27 results on '"Gaunt, TR."'
Search Results
2. Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones
- Author
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Swain, CTV, Drummond, AE, Boing, L, Milne, RL, English, DR, Brown, KA, Van Roekel, EH, Dixon-Suen, Suzanne, Lynch, MJ, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, Lynch, BM, Swain, CTV, Drummond, AE, Boing, L, Milne, RL, English, DR, Brown, KA, Van Roekel, EH, Dixon-Suen, Suzanne, Lynch, MJ, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, and Lynch, BM
- Published
- 2022
3. Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones
- Author
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Swain, CTV, Drummond, AE, Boing, L, Milne, RL, English, DR, Brown, KA, van Roekel, EH, Dixon-Suen, SC, Lynch, MJ, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, Lynch, BM, Swain, CTV, Drummond, AE, Boing, L, Milne, RL, English, DR, Brown, KA, van Roekel, EH, Dixon-Suen, SC, Lynch, MJ, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, and Lynch, BM
- Abstract
The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity-sex hormone-breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer.See related reviews by Lynch et al., p. 11 and Drummond et al., p. 28.
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- 2022
4. Linking Physical Activity to Breast Cancer via Sex Steroid Hormones, Part 2: The Effect of Sex Steroid Hormones on Breast Cancer Risk
- Author
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Drummond, AE, Swain, CT, Brown, KA, Dixon-Suen, SC, Boing, L, van Roekel, EH, Moore, MM, Gaunt, TR, Milne, RL, English, DR, Martin, RM, Lewis, SJ, Lynch, BM, Drummond, AE, Swain, CT, Brown, KA, Dixon-Suen, SC, Boing, L, van Roekel, EH, Moore, MM, Gaunt, TR, Milne, RL, English, DR, Martin, RM, Lewis, SJ, and Lynch, BM
- Abstract
We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone-binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose-response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer.See related reviews by Lynch et al., p. 11 and Swain et al., p. 16.
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- 2022
5. Linking Physical Activity to Breast Cancer: Text Mining Results and a Protocol for Systematically Reviewing Three Potential Mechanistic Pathways
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Lynch, BM, Milne, RL, English, DR, Brown, KA, Drummond, AE, Swain, CT, van Roekel, EH, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, Lynch, BM, Milne, RL, English, DR, Brown, KA, Drummond, AE, Swain, CT, van Roekel, EH, Moore, MM, Gaunt, TR, Martin, RM, and Lewis, SJ
- Abstract
Epidemiologic research suggests that physical activity is associated with a reduced risk of breast cancer, but the causal nature of this link is not clear. Investigating mechanistic pathways can provide evidence of biological plausibility and improve causal inference. This project will examine three putative pathways (sex steroid hormones, insulin signaling, and inflammation) in a series of two-stage systematic reviews. Stage 1 used Text Mining for Mechanism Prioritisation (TeMMPo) to identify and prioritize relevant biological intermediates. Stage 2 will systematically review the findings from studies of (i) physical activity and intermediates and (ii) intermediates and breast cancer. Ovid MEDLINE, EMBASE, and SPORTDiscus will be searched using a combination of subject headings and free-text terms. Human intervention and prospective, observational studies will be eligible for inclusion. Meta-analysis will be performed where possible. Risk of bias will be assessed using the Cochrane Collaboration tool, or the ROBINS-I or ROBINS-E tool, depending on study type. Strength of evidence will be assessed using the GRADE system. In addition to synthesizing the mechanistic evidence that links physical activity with breast cancer risk, this project may also identify priority areas for future research and help inform the design and implementation of physical activity interventions.See related reviews by Swain et al., p. 16 and Drummond et al., p. 28.
- Published
- 2022
6. Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.
- Author
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Longchamps, RJ, Longchamps, RJ, Yang, SY, Castellani, CA, Shi, W, Lane, J, Grove, ML, Bartz, TM, Sarnowski, C, Liu, C, Burrows, K, Guyatt, AL, Gaunt, TR, Kacprowski, T, Yang, J, De Jager, PL, Yu, L, Bergman, A, Xia, R, Fornage, M, Feitosa, MF, Wojczynski, MK, Kraja, AT, Province, MA, Amin, N, Rivadeneira, F, Tiemeier, H, Uitterlinden, AG, Broer, L, Van Meurs, JBJ, Van Duijn, CM, Raffield, LM, Lange, L, Rich, SS, Lemaitre, RN, Goodarzi, MO, Sitlani, CM, Mak, ACY, Bennett, DA, Rodriguez, S, Murabito, JM, Lunetta, KL, Sotoodehnia, N, Atzmon, G, Ye, K, Barzilai, N, Brody, JA, Psaty, BM, Taylor, KD, Rotter, JI, Boerwinkle, E, Pankratz, N, Arking, DE, Longchamps, RJ, Longchamps, RJ, Yang, SY, Castellani, CA, Shi, W, Lane, J, Grove, ML, Bartz, TM, Sarnowski, C, Liu, C, Burrows, K, Guyatt, AL, Gaunt, TR, Kacprowski, T, Yang, J, De Jager, PL, Yu, L, Bergman, A, Xia, R, Fornage, M, Feitosa, MF, Wojczynski, MK, Kraja, AT, Province, MA, Amin, N, Rivadeneira, F, Tiemeier, H, Uitterlinden, AG, Broer, L, Van Meurs, JBJ, Van Duijn, CM, Raffield, LM, Lange, L, Rich, SS, Lemaitre, RN, Goodarzi, MO, Sitlani, CM, Mak, ACY, Bennett, DA, Rodriguez, S, Murabito, JM, Lunetta, KL, Sotoodehnia, N, Atzmon, G, Ye, K, Barzilai, N, Brody, JA, Psaty, BM, Taylor, KD, Rotter, JI, Boerwinkle, E, Pankratz, N, and Arking, DE
- Abstract
Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).
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- 2022
7. Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020
- Author
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Tobias, JH, Duncan, EL, Kague, E, Hammond, CL, Gregson, CL, Bassett, D, Williams, GR, Min, JL, Gaunt, TR, Karasik, D, Ohlsson, C, Rivadeneira, Fernando, Edwards, JR, Hannan, FM, Kemp, JP, Gilbert, SJ, Alonso, N, Hassan, N, Compston, JE, Ralston, SH, Tobias, JH, Duncan, EL, Kague, E, Hammond, CL, Gregson, CL, Bassett, D, Williams, GR, Min, JL, Gaunt, TR, Karasik, D, Ohlsson, C, Rivadeneira, Fernando, Edwards, JR, Hannan, FM, Kemp, JP, Gilbert, SJ, Alonso, N, Hassan, N, Compston, JE, and Ralston, SH
- Abstract
The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by “multi-omics” database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the “osteocyte signature”, by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.
- Published
- 2021
8. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- Author
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Surendran, P, Feofanova, E, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, A, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Edwards, DRV, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, de Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, T, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, Y, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, A, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Smith, GD, de Boer, RA, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, M, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, J, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, van der Harst, P, van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, D, Levy, D, Newton-Cheh, C, Munroe, PB, Howson, JMM, Surendran, P, Feofanova, E, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, A, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Edwards, DRV, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, de Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, T, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, Y, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, A, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Smith, GD, de Boer, RA, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, M, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, J, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, van der Harst, P, van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, D, Levy, D, Newton-Cheh, C, Munroe, PB, and Howson, JMM
- Abstract
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
- Published
- 2020
9. Appraising the causal relevance of DNA methylation for risk of lung cancer
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Battram, T, Richmond, RC, Baglietto, L, Haycock, PC, Perduca, V, Bojesen, SE, Gaunt, TR, Hemani, G, Guida, F, Carreras-Torres, R, Hung, R, Amos, C, Freeman, JR, Sandanger, TM, Nost, TH, Nordestgaard, BG, Teschendorff, AE, Polidoro, S, Vineis, P, Severi, G, Hodge, AM, Giles, GG, Grankvist, K, Johansson, MB, Johansson, M, Smith, GD, Relton, CL, Battram, T, Richmond, RC, Baglietto, L, Haycock, PC, Perduca, V, Bojesen, SE, Gaunt, TR, Hemani, G, Guida, F, Carreras-Torres, R, Hung, R, Amos, C, Freeman, JR, Sandanger, TM, Nost, TH, Nordestgaard, BG, Teschendorff, AE, Polidoro, S, Vineis, P, Severi, G, Hodge, AM, Giles, GG, Grankvist, K, Johansson, MB, Johansson, M, Smith, GD, and Relton, CL
- Abstract
BACKGROUND: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated. METHODS: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer. RESULTS: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk. CONCLUSIONS: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.
- Published
- 2019
10. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume
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Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gomez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, PRHJ, Al Turki, S, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, A, Down, T, Du, Y, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Howie, B, Huang, J, Huang, L, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Marenne, G, Maslen, J, Mathieson, I, McCarthy, S, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, A, Morris, J, Muddyman, D, Muntoni, F, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnstrom, K, Richards, JB, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, S-Y, Skuse, D, Small, KS, Smee, C, Smith, BH, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, C, Yang, J, Zhang, F, Zhang, P, Zheng, H-F, Smith, GD, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bonnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, VWV, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, St Pourcain, B, Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gomez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, PRHJ, Al Turki, S, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, A, Down, T, Du, Y, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Howie, B, Huang, J, Huang, L, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Marenne, G, Maslen, J, Mathieson, I, McCarthy, S, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, A, Morris, J, Muddyman, D, Muntoni, F, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnstrom, K, Richards, JB, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, S-Y, Skuse, D, Small, KS, Smee, C, Smith, BH, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, C, Yang, J, Zhang, F, Zhang, P, Zheng, H-F, Smith, GD, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bonnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, VWV, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, and St Pourcain, B
- Abstract
Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
- Published
- 2019
11. Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns Findings From the Pregnancy and Childhood Epigenetics Consortium
- Author
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Kazmi, N, Sharp, GC, Reese, SE, Vehmeijer, FO, Lahti, J, Page, CM, Zhang, WM, Rifas-Shiman, SL, Rezwan, FI, Simpkin, AJ, Burrows, K, Richardson, TG, Ferreira, D L S, Fraser, A, Harmon, QE, Zhao, SS, Jaddoe, Vincent, Czamara, D, Binder, EB, Magnus, MC, Haberg, SE, Nystad, W, Nohr, EA, Starling, AP, Kechris, KJ, Yang, IV, DeMeo, DL, Litonjua, AA, Baccarelli, A, Oken, E, Holloway, JW, Karmaus, W, Arshad, SH, Dabelea, D, Sorensen, TIA, Laivuori, H, Raikkonen, K, Felix, Janine, London, SJ, Hivert, MF, Gaunt, TR, Lawlor, DA, Relton, CL, Kazmi, N, Sharp, GC, Reese, SE, Vehmeijer, FO, Lahti, J, Page, CM, Zhang, WM, Rifas-Shiman, SL, Rezwan, FI, Simpkin, AJ, Burrows, K, Richardson, TG, Ferreira, D L S, Fraser, A, Harmon, QE, Zhao, SS, Jaddoe, Vincent, Czamara, D, Binder, EB, Magnus, MC, Haberg, SE, Nystad, W, Nohr, EA, Starling, AP, Kechris, KJ, Yang, IV, DeMeo, DL, Litonjua, AA, Baccarelli, A, Oken, E, Holloway, JW, Karmaus, W, Arshad, SH, Dabelea, D, Sorensen, TIA, Laivuori, H, Raikkonen, K, Felix, Janine, London, SJ, Hivert, MF, Gaunt, TR, Lawlor, DA, and Relton, CL
- Published
- 2019
12. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume
- Author
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Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, Janine, Medina Gomez, Maria, Rivadeneira, Fernando, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens Junyent, Monica, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, P, Al Turki, S, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, A, Down, T, Du, YP, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, XS, Guo, XQ, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Howie, B, Huang, J, Huang, LR, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, YR, Liang, JQ, Lin, H, Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Marenne, G, Maslen, J, Mathieson, I, McCarthy, S, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, A, Morris, J, Muddyman, D, Muntoni, F, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnstrom, K, Richards, JB, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, SY, Skuse, D, Small, KS, Smee, C, Smith, BH, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, Stalker, J, Stevens, E, Sun, JP, Surdulescu, G, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G B, Wang, Johnny, Wang, Y, Ward, K, Wheeler, E, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, CJ, Yang, Jiaqi, Zhang, F, Zhang, PB, Zheng, HF, Smith, GD, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bonnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, Vincent, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, St Pourcain, B, Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, Janine, Medina Gomez, Maria, Rivadeneira, Fernando, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens Junyent, Monica, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, P, Al Turki, S, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, A, Down, T, Du, YP, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, XS, Guo, XQ, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Howie, B, Huang, J, Huang, LR, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, YR, Liang, JQ, Lin, H, Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Marenne, G, Maslen, J, Mathieson, I, McCarthy, S, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, A, Morris, J, Muddyman, D, Muntoni, F, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnstrom, K, Richards, JB, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, SY, Skuse, D, Small, KS, Smee, C, Smith, BH, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, Stalker, J, Stevens, E, Sun, JP, Surdulescu, G, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G B, Wang, Johnny, Wang, Y, Ward, K, Wheeler, E, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, CJ, Yang, Jiaqi, Zhang, F, Zhang, PB, Zheng, HF, Smith, GD, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bonnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, Vincent, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, and St Pourcain, B
- Published
- 2019
13. Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium.
- Author
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Felix, JF, Joubert, BR, Baccarelli, AA, Sharp, GC, Almqvist, C, Annesi-Maesano, I, Arshad, H, Baïz, N, Bakermans-Kranenburg, MJ, Bakulski, KM, Binder, EB, Bouchard, L, Breton, CV, Brunekreef, B, Brunst, KJ, Burchard, EG, Bustamante, M, Chatzi, L, Cheng Munthe-Kaas, M, Corpeleijn, E, Czamara, D, Dabelea, D, Davey Smith, G, De Boever, P, Duijts, L, Dwyer, T, Eng, C, Eskenazi, B, Everson, TM, Falahi, F, Fallin, MD, Farchi, S, Fernandez, MF, Gao, L, Gaunt, TR, Ghantous, A, Gillman, MW, Gonseth, S, Grote, V, Gruzieva, O, Håberg, SE, Herceg, Z, Hivert, M-F, Holland, N, Holloway, JW, Hoyo, C, Hu, D, Huang, R-C, Huen, K, Järvelin, M-R, Jima, DD, Just, AC, Karagas, MR, Karlsson, R, Karmaus, W, Kechris, KJ, Kere, J, Kogevinas, M, Koletzko, B, Koppelman, GH, Küpers, LK, Ladd-Acosta, C, Lahti, J, Lambrechts, N, Langie, SAS, Lie, RT, Liu, AH, Magnus, MC, Magnus, P, Maguire, RL, Marsit, CJ, McArdle, W, Melén, E, Melton, P, Murphy, SK, Nawrot, TS, Nisticò, L, Nohr, EA, Nordlund, B, Nystad, W, Oh, SS, Oken, E, Page, CM, Perron, P, Pershagen, G, Pizzi, C, Plusquin, M, Raikkonen, K, Reese, SE, Reischl, E, Richiardi, L, Ring, S, Roy, RP, Rzehak, P, Schoeters, G, Schwartz, DA, Sebert, S, Snieder, H, Sørensen, TIA, Starling, AP, Sunyer, J, Taylor, JA, Tiemeier, H, Ullemar, V, Vafeiadi, M, Van Ijzendoorn, MH, Vonk, JM, Vriens, A, Vrijheid, M, Wang, P, Wiemels, JL, Wilcox, AJ, Wright, RJ, Xu, C-J, Xu, Z, Yang, IV, Yousefi, P, Zhang, H, Zhang, W, Zhao, S, Agha, G, Relton, CL, Jaddoe, VWV, London, SJ, Felix, JF, Joubert, BR, Baccarelli, AA, Sharp, GC, Almqvist, C, Annesi-Maesano, I, Arshad, H, Baïz, N, Bakermans-Kranenburg, MJ, Bakulski, KM, Binder, EB, Bouchard, L, Breton, CV, Brunekreef, B, Brunst, KJ, Burchard, EG, Bustamante, M, Chatzi, L, Cheng Munthe-Kaas, M, Corpeleijn, E, Czamara, D, Dabelea, D, Davey Smith, G, De Boever, P, Duijts, L, Dwyer, T, Eng, C, Eskenazi, B, Everson, TM, Falahi, F, Fallin, MD, Farchi, S, Fernandez, MF, Gao, L, Gaunt, TR, Ghantous, A, Gillman, MW, Gonseth, S, Grote, V, Gruzieva, O, Håberg, SE, Herceg, Z, Hivert, M-F, Holland, N, Holloway, JW, Hoyo, C, Hu, D, Huang, R-C, Huen, K, Järvelin, M-R, Jima, DD, Just, AC, Karagas, MR, Karlsson, R, Karmaus, W, Kechris, KJ, Kere, J, Kogevinas, M, Koletzko, B, Koppelman, GH, Küpers, LK, Ladd-Acosta, C, Lahti, J, Lambrechts, N, Langie, SAS, Lie, RT, Liu, AH, Magnus, MC, Magnus, P, Maguire, RL, Marsit, CJ, McArdle, W, Melén, E, Melton, P, Murphy, SK, Nawrot, TS, Nisticò, L, Nohr, EA, Nordlund, B, Nystad, W, Oh, SS, Oken, E, Page, CM, Perron, P, Pershagen, G, Pizzi, C, Plusquin, M, Raikkonen, K, Reese, SE, Reischl, E, Richiardi, L, Ring, S, Roy, RP, Rzehak, P, Schoeters, G, Schwartz, DA, Sebert, S, Snieder, H, Sørensen, TIA, Starling, AP, Sunyer, J, Taylor, JA, Tiemeier, H, Ullemar, V, Vafeiadi, M, Van Ijzendoorn, MH, Vonk, JM, Vriens, A, Vrijheid, M, Wang, P, Wiemels, JL, Wilcox, AJ, Wright, RJ, Xu, C-J, Xu, Z, Yang, IV, Yousefi, P, Zhang, H, Zhang, W, Zhao, S, Agha, G, Relton, CL, Jaddoe, VWV, and London, SJ
- Published
- 2018
14. MELODI: Mining Enriched Literature Objects to Derive Intermediates
- Author
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Elsworth, B, Dawe, K, Vincent, EE, Langdon, R, Lynch, BM, Martin, RM, Relton, C, Higgins, JPT, Gaunt, TR, Elsworth, B, Dawe, K, Vincent, EE, Langdon, R, Lynch, BM, Martin, RM, Relton, C, Higgins, JPT, and Gaunt, TR
- Abstract
BACKGROUND: The scientific literature contains a wealth of information from different fields on potential disease mechanisms. However, identifying and prioritizing mechanisms for further analytical evaluation presents enormous challenges in terms of the quantity and diversity of published research. The application of data mining approaches to the literature offers the potential to identify and prioritize mechanisms for more focused and detailed analysis. METHODS: Here we present MELODI, a literature mining platform that can identify mechanistic pathways between any two biomedical concepts. RESULTS: Two case studies demonstrate the potential uses of MELODI and how it can generate hypotheses for further investigation. First, an analysis of ETS-related gene ERG and prostate cancer derives the intermediate transcription factor SP1, recently confirmed to be physically interacting with ERG. Second, examining the relationship between a new potential risk factor for pancreatic cancer identifies possible mechanistic insights which can be studied in vitro. CONCLUSIONS: We have demonstrated the possible applications of MELODI, including two case studies. MELODI has been implemented as a Python/Django web application, and is freely available to use at [www.melodi.biocompute.org.uk].
- Published
- 2018
15. Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium
- Author
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Felix, Janine, Joubert, BR, Baccarelli, AA, Sharp, GC, Almqvist, C, Annesi-Maesano, I, Arshad, H, Baiz, N, Bakermans-Kranenburg, MJ, Bakulski, KM, Binder, EB, Bouchard, L, Breton, CV, Brunekreef, B, Brunst, KJ, Burchard, EG, Bustamante, M, Chatzi, L, Munthe-Kaas, MC, Corpeleijn, E, Czamara, D, Dabelea, D, Smith, GD, De Boever, P, Duijts, Liesbeth, Dwyer, T, Eng, C, Eskenazi, B, Everson, TM, Falahi, F, Fallin, MD, Farchi, S, Fernandez, MF, Gao, L, Gaunt, TR, Ghantous, A, Gillman, MW, Gonseth, S, Grote, V, Gruzieva, O, Haberg, SE, Herceg, Z, Hivert, MF, Holland, N, Holloway, JW, Hoyo, C, Hu, DL, Huang, RC, Huen, K, Jarvelin, MR, Jima, DD, Just, AC, Karagas, MR, Karlsson, R, Karmaus, W, Kechris, KJ, Kere, J, Kogevinas, M, Koletzko, B, Koppelman, GH, Kupers, LK, Ladd-Acosta, C, Lahti, J, Lambrechts, N, Langie, SAS, Lie, RT, Liu, AH, Magnus, MC, Magnus, P, Maguire, RL, Marsit, CJ, McArdle, W, Melen, E, Melton, P, Murphy, SK, Nawrot, TS, Nistico, L, Nohr, EA, Nordlund, B, Nystad, W, Oh, SS, Oken, E, Page, CM, Perron, P, Pershagen, G, Pizzi, C, Plusquin, M, Raikkonen, K, Reese, SE, Reischl, E, Richiardi, L, Ring, S, Roy, RP, Rzehak, P, Schoeters, G, Schwartz, DA, Sebert, S, Snieder, H, Sorensen, TIA, Starling, AP, Sunyer, J, Ataylor, J, Tiemeier, Henning, Ullemar, V, Vafeiadi, M, van IJzendoorn, Marinus, Vonk, JM, Vriens, A, Vrijheid, M, Wang, P, Wiemels, JL, Wilcox, AJ, Wright, RJ, Xu, CJ, Xu, ZL, Yang, IV, Yousefi, P, Zhang, HM, Zhang, WM, Zhao, SS, Agha, G, Relton, CL, Jaddoe, Vincent, London, SJ, Felix, Janine, Joubert, BR, Baccarelli, AA, Sharp, GC, Almqvist, C, Annesi-Maesano, I, Arshad, H, Baiz, N, Bakermans-Kranenburg, MJ, Bakulski, KM, Binder, EB, Bouchard, L, Breton, CV, Brunekreef, B, Brunst, KJ, Burchard, EG, Bustamante, M, Chatzi, L, Munthe-Kaas, MC, Corpeleijn, E, Czamara, D, Dabelea, D, Smith, GD, De Boever, P, Duijts, Liesbeth, Dwyer, T, Eng, C, Eskenazi, B, Everson, TM, Falahi, F, Fallin, MD, Farchi, S, Fernandez, MF, Gao, L, Gaunt, TR, Ghantous, A, Gillman, MW, Gonseth, S, Grote, V, Gruzieva, O, Haberg, SE, Herceg, Z, Hivert, MF, Holland, N, Holloway, JW, Hoyo, C, Hu, DL, Huang, RC, Huen, K, Jarvelin, MR, Jima, DD, Just, AC, Karagas, MR, Karlsson, R, Karmaus, W, Kechris, KJ, Kere, J, Kogevinas, M, Koletzko, B, Koppelman, GH, Kupers, LK, Ladd-Acosta, C, Lahti, J, Lambrechts, N, Langie, SAS, Lie, RT, Liu, AH, Magnus, MC, Magnus, P, Maguire, RL, Marsit, CJ, McArdle, W, Melen, E, Melton, P, Murphy, SK, Nawrot, TS, Nistico, L, Nohr, EA, Nordlund, B, Nystad, W, Oh, SS, Oken, E, Page, CM, Perron, P, Pershagen, G, Pizzi, C, Plusquin, M, Raikkonen, K, Reese, SE, Reischl, E, Richiardi, L, Ring, S, Roy, RP, Rzehak, P, Schoeters, G, Schwartz, DA, Sebert, S, Snieder, H, Sorensen, TIA, Starling, AP, Sunyer, J, Ataylor, J, Tiemeier, Henning, Ullemar, V, Vafeiadi, M, van IJzendoorn, Marinus, Vonk, JM, Vriens, A, Vrijheid, M, Wang, P, Wiemels, JL, Wilcox, AJ, Wright, RJ, Xu, CJ, Xu, ZL, Yang, IV, Yousefi, P, Zhang, HM, Zhang, WM, Zhao, SS, Agha, G, Relton, CL, Jaddoe, Vincent, and London, SJ
- Published
- 2018
16. Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems
- Author
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Rijlaarsdam, Jolien, Cecil, CAM, Walton, E, Mesirow, MSC, Relton, CL, Gaunt, TR, McArdle, W, Barker, ED, Rijlaarsdam, Jolien, Cecil, CAM, Walton, E, Mesirow, MSC, Relton, CL, Gaunt, TR, McArdle, W, and Barker, ED
- Published
- 2017
17. Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits
- Author
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Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, Zeggini, E, Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, and Zeggini, E
- Published
- 2017
18. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.
- Author
-
ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., Friedrich, N., Pattaro, C., Teumer, A., Gorski, M., Chu, A.Y., Mijatovic, V., Garnaas, M., Tin, A., Sorice, R., Taliun, D., Olden, M., Foster, M., Yang, Q., Chen, M.H., Pers, T.H., Johnson, A.D., Ko, Y.A., Fuchsberger, C., Tayo, B., Nalls, M., Feitosa, M.F., Isaacs, A., Dehghan, A., d'Adamo, P., Adeyemo, A., Dieffenbach, A.K., Zonderman, A.B., Nolte, I.M., van der Most, P.J., Wright, A.F., Shuldiner, A.R., Morrison, A.C., Hofman, A., Smith, A.V., Dreisbach, A.W., Franke, A., Uitterlinden, A.G., Metspalu, A., Tonjes, A., Lupo, A., Robino, A., Johansson, Å., Demirkan, A., Kollerits, B., Freedman, B.I., Ponte, B., Oostra, B.A., Paulweber, B., Krämer, B.K., Mitchell, B.D., Buckley, B.M., Peralta, C.A., Hayward, C., Helmer, C., Rotimi, C.N., Shaffer, C.M., Müller, C., Sala, C., van Duijn, C.M., Saint-Pierre, A., Ackermann, D., Shriner, D., Ruggiero, D., Toniolo, D., Lu, Y., Cusi, D., Czamara, D., Ellinghaus, D., Siscovick, D.S., Ruderfer, D., Gieger, C., Grallert, H., Rochtchina, E., Atkinson, E.J., Holliday, E.G., Boerwinkle, E., Salvi, E., Bottinger, E.P., Murgia, F., Rivadeneira, F., Ernst, F., Kronenberg, F., Hu, F.B., Navis, G.J., Curhan, G.C., Ehret, G.B., Homuth, G., Coassin, S., Thun, G.A., Pistis, G., Gambaro, G., Malerba, G., Montgomery, G.W., Eiriksdottir, G., Jacobs, G., Li, G., Wichmann, H.E., Campbell, H., Schmidt, H., Wallaschofski, H., Völzke, H., Brenner, H., Kroemer, H.K., Kramer, H., Lin, H., Leach, I.M., Ford, I., Guessous, I., Rudan, I., Prokopenko, I., Borecki, I., Heid, I.M., Kolcic, I., Persico, I., Jukema, J.W., Wilson, J.F., Felix, J.F., Divers, J., Lambert, J.C., Stafford, J.M., Gaspoz, J.M., Smith, J.A., Faul, J.D., Wang, J.J., Ding, J., Hirschhorn, J.N., Attia, J., Whitfield, J.B., Chalmers, J., Viikari, J., Coresh, J., Denny, J.C., Karjalainen, J., Fernandes, J.K., Endlich, K., Butterbach, K., Keene, K.L., Lohman, K., Portas, L., Launer, L.J., Lyytikäinen, L.P., Yengo, L., Franke, L., Ferrucci, L., Rose, L.M., Kedenko, L., Rao, M., Struchalin, M., Kleber, M.E., Cavalieri, M., Haun, M., Cornelis, M.C., Ciullo, M., Pirastu, M., de Andrade, M., McEvoy, M.A., Woodward, M., Adam, M., Cocca, M., Nauck, M., Imboden, M., Waldenberger, M., Pruijm, M., Metzger, M., Stumvoll, M., Evans, M.K., Sale, M.M., Kähönen, M., Boban, M., Bochud, M., Rheinberger, M., Verweij, N., Bouatia-Naji, N., Martin, N.G., Hastie, N., Probst-Hensch, N., Soranzo, N., Devuyst, O., Raitakari, O., Gottesman, O., Franco, O.H., Polasek, O., Gasparini, P., Munroe, P.B., Ridker, P.M., Mitchell, P., Muntner, P., Meisinger, C., Smit, J.H., Kovacs, P., Wild, P.S., Froguel, P., Rettig, R., Mägi, R., Biffar, R., Schmidt, R., Middelberg, R.P., Carroll, R.J., Penninx, B.W., Scott, R.J., Katz, R., Sedaghat, S., Wild, S.H., Kardia, S.L., Ulivi, S., Hwang, S.J., Enroth, S., Kloiber, S., Trompet, S., Stengel, B., Hancock, S.J., Turner, S.T., Rosas, S.E., Stracke, S., Harris, T.B., Zeller, T., Zemunik, T., Lehtimäki, T., Illig, T., Aspelund, T., Nikopensius, T., Esko, T., Gyllensten, U., Völker, U., Emilsson, V., Vitart, V., Aalto, V., Gudnason, V., Chouraki, V., Chen, W.M., Igl, W., März, W., Koenig, W., Lieb, W., Loos, R.J., Liu, Y., Snieder, H., Pramstaller, P.P., Parsa, A., O'Connell, J.R., Susztak, K., Hamet, P., Tremblay, J., de Boer, I.H., Böger, C.A., Goessling, W., Chasman, D.I., Köttgen, A., Kao, W.H., Fox, C.S., ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., 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R., Sedaghat, S., Wild, S.H., Kardia, S.L., Ulivi, S., Hwang, S.J., Enroth, S., Kloiber, S., Trompet, S., Stengel, B., Hancock, S.J., Turner, S.T., Rosas, S.E., Stracke, S., Harris, T.B., Zeller, T., Zemunik, T., Lehtimäki, T., Illig, T., Aspelund, T., Nikopensius, T., Esko, T., Gyllensten, U., Völker, U., Emilsson, V., Vitart, V., Aalto, V., Gudnason, V., Chouraki, V., Chen, W.M., Igl, W., März, W., Koenig, W., Lieb, W., Loos, R.J., Liu, Y., Snieder, H., Pramstaller, P.P., Parsa, A., O'Connell, J.R., Susztak, K., Hamet, P., Tremblay, J., de Boer, I.H., Böger, C.A., Goessling, W., Chasman, D.I., Köttgen, A., Kao, W.H., and Fox, C.S.
- Abstract
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
- Published
- 2016
19. Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
- Author
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Bonilla, C, Lewis, SJ, Rowlands, M-A, Gaunt, TR, Smith, GD, Gunnell, D, Palmer, T, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Groenberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Martin, RM, Holly, JMP, Bonilla, C, Lewis, SJ, Rowlands, M-A, Gaunt, TR, Smith, GD, Gunnell, D, Palmer, T, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Groenberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Martin, RM, and Holly, JMP
- Abstract
Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.
- Published
- 2016
20. New genetic loci link adipose and insulin biology to body fat distribution.
- Author
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ADIPOGen Consortium, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GEFOS Consortium, GENIE Consortium, International Endogene Consortium, LifeLines Cohort Study, MAGIC Investigators, MuTHER Consortium, PAGE Consortium, ReproGen Consortium, GLGC, ICBP, Dastani, Z., Hivert, MF., Timpson, N., Perry, JR., Yuan, X., Scott, RA., Henneman, P., Heid, IM., Kizer, JR., Lyytikainen, LP., Fuchsberger, C., Tanaka, T., Morris, AP., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, JS., Uh, HW., Wu, Y., Bidulescu, A., Rasmussen-Torvik, LJ., Greenwood, CM., Ladouceur, M., Grimsby, J., Manning, AK., Liu, CT., Kooner, J., Mooser, VE., Vollenweider, P., Kapur, KA., Chambers, J., Wareham, NJ., Langenberg, C., Frants, R., Willemsvan-vanDijk, K., Oostra, BA., Willems, SM., Lamina, C., Winkler, T., Psaty, BM., Tracy, RP., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, PP., Evans, DM., St Pourcain, B., Sattar, N., Wood, A., Bandinelli, S., Carlson, OD., Egan, JM., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, ML., Loo, BM., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, HE., Deloukas, P., Katsareli, E., Couper, DJ., Duncan, BB., Kloppenburg, M., Adair, LS., Borja, JB., Wilson, JG., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, TM., Allison, MA., Redline, S., Buxbaum, SG., Mohlke, KL., Meulenbelt, I., Ballantyne, CM., Dedoussis, GV., Hu, FB., Liu, Y., Paulweber, B., Spector, TD., Slagboom, P., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, JC., Salomaa, V., Eriksson, JG., Frayling, TM., Hicks, AA., Lehtimäki, T., Smith, GD., Siscovick, DS., Kronenberg, F., van Duijn, C., Loos, RJ., Waterworth, DM., Meigs, JB., Dupuis, J., Richards, JB., Willenborg, C., Farrall, M., Assimes, TL., Thompson, JR., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, BA., Stirrups, K., König, IR., Cazier, JB., Johansson£££Åsa£££ Å., Hall, AS., Lee, JY., Willer, CJ., Chambers, JC., 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Bouatia-Naji, N., Ahmadi, KR., Ainali, C., Barrett, A., Bataille, V., Bell, JT., Buil, A., Dermitzakis, ET., Dimas, AS., Durbin, R., Glass, D., Hassanali, N., Hedman£££Åsa K£££ ÅK., Ingle, C., Keildson, S., Knowles, D., Krestyaninova, M., Lowe, CE., Meduri, E., di Meglio, P., Min, JL., Montgomery, SB., Nestle, FO., Nica, AC., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, SY., Small, KS., Surdulescu, G., Travers, ME., Tsaprouni, L., Tsoka, S., Wilk, A., Matise, T., Buyske, S., Higashio, J., Williams, R., Nato, A., Ambite, JL., Deelman, E., Manolio, T., Hindorff, L., Heiss, G., Taylor, K., Avery, C., Graff, M., Lin, D., Quibrera, M., Cochran, B., Kao, L., Umans, J., Cole, S., MacCluer, J., Person, S., Pankow, J., Gross, M., Fornage, M., Durda, P., Jenny, N., Patsy, B., Arnold, A., Buzkova, P., Crawford, D., Haines, J., Murdock, D., Glenn, K., Brown-Gentry, K., Thornton-Wells, T., Dumitrescu, L., Jeff, J., Bush, WS., Mitchell, SL., Goodloe, R., Wilson, S., Boston, J., Malinowski, J., Restrepo, N., Oetjens, M., Fowke, J., Zheng, W., Spencer, K., Ritchie, M., Pendergrass, S., Le Marchand£££Loïc£££ L., Wilkens, L., Park, L., Tiirikainen, M., Kolonel, L., Lim, U., Cheng, I., Wang, H., Shohet, R., Haiman, C., Stram, D., Henderson, B., Monroe, K., Schumacher, F., Peters, U., Anderson, G., Carlson, C., Prentice, R., LaCroix, A., Wu, C., Carty, C., Gong, J., Rosse, S., Young, A., Haessler, J., Kocarnik, J., Lin, Y., Jackson, R., Duggan, D., Kuller, L., Stolk, L., He, C., Sulem, P., Barbalic, M., Broer, L., Byrne, EM., Gudbjartsson, DF., McArdle, PF., Porcu, E., van Wingerden, S., Zhuang, W., Albrecht, E., Alizadeh, BZ., Lauc, LB., Broekmans, FJ., Burri, A., Chanock, SJ., Chen, C., Corre, T., Coviello, AD., d'Adamo, P., Davies, G., Deary, IJ., Ebrahim, S., Fauser, BC., Ferreli, L., Folsom, AR., Garcia, ME., Hall, P., Haller, T., Hankinson, SE., Hass, M., Heath, AC., Janssens, AC., Keyzer, J., Lahti, J., Lai, S., Laisk, T., Laven, JS., Liu, J., Lopez, LM., Louwers, YV., Marongiu, M., Klaric, IM., Masciullo, C., McKnight, B., Medland, SE., Melzer, D., Newman, AB., Paré, G., Peeters, PH., Plump, AS., Pop, VJ., Räikkönen, K., Salumets, A., Smith, JA., Stacey, SN., Starr, JM., Stathopoulou, MG., Tenesa, A., Thorand, B., Tryggvadottir, L., Tsui, K., van Dam RM., van Gils CH., van Nierop, P., Vink, JM., Voorhuis, M., Wallaschofski, H., Widen, E., Wijnands-van Gent CJ., Zgaga, L., Zygmunt, M., Arnold, AM., Buring, JE., Crisponi, L., Demerath, EW., Hunter, DJ., Schlessinger, D., Murray, A., Murabito, JM., Visser, JA., Lunetta, KL., Elks, CE., Cousminer, DL., Feenstra, B., Lin, P., van Wingerden SW., Smith, EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., Weedon, MN., Wichmann, H., Young, L., Zhuang, WV., Bierut, LJ., Boyd, HA., Winkler, T.W., Croteau-Chonka, D.C., Locke, A.E., Strawbridge, R.J., Pers, T.H., Justice, A.E., Workalemahu, T., Wu, J.M., Buchkovich, M.L., Heard-Costa, N.L., Roman, T.S., Drong, A.W., Day, F.R., Luan, J., Randall, J.C., Scherag, A., Wood, A.R., Fehrmann, R., Karjalainen, J., Kahali, B., Liu, C.T., Schmidt, E.M., Anderson, D., Bragg-Gresham, J.L., Ehret, G.B., Feitosa, M.F., Jackson, A.U., Kleber, M.E., Mateo Leach, I., Medina-Gomez, C., Palmer, C.D., Pasko, D., Pechlivanis, S., Peters, M.J., Ju Sung, Y., Van Vliet-Ostaptchouk, J.V., Yengo, L., Arscott, G.M., Bellis, C., Bennett, A.J., Berne, C., Blüher, M., Bonnet, F., Böttcher, Y., Carba, D.B., Caspersen, I.H., Daw, E.W., Deelen, J., Delgado, G., Doney, A.S., Eklund, N., Erdos, M.R., Eury, E., Friedrich, N., Garcia, M.E., Giedraitis, V., Go, A.S., Golay, A., Grammer, T.B., Gräßler, J., Grewal, J., Groves, C.J., Hartman, C.A., Hassinen, M., Herzig, K.H., Helmer, Q., Hillege, H.L., Holmen, O., Hunt, S.C., Ittermann, T., James, A.L., Johansson, I., Juliusdottir, T., Kalafati, I.P., Kinnunen, L., Kooner, I.K., Lee, N.R., Lichtner, P., Lobbens, S., Magnusson, P.K., McArdle, W.L., Menni, C., Merger, S., Milani, L., Mills, R., Monda, K.L., Mooijaart, S.P., Mühleisen, T.W., Mulas, A., Nalls, M.A., Glorioso, N., Nolte, I.M., Rayner, N.W., Renstrom, F., Ried, J.S., Robertson, N.R., Rose, L.M., Scholtens, S., Seufferlein, T., Sitlani, C.M., Vernon Smith, A., Stringham, H.M., Sundström, J., Swertz, M.A., Swift, A.J., Syvänen, A.C., Tayo, B.O., Tomaschitz, A., Troffa, C., van Oort, F.V., Vonk, J.M., Waite, L.L., Wennauer, R., Wojczynski, M.K., Zhang, Q., Hua Zhao, J., Brennan, E.P., Choi, M., Gharavi, A.G., Hedman, Å.K., Hivert, M.F., Huang, J., Karpe, F., Kiryluk, K., Liang, L., Lifton, R.P., Ma, B., McKnight, A.J., McPherson, R., Min, J.L., Moffatt, M.F., Montgomery, G.W., Murabito, J.M., Nicholson, G., Nyholt, D.R., Olsson, C., Perry, J.R., Reinmaa, E., Salem, R.M., Schadt, E.E., Scott, R.A., Vallejo, E.E., Westra, H.J., Zondervan, K.T., Bakker, S.J., Beilby, J., Bergman, R.N., Blangero, J., Brown, M.J., Chines, P.S., Collins, F.S., Crawford, D.C., de Geus, E.J., Erbel, R., Eriksson, J.G., Ferrannini, E., Forouhi, N.G., Franco, O.H., Gansevoort, R.T., Haiman, C.A., Harris, T.B., Hattersley, A.T., Heliövaara, M., Hicks, A.A., Hingorani, A.D., Hoffmann, W., Humphries, S.E., Jarvelin, M.R., Johansen, B., Jousilahti, P., Jula, A.M., Keinanen-Kiukaanniemi, S.M., Kooner, J.S., Kraja, A.T., Lakka, T.A., Le Marchand, L., Lyssenko, V., Männistö, S., Marette, A., Matise, T.C., McKenzie, C.A., Musk, A.W., Möhlenkamp, S., Morris, A.D., Oldehinkel, A.J., Ong, K.K., Palmer, L.J., Penninx, B.W., Pramstaller, P.P., Raitakari, O.T., Rankinen, T., Rao, D.C., Rice, T.K., Ridker, P.M., Ritchie, M.D., Samani, N.J., Sarzynski, M.A., Schwarz, P.E., Shuldiner, A.R., Staessen, J.A., Steinthorsdottir, V., Stolk, R.P., Strauch, K., Tremblay, A., Vohl, M.C., Wilson, J.F., Witteman, J.C., Adair, L.S., Boehm, B.O., Bornstein, S.R., Bouchard, C., Cauchi, S., Caulfield, M.J., Chambers, J.C., Chasman, D.I., Cooper, R.S., Grabe, H.J., Jöckel, K.H., Munroe, P.B., Oostra, B.A., Palmer, C.N., Pedersen, N.L., Pérusse, L., Saaristo, T.E., Slagboom, P.E., Spector, T.D., Uitterlinden, A.G., Veronesi, G., Walker, M., Wareham, N.J., Wichmann, H.E., Abecasis, G.R., Assimes, T.L., Berndt, S.I., Borecki, I.B., Frayling, T.M., Groop, L.C., Hunter, D.J., Kaplan, R.C., O'Connell, J.R., Strachan, D.P., van Duijn, C.M., Willer, C.J., Visscher, P.M., Yang, J., Hirschhorn, J.N., Zillikens, M.C., McCarthy, M.I., Speliotes, E.K., North, K.E., Fox, C.S., Franks, P.W., Heid, I.M., Loos, R.J., Cupples, L.A., Morris, A.P., Lindgren, C.M., and Mohlke, K.L.
- Abstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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- 2015
21. The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium
- Author
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Davies, NM, Gaunt, TR, Lewis, SJ, Holly, J, Donovan, JL, Hamdy, FC, Kemp, JP, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Neal, D, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, Martin, RM, Davies, NM, Gaunt, TR, Lewis, SJ, Holly, J, Donovan, JL, Hamdy, FC, Kemp, JP, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Neal, D, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, and Martin, RM
- Abstract
BACKGROUND: Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. METHODS: We conducted a case-control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man's number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. RESULTS: The genetic risk scores explained 6.31 and 1.46% of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95% CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95% CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). CONCLUSIONS: We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with inc
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- 2015
22. The UK10K project identifies rare variants in health and disease
- Author
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Walter, K, Min, JL, Huang, J, Crooks, L, Memari, Y, McCarthy, S, Perry, JRB, Xu, C, Futema, M, Lawson, D, Iotchkova, V, Schiffels, S, Hendricks, AE, Danecek, P, Li, R, Floyd, J, Wain, LV, Barroso, I, Humphries, SE, Hurles, ME, Zeggini, E, Barrett, JC, Plagnol, V, Richards, JB, Greenwood, CMT, Timpson, NJ, Durbin, R, Soranzo, N, Bala, S, Clapham, P, Coates, G, Cox, T, Daly, A, Du, Y, Edkins, S, Ellis, P, Flicek, P, Guo, X, Huang, L, Jackson, DK, Joyce, C, Keane, T, Kolb-Kokocinski, A, Langford, C, Li, Y, Liang, J, Lin, H, Liu, R, Maslen, J, Muddyman, D, Quail, MA, Stalker, J, Sun, J, Tian, J, Wang, G, Wang, J, Wang, Y, Wong, K, Zhang, P, Birney, E, Boustred, C, Chen, L, Clement, G, Cocca, M, Smith, GD, Day, INM, Day-Williams, A, Down, T, Dunham, I, Evans, DM, Gaunt, TR, Geihs, M, Hart, D, Howie, B, Hubbard, T, Hysi, P, Jamshidi, Y, Karczewski, KJ, Kemp, JP, Lachance, G, Lek, M, Lopes, M, MacArthur, DG, Marchini, J, Mangino, M, Mathieson, I, Metrustry, S, Moayyeri, A, Northstone, K, Panoutsopoulou, K, Paternoster, L, Quaye, L, Ring, S, Ritchie, GRS, Shihab, HA, Shin, S-Y, Small, KS, Artigas, MS, Southam, L, Spector, TD, St Pourcain, B, Surdulescu, G, Tachmazidou, I, Tobin, MD, Valdes, AM, Visscher, PM, Ward, K, Wilson, SG, Yang, J, Zhang, F, Zheng, H-F, Anney, R, Ayub, M, Blackwood, D, Bolton, PF, Breen, G, Collier, DA, Craddock, N, Curran, S, Curtis, D, Gallagher, L, Geschwind, D, Gurling, H, Holmans, P, Lee, I, Lonnqvist, J, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Morris, J, O'Donovan, MC, Owen, MJ, Palotie, A, Parr, JR, Paunio, T, Pietilainen, O, Rehnstrom, K, Sharp, SI, Skuse, D, St Clair, D, Suvisaari, J, Walters, JTR, Williams, HJ, Bochukova, E, Bounds, R, Dominiczak, A, Farooqi, IS, Keogh, J, Marenne, GL, Morris, A, O'Rahilly, S, Porteous, DJ, Smith, BH, Wheeler, E, Al Turki, S, Anderson, CA, Antony, D, Beales, P, Bentham, J, Bhattacharya, S, Calissano, M, Carss, K, Chatterjee, K, Cirak, S, Cosgrove, C, Fitzpatrick, DR, Foley, AR, Franklin, CS, Grozeva, D, Mitchison, HM, Muntoni, F, Onoufriadis, A, Parker, V, Payne, F, Raymond, FL, Roberts, N, Savage, DB, Scambler, P, Schmidts, M, Schoenmakers, N, Semple, RK, Serra, E, Spasic-Boskovic, O, Stevens, E, van Kogelenberg, M, Vijayarangakannan, P, Williamson, KA, Wilson, C, Whyte, T, Ciampi, A, Oualkacha, K, Bobrow, M, Griffin, H, Kaye, J, Kennedy, K, Kent, A, Smee, C, Charlton, R, Ekong, R, Khawaja, F, Lopes, LR, Migone, N, Payne, SJ, Pollitt, RC, Povey, S, Ridout, CK, Robinson, RL, Scott, RH, Shaw, A, Syrris, P, Taylor, R, Vandersteen, AM, Amuzu, A, Casas, JP, Chambers, JC, Dedoussis, G, Gambaro, G, Gasparini, P, Isaacs, A, Johnson, J, Kleber, ME, Kooner, JS, Langenberg, C, Luan, J, Malerba, G, Maerz, W, Matchan, A, Morris, R, Nordestgaard, BG, Benn, M, Scott, RA, Toniolo, D, Traglia, M, Tybjaerg-Hansen, A, van Duijn, CM, van Leeuwen, EM, Varbo, A, Whincup, P, Zaza, G, Zhang, W, Walter, K, Min, JL, Huang, J, Crooks, L, Memari, Y, McCarthy, S, Perry, JRB, Xu, C, Futema, M, Lawson, D, Iotchkova, V, Schiffels, S, Hendricks, AE, Danecek, P, Li, R, Floyd, J, Wain, LV, Barroso, I, Humphries, SE, Hurles, ME, Zeggini, E, Barrett, JC, Plagnol, V, Richards, JB, Greenwood, CMT, Timpson, NJ, Durbin, R, Soranzo, N, Bala, S, Clapham, P, Coates, G, Cox, T, Daly, A, Du, Y, Edkins, S, Ellis, P, Flicek, P, Guo, X, Huang, L, Jackson, DK, Joyce, C, Keane, T, Kolb-Kokocinski, A, Langford, C, Li, Y, Liang, J, Lin, H, Liu, R, Maslen, J, Muddyman, D, Quail, MA, Stalker, J, Sun, J, Tian, J, Wang, G, Wang, J, Wang, Y, Wong, K, Zhang, P, Birney, E, Boustred, C, Chen, L, Clement, G, Cocca, M, Smith, GD, Day, INM, Day-Williams, A, Down, T, Dunham, I, Evans, DM, Gaunt, TR, Geihs, M, Hart, D, Howie, B, Hubbard, T, Hysi, P, Jamshidi, Y, Karczewski, KJ, Kemp, JP, Lachance, G, Lek, M, Lopes, M, MacArthur, DG, Marchini, J, Mangino, M, Mathieson, I, Metrustry, S, Moayyeri, A, Northstone, K, Panoutsopoulou, K, Paternoster, L, Quaye, L, Ring, S, Ritchie, GRS, Shihab, HA, Shin, S-Y, Small, KS, Artigas, MS, Southam, L, Spector, TD, St Pourcain, B, Surdulescu, G, Tachmazidou, I, Tobin, MD, Valdes, AM, Visscher, PM, Ward, K, Wilson, SG, Yang, J, Zhang, F, Zheng, H-F, Anney, R, Ayub, M, Blackwood, D, Bolton, PF, Breen, G, Collier, DA, Craddock, N, Curran, S, Curtis, D, Gallagher, L, Geschwind, D, Gurling, H, Holmans, P, Lee, I, Lonnqvist, J, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Morris, J, O'Donovan, MC, Owen, MJ, Palotie, A, Parr, JR, Paunio, T, Pietilainen, O, Rehnstrom, K, Sharp, SI, Skuse, D, St Clair, D, Suvisaari, J, Walters, JTR, Williams, HJ, Bochukova, E, Bounds, R, Dominiczak, A, Farooqi, IS, Keogh, J, Marenne, GL, Morris, A, O'Rahilly, S, Porteous, DJ, Smith, BH, Wheeler, E, Al Turki, S, Anderson, CA, Antony, D, Beales, P, Bentham, J, Bhattacharya, S, Calissano, M, Carss, K, Chatterjee, K, Cirak, S, Cosgrove, C, Fitzpatrick, DR, Foley, AR, Franklin, CS, Grozeva, D, Mitchison, HM, Muntoni, F, Onoufriadis, A, Parker, V, Payne, F, Raymond, FL, Roberts, N, Savage, DB, Scambler, P, Schmidts, M, Schoenmakers, N, Semple, RK, Serra, E, Spasic-Boskovic, O, Stevens, E, van Kogelenberg, M, Vijayarangakannan, P, Williamson, KA, Wilson, C, Whyte, T, Ciampi, A, Oualkacha, K, Bobrow, M, Griffin, H, Kaye, J, Kennedy, K, Kent, A, Smee, C, Charlton, R, Ekong, R, Khawaja, F, Lopes, LR, Migone, N, Payne, SJ, Pollitt, RC, Povey, S, Ridout, CK, Robinson, RL, Scott, RH, Shaw, A, Syrris, P, Taylor, R, Vandersteen, AM, Amuzu, A, Casas, JP, Chambers, JC, Dedoussis, G, Gambaro, G, Gasparini, P, Isaacs, A, Johnson, J, Kleber, ME, Kooner, JS, Langenberg, C, Luan, J, Malerba, G, Maerz, W, Matchan, A, Morris, R, Nordestgaard, BG, Benn, M, Scott, RA, Toniolo, D, Traglia, M, Tybjaerg-Hansen, A, van Duijn, CM, van Leeuwen, EM, Varbo, A, Whincup, P, Zaza, G, and Zhang, W
- Abstract
The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
- Published
- 2015
23. New genetic loci link adipose and insulin biology to body fat distribution
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Shungin, D, Winkler, T, Croteau Chonka, D, Ferreira, T, Locke, A, Mägi, R, Strawbridge, R, Pers, T, Fischer, K, Justice, A, Workalemahu, T, Wu, J, Buchkovich, M, Heard Costa, N, Roman, T, Drong, A, Song, C, Gustafsson, S, Day, F, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, J, Scherag, A, Vedantam, S, Wood, A, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg Gresham, J, Buyske, S, Demirkan, A, Ehret, G, Feitosa, M, Goel, A, Jackson, A, Johnson, T, Kleber, M, Kristiansson, K, Mangino, M, Leach, I, Medina Gomez, C, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Stanca'Kova', A, Sung, Y, Tanaka, T, Teumer, A, Van Vliet Ostaptchouk, J, Yengo, L, Zhang, W, Albrecht, E, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Böhringer, S, Bonnet, F, Böttcher, Y, Bruinenberg, M, Carba, D, Caspersen, I, Clarke, R, Daw, E, Deelen, J, Deelman, E, Delgado, G, Doney, A, Eklund, N, Erdos, M, Estrada, K, Eury, E, Friedrich, N, Garcia, M, Giedraitis, V, Gigante, B, Go, A, Golay, A, Grallert, H, Grammer, T, Gräsler, J, Grewal, J, Groves, C, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heikkilä, K, Herzig, K, Helmer, Q, Hillege, H, Holmen, O, Hunt, S, Isaacs, A, Ittermann, T, James, A, Johansson, I, Juliusdottir, T, Kalafati, I, Kinnunen, L, Koenig, W, Kooner, I, Kratzer, W, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Menni, C, Merger, S, Mihailov, E, Milani, L, Mills, R, Moayyeri, A, Monda, K, Mooijaart, S, Mühleisen, T, Mulas, A, Müller, G, Müller Nurasyid, M, Nagaraja, R, Nalls, M, Narisu, N, Glorioso, N, Nolte, I, Olden, M, Rayner, N, Renstrom, F, Ried, J, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Sennblad, B, Seufferlein, T, Sitlani, C, Smith, A, Stirrups, K, Stringham, H, Sundström, J, Swertz, M, Swift, A, Syvänen, A, 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- Abstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10-8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
- Published
- 2015
24. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data
- Author
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Holmes, MV, Dale, CE, Zuccolo, L, Silverwood, RJ, Guo, Y, Ye, Z, Prieto-Merino, D, Dehghan, Abbas, Trompet, S, Wong, A, Cavadino, A, Drogan, D, Padmanabhan, S, Li, Shan, Yesupriya, A, Leusink, M, Sundstrom, J, Hubacek, JA, Pikhart, H, Swerdlow, DI, Panayiotou, AG, Borinskaya, SA, Finan, C, Shah, S, Kuchenbaecker, KB, Shah, T, Engmann, J, Folkersen, L, Eriksson, P, Ricceri, F, Melander, O, Sacerdote, C, Gamble, DM, Rayaprolu, S, Ross, OA, McLachlan, S, Vikhireva, O, Sluijs, Iris, Scott, RA, Adamkova, V, Flicker, L, van Bockxmeer, FM, Power, C, Marques-Vidal, P, Meade, T, Marmot, MG, Ferro, JM, Paulos-Pinheiro, S, Humphries, SE, Talmud, PJ, Leach, IM, Verweij, N (Niek), Linneberg, A, Skaaby, T, Doevendans, PA, Cramer, MJ, van der Harst, P, Klungel, OH, Dowling, NF, Dominiczak, AF, Kumari, M, Nicolaides, AN, Weikert, C, Boeing, H, Ebrahim, S, Gaunt, TR, Price, JF, Lannfelt, L, Peasey, A, Kubinova, R, Pajak, A, Malyutina, S, Voevoda, MI, Tamosiunas, A, Zee, AH, Norman, PE, Hankey, GJ, Bergmann, MM, Hofman, Bert, Franco Duran, OH, Cooper, J, Palmen, J, Spiering, W, Jong, PA, Kuh, D, Hardy, R, Uitterlinden, André, Ikram, Arfan, Ford, I, Hyppoenen, E, Almeida, OP, Wareham, NJ, Khaw, KT, Hamsten, A, Husemoen, LLN, Tjonneland, A, Tolstrup, JS, Rimm, E, Beulens, JWJ, Verschuren, WMM, Onland-Moret, NC, Hofker, MH, Wannamethee, SG, Whincup, PH, Morris, R, Vicente, AM, Watkins, H, Farrall, M, Jukema, JW, Meschia, J, Cupples, LA, Sharp, SJ, Fornage, M, Kooperberg, C, Lacroix, AZ, Dai, JY, Lanktree, MB, Siscovick, DS, Jorgenson, E, Spring, B, Coresh, J, Li, YR, Buxbaum, SG, Schreiner, PJ, Ellison, RC, Tsai, MY, Patel, SR, Redline, S, Johnson, AD, Hoogeveen, RC, Rotter, JI, Boerwinkle, E, de Bakker, PIW, Kivimaki, M, Asselbergs, FW, Sattar, N, Lawlor, DA, Whittaker, J, Smith, GD, Mukamal, K, Psaty, BM, Wilson, JG, Lange, LA, Hamidovic, A, Hingorani, AD, Nordestgaard, BG, Bobak, M, Leon, DA, Langenberg, C, Palmer, TM, Reiner, AP, Keating, BJ, Dudbridge, F, Casas, JP, Holmes, MV, Dale, CE, Zuccolo, L, Silverwood, RJ, Guo, Y, Ye, Z, Prieto-Merino, D, Dehghan, Abbas, Trompet, S, Wong, A, Cavadino, A, Drogan, D, Padmanabhan, S, Li, Shan, Yesupriya, A, Leusink, M, Sundstrom, J, Hubacek, JA, Pikhart, H, Swerdlow, DI, Panayiotou, AG, Borinskaya, SA, Finan, C, Shah, S, Kuchenbaecker, KB, Shah, T, Engmann, J, Folkersen, L, Eriksson, P, Ricceri, F, Melander, O, Sacerdote, C, Gamble, DM, Rayaprolu, S, Ross, OA, McLachlan, S, Vikhireva, O, Sluijs, Iris, Scott, RA, Adamkova, V, Flicker, L, van Bockxmeer, FM, Power, C, Marques-Vidal, P, Meade, T, Marmot, MG, Ferro, JM, Paulos-Pinheiro, S, Humphries, SE, Talmud, PJ, Leach, IM, Verweij, N (Niek), Linneberg, A, Skaaby, T, Doevendans, PA, Cramer, MJ, van der Harst, P, Klungel, OH, Dowling, NF, Dominiczak, AF, Kumari, M, Nicolaides, AN, Weikert, C, Boeing, H, Ebrahim, S, Gaunt, TR, Price, JF, Lannfelt, L, Peasey, A, Kubinova, R, Pajak, A, Malyutina, S, Voevoda, MI, Tamosiunas, A, Zee, AH, Norman, PE, Hankey, GJ, Bergmann, MM, Hofman, Bert, Franco Duran, OH, Cooper, J, Palmen, J, Spiering, W, Jong, PA, Kuh, D, Hardy, R, Uitterlinden, André, Ikram, Arfan, Ford, I, Hyppoenen, E, Almeida, OP, Wareham, NJ, Khaw, KT, Hamsten, A, Husemoen, LLN, Tjonneland, A, Tolstrup, JS, Rimm, E, Beulens, JWJ, Verschuren, WMM, Onland-Moret, NC, Hofker, MH, Wannamethee, SG, Whincup, PH, Morris, R, Vicente, AM, Watkins, H, Farrall, M, Jukema, JW, Meschia, J, Cupples, LA, Sharp, SJ, Fornage, M, Kooperberg, C, Lacroix, AZ, Dai, JY, Lanktree, MB, Siscovick, DS, Jorgenson, E, Spring, B, Coresh, J, Li, YR, Buxbaum, SG, Schreiner, PJ, Ellison, RC, Tsai, MY, Patel, SR, Redline, S, Johnson, AD, Hoogeveen, RC, Rotter, JI, Boerwinkle, E, de Bakker, PIW, Kivimaki, M, Asselbergs, FW, Sattar, N, Lawlor, DA, Whittaker, J, Smith, GD, Mukamal, K, Psaty, BM, Wilson, JG, Lange, LA, Hamidovic, A, Hingorani, AD, Nordestgaard, BG, Bobak, M, Leon, DA, Langenberg, C, Palmer, TM, Reiner, AP, Keating, BJ, Dudbridge, F, and Casas, JP
- Abstract
Objective To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Main outcome measures Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Results Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P= 0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). Conclusions Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
- Published
- 2014
25. A multi-cohort study of polymorphisms in the GH/IGF axis and physical capability: The HALCyon programme
- Author
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Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gaunt, TR, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Sayer, AA, Starr, JM, Kuh, D, Day, INM, Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gaunt, TR, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Sayer, AA, Starr, JM, Kuh, D, and Day, INM
- Abstract
Background Low muscle mass and function have been associated with poorer indicators of physical capability in older people, which are in-turn associated with increased mortality rates. The growth hormone/insulin-like growth factor (GH/IGF) axis is involved in muscle function and genetic variants in genes in the axis may influence measures of physical capability. Methods As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women from seven UK cohorts aged between 52 and 90 years old were genotyped for six polymorphisms: rs35767 (IGF1), rs7127900 (IGF2), rs2854744 (IGFBP3), rs2943641 (IRS1), rs2665802 (GH1) and the exon-3 deletion of GHR. The polymorphisms have previously been robustly associated with age-related traits or are potentially functional. Meta-analysis was used to pool within-study genotypic effects of the associations between the polymorphisms and four measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance. Results Few important associations were observed among the several tests. We found evidence that rs2665802 in GH1 was associated with inability to balance for 5 s (pooled odds ratio per minor allele = 0.90, 95% CI: 0.82–0.98, p-value = 0.01, n = 10,748), after adjusting for age and sex. We found no evidence for other associations between the polymorphisms and physical capability traits. Conclusion Our findings do not provide evidence for a substantial influence of these common polymorphisms in the GH/IGF axis on objectively measured physical capability levels in older adults.
- Published
- 2012
26. A multi-cohort study of polymorphisms in the GH/IGF axis and physical capability: The HALCyon programme
- Author
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Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gaunt, TR, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Sayer, AA, Starr, JM, Kuh, D, Day, INM, Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gaunt, TR, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Sayer, AA, Starr, JM, Kuh, D, and Day, INM
- Abstract
Background Low muscle mass and function have been associated with poorer indicators of physical capability in older people, which are in-turn associated with increased mortality rates. The growth hormone/insulin-like growth factor (GH/IGF) axis is involved in muscle function and genetic variants in genes in the axis may influence measures of physical capability. Methods As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women from seven UK cohorts aged between 52 and 90 years old were genotyped for six polymorphisms: rs35767 (IGF1), rs7127900 (IGF2), rs2854744 (IGFBP3), rs2943641 (IRS1), rs2665802 (GH1) and the exon-3 deletion of GHR. The polymorphisms have previously been robustly associated with age-related traits or are potentially functional. Meta-analysis was used to pool within-study genotypic effects of the associations between the polymorphisms and four measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance. Results Few important associations were observed among the several tests. We found evidence that rs2665802 in GH1 was associated with inability to balance for 5 s (pooled odds ratio per minor allele = 0.90, 95% CI: 0.82–0.98, p-value = 0.01, n = 10,748), after adjusting for age and sex. We found no evidence for other associations between the polymorphisms and physical capability traits. Conclusion Our findings do not provide evidence for a substantial influence of these common polymorphisms in the GH/IGF axis on objectively measured physical capability levels in older adults.
- Published
- 2012
27. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
- Author
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Ehret, GB, Munroe, PB, Rice, KM, Bochud, M, Johnson, AD, Chasman, DI, Smith, AV, Tobin, MD, Verwoert, GC, Hwang, S-J, Pihur, V, Vollenweider, P, O'Reilly, PF, Amin, N, Bragg-Gresham, JL, Teumer, A, Glazer, NL, Launer, L, Zhao, JH, Aulchenko, Y, Heath, S, Sober, S, Parsa, A, Luan, J, Arora, P, Dehghan, A, Zhang, F, Lucas, G, Hicks, AA, Jackson, AU, Peden, JF, Tanaka, T, Wild, SH, Rudan, I, Igl, W, Milaneschi, Y, Parker, AN, Fava, C, Chambers, JC, Fox, ER, Kumari, M, Go, MJ, van der Harst, P, Kao, WHL, Sjogren, M, Vinay, DG, Alexander, M, Tabara, Y, Shaw-Hawkins, S, Whincup, PH, Liu, Y, Shi, G, Kuusisto, J, Tayo, B, Seielstad, M, Sim, X, Khanh-Dung, HN, Lehtimaki, T, Matullo, G, Wu, Y, Gaunt, TR, Onland-Moret, NC, Cooper, MN, Platou, CGP, Org, E, Hardy, R, Dahgam, S, Palmen, J, Vitart, V, Braund, PS, Kuznetsova, T, Uiterwaal, CSPM, Adeyemo, A, Palmas, W, Campbell, H, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, ND, Aspelund, T, Garcia, M, Chang, Y-PC, O'Connell, JR, Steinle, NI, Grobbee, DE, Arking, DE, Kardia, SL, Morrison, AC, Hernandez, D, Najjar, S, McArdle, WL, Hadley, D, Brown, MJ, Connell, JM, Hingorani, AD, Day, INM, Lawlor, DA, Beilby, JP, Lawrence, RW, Clarke, R, Hopewell, JC, Ongen, H, Dreisbach, AW, Li, Y, Young, JH, Bis, JC, Kahonen, M, Viikari, J, Adair, LS, Lee, NR, Chen, M-H, Olden, M, Pattaro, C, Bolton, JAH, Koettgen, A, Bergmann, S, Mooser, V, Chaturvedi, N, Frayling, TM, Islam, M, Jafar, TH, Erdmann, J, Kulkarni, SR, Bornstein, SR, Graessler, J, Groop, L, Voight, BF, Kettunen, J, Howard, P, Taylor, A, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Barroso, IS, Khaw, K-T, Weder, AB, Hunt, SC, Sun, YV, Bergman, RN, Collins, FS, Bonnycastle, LL, Scott, LJ, Stringham, HM, Peltonen, L, Perola, M, Vartiainen, E, Brand, S-M, Staessen, JA, Wang, TJ, Burton, PR, Artigas, MS, Dong, Y, Snieder, H, Wang, X, Zhu, H, Lohman, KK, Rudock, ME, Heckbert, SR, Smith, NL, Wiggins, KL, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, CD, Rosengren, A, Thelle, DS, Corsi, AM, Singleton, A, Forrester, T, Hilton, G, McKenzie, CA, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Wichmann, H-E, Cho, YS, Kim, H-L, Lee, J-Y, Scott, J, Sehmi, JS, Zhang, W, Hedblad, B, Nilsson, P, Smith, GD, Wong, A, Narisu, N, Stancakova, A, Raffel, LJ, Yao, J, Kathiresan, S, O'Donnell, CJ, Schwartz, SM, Ikram, MA, Longstreth, WT, Mosley, TH, Seshadri, S, Shrine, NRG, Wain, LV, Morken, MA, Swift, AJ, Laitinen, J, Prokopenko, I, Zitting, P, Cooper, JA, Humphries, SE, Danesh, J, Rasheed, A, Goel, A, Hamsten, A, Watkins, H, Bakker, SJL, van Gilst, WH, Janipalli, CS, Mani, KR, Yajnik, CS, Hofman, A, Mattace-Raso, FUS, Oostra, BA, Demirkan, A, Isaacs, A, Rivadeneira, F, Lakatta, EG, Orru, M, Scuteri, A, Ala-Korpela, M, Kangas, AJ, Lyytikainen, L-P, Soininen, P, Tukiainen, T, Wurtz, P, Ong, RT-H, Doerr, M, Kroemer, HK, Voelker, U, Voelzke, H, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Deloukas, P, Mangino, M, Spector, TD, Zhai, G, Meschia, JF, Nalls, MA, Sharma, P, Terzic, J, Kumar, MVK, Denniff, M, Zukowska-Szczechowska, E, Wagenknecht, LE, Fowkes, FGR, Charchar, FJ, Schwarz, PEH, Hayward, C, Guo, X, Rotimi, C, Bots, ML, Brand, E, Samani, NJ, Polasek, O, Talmud, PJ, Nyberg, F, Kuh, D, Laan, M, Hveem, K, Palmer, LJ, van der Schouw, YT, Casas, JP, Mohlke, KL, Vineis, P, Raitakari, O, Ganesh, SK, Wong, TY, Tai, ES, Cooper, RS, Laakso, M, Rao, DC, Harris, TB, Morris, RW, Dominiczak, AF, Kivimaki, M, Marmot, MG, Miki, T, Saleheen, D, Chandak, GR, Coresh, J, Navis, G, Salomaa, V, Han, B-G, Zhu, X, Kooner, JS, Melander, O, Ridker, PM, Bandinelli, S, Gyllensten, UB, Wright, AF, Wilson, JF, Ferrucci, L, Farrall, M, Tuomilehto, J, Pramstaller, PP, Elosua, R, Soranzo, N, Sijbrands, EJG, Altshuler, D, Loos, RJF, Shuldiner, AR, Gieger, C, Meneton, P, Uitterlinden, AG, Wareham, NJ, Gudnason, V, Rotter, JI, Rettig, R, Uda, M, Strachan, DP, Witteman, JCM, Hartikainen, A-L, Beckmann, JS, Boerwinkle, E, Vasan, RS, Boehnke, M, Larson, MG, Jarvelin, M-R, Psaty, BM, Abecasis, GR, Chakravarti, A, Elliott, P, van Duijn, CM, Newton-Cheh, C, Levy, D, Caulfield, MJ, Johnson, T, Ehret, GB, Munroe, PB, Rice, KM, Bochud, M, Johnson, AD, Chasman, DI, Smith, AV, Tobin, MD, Verwoert, GC, Hwang, S-J, Pihur, V, Vollenweider, P, O'Reilly, PF, Amin, N, Bragg-Gresham, JL, Teumer, A, Glazer, NL, Launer, L, Zhao, JH, Aulchenko, Y, Heath, S, Sober, S, Parsa, A, Luan, J, Arora, P, Dehghan, A, Zhang, F, Lucas, G, Hicks, AA, Jackson, AU, Peden, JF, Tanaka, T, Wild, SH, Rudan, I, Igl, W, Milaneschi, Y, Parker, AN, Fava, C, Chambers, JC, Fox, ER, Kumari, M, Go, MJ, van der Harst, P, Kao, WHL, Sjogren, M, Vinay, DG, Alexander, M, Tabara, Y, Shaw-Hawkins, S, Whincup, PH, Liu, Y, Shi, G, Kuusisto, J, Tayo, B, Seielstad, M, Sim, X, Khanh-Dung, HN, Lehtimaki, T, Matullo, G, Wu, Y, Gaunt, TR, Onland-Moret, NC, Cooper, MN, Platou, CGP, Org, E, Hardy, R, Dahgam, S, Palmen, J, Vitart, V, Braund, PS, Kuznetsova, T, Uiterwaal, CSPM, Adeyemo, A, Palmas, W, Campbell, H, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, ND, Aspelund, T, Garcia, M, Chang, Y-PC, O'Connell, JR, Steinle, NI, Grobbee, DE, Arking, DE, Kardia, SL, Morrison, AC, Hernandez, D, Najjar, S, McArdle, WL, Hadley, D, Brown, MJ, Connell, JM, Hingorani, AD, Day, INM, Lawlor, DA, Beilby, JP, Lawrence, RW, Clarke, R, Hopewell, JC, Ongen, H, Dreisbach, AW, Li, Y, Young, JH, Bis, JC, Kahonen, M, Viikari, J, Adair, LS, Lee, NR, Chen, M-H, Olden, M, Pattaro, C, Bolton, JAH, Koettgen, A, Bergmann, S, Mooser, V, Chaturvedi, N, Frayling, TM, Islam, M, Jafar, TH, Erdmann, J, Kulkarni, SR, Bornstein, SR, Graessler, J, Groop, L, Voight, BF, Kettunen, J, Howard, P, Taylor, A, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Barroso, IS, Khaw, K-T, Weder, AB, Hunt, SC, Sun, YV, Bergman, RN, Collins, FS, Bonnycastle, LL, Scott, LJ, Stringham, HM, Peltonen, L, Perola, M, Vartiainen, E, Brand, S-M, Staessen, JA, Wang, TJ, Burton, PR, Artigas, MS, Dong, Y, Snieder, H, Wang, X, Zhu, H, Lohman, KK, Rudock, ME, Heckbert, SR, Smith, NL, Wiggins, KL, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, CD, Rosengren, A, Thelle, DS, Corsi, AM, Singleton, A, Forrester, T, Hilton, G, McKenzie, CA, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Wichmann, H-E, Cho, YS, Kim, H-L, Lee, J-Y, Scott, J, Sehmi, JS, Zhang, W, Hedblad, B, Nilsson, P, Smith, GD, Wong, A, Narisu, N, Stancakova, A, Raffel, LJ, Yao, J, Kathiresan, S, O'Donnell, CJ, Schwartz, SM, Ikram, MA, Longstreth, WT, Mosley, TH, Seshadri, S, Shrine, NRG, Wain, LV, Morken, MA, Swift, AJ, Laitinen, J, Prokopenko, I, Zitting, P, Cooper, JA, Humphries, SE, Danesh, J, Rasheed, A, Goel, A, Hamsten, A, Watkins, H, Bakker, SJL, van Gilst, WH, Janipalli, CS, Mani, KR, Yajnik, CS, Hofman, A, Mattace-Raso, FUS, Oostra, BA, Demirkan, A, Isaacs, A, Rivadeneira, F, Lakatta, EG, Orru, M, Scuteri, A, Ala-Korpela, M, Kangas, AJ, Lyytikainen, L-P, Soininen, P, Tukiainen, T, Wurtz, P, Ong, RT-H, Doerr, M, Kroemer, HK, Voelker, U, Voelzke, H, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Deloukas, P, Mangino, M, Spector, TD, Zhai, G, Meschia, JF, Nalls, MA, Sharma, P, Terzic, J, Kumar, MVK, Denniff, M, Zukowska-Szczechowska, E, Wagenknecht, LE, Fowkes, FGR, Charchar, FJ, Schwarz, PEH, Hayward, C, Guo, X, Rotimi, C, Bots, ML, Brand, E, Samani, NJ, Polasek, O, Talmud, PJ, Nyberg, F, Kuh, D, Laan, M, Hveem, K, Palmer, LJ, van der Schouw, YT, Casas, JP, Mohlke, KL, Vineis, P, Raitakari, O, Ganesh, SK, Wong, TY, Tai, ES, Cooper, RS, Laakso, M, Rao, DC, Harris, TB, Morris, RW, Dominiczak, AF, Kivimaki, M, Marmot, MG, Miki, T, Saleheen, D, Chandak, GR, Coresh, J, Navis, G, Salomaa, V, Han, B-G, Zhu, X, Kooner, JS, Melander, O, Ridker, PM, Bandinelli, S, Gyllensten, UB, Wright, AF, Wilson, JF, Ferrucci, L, Farrall, M, Tuomilehto, J, Pramstaller, PP, Elosua, R, Soranzo, N, Sijbrands, EJG, Altshuler, D, Loos, RJF, Shuldiner, AR, Gieger, C, Meneton, P, Uitterlinden, AG, Wareham, NJ, Gudnason, V, Rotter, JI, Rettig, R, Uda, M, Strachan, DP, Witteman, JCM, Hartikainen, A-L, Beckmann, JS, Boerwinkle, E, Vasan, RS, Boehnke, M, Larson, MG, Jarvelin, M-R, Psaty, BM, Abecasis, GR, Chakravarti, A, Elliott, P, van Duijn, CM, Newton-Cheh, C, Levy, D, Caulfield, MJ, and Johnson, T
- Abstract
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
- Published
- 2011
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