hu, F.B. (Frank), Liu, S. (Simin), Metspalu, A. (Andres), Pennell, C.E. (Craig), Ridker, P.M. (Paul), Strauch, K. (Konstantin), Streeten, E.A. (Elizabeth), Toniolo, D. (Daniela), Uitterlinden, A.G. (André), Ulivi, S. (Shelia), Völzke, H. (Henry), Wareham, N.J. (Nick), Wellons, M. (Melissa), Franceschini, N. (Nora), Chasman, D.I. (Daniel), Thorsteinsdottir, U. (Unnur), Murray, A. (Anna), Zwart, J-A. (John-Anker), Murabito, J. (Joanne), Ong, K.K. (Ken), Perry, J.R.B. (John), Forouhi, N.G. (Nita G.), Kerrison, N.D. (Nicola D.), Sharp, S.J. (Stephen J.), Sims, M.A. (Matthew), Barroso, I.E. (Inês), Deloukas, P. (Panagiotis), McCarthy, M.I. (Mark), Arriola, L. (Larraitz), Balkau, B. (Beverley), Barricarte, A. (Aurelio), Boeing, H. (Heiner), Franks, P.W., Gonzalez, C. (Carlos), Grioni, S. (Sara), Kaaks, R. (Rudolf), Key, T.J. (Timothy J.), Navarro, C. (Carmen), Nilsson, P.M. (Peter M.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Quirós, J.R., Rolandsson, O. (Olov), Sacerdote, C. (Carlotta), Sánchez, M.-J. (María-José), Slimani, N. (Nadia), Tjonneland, A. (Anne), Tumino, R. (Rosario), Van Der A, D.L. (Daphne L.), Schouw, Y.T. (Yvonne) van der, Riboli, E. (Elio), Smith, B.H. (Blair), Campbell, A. (Archie), Deary, I.J. (Ian), and McIntosh, A.M. (Andrew)

Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Published
2015
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4. Social inequalities and mortality in europe - results from a large multi-national cohort

Author

Gallo, V. (Valentina), Mackenbach, J.P. (Johan), Ezzati, M. (Majid), Menvielle, G. (Gwenn), Kunst, A.E. (Anton), Rohrmann, S. (Sabine), Kaaks, R. (Rudolf), Teucher, B. (Birgit), Boeing, H. (Heiner), Bergmann, M.M. (Manuela), Tjønneland, A. (Anne), Dalton, S.O. (Susanne), Overvad, K. (Kim), Redondo, M.-L. (Maria-Luisa), Agudo, A. (Antonio), Daponte, A. (Antonio), Arriola, L. (Larraitz), Navarro, C. (Carmen), Barricante Gurrea, A. (Aurelio), Khaw, K-T. (Kay-Tee), Wareham, N.J. (Nick), Key, T. (Tim), Naska, A. (Androniki), Trichopoulou, A. (Antonia), Trichopoulos, D. (Dimitrios), Masala, G. (Giovanna), Panico, S. (Salvatore), Contiero, P. (Paolo), Tumino, R. (Rosario), Bueno-De-Mesquita, H.B. (Bas), Siersema, P.D. (Peter), Peeters, P.H.M. (Petra), Zackrisson, S. (Sophia), Almquist, M. (Martin), Eriksson, S. (Sture), Hallmans, G. (Göran), Skeie, G. (Guri), Braaten, T. (Tonje), Lund, E. (Eiliv), Illner, A.-K. (Anne-Kathrin), Mouw, T. (Traci), Riboli, E. (Elio), Vineis, P. (Paolo), Gallo, V. (Valentina), Mackenbach, J.P. (Johan), Ezzati, M. (Majid), Menvielle, G. (Gwenn), Kunst, A.E. (Anton), Rohrmann, S. (Sabine), Kaaks, R. (Rudolf), Teucher, B. (Birgit), Boeing, H. (Heiner), Bergmann, M.M. (Manuela), Tjønneland, A. (Anne), Dalton, S.O. (Susanne), Overvad, K. (Kim), Redondo, M.-L. (Maria-Luisa), Agudo, A. (Antonio), Daponte, A. (Antonio), Arriola, L. (Larraitz), Navarro, C. (Carmen), Barricante Gurrea, A. (Aurelio), Khaw, K-T. (Kay-Tee), Wareham, N.J. (Nick), Key, T. (Tim), Naska, A. (Androniki), Trichopoulou, A. (Antonia), Trichopoulos, D. (Dimitrios), Masala, G. (Giovanna), Panico, S. (Salvatore), Contiero, P. (Paolo), Tumino, R. (Rosario), Bueno-De-Mesquita, H.B. (Bas), Siersema, P.D. (Peter), Peeters, P.H.M. (Petra), Zackrisson, S. (Sophia), Almquist, M. (Martin), Eriksson, S. (Sture), Hallmans, G. (Göran), Skeie, G. (Guri), Braaten, T. (Tonje), Lund, E. (Eiliv), Illner, A.-K. (Anne-Kathrin), Mouw, T. (Traci), Riboli, E. (Elio), and Vineis, P. (Paolo)

Abstract

Background: Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans. Methods: A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model's with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality. Results: Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52-0.61); among women by 29% (HR 0.71, 95% C.I. 0.64-0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries. Discussion: In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.

Published
2012
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