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Your search keyword '"Pankow, J.S."' showing total 85 results
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85 results on '"Pankow, J.S."'

1. Environmental Urinary Cadmium Levels and Longitudinal Lung Function in the Multi-ethnic Study of Atherosclerosis

Author

Sobel, M.H., primary, McGraw, K., additional, Malinsky, D., additional, Schilling, K., additional, Glabonjat, R.A., additional, Galvez Fernandez, M., additional, Oelsner, E., additional, Smith, B.M., additional, Allen, N.B., additional, Bertoni, A., additional, Pankow, J.S., additional, Watson, K.E., additional, Post, W.S., additional, Kaufman, J.D., additional, Barr, R.G., additional, Navas-Acien, A., additional, and Sanchez, T.R., additional

Published
2024
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2. Proteomics of CT Emphysema Subtypes. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)

Author

Guzman, D.E., primary, Ruvuna, L., additional, Guo, C., additional, Sun, Y., additional, Smith, B.M., additional, Post, W., additional, Bertoni, A., additional, Allen, N.B., additional, Durda, P., additional, Kent, T., additional, Tracy, R., additional, Liu, Y., additional, Johnson, W.C., additional, Gerszten, R.E., additional, Watson, K.E., additional, Hoesterey, D., additional, Pankow, J.S., additional, Manichaikul, A.W., additional, Hoffman, E.A., additional, Angelini, E., additional, Barjaktarevic, I., additional, Bleecker, E.R., additional, Couper, D., additional, Han, M.K., additional, Hansel, N.N., additional, Pratte, K.A., additional, Krishnan, J.A., additional, Hastie, A.T., additional, Labaki, W.W., additional, Laine, A., additional, Martinez, F.J., additional, Ortega, V.E., additional, Paine, R., additional, Wells, J.M., additional, Curtis, J.L., additional, Silverman, E.K., additional, Woodruff, P., additional, Rich, S.S., additional, Rotter, J.I., additional, Bowler, R.P., additional, and Barr, R.G., additional

Published
2024
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4. Proteomics of COPD-Related Phenotypes in the General Population. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

Author

Guzman, D.E., primary, Sun, Y., additional, Smith, B., additional, Shea, S.J.C., additional, Post, W.S., additional, Bertoni, A., additional, Allen, N.B., additional, Durda, P., additional, Taylor, K., additional, Tracy, R., additional, Liu, Y., additional, Johnson, C., additional, Gerszten, R.E., additional, Watson, K.E., additional, Pankow, J.S., additional, Manichaikul, A.W., additional, Rich, S.S., additional, Rotter, J.I., additional, and Barr, R.G., additional

Published
2023
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5. Race/ethnic, Ancestral, Social, and Environmental Correlates of Lung Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

Author

Elmaleh-Sachs, A., primary, Malinsky, D., additional, Sun, Y., additional, Allen, N.B., additional, Baugh, A.D., additional, Balte, P., additional, Bertoni, A.G., additional, Hankinson, J.L., additional, Hirsch, J.A., additional, Kaufman, J.D., additional, Lovinsky-Desir, S., additional, Manichaikul, A., additional, Oelsner, E., additional, Pankow, J.S., additional, Post, W.S., additional, Pottinger, T., additional, Rich, S.S., additional, Smith, B.M., additional, Watson, K., additional, and Barr, R.G., additional

Published
2023
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9. Cross-ancestry investigation of venousc genomic predictors

Author

Thibord, F., Klarin, D., Brody, J.A., Chen, M.H., Levin, M.G., Chasman, D.I., Goode, E.L., Hveem, K., Teder-Laving, M., Martinez-Perez, A., Aissi, D., Daian-Bacq, D., Ito, K., Natarajan, P., Lutsey, P.L., Nadkarni, G.N., Vries, P.S. de, Cuellar-Partida, G., Wolford, B.N., Pattee, J.W., Kooperberg, C., Braekkan, S.K., Li-Gao, R.F., Saut, N., Sept, C., Germain, M., Judy, R.L., Wiggins, K.L., Ko, D., O'Donnell, C.J., Taylor, K.D., Giulianini, F., Andrade, M. de, Nost, T.H., Boland, A., Empana, J.P., Koyama, S., Gilliland, T., R. do, Huffman, J.E., Wang, X., Zhou, W., Soria, J.M., Souto, J.C., Pankratz, N., Haessler, J., Hindberg, K., Rosendaal, F.R., Turman, C., Olaso, R., Kember, R.L., Bartz, T.M., Lynch, J.A., Heckbert, S.R., Armasu, S.M., Brumpton, B., Smadja, D.M., Jouven, X., Komuro, I., Clapham, K.R., Loos, R.J.F., Willer, C.J., Sabater-Lleal, M., Pankow, J.S., Reiner, A.P., Morelli, V.M., Ridker, P.M., Vlieg, A.V., Deleuze, J.F., Kraft, P., Rader, D.J., Lee, K.M., Psaty, B.M., Skogholt, A.H., Emmerich, J., Suchon, P., Rich, S.S., Vy, H.T., Tang, W.H., Jackson, R.D., Hansen, J.B., Morange, P.E., Kabrhel, C., Tregouet, D.A., Damrauer, S.M., Johnson, A.D., and Smith, N.L.

Subjects
meta-analysis, genome-wide association study, venous thromboembolism, genetics, venous thrombosis
Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Published
2022

10. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Author

McCartney D.L., Min J.L., Richmond R.C., Lu A.T., Sobczyk M.K., Davies G., Broer L., Guo X., Jeong A., Jung J., Kasela S., Katrinli S., Kuo P.-L., Matias-Garcia P.R., Mishra P.P., Nygaard M., Palviainen T., Patki A., Raffield L.M., Ratliff S.M., Richardson T.G., Robinson O., Soerensen M., Sun D., Tsai P.-C., van der Zee M.D., Walker R.M., Wang X., Wang Y., Xia R., Xu Z., Yao J., Zhao W., Correa A., Boerwinkle E., Dugue P.-A., Durda P., Elliott H.R., Gieger C., de Geus E.J.C., Harris S.E., Hemani G., Imboden M., Kahonen M., Kardia S.L.R., Kresovich J.K., Li S., Lunetta K.L., Mangino M., Mason D., McIntosh A.M., Mengel-From J., Moore A.Z., Murabito J.M., Ollikainen M., Pankow J.S., Pedersen N.L., Peters A., Polidoro S., Porteous D.J., Raitakari O., Rich S.S., Sandler D.P., Sillanpaa E., Smith A.K., Southey M.C., Strauch K., Tiwari H., Tanaka T., Tillin T., Uitterlinden A.G., Van Den Berg D.J., van Dongen J., Wilson J.G., Wright J., Yet I., Arnett D., Bandinelli S., Bell J.T., Binder A.M., Boomsma D.I., Chen W., Christensen K., Conneely K.N., Elliott P., Ferrucci L., Fornage M., Hagg S., Hayward C., Irvin M., Kaprio J., Lawlor D.A., Lehtimaki T., Lohoff F.W., Milani L., Milne R.L., Probst-Hensch N., Reiner A.P., Ritz B., Rotter J.I., Smith J.A., Taylor J.A., van Meurs J.B.J., Vineis P., Waldenberger M., Deary I.J., Relton C.L., Horvath S., Marioni R.E., McCartney D.L., Min J.L., Richmond R.C., Lu A.T., Sobczyk M.K., Davies G., Broer L., Guo X., Jeong A., Jung J., Kasela S., Katrinli S., Kuo P.-L., Matias-Garcia P.R., Mishra P.P., Nygaard M., Palviainen T., Patki A., Raffield L.M., Ratliff S.M., Richardson T.G., Robinson O., Soerensen M., Sun D., Tsai P.-C., van der Zee M.D., Walker R.M., Wang X., Wang Y., Xia R., Xu Z., Yao J., Zhao W., Correa A., Boerwinkle E., Dugue P.-A., Durda P., Elliott H.R., Gieger C., de Geus E.J.C., Harris S.E., Hemani G., Imboden M., Kahonen M., Kardia S.L.R., Kresovich J.K., Li S., Lunetta K.L., Mangino M., Mason D., McIntosh A.M., Mengel-From J., Moore A.Z., Murabito J.M., Ollikainen M., Pankow J.S., Pedersen N.L., Peters A., Polidoro S., Porteous D.J., Raitakari O., Rich S.S., Sandler D.P., Sillanpaa E., Smith A.K., Southey M.C., Strauch K., Tiwari H., Tanaka T., Tillin T., Uitterlinden A.G., Van Den Berg D.J., van Dongen J., Wilson J.G., Wright J., Yet I., Arnett D., Bandinelli S., Bell J.T., Binder A.M., Boomsma D.I., Chen W., Christensen K., Conneely K.N., Elliott P., Ferrucci L., Fornage M., Hagg S., Hayward C., Irvin M., Kaprio J., Lawlor D.A., Lehtimaki T., Lohoff F.W., Milani L., Milne R.L., Probst-Hensch N., Reiner A.P., Ritz B., Rotter J.I., Smith J.A., Taylor J.A., van Meurs J.B.J., Vineis P., Waldenberger M., Deary I.J., Relton C.L., Horvath S., and Marioni R.E.

Abstract

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Result(s): Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion(s): This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.Copyright © 2021, The Author(s).

Published
2021

11. Pulmonary Blood Volume in Older Adults Assessed by Dual-Energy Computed Tomography: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

Author

Hermann, E.A., primary, Hiura, G., additional, Hoffman, E.A., additional, Motahari, A., additional, Gerard, S.E., additional, Nagpal, P., additional, Eskandari, A., additional, Go, J., additional, Allen, N., additional, Bertoni, A., additional, Bluemke, D., additional, Pankow, J.S., additional, Michos, E.D., additional, Hinckley Stukovsky, K.D., additional, Kaczka, D.W., additional, Watson, K., additional, and Barr, R.G., additional

Published
2021
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13. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Author

Lindstrom, S., Wang, L., Smith, E.N., Gordon, W., Vlieg, A.V., Andrade, M. de, Brody, J.A., Pattee, J.W., Haessler, J., Brumpton, B., Chasman, D.I., Suchon, P., Chen, M.H., Turman, C., Germain, M., Wiggins, K.L., MacDonald, J., Braekkan, S.K., Armasu, S.M., Pankratz, N., Jackson, R.D., Nielsen, J.B., Giulianini, F., Puurunen, M.K., Ibrahim, M., Heckbert, S.R., Damrauer, S.M., Natarajan, P., Klarin, D., Vries, P.S. de, Sabater-Lleal, M., Huffman, J.E., Bammler, T.K., Frazer, K.A., McCauley, B.M., Taylor, K., Pankow, J.S., Reiner, A.P., Gabrielsen, M.E., Deleuze, J.F., O'Donnell, C.J., Kim, J., McKnight, B., Kraft, P., Hansen, J.B., Rosendaal, F.R., Heit, J.A., Psaty, B.M., Tang, W.H., Kooperberg, C., Hveem, K., Ridker, P.M., Morange, P.E., Johnson, A.D., Kabrhel, C., Tregouet, D.A., Smith, N.L., Busenkell, E., Judy, R., Lynch, J., Levin, M., Aragam, J.H.K., Chaffin, M., Haas, M., Assimes, T.L., Huang, J., Lee, K.M., Shao, Q., Huang, Y.F., Sun, Y.V., Vujkovic, M., Saleheen, D., Miller, D.R., Reaven, P., DuVall, S., Boden, W., Pyarajan, S., Henke, P., Gaziano, J.M., Concato, J., Rader, D.J., Cho, K., Chang, K.M., Wilson, P.W.F., Tsao, P.S., Kathiresan, S., Obi, A., Million Veteran Program, CHARGE Hemostasis Working Grp, INVENT Consortium, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, University of Washington [Seattle], The Scripps Translational Science Institute and Scripps Health, Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Minnesota System, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Brigham and Women's Hospital [Boston], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), National Institutes of Health [Bethesda] (NIH), Harvard T.H. Chan School of Public Health, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biorobotics Lab (University of Washington), University of South-Eastern Norway (USN), Department of Health Sciences Research, Ohio State University [Columbus] (OSU), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Los Angeles Biomedical Research Institute (LA BioMed), University of Augsburg [Augsburg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Epidemiology, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, University of Minnesota [Twin Cities] (UMN), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Department of Emergency Medicine, Massachusetts General Hospital [Boston], Universiteit Leiden-Universiteit Leiden, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Augsburg (UNIA), and Universiteit Leiden

Subjects
0301 basic medicine, Genetics, [SDV]Life Sciences [q-bio], Immunology, Genome-wide association study, Cell Biology, Hematology, 030204 cardiovascular system & hematology, Biology, equipment and supplies, Biochemistry, 3. Good health, Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Mendelian randomization, Expression quantitative trait loci, Gene expression, cardiovascular diseases, Gene, Genetic association, Whole blood
Abstract

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Published
2019
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14. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

Mahajan, A. Taliun, D. Thurner, M. Robertson, N.R. Torres, J.M. Rayner, N.W. Payne, A.J. Steinthorsdottir, V. Scott, R.A. Grarup, N. Cook, J.P. Schmidt, E.M. Wuttke, M. Sarnowski, C. Mägi, R. Nano, J. Gieger, C. Trompet, S. Lecoeur, C. Preuss, M.H. Prins, B.P. Guo, X. Bielak, L.F. Below, J.E. Bowden, D.W. Chambers, J.C. Kim, Y.J. Ng, M.C.Y. Petty, L.E. Sim, X. Zhang, W. Bennett, A.J. Bork-Jensen, J. Brummett, C.M. Canouil, M. Ec kardt, K.-U. Fischer, K. Kardia, S.L.R. Kronenberg, F. Läll, K. Liu, C.-T. Locke, A.E. Luan, J. Ntalla, I. Nylander, V. Schönherr, S. Schurmann, C. Yengo, L. Bottinger, E.P. Brandslund, I. Christensen, C. Dedoussis, G. Florez, J.C. Ford, I. Franco, O.H. Frayling, T.M. Giedraitis, V. Hackinger, S. Hattersley, A.T. Herder, C. Ikram, M.A. Ingelsson, M. Jørgensen, M.E. Jørgensen, T. Kriebel, J. Kuusisto, J. Ligthart, S. Lindgren, C.M. Linneberg, A. Lyssenko, V. Mamakou, V. Meitinger, T. Mohlke, K.L. Morris, A.D. Nadkarni, G. Pankow, J.S. Peters, A. Sattar, N. Stančáková, A. Strauch, K. Taylor, K.D. Thorand, B. Thorleifsson, G. Thorsteinsdottir, U. Tuomilehto, J. Witte, D.R. Dupuis, J. Peyser, P.A. Zeggini, E. Loos, R.J.F. Froguel, P. Ingelsson, E. Lind, L. Groop, L. Laakso, M. Collins, F.S. Jukema, J.W. Palmer, C.N.A. Grallert, H. Metspalu, A. Dehghan, A. Köttgen, A. Abecasis, G.R. Meigs, J.B. Rotter, J.I. Marchini, J. Pedersen, O. Hansen, T. Langenberg, C. Wareham, N.J. Stefansson, K. Gloyn, A.L. Morris, A.P. Boehnke, M. McCarthy, M.I.

Abstract

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence). © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

Published
2018

15. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes article

Author

Mahajan, A. Wessel, J. Willems, S.M. Zhao, W. Robertson, N.R. Chu, A.Y. Gan, W. Kitajima, H. Taliun, D. Rayner, N.W. Guo, X. Lu, Y. Li, M. Jensen, R.A. Hu, Y. Huo, S. Lohman, K.K. Zhang, W. Cook, J.P. Prins, B.P. Flannick, J. Grarup, N. Trubetskoy, V.V. Kravic, J. Kim, Y.J. Rybin, D.V. Yaghootkar, H. Müller-Nurasyid, M. Meidtner, K. Li-Gao, R. Varga, T.V. Marten, J. Li, J. Smith, A.V. An, P. Ligthart, S. Gustafsson, S. Malerba, G. Demirkan, A. Tajes, J.F. Steinthorsdottir, V. Wuttke, M. Lecoeur, C. Preuss, M. Bielak, L.F. Graff, M. Highland, H.M. Justice, A.E. Liu, D.J. Marouli, E. Peloso, G.M. Warren, H.R. Afaq, S. Afzal, S. Ahlqvist, E. Bang, L.B. Bertoni, A.G. Bombieri, C. Bork-Jensen, J. Brandslund, I. Brody, J.A. Burtt, N.P. Canouil, M. Chen, Y.-D.I. Cho, Y.S. Christensen, C. Eastwood, S.V. Eckardt, K.-U. Fischer, K. Gambaro, G. Giedraitis, V. Grove, M.L. De Haan, H.G. Hackinger, S. Hai, Y. Han, S. Tybjærg-Hansen, A. Hivert, M.-F. Isomaa, B. Jäger, S. Jørgensen, M.E. Jørgensen, T. Käräjämäki, A. Kim, B.-J. Kim, S.S. Koistinen, H.A. Kovacs, P. Kriebel, J. Kronenberg, F. Läll, K. Lange, L.A. Lee, J.-J. Lehne, B. Li, H. Lin, K.-H. Linneberg, A. Liu, C.-T. Liu, J. Loh, M. Mägi, R. Mamakou, V. McKean-Cowdin, R. Nadkarni, G. Neville, M. Nielsen, S.F. Ntalla, I. Peyser, P.A. Rathmann, W. Rice, K. Rich, S.S. Rode, L. Rolandsson, O. Schönherr, S. Selvin, E. Small, K.S. Stančáková, A. Surendran, P. Taylor, K.D. Teslovich, T.M. Thorand, B. Thorleifsson, G. Tin, A. Tönjes, A. Varbo, A. Witte, D.R. Wood, A.R. Yajnik, P. Yao, J. Yengo, L. Young, R. Boeing, H. Boerwinkle, E. Bottinger, E.P. Chowdhury, R. Dedoussis, G. Dehghan, A. Deloukas, P. Ferrario, M.M. Ferrières, J. Florez, J.C. Frossard, P. Gudnason, V. Harris, T.B. Heckbert, S.R. Howson, J.M.M. Ingelsson, M. Kathiresan, S. Kee, F. Kuusisto, J. Langenberg, C. Launer, L.J. Lindgren, C.M. Männistö, S. Meitinger, T. Mohlke, K.L. Moitry, M. Morris, A.D. Murray, A.D. De Mutsert, R. Orho-Melander, M. Owen, K.R. Perola, M. Peters, A. Province, M.A. Rasheed, A. Ridker, P.M. Rivadineira, F. Rosendaal, F.R. Rosengren, A.H. Salomaa, V. Sheu, W.H.-H. Sladek, R. Smith, B.H. Strauch, K. Uitterlinden, A.G. Varma, R. Willer, C.J. Blüher, M. Chambers, J.C. Danesh, J. Van Duijn, C. Dupuis, J. Franco, O.H. Franks, P.W. Froguel, P. Grallert, H. Groop, L. Han, B.-G. Hansen, T. Hattersley, A.T. Hayward, C. Ingelsson, E. Kardia, S.L.R. Karpe, F. Kooner, J.S. Köttgen, A. Kuulasmaa, K. Laakso, M. Lin, X. Lind, L. Liu, Y. Loos, R.J.F. Marchini, J. Metspalu, A. Mook-Kanamori, D. Nordestgaard, Bø.G. Palmer, C.N.A. Pankow, J.S. Pedersen, O. Psaty, B.M. Rauramaa, R. Sattar, N. Schulze, M.B. Soranzo, N. Spector, T.D. Stefansson, K. Stumvoll, M. Thorsteinsdottir, U. Tuomi, T. Tuomilehto, J. Wareham, N.J. Wilson, J.G. Zeggini, E. Scott, R.A. Barroso, I. Frayling, T.M. Goodarzi, M.O. Meigs, J.B. Boehnke, M. Saleheen, D. Morris, A.P. Rotter, J.I. McCarthy, M.I. ExomeBP Consortium MAGIC Consortium GIANT Consortium

Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition. © 2018 The Author(s).

Published
2018

17. A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium

Author

Tang, W., Teichert, M., Chasman, D.I., Heit, J.A., Morange, P.E., Li, G., Pankratz, N., Leebeek, F.W., Pare, G., Andrade, M. de, Tzourio, C., Psaty, B.M., Basu, S., Ruiter, R. de, Rose, L., Armasu, S.M., Lumley, T., Heckbert, S.R., Uitterlinden, A.G., Lathrop, M., Rice, K.M., Cushman, M., Hofman, A., Lambert, J.C., Glazer, N.L., Pankow, J.S., Witteman, J.C., Amouyel, P., Bis, J.C., Bovill, E.G., Kong, X., Tracy, R.P., Boerwinkle, E., Rotter, J.I., Tregouet, D.A., Loth, D.W., Stricker, B.H., Ridker, P.M., Folsom, A.R., Smith, N.L., Epidemiology, Erasmus School of Social and Behavioural Sciences, Hematology, Cell biology, Cardiology, and Internal Medicine

Subjects
Male, Aging, Implementation Science [NCEBP 3], Venous Thromboembolism, Middle Aged, Polymorphism, Single Nucleotide, Article, Cohort Studies, Meta-Analysis as Topic, Risk Factors, Case-Control Studies, Humans, Regression Analysis, Female, Aged, Genome-Wide Association Study
Abstract

Item does not contain fulltext Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P

Published
2013

18. Parental origin of sequence variants associated with complex diseases

Author

Voight, B.F., Raychaudhuri, S., Purcell, S., McCarroll, S.A., Segrè, A.V., Ardlie, K., Burtt, N.P., Crawford, G., Elliott, A.L., Green, T., Guiducci, C., Saxena, R., Daly, M.J., Florez, J.C., Altshuler, D., Meigs, J.B., Scott, L.J., Welch, R.P., Willer, C.J., Ganser, M., Jackson, A.U., Stringham, H.M., Abecasis, G.R., Boehnke, M., Steinthorsdottir, V., Thorleifsson, G., Kong, A., Walters, G.B., Thorsteinsdottir, U., Stefansson, K., Dina, C., Proença, C., Cauchi, S., Froguel, P., Zeggini, E., Bumpstead, S., Payne, F., Smith, N., Barroso, I., Ferreira, T., Elliott, K.S., Lindgren, C.M., Prokopenko, I., Rayner, N.W., Robertson, N.R., Morris, A.P., McCarthy, M.I., Huth, C., Grallert, H., Gieger, C., Klopp, N., Meitinger, T., Petersen, A.-K., Thorand, B., Wichmann, H.-E., Illig, T., Aulchenko, Y.S., Amin, N., Witteman, J., Hofman, A., Van Duijn, C.M., McCulloch, L.J., Bennett, A.J., Groves, C.J., Hassanali, N., Owen, K.R., Gloyn, A.L., Wu, G., Stein, L.D., Langenberg, C., Griffin, S., Wareham, N.J., Hoffmann, O.M., Hide, W.A., Dupuis, J., Qi, L., Kraft, P., Sun, Q., Hunter, D., Hu, F.B., Cornelis, M., VanDam, R., Van Hoek, M., Van Herpt, T., Sijbrands, E., Uitterlinden, A., Navarro, P., Balkau, B., Benediktsson, R., Sigurdsson, G., Blagieva, R., Boehm, B.O., Boerwinkle, E., Bonnycastle, L.L., Chines, P.S., Erdos, M.R., Morken, M.A., Narisu, N., Swift, A.J., Boström, K.B., Bravenboer, B., Charpentier, G., Couper, D.J., Doney, A.S.F., Morris, A.D., Palmer, C.N.A., Fox, C.S., Franklin, C.S., Rudan, I., Grarup, N., Hadjadj, S., Thomas Sparsø, [No Value], Campbell, H., Wilson, J.F., Hansen, T., Pedersen, O., Herder, C., Roden, M., Isomaa, B., Tuomi, T., Johnson, P.R.V., Jørgensen, T., Kao, W.H.L., Kuusisto, J., Laakso, M., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Nilsson, P., Groop, L., Marre, M., Midthjell, K., Platou, C., Hveem, K., Perry, J.R.B., Shields, B.M., Weedon, M.N., Frayling, T.M., Hattersley, A.T., Rathmann, W., Strassburger, K., Rocheleau, G., Sladek, R., Sampson, M.J., Shrader, P., Tichet, J., Bergman, R.N., Collins, F.S., Gyllensten, U., Hitman, G.A., Mohlke, K.L., Pramstaller, P.P., Tuomilehto, J., Walker, M., Watanabe, R.M., Pankow, J.S., and deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland. kong@decode.is

Subjects
Male, CCCTC-Binding Factor, Iceland, Mothers, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Fathers, Genomic Imprinting, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Humans, SNP, Genetic Predisposition to Disease, Allele, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, Binding Sites, Multidisciplinary, Genome, Human, Chromosomes, Human, Pair 11, Haplotype, DNA Methylation, Pedigree, Repressor Proteins, Diabetes Mellitus, Type 2, Haplotypes, Carcinoma, Basal Cell, DNA methylation, Female, Human genome, Genomic imprinting, Chromosomes, Human, Pair 7, 030217 neurology & neurosurgery
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site. info:eu-repo/grantAgreement/EC/FP7/218071

Published
2009
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20. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Wessel, J. Chu, A.Y. Willems, S.M. Wang, S. Yaghootkar, H. Brody, J.A. Dauriz, M. Hivert, M.-F. Raghavan, S. Lipovich, L. Hidalgo, B. Fox, K. Huffman, J.E. An, P. Lu, Y. Rasmussen-Torvik, L.J. Grarup, N. Ehm, M.G. Li, L. Baldridge, A.S. Stančáková, A. Abrol, R. Besse, C. Boland, A. Bork-Jensen, J. Fornage, M. Freitag, D.F. Garcia, M.E. Guo, X. Hara, K. Isaacs, A. Jakobsdottir, J. Lange, L.A. Layton, J.C. Li, M. Hua Zhao, J. Meidtner, K. Morrison, A.C. Nalls, M.A. Peters, M.J. Sabater-Lleal, M. Schurmann, C. Silveira, A. Smith, A.V. Southam, L. Stoiber, M.H. Strawbridge, R.J. Taylor, K.D. Varga, T.V. Allin, K.H. Amin, N. Aponte, J.L. Aung, T. Barbieri, C. Bihlmeyer, N.A. Boehnke, M. Bombieri, C. Bowden, D.W. Burns, S.M. Chen, Y. Chen, Y.-D. Cheng, C.-Y. Correa, A. Czajkowski, J. Dehghan, A. Ehret, G.B. Eiriksdottir, G. Escher, S.A. Farmaki, A.-E. Frånberg, M. Gambaro, G. Giulianini, F. Goddard, W.A. Goel, A. Gottesman, O. Grove, M.L. Gustafsson, S. Hai, Y. Hallmans, G. Heo, J. Hoffmann, P. Ikram, M.K. Jensen, R.A. Jørgensen, M.E. Jørgensen, T. Karaleftheri, M. Khor, C.C. Kirkpatrick, A. Kraja, A.T. Kuusisto, J. Lange, E.M. Lee, I.T. Lee, W.-J. Leong, A. Liao, J. Liu, C. Liu, Y. Lindgren, C.M. Linneberg, A. Malerba, G. Mamakou, V. Marouli, E. Maruthur, N.M. Matchan, A. McKean-Cowdin, R. McLeod, O. Metcalf, G.A. Mohlke, K.L. Muzny, D.M. Ntalla, I. Palmer, N.D. Pasko, D. Peter, A. Rayner, N.W. Renström, F. Rice, K. Sala, C.F. Sennblad, B. Serafetinidis, I. Smith, J.A. Soranzo, N. Speliotes, E.K. Stahl, E.A. Stirrups, K. Tentolouris, N. Thanopoulou, A. Torres, M. Traglia, M. Tsafantakis, E. Javad, S. Yanek, L.R. Zengini, E. Becker, D.M. Bis, J.C. Brown, J.B. Adrienne Cupples, L. Hansen, T. Ingelsson, E. Karter, A.J. Lorenzo, C. Mathias, R.A. Norris, J.M. Peloso, G.M. Sheu, W.H.-H. Toniolo, D. Vaidya, D. Varma, R. Wagenknecht, L.E. Boeing, H. Bottinger, E.P. Dedoussis, G. Deloukas, P. Ferrannini, E. Franco, O.H. Franks, P.W. Gibbs, R.A. Gudnason, V. Hamsten, A. Harris, T.B. Hattersley, A.T. Hayward, C. Hofman, A. Jansson, J.-H. Langenberg, C. Launer, L.J. Levy, D. Oostra, B.A. O'Donnell, C.J. O'Rahilly, S. Padmanabhan, S. Pankow, J.S. Polasek, O. Province, M.A. Rich, S.S. Ridker, P.M. Rudan, I. Schulze, M.B. Smith, B.H. Uitterlinden, A.G. Walker, M. Watkins, H. Wong, T.Y. Zeggini, E. Laakso, M. Borecki, I.B. Chasman, D.I. Pedersen, O. Psaty, B.M. Shyong Tai, E. Van Duijn, C.M. Wareham, N.J. Waterworth, D.M. Boerwinkle, E. Linda Kao, W.H. Florez, J.C. Loos, R.J.F. Wilson, J.G. Frayling, T.M. Siscovick, D.S. Dupuis, J. Rotter, J.I. Meigs, J.B. Scott, R.A. Goodarzi, M.O.

Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01mmoll-1, P=3.4 × 10-12), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035pmolinsulin mmolglucose-1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =6.8 × 10-6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004mmoll-1, P=1.3 × 10-8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility. © 2015 Macmillan Publishers Limited. All rights reserved.

Published
2015

21. Association of the IGF1 gene with fasting insulin levels

Author

Willems, S.M. (Sara), Cornes, B.K. (Belinda), Brody, J.A. (Jennifer A.), Morrison, A.C. (Alanna), Lipovich, L. (Leonard), Dauriz, M. (Marco), Chen, Y. (Yuning), Liu, C.-T. (Ching-Ti), Rybin, D. (Denis), Gibbs, R.A. (Richard A), Muzny, D. (Donna), Pankow, J.S. (James), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Rotter, J.I. (Jerome I.), Siscovick, D.S. (David), Vasan, R.S. (Ramachandran S), Kaplan, R.C. (Robert C), Isaacs, A.J. (Aaron), Dupuis, J. (Josée), Duijn, C.M. (Cornelia) van, Meigs, J.B. (James), Willems, S.M. (Sara), Cornes, B.K. (Belinda), Brody, J.A. (Jennifer A.), Morrison, A.C. (Alanna), Lipovich, L. (Leonard), Dauriz, M. (Marco), Chen, Y. (Yuning), Liu, C.-T. (Ching-Ti), Rybin, D. (Denis), Gibbs, R.A. (Richard A), Muzny, D. (Donna), Pankow, J.S. (James), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Rotter, J.I. (Jerome I.), Siscovick, D.S. (David), Vasan, R.S. (Ramachandran S), Kaplan, R.C. (Robert C), Isaacs, A.J. (Aaron), Dupuis, J. (Josée), Duijn, C.M. (Cornelia) van, and Meigs, J.B. (James)

Abstract

Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (F

Published
2016
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22. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

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

Abstract

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

Published
2016
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23. Epigenetic Signatures of Cigarette Smoking

Author

Joehanes, R. (Roby), Just, A.C. (Allan C.), Marioni, R.E. (Riccardo), Pilling, L.C. (Luke), Reynolds, L.M. (Lindsay), Mandaviya, P.R. (Pooja R.), Guan, W. (Weihua), Xu, T. (Tao), Elks, C.E. (Cathy), Aslibekyan, S. (Stella), Moreno-Macías, H. (Hortensia), Smith, J.A. (Jennifer A), Brody, J.A. (Jennifer A.), Dhingra, R. (Radhika), Yousefi, P. (Paul), Pankow, J.S. (James), Kunze, S. (Sonja), Shah, S.H. (Sonia H.), McRae, A.F. (Allan F.), Lohman, K. (Kurt), Sha, J. (Jin), Absher, D. (Devin), Ferrucci, L. (Luigi), Zhao, W. (Wei), Demerath, E.W. (Ellen), Bressler, J. (Jan), Grove, M.L. (Megan), Huan, T. (Tianxiao), Liu, C. (Chunyu), Mendelson, M.M. (Michael M.), Yao, C. (Chen), Kiel, D.P. (Douglas P.), Peters, A. (Annette), Wang-Sattler, R. (Rui), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Starr, J.M. (John), Ding, J. (Jingzhong), Rodriguez, C.J. (Carlos J.), Wareham, N.J. (Nick), Irvin, M.R. (Marguerite R.), Zhi, D. (Degui), Barrdahl, M. (Myrto), Vineis, P. (Paolo), Ambatipudi, S. (Srikant), Uitterlinden, A.G. (André), Hofman, A. (Albert), Schwartz, J. (Joel), Colicino, E. (Elena), Hou, L. (Lifang), Vokonas, P.S. (Pantel S.), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Turner, S.T. (Stephen), Ware, E.B. (Erin B.), Smith, A.K. (Alicia K.), Klengel, T. (Torsten), Binder, E.B. (Elisabeth B.), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Gharib, S.A. (Sina), Swenson, B.R. (Brenton R.), Liang, L. (Liming), Demeo, D.L. (Dawn), O'Connor, G.T. (George), Herceg, Z. (Zdenko), Ressler, K.J. (Kerry J.), Conneely, K.N. (Karen N.), Sotoodehnia, N. (Nona), Kardia, S.L.R. (Sharon L. R.), Melzer, D. (David), Baccarelli, A.A. (Andrea), Meurs, J.B.J. (Joyce) van, Romieu, I. (Isabelle), Arnett, D.K. (Donna), Ong, K.K. (Ken K.), Liu, Y. (YongMei), Waldenberger, M. (Melanie), Deary, I.J. (Ian), Fornage, M. (Myriam), Levy, D. (Daniel), London, S.J. (Stephanie J.), Joehanes, R. (Roby), Just, A.C. (Allan C.), Marioni, R.E. (Riccardo), Pilling, L.C. (Luke), Reynolds, L.M. (Lindsay), Mandaviya, P.R. (Pooja R.), Guan, W. (Weihua), Xu, T. (Tao), Elks, C.E. (Cathy), Aslibekyan, S. (Stella), Moreno-Macías, H. (Hortensia), Smith, J.A. (Jennifer A), Brody, J.A. (Jennifer A.), Dhingra, R. (Radhika), Yousefi, P. (Paul), Pankow, J.S. (James), Kunze, S. (Sonja), Shah, S.H. (Sonia H.), McRae, A.F. (Allan F.), Lohman, K. (Kurt), Sha, J. (Jin), Absher, D. (Devin), Ferrucci, L. (Luigi), Zhao, W. (Wei), Demerath, E.W. (Ellen), Bressler, J. (Jan), Grove, M.L. (Megan), Huan, T. (Tianxiao), Liu, C. (Chunyu), Mendelson, M.M. (Michael M.), Yao, C. (Chen), Kiel, D.P. (Douglas P.), Peters, A. (Annette), Wang-Sattler, R. (Rui), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Starr, J.M. (John), Ding, J. (Jingzhong), Rodriguez, C.J. (Carlos J.), Wareham, N.J. (Nick), Irvin, M.R. (Marguerite R.), Zhi, D. (Degui), Barrdahl, M. (Myrto), Vineis, P. (Paolo), Ambatipudi, S. (Srikant), Uitterlinden, A.G. (André), Hofman, A. (Albert), Schwartz, J. (Joel), Colicino, E. (Elena), Hou, L. (Lifang), Vokonas, P.S. (Pantel S.), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Turner, S.T. (Stephen), Ware, E.B. (Erin B.), Smith, A.K. (Alicia K.), Klengel, T. (Torsten), Binder, E.B. (Elisabeth B.), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Gharib, S.A. (Sina), Swenson, B.R. (Brenton R.), Liang, L. (Liming), Demeo, D.L. (Dawn), O'Connor, G.T. (George), Herceg, Z. (Zdenko), Ressler, K.J. (Kerry J.), Conneely, K.N. (Karen N.), Sotoodehnia, N. (Nona), Kardia, S.L.R. (Sharon L. R.), Melzer, D. (David), Baccarelli, A.A. (Andrea), Meurs, J.B.J. (Joyce) van, Romieu, I. (Isabelle), Arnett, D.K. (Donna), Ong, K.K. (Ken K.), Liu, Y. (YongMei), Waldenberger, M. (Melanie), Deary, I.J. (Ian), Fornage, M. (Myriam), Levy, D. (Daniel), and London, S.J. (Stephanie J.)

Abstract

Background-DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results-To comprehensively determine the association between cigarette smoki

Published
2016
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24. DNA methylation-based measures of biological age: Meta-analysis predicting time to death

Author

Chen, B.H. (Brian), Marioni, R.E. (Riccardo), Colicino, E. (Elena), Peters, M.J. (Marjolein), Ward-Caviness, C.K. (Cavin K.), Tsai, P.-C. (Pei-Chien), Roetker, N.S. (Nicholas S.), Just, A.C. (Allan C.), Demerath, E.W. (Ellen), Guan, W. (Weihua), Bressler, J. (Jan), Fornage, M. (Myriam), Studenski, S. (Stephanie), Vandiver, A.R. (Amy R.), Moore, A.Z. (Ann Zenobia), Tanaka, T. (Toshiko), Kiel, D.P. (Douglas P.), Liang, L. (Liming), Vokonas, P. (Pantel), Schwartz, J. (Joel), Lunetta, K.L. (Kathryn), Murabito, J. (Joanne), Bandinelli, S. (Stefania), Hernandez, D.G. (Dena), Melzer, D. (David), Nalls, M.A. (Michael), Pilling, L.C. (Luke), Price, T.R. (Timothy R.), Singleton, A. (Andrew), Gieger, C. (Christian), Holle, R. (Rolf), Kretschmer, A. (Anja), Kronenberg, F. (Florian), Kunze, S. (Sonja), Linseisen, J. (Jakob), Meisinger, C. (Christine), Rathmann, W. (Wolfgang), Waldenberger, M. (Melanie), Visscher, P.M. (Peter), Shah, S. (Sonia), Wray, N.R. (Naomi), McRae, A.F. (Allan F.), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Absher, D. (Devin), Assimes, T.L. (Themistocles), Levine, M.E. (Morgan E.), Lu, A.T. (Ake T.), Tsao, P.S. (Philip S.), Hou, L. (Lifang), Manson, J.E. (Joann), Carty, C. (Cara), LaCroix, A.Z. (Andrea Z.), Reiner, A. (Alexander), Spector, T.D. (Timothy), Feinberg, A.P. (Andrew P.), Levy, D. (Daniel), Baccarelli, A.A. (Andrea), Meurs, J. (Joyce van), Bell, J.T. (Jordana), Peters, A. (Annette), Deary, I.J. (Ian), Pankow, J.S. (James), Ferrucci, L. (Luigi), Horvath, S. (Steve), Chen, B.H. (Brian), Marioni, R.E. (Riccardo), Colicino, E. (Elena), Peters, M.J. (Marjolein), Ward-Caviness, C.K. (Cavin K.), Tsai, P.-C. (Pei-Chien), Roetker, N.S. (Nicholas S.), Just, A.C. (Allan C.), Demerath, E.W. (Ellen), Guan, W. (Weihua), Bressler, J. (Jan), Fornage, M. (Myriam), Studenski, S. (Stephanie), Vandiver, A.R. (Amy R.), Moore, A.Z. (Ann Zenobia), Tanaka, T. (Toshiko), Kiel, D.P. (Douglas P.), Liang, L. (Liming), Vokonas, P. (Pantel), Schwartz, J. (Joel), Lunetta, K.L. (Kathryn), Murabito, J. (Joanne), Bandinelli, S. (Stefania), Hernandez, D.G. (Dena), Melzer, D. (David), Nalls, M.A. (Michael), Pilling, L.C. (Luke), Price, T.R. (Timothy R.), Singleton, A. (Andrew), Gieger, C. (Christian), Holle, R. (Rolf), Kretschmer, A. (Anja), Kronenberg, F. (Florian), Kunze, S. (Sonja), Linseisen, J. (Jakob), Meisinger, C. (Christine), Rathmann, W. (Wolfgang), Waldenberger, M. (Melanie), Visscher, P.M. (Peter), Shah, S. (Sonia), Wray, N.R. (Naomi), McRae, A.F. (Allan F.), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Absher, D. (Devin), Assimes, T.L. (Themistocles), Levine, M.E. (Morgan E.), Lu, A.T. (Ake T.), Tsao, P.S. (Philip S.), Hou, L. (Lifang), Manson, J.E. (Joann), Carty, C. (Cara), LaCroix, A.Z. (Andrea Z.), Reiner, A. (Alexander), Spector, T.D. (Timothy), Feinberg, A.P. (Andrew P.), Levy, D. (Daniel), Baccarelli, A.A. (Andrea), Meurs, J. (Joyce van), Bell, J.T. (Jordana), Peters, A. (Annette), Deary, I.J. (Ian), Pankow, J.S. (James), Ferrucci, L. (Luigi), and Horvath, S. (Steve)

Abstract

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p ≤ 8.2 x 10-9), independent of chronological age, even after adjusting for additional risk factors (p < 5.4 x 10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p≤ 7.5 x 10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

Published
2016
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25. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Author

Ligthart, S. (Symen), Marzi, C. (Carola), Aslibekyan, S. (Stella), Mendelson, M.M. (Michael M.), Conneely, K.N. (Karen N.), Tanaka, T. (Toshiko), Colicino, E. (Elena), Waite, L. (Lindsay), Joehanes, R. (Roby), Guan, W. (Weihua), Brody, J.A. (Jennifer A.), Elks, C.E. (Cathy), Marioni, R.E. (Riccardo), Jhun, M.A. (Min A.), Agha, G. (Golareh), Bressler, J. (Jan), Ward-Caviness, C.K. (Cavin K.), Chen, B.H. (Brian), Huan, T. (Tianxiao), Bakulski, K.M. (Kelly M.), Salfati, E. (Elias), Fiorito, G. (Giovanni), Wahl, S. (Simone), Schramm, K. (Katharina), Sha, J. (Jin), Hernandez, D.G. (Dena), Just, A.C. (Allan C.), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Pilling, L.C. (Luke), Pankow, J.S. (James), Tsao, P.S. (Phil S.), Liu, C. (Chunyu), Zhao, W. (Wei), Guarrera, S. (Simonetta), Michopoulos, V.J. (Vasiliki J.), Smith, A.K. (Alicia K.), Peters, M.J. (Marjolein), Melzer, D. (David), Vokonas, P. (Pantel), Fornage, M. (Myriam), Prokisch, H. (Holger), Bis, J.C. (Joshua), Chu, A.Y. (Audrey), Herder, C. (Christian), Grallert, H. (Harald), Yao, C. (Chen), Shah, S. (Sonia), McRae, A.F. (Allan F.), Lin, H., Horvath, S. (Steve), Fallin, D. (Daniele), Hofman, A. (Albert), Wareham, N.J. (Nick), Wiggins, K.L. (Kerri), Feinberg, A.P. (Andrew P.), Starr, J.M. (John), Visscher, P.M. (Peter), Murabito, J. (Joanne), Kardia, S.L.R. (Sharon L.R.), Absher, D. (Devin), Binder, E.B. (Elisabeth), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Peters, A. (Annette), Waldenberger, M. (Melanie), Matullo, G., Schwartz, J.D. (Joel D.), Demerath, E.W. (Ellen), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce B.J.), Franco, O.H. (Oscar), Chen, Y.D. (Y.), Levy, D. (Daniel), Turner, S.T. (Stephen), Deary, I.J. (Ian), Ressler, K.J. (Kerry), Dupuis, J. (Josée), Ferrucci, L. (Luigi), Ong, K.K. (Ken K.), Assimes, T.L. (Themistocles), Boerwinkle, E.A. (Eric), Koenig, W. (Wolfgang), Arnett, D.K. (Donna), Baccarelli, A.A. (Andrea), Benjamin, E.J. (Emelia), Dehghan, A. (Abbas), Ligthart, S. (Symen), Marzi, C. (Carola), Aslibekyan, S. (Stella), Mendelson, M.M. (Michael M.), Conneely, K.N. (Karen N.), Tanaka, T. (Toshiko), Colicino, E. (Elena), Waite, L. (Lindsay), Joehanes, R. (Roby), Guan, W. (Weihua), Brody, J.A. (Jennifer A.), Elks, C.E. (Cathy), Marioni, R.E. (Riccardo), Jhun, M.A. (Min A.), Agha, G. (Golareh), Bressler, J. (Jan), Ward-Caviness, C.K. (Cavin K.), Chen, B.H. (Brian), Huan, T. (Tianxiao), Bakulski, K.M. (Kelly M.), Salfati, E. (Elias), Fiorito, G. (Giovanni), Wahl, S. (Simone), Schramm, K. (Katharina), Sha, J. (Jin), Hernandez, D.G. (Dena), Just, A.C. (Allan C.), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Pilling, L.C. (Luke), Pankow, J.S. (James), Tsao, P.S. (Phil S.), Liu, C. (Chunyu), Zhao, W. (Wei), Guarrera, S. (Simonetta), Michopoulos, V.J. (Vasiliki J.), Smith, A.K. (Alicia K.), Peters, M.J. (Marjolein), Melzer, D. (David), Vokonas, P. (Pantel), Fornage, M. (Myriam), Prokisch, H. (Holger), Bis, J.C. (Joshua), Chu, A.Y. (Audrey), Herder, C. (Christian), Grallert, H. (Harald), Yao, C. (Chen), Shah, S. (Sonia), McRae, A.F. (Allan F.), Lin, H., Horvath, S. (Steve), Fallin, D. (Daniele), Hofman, A. (Albert), Wareham, N.J. (Nick), Wiggins, K.L. (Kerri), Feinberg, A.P. (Andrew P.), Starr, J.M. (John), Visscher, P.M. (Peter), Murabito, J. (Joanne), Kardia, S.L.R. (Sharon L.R.), Absher, D. (Devin), Binder, E.B. (Elisabeth), Singleton, A. (Andrew), Bandinelli, S. (Stefania), Peters, A. (Annette), Waldenberger, M. (Melanie), Matullo, G., Schwartz, J.D. (Joel D.), Demerath, E.W. (Ellen), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce B.J.), Franco, O.H. (Oscar), Chen, Y.D. (Y.), Levy, D. (Daniel), Turner, S.T. (Stephen), Deary, I.J. (Ian), Ressler, K.J. (Kerry), Dupuis, J. (Josée), Ferrucci, L. (Luigi), Ong, K.K. (Ken K.), Assimes, T.L. (Themistocles), Boerwinkle, E.A. (Eric), Koenig, W. (Wolfgang), Arnett, D.K. (Donna), Baccarelli, A.A. (Andrea), Benjamin, E.J. (Emelia), and Dehghan, A. (Abbas)

Abstract

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is as

Published
2016
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26. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Ried, J.S. (Janina), Jeff, J. (Janina), Chu, A.Y. (Audrey Y), Bragg-Gresham, J.L. (Jennifer L.), Dongen, J. (Jenny) van, Huffman, J.E. (Jennifer), Ahluwalia, T.S. (Tarunveer Singh), Cadby, G. (Gemma), Eklund, N. (Niina), Eriksson, J. (Joel), Esko, T. (Tõnu), Feitosa, M.F. (Mary Furlan), Goel, A. (Anuj), Gorski, M. (Mathias), Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Jackson, A.U. (Anne), Jokinen, E. (Eero), Kanoni, S. (Stavroula), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Luan, J. (Jian'An), Mägi, R. (Reedik), Mahajan, A. (Anubha), Mangino, M. (Massimo), Medina-Gomez, M.C. (Carolina), Monda, K.L. (Keri), Nolte, I.M. (Ilja), Perusse, L. (Louis), Prokopenko, I. (Inga), Qi, L. (Lu), Rose, L.M. (Lynda), Salvi, E. (Erika), Smith, M.T. (Megan T.), Snieder, H. (Harold), Standáková, A. (Alena), Ju Sung, Y. (Yun), Tachmazidou, I. (Ioanna), Teumer, A. (Alexander), Thorleifsson, G. (Gudmar), Harst, P. (Pim) van der, Walker, R.W. (Ryan W.), Wang, S.R. (Sophie), Wild, S.H. (Sarah), Willems, S.M. (Sara), Wong, A. (Andrew), Zhang, W. (Weihua), Albrecht, E. (Eva), Couto-Alves, A. (Alexessander), Bakker, S.J.L. (Stephan), Barlassina, C. (Cristina), Bartz, T.M. (Traci M.), Beilby, J.P. (John), Bellis, C. (Claire), Bergman, R.N. (Richard N.), Bergmann, S.M. (Sven), Blangero, J. (John), Blüher, M. (Matthias), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Bornstein, S.R. (Stefan R.), Bruinenberg, M. (M.), Campbell, H. (Harry), Chen, Y.-D.I. (Yii-Der Ida), Chiang, C.W.K. (Charleston W. K.), Chines, P.S. (Peter), Collins, F.S. (Francis), Cucca, F. (Fracensco), Cupples, L.A. (Adrienne), D'avila, F. (Francesca), Geus, E.J.C. (Eco) de, Dedoussis, G.V. (George), Dimitriou, M. (Maria), Döring, A. (Angela), Hagen, K. (Knut), Farmaki, A.-E. (Aliki-Eleni), Farrall, M. (Martin), Ferreira, T. (Teresa), Fischer, K. (Krista), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gjesing, A.P. (Anette), Glorioso, N. (Nicola), Graff, M.J. (Maud J.L.), Grallert, H. (Harald), Grarup, N. (Niels), Gräßler, J. (Jürgen), Grewal, J. (Jagvir), Hamsten, A. (Anders), Harder, M.N. (Marie Neergaard), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Havulinna, A.S. (Aki), Heliovaara, M. (Markku), Hillege, H.L. (Hans), Hofman, A. (Albert), Holmen, O.L. (Oddgeir), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Hui, J. (Jennie), Husemoen, L.L.N. (Lise Lotte), Hysi, P.G. (Pirro), Isaacs, A.J. (Aaron), Ittermann, T. (Till), Jalilzadeh, S. (Shapour), James, A. (Alan), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jula, A. (Antti), Marie Justesen, J. (Johanne), Justice, A.E. (Anne), Kähönen, M. (Mika), Karaleftheri, M. (Maria), Tee Khaw, K. (Kay), Keinanen-Kiukaanniemi, S. (Sirkka), Kinnunen, L. (Leena), Knekt, P., Koistinen, H. (Heikki), Kolcic, I. (Ivana), Kooner, I.K. (Ishminder K.), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyriakou, T. (Theodosios), Laitinen, T. (Tomi), Langenberg, C. (Claudia), Lewin, A. (Alex), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia), Lindström, J. (Jaana), Linneberg, A. (Allan), Lorbeer, R. (Roberto), Lorentzon, M. (Mattias), Luben, R.N. (Robert), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Manunta, P. (Paolo), Leach, I.M. (Irene Mateo), McArdle, W.L. (Wendy), Mcknight, B. (Barbara), Mohlke, K.L. (Karen), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Montasser, M.E. (May E.), Morris, A.P. (Andrew), Müller, G. (Gabriele), Musk, A.W. (Arthur W.), Narisu, N. (Narisu), Ong, K.K. (Ken K.), Oostra, B.A. (Ben), Osmond, C. (Clive), Palotie, A. (Aarno), Pankow, J.S. (James), Paternoster, L. (Lavinia), Penninx, B.W.J.H. (Brenda), Pichler, I. (Irene), Pilia, M.G. (Maria Grazia), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rao, D.C., Rayner, N.W. (Nigel William), Ribel-Madsen, R. (Rasmus), Rice, T.K. (Treva K.), Richards, M. (Marcus), Ridker, P.M. (Paul), Rivadeneira Ramirez, F. (Fernando), Ryan, K.A. (Kathy A.), Sanna, S. (Serena), Sarzynski, M.A. (Mark A.), Scholtens, S. (Salome), Scott, R.A. (Robert), Sebert, S. (Sylvain), Southam, L. (Lorraine), Sparsø, T. (Thomas), Steinthorsdottir, V. (Valgerdur), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Swertz, M. (Morris), Swift, A.J. (Amy), Tönjes, A. (Anke), Tsafantakis, E. (Emmanouil), Most, P.J. (Peter) van der, Vliet-Ostaptchouk, J.V. (Jana) van, Vandenput, L. (Liesbeth), Vartiainen, E. (Erkki), Venturini, C. (Cristina), Verweij, N. (Niek), Viikari, J. (Jorma), Vitart, V. (Veronique), Vohl, M.-C. (Marie-Claude), Vonk, J.M. (Judith), Waeber, G. (Gérard), Widen, E. (Elisabeth), Willemsen, G.A.H.M. (Gonneke), Wilsgaard, T. (Tom), Winkler, T.W. (Thomas W.), Wright, A.F. (Alan), Yerges-Armstrong, L.M. (Laura), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Boomsma, D.I. (Dorret), Bouchard, C. (Claude), Chambers, J.C. (John), Chasman, D.I. (Daniel), Cusi, D. (Daniele), Gansevoort, R.T. (Ron), Gieger, C. (Christian), Hansen, T. (T.), Hicks, A.A. (Andrew), Hu, F. (Frank), Hveem, K. (Kristian), Jarvelin, M.-R. (Marjo-Riitta), Kajantie, E. (Eero), Kooner, J.S. (Jaspal S.), Kuh, D. (Diana), Kuusisto, J. (Johanna), Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), Metspalu, A. (Andres), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Palmer, L.J. (Lyle J.), Pedersen, O. (Oluf), Perola, M. (Markus), Peters, A. (Annette), Psaty, B.M. (Bruce), Puolijoki, H. (Hannu), Rauramaa, R. (Rainer), Rudan, I. (Igor), Salomaa, V. (Veikko), Schwarz, P.E.H. (Peter), Shudiner, A.R. (Alan R.), Smit, J.H. (Jan), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Stumvoll, M. (Michael), Tremblay, A. (Angelo), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Völker, U. (Uwe), Vollenweider, P. (Peter), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wilson, J.F. (James), Zeggini, E. (Eleftheria), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Duijn, C.M. (Cornelia) van, Fox, C.S. (Caroline), Groop, L. (Leif), Heid, I.M. (Iris), Hunter, D.J. (David J.), Kaplan, R.C. (Robert), McCarthy, M.I. (Mark), North, K.E. (Kari), O´Connell, J.R., Schlessinger, D. (David), Thorsteinsdottir, U. (Unnur), Strachan, D.P. (David), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Müller-Nurasyid, M. (Martina), Loos, R.J.F. (Ruth), Ried, J.S. (Janina), Jeff, J. (Janina), Chu, A.Y. (Audrey Y), Bragg-Gresham, J.L. (Jennifer L.), Dongen, J. (Jenny) van, Huffman, J.E. (Jennifer), Ahluwalia, T.S. (Tarunveer Singh), Cadby, G. (Gemma), Eklund, N. (Niina), Eriksson, J. (Joel), Esko, T. (Tõnu), Feitosa, M.F. (Mary Furlan), Goel, A. (Anuj), Gorski, M. (Mathias), Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Jackson, A.U. (Anne), Jokinen, E. (Eero), Kanoni, S. (Stavroula), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Luan, J. (Jian'An), Mägi, R. (Reedik), Mahajan, A. (Anubha), Mangino, M. (Massimo), Medina-Gomez, M.C. (Carolina), Monda, K.L. (Keri), Nolte, I.M. (Ilja), Perusse, L. (Louis), Prokopenko, I. (Inga), Qi, L. (Lu), Rose, L.M. (Lynda), Salvi, E. (Erika), Smith, M.T. (Megan T.), Snieder, H. (Harold), Standáková, A. (Alena), Ju Sung, Y. (Yun), Tachmazidou, I. (Ioanna), Teumer, A. (Alexander), Thorleifsson, G. (Gudmar), Harst, P. (Pim) van der, Walker, R.W. (Ryan W.), Wang, S.R. (Sophie), Wild, S.H. (Sarah), Willems, S.M. (Sara), Wong, A. (Andrew), Zhang, W. (Weihua), Albrecht, E. (Eva), Couto-Alves, A. (Alexessander), Bakker, S.J.L. (Stephan), Barlassina, C. (Cristina), Bartz, T.M. (Traci M.), Beilby, J.P. (John), Bellis, C. (Claire), Bergman, R.N. (Richard N.), Bergmann, S.M. (Sven), Blangero, J. (John), Blüher, M. (Matthias), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Bornstein, S.R. (Stefan R.), Bruinenberg, M. (M.), Campbell, H. (Harry), Chen, Y.-D.I. (Yii-Der Ida), Chiang, C.W.K. (Charleston W. K.), Chines, P.S. (Peter), Collins, F.S. (Francis), Cucca, F. (Fracensco), Cupples, L.A. (Adrienne), D'avila, F. (Francesca), Geus, E.J.C. (Eco) de, Dedoussis, G.V. (George), Dimitriou, M. (Maria), Döring, A. (Angela), Hagen, K. (Knut), Farmaki, A.-E. (Aliki-Eleni), Farrall, M. (Martin), Ferreira, T. (Teresa), Fischer, K. (Krista), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gjesing, A.P. (Anette), Glorioso, N. (Nicola), Graff, M.J. (Maud J.L.), Grallert, H. (Harald), Grarup, N. (Niels), Gräßler, J. (Jürgen), Grewal, J. (Jagvir), Hamsten, A. (Anders), Harder, M.N. (Marie Neergaard), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Havulinna, A.S. (Aki), Heliovaara, M. (Markku), Hillege, H.L. (Hans), Hofman, A. (Albert), Holmen, O.L. (Oddgeir), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Hui, J. (Jennie), Husemoen, L.L.N. (Lise Lotte), Hysi, P.G. (Pirro), Isaacs, A.J. (Aaron), Ittermann, T. (Till), Jalilzadeh, S. (Shapour), James, A. (Alan), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jula, A. (Antti), Marie Justesen, J. (Johanne), Justice, A.E. (Anne), Kähönen, M. (Mika), Karaleftheri, M. (Maria), Tee Khaw, K. (Kay), Keinanen-Kiukaanniemi, S. (Sirkka), Kinnunen, L. (Leena), Knekt, P., Koistinen, H. (Heikki), Kolcic, I. (Ivana), Kooner, I.K. (Ishminder K.), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyriakou, T. (Theodosios), Laitinen, T. (Tomi), Langenberg, C. (Claudia), Lewin, A. (Alex), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia), Lindström, J. (Jaana), Linneberg, A. (Allan), Lorbeer, R. (Roberto), Lorentzon, M. (Mattias), Luben, R.N. (Robert), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Manunta, P. (Paolo), Leach, I.M. (Irene Mateo), McArdle, W.L. (Wendy), Mcknight, B. (Barbara), Mohlke, K.L. (Karen), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Montasser, M.E. (May E.), Morris, A.P. (Andrew), Müller, G. (Gabriele), Musk, A.W. (Arthur W.), Narisu, N. (Narisu), Ong, K.K. (Ken K.), Oostra, B.A. (Ben), Osmond, C. (Clive), Palotie, A. (Aarno), Pankow, J.S. (James), Paternoster, L. (Lavinia), Penninx, B.W.J.H. (Brenda), Pichler, I. (Irene), Pilia, M.G. (Maria Grazia), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rao, D.C., Rayner, N.W. (Nigel William), Ribel-Madsen, R. (Rasmus), Rice, T.K. (Treva K.), Richards, M. (Marcus), Ridker, P.M. (Paul), Rivadeneira Ramirez, F. (Fernando), Ryan, K.A. (Kathy A.), Sanna, S. (Serena), Sarzynski, M.A. (Mark A.), Scholtens, S. (Salome), Scott, R.A. (Robert), Sebert, S. (Sylvain), Southam, L. (Lorraine), Sparsø, T. (Thomas), Steinthorsdottir, V. (Valgerdur), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Swertz, M. (Morris), Swift, A.J. (Amy), Tönjes, A. (Anke), Tsafantakis, E. (Emmanouil), Most, P.J. (Peter) van der, Vliet-Ostaptchouk, J.V. (Jana) van, Vandenput, L. (Liesbeth), Vartiainen, E. (Erkki), Venturini, C. (Cristina), Verweij, N. (Niek), Viikari, J. (Jorma), Vitart, V. (Veronique), Vohl, M.-C. (Marie-Claude), Vonk, J.M. (Judith), Waeber, G. (Gérard), Widen, E. (Elisabeth), Willemsen, G.A.H.M. (Gonneke), Wilsgaard, T. (Tom), Winkler, T.W. (Thomas W.), Wright, A.F. (Alan), Yerges-Armstrong, L.M. (Laura), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Boomsma, D.I. (Dorret), Bouchard, C. (Claude), Chambers, J.C. (John), Chasman, D.I. (Daniel), Cusi, D. (Daniele), Gansevoort, R.T. (Ron), Gieger, C. (Christian), Hansen, T. (T.), Hicks, A.A. (Andrew), Hu, F. (Frank), Hveem, K. (Kristian), Jarvelin, M.-R. (Marjo-Riitta), Kajantie, E. (Eero), Kooner, J.S. (Jaspal S.), Kuh, D. (Diana), Kuusisto, J. (Johanna), Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), Metspalu, A. (Andres), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Palmer, L.J. (Lyle J.), Pedersen, O. (Oluf), Perola, M. (Markus), Peters, A. (Annette), Psaty, B.M. (Bruce), Puolijoki, H. (Hannu), Rauramaa, R. (Rainer), Rudan, I. (Igor), Salomaa, V. (Veikko), Schwarz, P.E.H. (Peter), Shudiner, A.R. (Alan R.), Smit, J.H. (Jan), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Stumvoll, M. (Michael), Tremblay, A. (Angelo), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Völker, U. (Uwe), Vollenweider, P. (Peter), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wilson, J.F. (James), Zeggini, E. (Eleftheria), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Duijn, C.M. (Cornelia) van, Fox, C.S. (Caroline), Groop, L. (Leif), Heid, I.M. (Iris), Hunter, D.J. (David J.), Kaplan, R.C. (Robert), McCarthy, M.I. (Mark), North, K.E. (Kari), O´Connell, J.R., Schlessinger, D. (David), Thorsteinsdottir, U. (Unnur), Strachan, D.P. (David), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Müller-Nurasyid, M. (Martina), and Loos, R.J.F. (Ruth)

Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Published
2016
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27. Association of lipid-related genetic variants with the incidence of atrial fibrillation: The AFGen consortium

Author

Norby, F.L. (Faye L.), Eryd, S.A. (Samuel Adamsson), Niemeijer, M.N. (Maartje), Rose, L.M. (Lynda), Smith, A.V. (Albert V.), Yin, X. (Xiaoyan), Agarwal, S.K. (Sunil), Arking, D.E. (Dan E.), Chasman, D.L. (Daniel L.), Chen, L.Y. (Lin Y.), Eijgelsheim, M. (Mark), Engström, G., Franco, O.H. (Oscar), Heeringa, J. (Jan), Hindy, G. (George), Hofman, A. (Albert), Lutsey, P.L. (Pamela L.), Magnani, J.W. (Jared), McManus, D.D. (David), Orho-Melander, M. (Marju), Pankow, J.S. (James S.), Rukh, G. (Gull), Schulz, C.A. (Christina Alexandra), Uitterlinden, A.G. (André), Albert, C.M. (Christine), Benjamin, E.J. (Emelia), Gudnason, V. (Vilmundur), Smith, J.G. (J Gustav), Stricker, B.H.Ch. (Bruno), Alonso, A. (Alvaro), Norby, F.L. (Faye L.), Eryd, S.A. (Samuel Adamsson), Niemeijer, M.N. (Maartje), Rose, L.M. (Lynda), Smith, A.V. (Albert V.), Yin, X. (Xiaoyan), Agarwal, S.K. (Sunil), Arking, D.E. (Dan E.), Chasman, D.L. (Daniel L.), Chen, L.Y. (Lin Y.), Eijgelsheim, M. (Mark), Engström, G., Franco, O.H. (Oscar), Heeringa, J. (Jan), Hindy, G. (George), Hofman, A. (Albert), Lutsey, P.L. (Pamela L.), Magnani, J.W. (Jared), McManus, D.D. (David), Orho-Melander, M. (Marju), Pankow, J.S. (James S.), Rukh, G. (Gull), Schulz, C.A. (Christina Alexandra), Uitterlinden, A.G. (André), Albert, C.M. (Christine), Benjamin, E.J. (Emelia), Gudnason, V. (Vilmundur), Smith, J.G. (J Gustav), Stricker, B.H.Ch. (Bruno), and Alonso, A. (Alvaro)

Abstract

Background: Several studies have shown associations between blood lipid levels and the risk of atrial fibrillation (AF). To test the potential effect of blood lipids with AF risk, we assessed whether previously developed lipid gene scores, used as instrumental variables, are associated with the incidence of AF in 7 large cohorts. Methods: We analyzed 64,901 individuals of European ancestry without previous AF at baseline and with lipid gene scores. Lipid-specific gene scores, based on loci significantly associated with lipid levels, were calculated. Additionally, non-pleiotropic gene scores for high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were calculated using SNPs that were only associated with the specific lipid fraction. Cox models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of AF per 1-standard deviation (SD) increase of each lipid gene score. Results: During a mean follow-up of 12.0 years, 5434 (8.4%) incident AF cases were identified. After meta-analysis, the HDLc, LDLc, total cholesterol, and triglyceride gene scores were not associated with incidence of AF. Multivariable-adjusted HR (95% CI) were 1.01 (0.98-1.03); 0.98 (0.96-1.01); 0.98 (0.95-1.02); 0.99 (0.97-1.02), respectively. Similarly, non-pleiotropic HDLc and LDLc gene scores showed no association with incident AF: HR (95% CI) = 1.00 (0.97-1.03); 1.01 (0.99-1.04). Conclusions In this large cohort study of individuals of European ancestry, gene scores for lipid fractions were not associated with incident AF.

Published
2016
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28. Correction: The influence of age and sex on genetic associations with adult body size and shape : a large-scale genome-wide interaction study.

Author

Winkler, T.W., Justice, A.E., Graff, M., Barata, L., Feitosa, M.F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T.O., Lu, Y., Mägi, R., Mihailov, E., Pers, T.H., Rüeger, S., Teumer, A., Ehret, G.B., Ferreira, T., Heard-Costa, N.L., Karjalainen, J., Lagou, V., Mahajan, A., Neinast, M.D., Prokopenko, I., Simino, J., Teslovich, T.M., Jansen, R., Westra, H.J., White, C.C., Absher, D., Ahluwalia, T.S., Ahmad, S., Albrecht, E., Alves, A.C., Bragg-Gresham, J.L., de Craen, A.J., Bis, J.C., Bonnefond, A., Boucher, G., Cadby, G., Cheng, Y.C., Chiang, C.W., Delgado, G., Demirkan, A., Dueker, N., Eklund, N., Eiriksdottir, G., Eriksson, J., Feenstra, B., Fischer, K., Frau, F., Galesloot, T.E., Geller, F., Goel, A., Gorski, M., Grammer, T.B., Gustafsson, S., Haitjema, S., Hottenga, J.J., Huffman, J.E., Jackson, A.U., Jacobs, K.B., Johansson, Å., Kaakinen, M., Kleber, M.E., Lahti, J., Mateo Leach, I., Lehne, B., Liu, Y., Lo, K.S., Lorentzon, M., Luan, J., Madden, P.A., Mangino, M., McKnight, B., Medina-Gomez, C., Monda, K.L., Montasser, M.E., Müller, G., Müller-Nurasyid, M., Nolte, I.M., Panoutsopoulou, K., Pascoe, L., Paternoster, L., Rayner, N.W., Renström, F., Rizzi, F., Rose, L.M., Ryan, K.A., Salo, P., Sanna, S., Scharnagl, H., Shi, J., Smith, A.V., Southam, L., Stančáková, A., Steinthorsdottir, V., Strawbridge, R.J., Sung, Y.J., Tachmazidou, I., Tanaka, T., Thorleifsson, G., Trompet, S., Pervjakova, N., Tyrer, J.P., Vandenput, L., van der Laan, S.W., van der Velde, N., van Setten, J., van Vliet-Ostaptchouk, J.V., Verweij, N., Vlachopoulou, E., Waite, L.L., Wang, S.R., Wang, Z., Wild, S.H., Willenborg, C., Wilson, J.F., Wong, A., Yang, J., Yengo, L., Yerges-Armstrong, L.M., Yu, L., Zhang, W., Zhao, J.H., Andersson, E.A., Bakker, S.J., Baldassarre, D., Banasik, K., Barcella, M., Barlassina, C., Bellis, C., Benaglio, P., Blangero, J., Blüher, M., Bonnet, F., Bonnycastle, L.L., Boyd, H.A., Bruinenberg, M., Buchman, A.S., Campbell, H., Chen, Y.I., Chines, P.S., Claudi-Boehm, S., Cole, J., Collins, F.S., de Geus, E.J., de Groot, L.C., Dimitriou, M., Duan, J., Enroth, S., Eury, E., Farmaki, A.E., Forouhi, N.G., Friedrich, N., Gejman, P.V., Gigante, B., Glorioso, N., Go, A.S., Gottesman, O., Gräßler, J., Grallert, H., Grarup, N., Gu, Y.M., Broer, L., Ham, A.C., Hansen, T., Harris, T.B., Hartman, C.A., Hassinen, M., Hastie, N., Hattersley, A.T., Heath, A.C., Henders, A.K., Hernandez, D., Hillege, H., Holmen, O., Hovingh, K.G., Hui, J., Husemoen, L.L., Hutri-Kähönen, N., Hysi, P.G., Illig, T., De Jager, P.L., Jalilzadeh, S., Jørgensen, T., Jukema, J.W., Juonala, M., Kanoni, S., Karaleftheri, M., Khaw, K.T., Kinnunen, L., Kittner, S.J., Koenig, W., Kolcic, I., Kovacs, P., Krarup, N.T., Kratzer, W., Krüger, J., Kuh, D., Kumari, M., Kyriakou, T., Langenberg, C., Lannfelt, L., Lanzani, C., Lotay, V., Launer, L.J., Leander, K., Lindström, J., Linneberg, A., Liu, Y.P., Lobbens, S., Luben, R., Lyssenko, V., Männistö, S., Magnusson, P.K., McArdle, W.L., Menni, C., Merger, S., Milani, L., Montgomery, G.W., Morris, A.P., Narisu, N., Nelis, M., Ong, K.K., Palotie, A., Pérusse, L., Pichler, I., Pilia, M.G., Pouta, A., Rheinberger, M., Ribel-Madsen, R., Richards, M., Rice, K.M., Rice, T.K., Rivolta, C., Salomaa, V., Sanders, A.R., Sarzynski, M.A., Scholtens, S., Scott, R.A., Scott, W.R., Sebert, S., Sengupta, S., Sennblad, B., Seufferlein, T., Silveira, A., Slagboom, P.E., Smit, J.H., Sparsø, T.H., Stirrups, K., Stolk, R.P., Stringham, H.M., Swertz, M.A., Swift, A.J., Syvänen, A.C., Tan, S.T., Thorand, B., Tönjes, A., Tremblay, A., Tsafantakis, E., van der Most, P.J., Völker, U., Vohl, M.C., Vonk, J.M., Waldenberger, M., Walker, R.W., Wennauer, R., Widén, E., Willemsen, G., Wilsgaard, T., Wright, A.F., Zillikens, M.C., van Dijk, S.C., van Schoor, N.M., Asselbergs, F.W., de Bakker, P.I., Beckmann, J.S., Beilby, J., Bennett, D.A., Bergman, R.N., Bergmann, S., Böger, C.A., Boehm, B.O., Boerwinkle, E., Boomsma, D.I., Bornstein, S.R., Bottinger, E.P., Bouchard, C., Chambers, J.C., Chanock, S.J., Chasman, D.I., Cucca, F., Cusi, D., Dedoussis, G., Erdmann, J., Eriksson, J.G., Evans, D.A., de Faire, U., Farrall, M., Ferrucci, L., Ford, I., Franke, L., Franks, P.W., Froguel, P., Gansevoort, R.T., Gieger, C., Grönberg, H., Gudnason, V., Gyllensten, U., Hall, P., Hamsten, A., van der Harst, P., Hayward, C., Heliövaara, M., Hengstenberg, C., Hicks, A.A., Hingorani, A., Hofman, A., Hu, F., Huikuri, H.V., Hveem, K., James, A.L., Jordan, J.M., Jula, A., Kähönen, M., Kajantie, E., Kathiresan, S., Kiemeney, L.A., Kivimaki, M., Knekt, P.B., Koistinen, H.A., Kooner, J.S., Koskinen, S., Kuusisto, J., Maerz, W., Martin, N.G., Laakso, M., Lakka, T.A., Lehtimäki, T., Lettre, G., Levinson, D.F., Lind, L., Lokki, M.L., Mäntyselkä, P., Melbye, M., Metspalu, A., Mitchell, B.D., Moll, F.L., Murray, J.C., Musk, A.W., Nieminen, M.S., Njølstad, I., Ohlsson, C., Oldehinkel, A.J., Oostra, B.A., Palmer, L.J., Pankow, J.S., Pasterkamp, G., Pedersen, N.L., Pedersen, O., Penninx, B.W., Perola, M., Peters, A., Polaek, O., Pramstaller, P.P., Psaty, B.M., Qi, L., Quertermous, T., Raitakari, O.T., Rankinen, T., Rauramaa, R., Ridker, P.M., Rioux, J.D., Rivadeneira, F., Rotter, J.I., Rudan, I., den Ruijter, H.M., Saltevo, J., Sattar, N., Schunkert, H., Schwarz, P.E., Shuldiner, A.R., Sinisalo, J., Snieder, H., Sørensen, T.I., Spector, T.D., Staessen, J.A., Stefania, B., Thorsteinsdottir, U., Stumvoll, M., Tardif, J.C., Tremoli, E., Tuomilehto, J., Uitterlinden, A.G., Uusitupa, M., Verbeek, A.L., Vermeulen, S.H., Viikari, J.S., Vitart, V., Völzke, H., Vollenweider, P., Waeber, G., Walker, M., Wallaschofski, H., Wareham, N.J., Watkins, H., Zeggini, E., arcOGEN, Consortium, CHARGE, Consortium, DIAGRAM, Consortium, GLGC, Consortium, Global-BPGen, Consortium, ICBP, Consortium, MAGIC, Consortium, Chakravarti, A., Clegg, D.J., Cupples, L.A., Gordon-Larsen, P., Jaquish, C.E., Rao, D.C., Abecasis, G.R., Assimes, T.L., Barroso, I., Berndt, S.I., Boehnke, M., Deloukas, P., Fox, C.S., Groop, L.C., Hunter, D.J., Ingelsson, E., Kaplan, R.C., McCarthy, M.I., Mohlke, K.L., O'Connell, J.R., Schlessinger, D., Strachan, D.P., Stefansson, K., van Duijn, C.M., Hirschhorn, J.N., Lindgren, C.M., Heid, I.M., North, K.E., Borecki, I.B., Kutalik, Z., Loos, R.J., Winkler, T.W., Justice, A.E., Graff, M., Barata, L., Feitosa, M.F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T.O., Lu, Y., Mägi, R., Mihailov, E., Pers, T.H., Rüeger, S., Teumer, A., Ehret, G.B., Ferreira, T., Heard-Costa, N.L., Karjalainen, J., Lagou, V., Mahajan, A., Neinast, M.D., Prokopenko, I., Simino, J., Teslovich, T.M., Jansen, R., Westra, H.J., White, C.C., Absher, D., Ahluwalia, T.S., Ahmad, S., Albrecht, E., Alves, A.C., Bragg-Gresham, J.L., de Craen, A.J., Bis, J.C., Bonnefond, A., Boucher, G., Cadby, G., Cheng, Y.C., Chiang, C.W., Delgado, G., Demirkan, A., Dueker, N., Eklund, N., Eiriksdottir, G., Eriksson, J., Feenstra, B., Fischer, K., Frau, F., Galesloot, T.E., Geller, F., Goel, A., Gorski, M., Grammer, T.B., Gustafsson, S., Haitjema, S., Hottenga, J.J., Huffman, J.E., Jackson, A.U., Jacobs, K.B., Johansson, Å., Kaakinen, M., Kleber, M.E., Lahti, J., Mateo Leach, I., Lehne, B., Liu, Y., Lo, K.S., Lorentzon, M., Luan, J., Madden, P.A., Mangino, M., McKnight, B., Medina-Gomez, C., Monda, K.L., Montasser, M.E., Müller, G., Müller-Nurasyid, M., Nolte, I.M., Panoutsopoulou, K., Pascoe, L., Paternoster, L., Rayner, N.W., Renström, F., Rizzi, F., Rose, L.M., Ryan, K.A., Salo, P., Sanna, S., Scharnagl, H., Shi, J., Smith, A.V., Southam, L., Stančáková, A., Steinthorsdottir, V., Strawbridge, R.J., Sung, Y.J., Tachmazidou, I., Tanaka, T., Thorleifsson, G., Trompet, S., Pervjakova, N., Tyrer, J.P., Vandenput, L., van der Laan, S.W., van der Velde, N., van Setten, J., van Vliet-Ostaptchouk, J.V., Verweij, N., Vlachopoulou, E., Waite, L.L., Wang, S.R., Wang, Z., Wild, S.H., Willenborg, C., Wilson, J.F., Wong, A., Yang, J., Yengo, L., Yerges-Armstrong, L.M., Yu, L., Zhang, W., Zhao, J.H., Andersson, E.A., Bakker, S.J., Baldassarre, D., Banasik, K., Barcella, M., Barlassina, C., Bellis, C., Benaglio, P., Blangero, J., Blüher, M., Bonnet, F., Bonnycastle, L.L., Boyd, H.A., Bruinenberg, M., Buchman, A.S., Campbell, H., Chen, Y.I., Chines, P.S., Claudi-Boehm, S., Cole, J., Collins, F.S., de Geus, E.J., de Groot, L.C., Dimitriou, M., Duan, J., Enroth, S., Eury, E., Farmaki, A.E., Forouhi, N.G., Friedrich, N., Gejman, P.V., Gigante, B., Glorioso, N., Go, A.S., Gottesman, O., Gräßler, J., Grallert, H., Grarup, N., Gu, Y.M., Broer, L., Ham, A.C., Hansen, T., Harris, T.B., Hartman, C.A., Hassinen, M., Hastie, N., Hattersley, A.T., Heath, A.C., Henders, A.K., Hernandez, D., Hillege, H., Holmen, O., Hovingh, K.G., Hui, J., Husemoen, L.L., Hutri-Kähönen, N., Hysi, P.G., Illig, T., De Jager, P.L., Jalilzadeh, S., Jørgensen, T., Jukema, J.W., Juonala, M., Kanoni, S., Karaleftheri, M., Khaw, K.T., Kinnunen, L., Kittner, S.J., Koenig, W., Kolcic, I., Kovacs, P., Krarup, N.T., Kratzer, W., Krüger, J., Kuh, D., Kumari, M., Kyriakou, T., Langenberg, C., Lannfelt, L., Lanzani, C., Lotay, V., Launer, L.J., Leander, K., Lindström, J., Linneberg, A., Liu, Y.P., Lobbens, S., Luben, R., Lyssenko, V., Männistö, S., Magnusson, P.K., McArdle, W.L., Menni, C., Merger, S., Milani, L., Montgomery, G.W., Morris, A.P., Narisu, N., Nelis, M., Ong, K.K., Palotie, A., Pérusse, L., Pichler, I., Pilia, M.G., Pouta, A., Rheinberger, M., Ribel-Madsen, R., Richards, M., Rice, K.M., Rice, T.K., Rivolta, C., Salomaa, V., Sanders, A.R., Sarzynski, M.A., Scholtens, S., Scott, R.A., Scott, W.R., Sebert, S., Sengupta, S., Sennblad, B., Seufferlein, T., Silveira, A., Slagboom, P.E., Smit, J.H., Sparsø, T.H., Stirrups, K., Stolk, R.P., Stringham, H.M., Swertz, M.A., Swift, A.J., Syvänen, A.C., Tan, S.T., Thorand, B., Tönjes, A., Tremblay, A., Tsafantakis, E., van der Most, P.J., Völker, U., Vohl, M.C., Vonk, J.M., Waldenberger, M., Walker, R.W., Wennauer, R., Widén, E., Willemsen, G., Wilsgaard, T., Wright, A.F., Zillikens, M.C., van Dijk, S.C., van Schoor, N.M., Asselbergs, F.W., de Bakker, P.I., Beckmann, J.S., Beilby, J., Bennett, D.A., Bergman, R.N., Bergmann, S., Böger, C.A., Boehm, B.O., Boerwinkle, E., Boomsma, D.I., Bornstein, S.R., Bottinger, E.P., Bouchard, C., Chambers, J.C., Chanock, S.J., Chasman, D.I., Cucca, F., Cusi, D., Dedoussis, G., Erdmann, J., Eriksson, J.G., Evans, D.A., de Faire, U., Farrall, M., Ferrucci, L., Ford, I., Franke, L., Franks, P.W., Froguel, P., Gansevoort, R.T., Gieger, C., Grönberg, H., Gudnason, V., Gyllensten, U., Hall, P., Hamsten, A., van der Harst, P., Hayward, C., Heliövaara, M., Hengstenberg, C., Hicks, A.A., Hingorani, A., Hofman, A., Hu, F., Huikuri, H.V., Hveem, K., James, A.L., Jordan, J.M., Jula, A., Kähönen, M., Kajantie, E., Kathiresan, S., Kiemeney, L.A., Kivimaki, M., Knekt, P.B., Koistinen, H.A., Kooner, J.S., Koskinen, S., Kuusisto, J., Maerz, W., Martin, N.G., Laakso, M., Lakka, T.A., Lehtimäki, T., Lettre, G., Levinson, D.F., Lind, L., Lokki, M.L., Mäntyselkä, P., Melbye, M., Metspalu, A., Mitchell, B.D., Moll, F.L., Murray, J.C., Musk, A.W., Nieminen, M.S., Njølstad, I., Ohlsson, C., Oldehinkel, A.J., Oostra, B.A., Palmer, L.J., Pankow, J.S., Pasterkamp, G., Pedersen, N.L., Pedersen, O., Penninx, B.W., Perola, M., Peters, A., Polaek, O., Pramstaller, P.P., Psaty, B.M., Qi, L., Quertermous, T., Raitakari, O.T., Rankinen, T., Rauramaa, R., Ridker, P.M., Rioux, J.D., Rivadeneira, F., Rotter, J.I., Rudan, I., den Ruijter, H.M., Saltevo, J., Sattar, N., Schunkert, H., Schwarz, P.E., Shuldiner, A.R., Sinisalo, J., Snieder, H., Sørensen, T.I., Spector, T.D., Staessen, J.A., Stefania, B., Thorsteinsdottir, U., Stumvoll, M., Tardif, J.C., Tremoli, E., Tuomilehto, J., Uitterlinden, A.G., Uusitupa, M., Verbeek, A.L., Vermeulen, S.H., Viikari, J.S., Vitart, V., Völzke, H., Vollenweider, P., Waeber, G., Walker, M., Wallaschofski, H., Wareham, N.J., Watkins, H., Zeggini, E., arcOGEN, Consortium, CHARGE, Consortium, DIAGRAM, Consortium, GLGC, Consortium, Global-BPGen, Consortium, ICBP, Consortium, MAGIC, Consortium, Chakravarti, A., Clegg, D.J., Cupples, L.A., Gordon-Larsen, P., Jaquish, C.E., Rao, D.C., Abecasis, G.R., Assimes, T.L., Barroso, I., Berndt, S.I., Boehnke, M., Deloukas, P., Fox, C.S., Groop, L.C., Hunter, D.J., Ingelsson, E., Kaplan, R.C., McCarthy, M.I., Mohlke, K.L., O'Connell, J.R., Schlessinger, D., Strachan, D.P., Stefansson, K., van Duijn, C.M., Hirschhorn, J.N., Lindgren, C.M., Heid, I.M., North, K.E., Borecki, I.B., Kutalik, Z., and Loos, R.J.

Abstract

This corrects the article DOI: 10.1371/journal.pgen.1005378.

Published
2016

30. Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies

Author

Nettleton, J.A., McKeown, N.M., Kanoni, S., Lemaitre, R.N., Hivert, M.F., Ngwa, J., van Rooij, F.J., Sonestedt, E., Wojczynski, M.K., Ye, Z., Tanaka, T., Garcia, M., Anderson, J.S., Follis, J.L., Djousse, L., Mukamal, K., Papoutsakis, C., Mozaffarian, D., Zillikens, M.C., Bandinelli, S., Bennett, A.J., Borecki, I.B., Feitosa, M.F., Ferrucci, L., Forouhi, N.G., Groves, C.J., Hallmans, G., Harris, T., Hofman, A., Houston, D.K., Hu, F.B., Johansson, I., Kritchevsky, S.B., Langenberg, C., Launer, L., Liu, Y., Loos, R.J., Nalls, M., Orho-Melander, M., Renstrom, F., Rice, K., Riserus, U., Rolandsson, O., Rotter, J.I., Saylor, G., Sijbrands, E.J., Sjogren, P., Smith, A., Steingrímsdóttir, L., Uitterlinden, A.G., Wareham, N.J., Prokopenko, I., Pankow, J.S., van Duijn, C.M., Florez, J.C., Witteman, J.C., Dupuis, J., Dedoussis, G.V., Ordovas, J.M., Ingelsson, E., Cupples, L., Siscovick, D.S., Franks, P.W., Meigs, J.B., MAGIC Investigators, Dupuis, J., Claudia, L., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A.U., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Lindgren, C.M., Mägi, R., Morris, A.P., Randal, J., Rybin, D., Johnson, T., Henneman, P., Gieger, C., Thorleifsson, G., Steinthorsdottir, V., Dehghan, A., Hottenga, J.J., Franklin, C.S., Navarro, P., Song, K., Goe, A., Perry, J.R., Lajunen, T., Grallert, H., Li, M., Stringham, H.M., Kumari, M., Timpson, N.J., Shrader, P., Ingelsson, E., Zabena, C., O'Connell, J., Cavalcanti-Proença, C., Luan, J., Elliott, A., McCarroll, S.A., Payne, F., Roccasecca, R.M., Sethupathy, P., Andrew, T., Ariyurek, Y., Balkau, B., Barter, P., Bennett, A.J., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, L.L., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Crawford, G.J., Crisponi, L., Day, I.N., Geus, Ed, Dina, C., Doney, A., Egan, J.M., Elliott, P., Erdos, M.R., Fischer-Rosinsky, A., Forouhi, N.G., Fox, C.S., Frants, R., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Groves, C.J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Herder, C., Hicks, A.A., Hingorani, A.D., Hofman, A., Isomaa, B., Jula, A., Kaakinen, M., Kanoni, S., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Lathrop, G.M., Lawlor, D.A., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, A.K., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Morken, M.A., Naitza, S., Narisu, N., Neville, M.J., Oostra, B.A., Orrù, M., Pakyz, R., Palmer, C.N., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Perola, M., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Psaty, B.M., Rathmann, W., Rayner, N.W., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Scott, L.J., Seedorf, U., Sharp, S.J., Shields, B., Sijbrands, E.J., Silveira, A., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tanaka, T., Tönjes, A., Tuomi, T., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Watkins, H., Weedon, M.N., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., GIANT Consortium, X., Global BPgen Consortium, X., Loos, R.J., Meneton, P., Nathan, D.M., Williams, G.H., Hattersley, A.T., Silander, K., Salomaa, V., Smith, G.D., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Dedoussis, G.V., Serrano-Ríos, M., Morris, A.D., Lind, L., Franks, P.W., Ebrahim, S., Marmot, M., Kuusisto, J., Laakso, M., Kao, W.H., Pankow, J.S., Pramstaller, P.P., Wichmann, H.E., Illig, T., Rudan, I., Wright, A., Stumvoll, M., Campbell, H., Wilson, J.F., Hamsten, A., Bergman, R.N., Buchanan, T.A., Collins, F.S., Mohlke, K.L., Tuomilehto, J., Valle, T.T., Altshuler, D., Rotter, J.I., Siscovick, D.S., Penninx, B.W., Boomsma, D., Deloukas, P., Spector, T.D., Frayling, T.M., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn, C.M., Aulchenko, Y.S., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Waterworth, D.M., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, G.R., Wareham, N.J., Sladek, R., Froguel, P., Watanabe, R.M., Meigs, J.B., Groop, L., Boehnke, M., McCarthy, M.I., Florez, J.C., and Barroso, I.

Subjects
Adult, Blood Glucose, Male, Genotype, Reviews/Commentaries/ADA Statements, Fasting, Middle Aged, Polymorphism, Single Nucleotide, White People, Genetic Loci, Humans, Insulin, Female, Aged, Blood Glucose/genetics, Blood Glucose/metabolism, Edible Grain, European Continental Ancestry Group, Fasting/blood, Genetic Loci/genetics, Genome-Wide Association Study, Insulin/blood, Insulin/genetics, Polymorphism, Single Nucleotide/genetics, Meta-Analysis
Abstract

OBJECTIVE Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value

Published
2010

31. Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein

Author

Ligthart, S. (Symen), Vries, P.S. (Paul) de, Uitterlinden, A.G. (André), Hofman, A. (Albert), Franco, O.H. (Oscar), Chasman, D.I. (Daniel), Dehghan, A. (Abbas), Dupuis, J. (Josée), Barbalic, M. (maja), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Lu, C. (Chen), Pellikka, N. (Niina), Wallaschofski, H. (Henri), Kettunen, J. (Johannes), Henneman, P. (Peter), Baumert, J. (Jens), Strachan, D.P. (David), Fuchsberger, C. (Christian), Vitart, V. (Veronique), Wilson, J.F. (James F), Paré, G. (Guillaume), Naitza, S. (Silvia), Rudock, M.E. (Megan), Surakka, I. (Ida), Geus, E.J.C. (Eco) de, Alizadeh, B.Z. (Behrooz), Guralnik, J.M. (Jack), Shuldiner, A.R. (Alan), Tanaka, T. (Toshiko), Zee, R.Y.L. (Robert), Schnabel, R.B. (Renate), Nambi, V. (Vijay), Kavousi, M. (Maryam), Ripatti, S. (Samuli), Nauck, M. (Matthias), Smith, N.L. (Nicholas L.), Smith, A.V. (Albert Vernon), Sundvall, J. (Jouko), Scheet, P. (Paul), Liu, Y. (YongMei), Ruokonen, A. (Aimo), Rose, L.M. (Lynda), Larson, M.G. (Martin), Hoogeveen, R.C. (Ron), Freimer, N.B. (Nelson), Teumer, A. (Alexander), Tracy, R.P. (Russell), Launer, L.J. (Lenore), Buring, J.E. (Julie), Yamamoto, J.F. (Jennifer), Folsom, A.R. (Aaron), Sijbrands, E.J.G. (Eric), Pankow, J.S. (James), Elliott, P. (Paul), Keaney, J.F. (John), Sun, W. (Wei), Sarin, A.-P., Fontes, M. (Michel), Badola, S. (Sunita), Astor, B.C. (Brad), Pouta, A. (Anneli), Werda, K. (Karl), Greiser, K.H. (Karin Halina), Kuss, O. (Oliver), Schwabedissen, H.E.M.Z. (Henriette E. Meyer Zu), Thiery, J. (Joachim), Jamshidi, Y. (Yalda), Nolte, I.M. (Ilja M.), Soranzo, N. (Nicole), Spector, T.D. (Timothy), Völzke, H. (Henry), Parker, A.N. (Alex), Aspelund, T. (Thor), Bates, D. (David), Young, L. (Lauren), Tsui, K. (Kim), Siscovick, D.S. (David), Guo, X. (Xiuqing), Rotter, J.I. (Jerome I.), Uda, M. (Manuela), Schlessinger, D., Rudan, I. (Igor), Hicks, A.A. (Andrew), Penninx, B.W.J.H. (Brenda), Thorand, B. (Barbara), Gieger, C. (Christian), Coresh, J. (Josef), Willemsen, G.A.H.M. (Gonneke), Harris, T.B. (Tamara), Jarvelin, M.-R. (Marjo-Riitta), Rice, K.M. (Kenneth), Radke, D. (Dörte), Salomaa, V. (Veikko), Willems van Dijk, J.A.P. (Ko), Boerwinkle, E.A. (Eric), Vasan, R.S. (Ramachandran Srini), Ferrucci, L. (Luigi), Gibson, Q. (Quince), Bandinelli, S. (Stefania), Snieder, H. (Harold), Boomsma, D.I. (Dorret), Xiao, X. (Xiangjun), Campbell, H. (Harry), Hayward, C. (Caroline), Pramstaller, P.P. (Peter Paul), Duijn, C.M. (Cornelia) van, Peltonen, L. (Leena Johanna), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Homuth, G. (Georg), Koenig, W. (Wolfgang), Ballantyne, C. (Christie), Witteman, J.C.M. (Jacqueline), Benjamin, E.J. (Emelia), Perola, M. (Markus), Chasman., D.I. (Daniel I.), Ligthart, S. (Symen), Vries, P.S. (Paul) de, Uitterlinden, A.G. (André), Hofman, A. (Albert), Franco, O.H. (Oscar), Chasman, D.I. (Daniel), Dehghan, A. (Abbas), Dupuis, J. (Josée), Barbalic, M. (maja), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Lu, C. (Chen), Pellikka, N. (Niina), Wallaschofski, H. (Henri), Kettunen, J. (Johannes), Henneman, P. (Peter), Baumert, J. (Jens), Strachan, D.P. (David), Fuchsberger, C. (Christian), Vitart, V. (Veronique), Wilson, J.F. (James F), Paré, G. (Guillaume), Naitza, S. (Silvia), Rudock, M.E. (Megan), Surakka, I. (Ida), Geus, E.J.C. (Eco) de, Alizadeh, B.Z. (Behrooz), Guralnik, J.M. (Jack), Shuldiner, A.R. (Alan), Tanaka, T. (Toshiko), Zee, R.Y.L. (Robert), Schnabel, R.B. (Renate), Nambi, V. (Vijay), Kavousi, M. (Maryam), Ripatti, S. (Samuli), Nauck, M. (Matthias), Smith, N.L. (Nicholas L.), Smith, A.V. (Albert Vernon), Sundvall, J. (Jouko), Scheet, P. (Paul), Liu, Y. (YongMei), Ruokonen, A. (Aimo), Rose, L.M. (Lynda), Larson, M.G. (Martin), Hoogeveen, R.C. (Ron), Freimer, N.B. (Nelson), Teumer, A. (Alexander), Tracy, R.P. (Russell), Launer, L.J. (Lenore), Buring, J.E. (Julie), Yamamoto, J.F. (Jennifer), Folsom, A.R. (Aaron), Sijbrands, E.J.G. (Eric), Pankow, J.S. (James), Elliott, P. (Paul), Keaney, J.F. (John), Sun, W. (Wei), Sarin, A.-P., Fontes, M. (Michel), Badola, S. (Sunita), Astor, B.C. (Brad), Pouta, A. (Anneli), Werda, K. (Karl), Greiser, K.H. (Karin Halina), Kuss, O. (Oliver), Schwabedissen, H.E.M.Z. (Henriette E. Meyer Zu), Thiery, J. (Joachim), Jamshidi, Y. (Yalda), Nolte, I.M. (Ilja M.), Soranzo, N. (Nicole), Spector, T.D. (Timothy), Völzke, H. (Henry), Parker, A.N. (Alex), Aspelund, T. (Thor), Bates, D. (David), Young, L. (Lauren), Tsui, K. (Kim), Siscovick, D.S. (David), Guo, X. (Xiuqing), Rotter, J.I. (Jerome I.), Uda, M. (Manuela), Schlessinger, D., Rudan, I. (Igor), Hicks, A.A. (Andrew), Penninx, B.W.J.H. (Brenda), Thorand, B. (Barbara), Gieger, C. (Christian), Coresh, J. (Josef), Willemsen, G.A.H.M. (Gonneke), Harris, T.B. (Tamara), Jarvelin, M.-R. (Marjo-Riitta), Rice, K.M. (Kenneth), Radke, D. (Dörte), Salomaa, V. (Veikko), Willems van Dijk, J.A.P. (Ko), Boerwinkle, E.A. (Eric), Vasan, R.S. (Ramachandran Srini), Ferrucci, L. (Luigi), Gibson, Q. (Quince), Bandinelli, S. (Stefania), Snieder, H. (Harold), Boomsma, D.I. (Dorret), Xiao, X. (Xiangjun), Campbell, H. (Harry), Hayward, C. (Caroline), Pramstaller, P.P. (Peter Paul), Duijn, C.M. (Cornelia) van, Peltonen, L. (Leena Johanna), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Homuth, G. (Georg), Koenig, W. (Wolfgang), Ballantyne, C. (Christie), Witteman, J.C.M. (Jacqueline), Benjamin, E.J. (Emelia), Perola, M. (Markus), and Chasman., D.I. (Daniel I.)

Abstract

Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.

Published
2015
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32. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, T.W. (Thomas W.), Justice, A.E. (Anne), Graff, M.J. (Maud J.L.), Barata, L. (Llilda), Feitosa, M.F. (Mary Furlan), Chu, S. (Su), Czajkowski, J. (Jacek), Esko, T. (Tõnu), Fall, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Lu, Y. (Yingchang), Mägi, R. (Reedik), Mihailov, E. (Evelin), Pers, T.H. (Tune), Rüeger, S. (Sina), Teumer, A. (Alexander), Ehret, G.B. (Georg), Ferreira, T. (Teresa), Heard-Costa, N.L. (Nancy), Karjalainen, J. (Juha), Lagou, V. (Vasiliki), Mahajan, A. (Anubha), Neinast, M.D. (Michael D.), Prokopenko, I. (Inga), Simino, J. (Jeannette), Teslovich, T.M. (Tanya M.), Jansen, R., Westra, H.J. (Harm-Jan), White, C.C. (Charles), Absher, D. (Devin), Ahluwalia, T.S. (Tarunveer Singh), Ahmad, S. (Shafqat), Albrecht, E. (Eva), Alves, A.C. (Alexessander Couto), Bragg-Gresham, J.L. (Jennifer L.), Craen, A.J. (Anton) de, Bis, J.C. (Joshua), Bonnefond, A. (Amélie), Boucher, G. (Gabrielle), Cadby, G. (Gemma), Cheng, Y.-C. (Yu-Ching), Chiang, C.W. (Charleston W K), Delgado, G., Demirkan, A. (Ayşe), Dueker, N. (Nicole), Eklund, N. (Niina), Eiriksdottir, G. (Gudny), Eriksson, J. (Joel), Feenstra, B. (Bjarke), Fischer, K. (Krista), Frau, F. (Francesca), Galesloot, T.E. (Tessel), Geller, F. (Frank), Goel, A. (Anuj), Gorski, M. (Mathias), Grammer, T.B. (Tanja), Gustafsson, S. (Stefan), Haitjema, S. (Saskia), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jackson, A.U. (Anne), Jacobs, K.B. (Kevin), Johansson, A. (Åsa), Kaakinen, M. (Marika), Kleber, M.E. (Marcus), Lahti, J. (Jari), Leach, I.M. (Irene Mateo), Lehne, B. (Benjamin), Liu, Y. (Youfang), Lo, K.S., Lorentzon, M. (Mattias), Luan, J. (Jian'An), Madden, P.A. (Pamela), Mangino, M. (Massimo), McKnight, B. (Barbara), Medina-Gomez, C. (Carolina), Monda, K.L. (Keri), Montasser, M.E. (May E.), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Panoutsopoulou, K. (Kalliope), Pascoe, L. (Laura), Paternoster, L. (Lavinia), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rizzi, F. (Federica), Rose, L.M. (Lynda), Ryan, K.A. (Kathy A.), Salo, P. (Perttu), Sanna, S. (Serena), Scharnagl, H. (Hubert), Shi, J. (Jianxin), Smith, A.V. (Albert Vernon), Southam, L. (Lorraine), Stancáková, A. (Alena), Steinthorsdottir, V. (Valgerdur), Strawbridge, R.J. (Rona), Sung, Y.J. (Yun Ju), Tachmazidou, I. (Ioanna), Tanaka, T. (Toshiko), Thorleifsson, G. (Gudmar), Trompet, S. (Stella), Pervjakova, N. (Natalia), Tyrer, J.P. (Jonathan), Vandenput, L. (Liesbeth), Van Der Laan, S.W. (Sander W.), Velde, N. (Nathalie) van der, Setten, J. (Jessica) van, Vliet-Ostaptchouk, J.V. (Jana) van, Verweij, N. (Niek), Vlachopoulou, E. (Efthymia), Waite, L. (Lindsay), Wang, S.R. (Sophie), Wang, Z. (Zhaoming), Wild, S.H. (Sarah), Willenborg, C. (Christina), Wilson, J.F. (James), Wong, A. (Andrew), Yang, J. (Jian), Yengo, L. (Loic), Yerges-Armstrong, L.M. (Laura), Yu, L. (Lei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Andersson, E.A. (Ehm Astrid), Bakker, S.J.L. (Stephan), Baldassarre, D. (Damiano), Banasik, K. (Karina), Barcella, M. (Matteo), Barlassina, C. (Cristina), Bellis, C. (Claire), Benaglio, P. (Paola), Blangero, J. (John), Blüher, M. (Matthias), Bonnet, F. (Fabrice), Bonnycastle, L.L. (Lori), Boyd, H.A. (Heather), Bruinenberg, M. (M.), Buchman, A.S. (Aron S.), Campbell, H. (Harry), Chen, Y.D. (Y.), Chines, P.S. (Peter), Claudi-Boehm, S. (Simone), Cole, J.W. (John W.), Collins, F.S. (Francis), Geus, E.J.C. (Eco) de, Groot, L.C.P.G.M. (Lisette) de, Dimitriou, M. (Maria), Duan, J. (Jubao), Enroth, S. (Stefan), Eury, E. (Elodie), Farmaki, A.-E. (Aliki-Eleni), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gejman, P.V. (Pablo), Gigante, B. (Bruna), Glorioso, N. (Nicola), Go, A.T.J.I. (Attie), Gottesman, R.F. (Rebecca), Gräßler, J. (Jürgen), Grallert, H. (Harald), Grarup, N. (Niels), Gu, Y.-M. (Yu-Mei), Broer, L. (Linda), Ham, A.C. (Annelies), Hansen, T. (T.), Harris, T.B. (Tamara), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Heath, A.C. (Andrew), Henders, A.K. (Anjali), Hernandez, D.G. (Dena), Hillege, H.L. (Hans), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Hui, J. (Jennie), Husemoen, L.L. (Lise L.), Hutri-Kähönen, N. (Nina), Hysi, P.G. (Pirro), Illig, T. (Thomas), Jager, P.L. (Philip) de, Jalilzadeh, S. (Shapour), Jorgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Juonala, M. (Markus), Kanoni, S. (Stavroula), Karaleftheri, M. (Maria), Khaw, K.T., Kinnunen, L. (Leena), Kittner, T. (Thomas), Koenig, W. (Wolfgang), Kolcic, I. (Ivana), Kovacs, P. (Peter), Krarup, N.T. (Nikolaj T.), Kratzer, W. (Wolfgang), Krüger, J. (Janine), Kuh, D. (Diana), Kumari, M. (Meena), Kyriakou, T. (Theodosios), Langenberg, C. (Claudia), Lannfelt, L. (Lars), Lanzani, C. (Chiara), Lotay, V. (Vaneet), Launer, L.J. (Lenore), Leander, K. (Karin), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y.-P. (Yan-Ping), Lobbens, S. (Stéphane), Luben, R.N. (Robert), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Magnusson, P.K. (Patrik), McArdle, W.L. (Wendy), Menni, C. (Cristina), Merger, S. (Sigrun), Milani, L. (Lili), Montgomery, G.W. (Grant W.), Morris, A.P. (Andrew), Narisu, N. (Narisu), Nelis, M. (Mari), Ong, K.K. (Ken), Palotie, A. (Aarno), Perusse, L. (Louis), Pichler, I. (Irene), Pilia, M.G. (Maria Grazia), Pouta, A. (Anneli), Rheinberger, M. (Myriam), Ribel-Madsen, R. (Rasmus), Richards, M. (Marcus), Rice, K.M. (Kenneth), Rice, T.K. (Treva K.), Rivolta, C. (Carlo), Salomaa, V. (Veikko), Sanders, A.R. (Alan), Sarzynski, M.A. (Mark A.), Scholtens, S. (Salome), Scott, R.A. (Robert), Scott, W.R. (William R.), Sebert, S. (Sylvain), Sengupta, S. (Sebanti), Sennblad, B. (Bengt), Seufferlein, T. (Thomas), Silveira, A. (Angela), Slagboom, P.E. (Eline), Smit, J.H. (Jan), Sparsø, T. (Thomas), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Stringham, H.M. (Heather), Swertz, M.A. (Morris A.), Swift, A.J. (Amy), Syvänen, A.C., Tan, S.-T. (Sian-Tsung), Thorand, B. (Barbara), Tönjes, A. (Anke), Tremblay, A. (Angelo), Tsafantakis, E. (Emmanouil), Most, P.J. (Peter) van der, Völker, U. (Uwe), Vohl, M.-C. (Marie-Claude), Vonk, J.M. (Judith), Waldenberger, M. (Melanie), Walker, R.W. (Ryan W.), Wennauer, R. (Roman), Widen, E., Willemsen, G.A.H.M. (Gonneke), Wilsgaard, T. (Tom), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Van Dijk, S. (Suzanne), Schoor, N.M. (Natasja) van, Asselbergs, F.W. (Folkert), Bakker, P.I.W. (Paul) de, Beckmann, J.S. (Jacques), Beilby, J.P. (John), Bennett, D.A. (David A.), Bergman, R.N. (Richard), Bergmann, S.M. (Sven), Böger, C.A. (Carsten), Boehm, B.O. (Bernhard), Boerwinkle, E.A. (Eric), Boomsma, D.I. (Dorret), Bornstein, S.R. (Stefan), Bottinger, E.P. (Erwin), Bouchard, C. (Claude), Chambers, J.C. (John), Chanock, S.J. (Stephen), Chasman, D.I. (Daniel), Cucca, F. (Francesco), Cusi, D. (Daniele), Dedoussis, G.V. (George), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evans, D., Faire, U. (Ulf) de, Farrall, M. (Martin), Ferrucci, L. (Luigi), Ford, I. (Ian), Franke, L. (Lude), Franks, P.W. (Paul), Froguel, P. (Philippe), Gansevoort, R.T. (Ron), Gieger, C. (Christian), Grönberg, H. (Henrik), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hall, P. (Per), Hamsten, A. (Anders), Harst, P. (Pim) van der, Hayward, C. (Caroline), Heliovaara, M. (Markku), Hengstenberg, C. (Christian), Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hofman, A. (Albert), Hu, F. (Frank), Huikuri, H.V. (Heikki), Hveem, K. (Kristian), James, A. (Alan), Jordan, J.M. (Joanne M.), Jula, A. (Antti), Kähönen, M. (Mika), Kajantie, E. (Eero), Kathiresan, S. (Sekar), Kiemeney, L.A.L.M. (Bart), Kivimaki, M. (Mika), Knekt, P., Koistinen, H. (Heikki), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kuusisto, J. (Johanna), Maerz, W. (Winfried), Martin, N.G. (Nicholas), Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), Lettre, G. (Guillaume), Levinson, D.F. (Douglas), Kao, W.H.L. (Wen), Lokki, M.L., Mäntyselkä, P. (Pekka), Melbye, M. (Mads), Metspalu, A. (Andres), Mitchell, B.D. (Braxton), Moll, F.L. (Frans), Murray, J.C. (Jeffrey), Musk, A.W. (Arthur), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), Palmer, C. (Cameron), Pankow, J.S. (James), Pasterkamp, G. (Gerard), Pedersen, N.L. (Nancy), Pedersen, O. (Oluf), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce M.), Qi, L. (Lu), Quertermous, T. (Thomas), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Rioux, J.D. (John), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Saltevo, J. (Juha), Sattar, N. (Naveed), Schunkert, H. (Heribert), Schwarz, P.E.H. (Peter), Shuldiner, A.R. (Alan), Sinisalo, J. (Juha), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Staessen, J.A. (Jan A.), Stefania, B. (Bandinelli), Thorsteinsdottir, U. (Unnur), Stumvoll, M. (Michael), Tardif, J.-C. (Jean-Claude), Tremoli, E. (Elena), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Verbeek, A.L.M., Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Vitart, V. (Veronique), Völzke, H. (Henry), Vollenweider, P. (Peter), Waeber, G. (Gérard), Walker, M. (Mark), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Zeggini, E. (Eleftheria), Chakravarti, A. (Aravinda), Clegg, D.J. (Deborah J.), Cupples, L.A. (Adrienne), Gordon-Larsen, P. (Penny), Jaquish, C.E. (Cashell), Rao, D.C. (Dabeeru C.), Abecasis, G.R. (Goncalo R.), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Berndt, S.I. (Sonja), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C.S. (Caroline), Groop, L. (Leif), Hunter, D. (David), Ingelsson, E. (Erik), Kaplan, R.C. (Robert), McCarthy, M.I. (Mark I.), Mohlke, K.L. 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Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for B

Published
2015
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33. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Wessel, J. (Jennifer), Chu, A.Y. (Audrey Y), Willems, S.M. (Sara), Wang, S. (Shuai), Yaghootkar, H. (Hanieh), Brody, J.A. (Jennifer A.), Dauriz, M. (Marco), Hivert, M.-F. (Marie-France), Raghavan, S. (Sridharan), Lipovich, L. (Leonard), Hidalgo, B. (Bertha), Fox, K. (Keolu), Huffman, J.E. (Jennifer), An, P. (Ping), Lu, Y. (Yingchang), Rasmussen-Torvik, L.J. (Laura), Grarup, N. (Niels), Ehm, M.G. (Margaret G), L. Li, Baldridge, A.S. (Abigail S), Stancáková, A. (Alena), Abrol, R. (Ravinder), Besse, C. (Céline), Boland, A. (Anne), Bork-Jensen, J. (Jette), Fornage, M. (Myriam), Freitag, C.M. (Christine), Garcia, M. (Melissa), Guo, X. (Xiuqing), Hara, K. (Kazuo), Isaacs, A. (Aaron), Jakobsdottir, M. (Margret), Lange, L.A. (Leslie), Layton, J.C. (Jill C), Li, M. (Man), Zhao, J.H. (Jing Hua), Meidtner, K. (Karina), Morrison, A.C. (Alanna), Nalls, M.A. (Michael), Peters, M.J. (Marjolein), Sabater-Lleal, M. (Maria), Schurmann, C. (Claudia), Silveira, A. (Angela), Smith, A.V. (Davey), Southam, L. (Lorraine), Stoiber, M.H. (Marcus H), Strawbridge, R.J. (Rona), Taylor, K.D. (Kent), Varga, T.V. (Tibor V.), Allin, K.H. (Kristine H), Amin, N. (Najaf), Aponte, J.L. (Jennifer L), Aung, T. (Tin), Barbieri, C. (Caterina), Bihlmeyer, N.A. (Nathan A.), Boehnke, M. (Michael), Bombieri, C. (Cristina), Bowden, D.W. (Donald), Burns, S.M. (Sean M), Chen, Y. (Yuning), Chen, Y.-D. (Yii-Deri), Cheng, C-Y. (Ching-Yu), Correa, D.D., Czajkowski, J. (Jacek), Dehghan, A. (Abbas), Ehret, G.B. (Georg), Eiriksdottir, G. (Gudny), Escher, S.A. (Stefan A), Farmaki, A.-E. (Aliki-Eleni), Frånberg, M. (Mattias), Gambaro, G. (Giovanni), Giulianini, F. (Franco), Goddard, W.A. (William A), Goel, A. (Anuj), Gottesman, R.F. (Rebecca), Grove, M.L. (Megan), Gustafsson, S. (Stefan), Hai, Y. (Yang), Hallmans, G. (Göran), Heo, J. (Jiyoung), Hoffmann, P. (Per), Ikram, M.K. (Kamran), Jensen, R.A. (Richard), Jørgensen, M.E. (Marit), Jorgensen, T. (Torben), Karaleftheri, M. (Maria), Khor, C.C., Kirkpatrick, A. (Andrea), Kraja, A. (Aldi), Kuusisto, J. (Johanna), Lange, E.M. (Ethan), Lee, I.T., Lee, W.-J. (Wen-Jane), Leong, A. (Aaron), Liao, J. (Jie), Liu, C. (Chunyu), Liu, Y. (YongMei), Lindgren, C.M. (Cecilia), Linneberg, A. (Allan), Malerba, G. (Giovanni), Mamakou, V. (Vasiliki), Marouli, E. (Eirini), Maruthur, N.M. (Nisa M), Matchan, A. (Angela), McKean-Cowdin, R. (Roberta), McLeod, O. (Olga), Metcalf, G.A. (Ginger A.), Mohlke, K.L. (Karen), Muzny, D. (Donna), Ntalla, I. (Ioanna), Palmer, N.D. (Nicholette), Pasko, D. (Dorota), Peter, A. (Andreas), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rice, K.M. (Kenneth), Sala, C. (Cinzia), Sennblad, B. (Bengt), Serafetinidis, I. (Ioannis), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Speliotes, E.K. (Elizabeth), Stahl, E.A. (Eli), Stirrups, K. (Kathy), Tentolouris, N. (Nikos), Thanopoulou, A. (Anastasia), Torres, M. (Mina), Traglia, M. (Michela), Tsafantakis, E. (Emmanouil), Javad, S. (Sundas), Yanek, L.R. (Lisa), Zengini, E. (Eleni), Becker, D.M. (Diane), Bis, J.C. (Joshua), Brown, J.B. (James B), Cupples, L.A. (Adrienne), Hansen, T. (T.), Ingelsson, E. (Erik), Karter, A.J. (Andrew J), Lorenzo, C. (Carlos), Mathias, J. (Jasmine), Norris, J.M. (Jill M), Peloso, G.M. (Gina), Sheu, W.H.-H. (Wayne H.-H.), Toniolo, D. (Daniela), Vaidya, D. (Dhananjay), Varma, R. (Rohit), Wagenknecht, L.E. (Lynne), Boeing, H. (Heiner), Bottinger, E.P. (Erwin P.), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Ferrannini, E. (Ele), Franco, O.H. (Oscar), Franks, P.W. (Paul), Gibbs, R.A. (Richard A), Gudnason, V. (Vilmundur), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), Hofman, A. (Albert), Jansson, J.-H. (Jan-Håkan), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Levy, D. (Daniel), Oostra, B.A. (Ben), O'Donnell, C.J. (Christopher J.), O'Rahilly, S. (Stephen), Padmanabhan, S. (Sandosh), Pankow, J.S. (James), Polasek, O. (Ozren), Province, M.A. (Mike), Rich, S.S. (Stephen S.), Ridker, P.M. (Paul), Rudan, I. (Igor), Schulze, M.B. (Matthias B), Smith, B.H. (Blair), Uitterlinden, A.G. (André), Walker, M. (Mark), Watkins, H. (Hugh), Wong, T.Y. (Tien Yin), Zeggini, E. (Eleftheria), Laakso, M. (Markku), Borecki, I.B. (Ingrid), Chasman, D.I. (Daniel), Pedersen, O. (Oluf), Psaty, B.M. (Bruce), Shyong Tai, E., Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Waterworth, D.M. (Dawn), Boerwinkle, E.A. (Eric), Kao, W.H.L. (Wen), Florez, J.C. (Jose), Loos, R.J.F. (Ruth), Wilson, J.G. (James), Frayling, T.M. (Timothy M.), Siscovick, D.S. (David), Dupuis, J. (Josée), Rotter, J.I. (Jerome I.), Meigs, J.B. (James), Scott, R.A. (Robert), Goodarzi, M. (Mark), Wessel, J. (Jennifer), Chu, A.Y. (Audrey Y), Willems, S.M. (Sara), Wang, S. (Shuai), Yaghootkar, H. (Hanieh), Brody, J.A. (Jennifer A.), Dauriz, M. (Marco), Hivert, M.-F. (Marie-France), Raghavan, S. (Sridharan), Lipovich, L. (Leonard), Hidalgo, B. (Bertha), Fox, K. (Keolu), Huffman, J.E. (Jennifer), An, P. (Ping), Lu, Y. (Yingchang), Rasmussen-Torvik, L.J. (Laura), Grarup, N. (Niels), Ehm, M.G. (Margaret G), L. Li, Baldridge, A.S. (Abigail S), Stancáková, A. (Alena), Abrol, R. (Ravinder), Besse, C. (Céline), Boland, A. (Anne), Bork-Jensen, J. (Jette), Fornage, M. (Myriam), Freitag, C.M. (Christine), Garcia, M. (Melissa), Guo, X. (Xiuqing), Hara, K. (Kazuo), Isaacs, A. (Aaron), Jakobsdottir, M. (Margret), Lange, L.A. (Leslie), Layton, J.C. (Jill C), Li, M. (Man), Zhao, J.H. (Jing Hua), Meidtner, K. (Karina), Morrison, A.C. (Alanna), Nalls, M.A. (Michael), Peters, M.J. (Marjolein), Sabater-Lleal, M. (Maria), Schurmann, C. (Claudia), Silveira, A. (Angela), Smith, A.V. (Davey), Southam, L. (Lorraine), Stoiber, M.H. (Marcus H), Strawbridge, R.J. (Rona), Taylor, K.D. (Kent), Varga, T.V. (Tibor V.), Allin, K.H. (Kristine H), Amin, N. (Najaf), Aponte, J.L. (Jennifer L), Aung, T. (Tin), Barbieri, C. (Caterina), Bihlmeyer, N.A. (Nathan A.), Boehnke, M. (Michael), Bombieri, C. (Cristina), Bowden, D.W. (Donald), Burns, S.M. (Sean M), Chen, Y. (Yuning), Chen, Y.-D. (Yii-Deri), Cheng, C-Y. (Ching-Yu), Correa, D.D., Czajkowski, J. (Jacek), Dehghan, A. (Abbas), Ehret, G.B. (Georg), Eiriksdottir, G. (Gudny), Escher, S.A. (Stefan A), Farmaki, A.-E. (Aliki-Eleni), Frånberg, M. (Mattias), Gambaro, G. (Giovanni), Giulianini, F. (Franco), Goddard, W.A. (William A), Goel, A. (Anuj), Gottesman, R.F. (Rebecca), Grove, M.L. (Megan), Gustafsson, S. (Stefan), Hai, Y. (Yang), Hallmans, G. (Göran), Heo, J. (Jiyoung), Hoffmann, P. (Per), Ikram, M.K. (Kamran), Jensen, R.A. (Richard), Jørgensen, M.E. (Marit), Jorgensen, T. (Torben), Karaleftheri, M. (Maria), Khor, C.C., Kirkpatrick, A. (Andrea), Kraja, A. (Aldi), Kuusisto, J. (Johanna), Lange, E.M. (Ethan), Lee, I.T., Lee, W.-J. (Wen-Jane), Leong, A. (Aaron), Liao, J. (Jie), Liu, C. (Chunyu), Liu, Y. (YongMei), Lindgren, C.M. (Cecilia), Linneberg, A. (Allan), Malerba, G. (Giovanni), Mamakou, V. (Vasiliki), Marouli, E. (Eirini), Maruthur, N.M. (Nisa M), Matchan, A. (Angela), McKean-Cowdin, R. (Roberta), McLeod, O. (Olga), Metcalf, G.A. (Ginger A.), Mohlke, K.L. (Karen), Muzny, D. (Donna), Ntalla, I. (Ioanna), Palmer, N.D. (Nicholette), Pasko, D. (Dorota), Peter, A. (Andreas), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rice, K.M. (Kenneth), Sala, C. (Cinzia), Sennblad, B. (Bengt), Serafetinidis, I. (Ioannis), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Speliotes, E.K. (Elizabeth), Stahl, E.A. (Eli), Stirrups, K. (Kathy), Tentolouris, N. (Nikos), Thanopoulou, A. (Anastasia), Torres, M. (Mina), Traglia, M. (Michela), Tsafantakis, E. (Emmanouil), Javad, S. (Sundas), Yanek, L.R. (Lisa), Zengini, E. (Eleni), Becker, D.M. (Diane), Bis, J.C. (Joshua), Brown, J.B. (James B), Cupples, L.A. (Adrienne), Hansen, T. (T.), Ingelsson, E. (Erik), Karter, A.J. (Andrew J), Lorenzo, C. (Carlos), Mathias, J. (Jasmine), Norris, J.M. (Jill M), Peloso, G.M. (Gina), Sheu, W.H.-H. (Wayne H.-H.), Toniolo, D. (Daniela), Vaidya, D. (Dhananjay), Varma, R. (Rohit), Wagenknecht, L.E. (Lynne), Boeing, H. (Heiner), Bottinger, E.P. (Erwin P.), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Ferrannini, E. (Ele), Franco, O.H. (Oscar), Franks, P.W. (Paul), Gibbs, R.A. (Richard A), Gudnason, V. (Vilmundur), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), Hofman, A. (Albert), Jansson, J.-H. (Jan-Håkan), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Levy, D. (Daniel), Oostra, B.A. (Ben), O'Donnell, C.J. (Christopher J.), O'Rahilly, S. (Stephen), Padmanabhan, S. (Sandosh), Pankow, J.S. (James), Polasek, O. (Ozren), Province, M.A. (Mike), Rich, S.S. (Stephen S.), Ridker, P.M. (Paul), Rudan, I. (Igor), Schulze, M.B. (Matthias B), Smith, B.H. (Blair), Uitterlinden, A.G. (André), Walker, M. (Mark), Watkins, H. (Hugh), Wong, T.Y. (Tien Yin), Zeggini, E. (Eleftheria), Laakso, M. (Markku), Borecki, I.B. (Ingrid), Chasman, D.I. (Daniel), Pedersen, O. (Oluf), Psaty, B.M. (Bruce), Shyong Tai, E., Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Waterworth, D.M. (Dawn), Boerwinkle, E.A. (Eric), Kao, W.H.L. (Wen), Florez, J.C. (Jose), Loos, R.J.F. (Ruth), Wilson, J.G. (James), Frayling, T.M. (Timothy M.), Siscovick, D.S. (David), Dupuis, J. (Josée), Rotter, J.I. (Jerome I.), Meigs, J.B. (James), Scott, R.A. (Robert), and Goodarzi, M. (Mark)

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2015
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34. Directional dominance on stature and cognition in diverse human populations.

Author

BioBank Japan, Project, Joshi, P.K., Esko, T., Mattsson, H., Eklund, N., Gandin, I., Nutile, T., Jackson, A.U., Schurmann, C., Smith, A.V., Zhang, W., Okada, Y., Stančáková, A., Faul, J.D., Zhao, W., Bartz, T.M., Concas, M.P., Franceschini, N., Enroth, S., Vitart, V., Trompet, S., Guo, X., Chasman, D.I., O'Connel, J.R., Corre, T., Nongmaithem, S.S., Chen, Y., Mangino, M., Ruggiero, D., Traglia, M., Farmaki, A.E., Kacprowski, T., Bjonnes, A., van der Spek, A., Wu, Y., Giri, A.K., Yanek, L.R., Wang, L., Hofer, E., Rietveld, C.A., McLeod, O., Cornelis, M.C., Pattaro, C., Verweij, N., Baumbach, C., Abdellaoui, A., Warren, H.R., Vuckovic, D., Mei, H., Bouchard, C., Perry, J.R., Cappellani, S., Mirza, S.S., Benton, M.C., Broeckel, U., Medland, S.E., Lind, P.A., Malerba, G., Drong, A., Yengo, L., Bielak, L.F., Zhi, D., van der Most, P.J., Shriner, D., Mägi, R., Hemani, G., Karaderi, T., Wang, Z., Liu, T., Demuth, I., Zhao, J.H., Meng, W., Lataniotis, L., van der Laan, S.W., Bradfield, J.P., Wood, A.R., Bonnefond, A., Ahluwalia, T.S., Hall, L.M., Salvi, E., Yazar, S., Carstensen, L., de Haan, H.G., Abney, M., Afzal, U., Allison, M.A., Amin, N., Asselbergs, F.W., Bakker, S.J., Barr, R.G., Baumeister, S.E., Benjamin, D.J., Bergmann, S., Boerwinkle, E., Bottinger, E.P., Campbell, A., Chakravarti, A., Chan, Y., Chanock, S.J., Chen, C., Chen, Y.D., Collins, F.S., Connell, J., Correa, A., Cupples, L.A., Smith, G.D., Davies, G., Dörr, M., Ehret, G., Ellis, S.B., Feenstra, B., Feitosa, M.F., Ford, I., Fox, C.S., Frayling, T.M., Friedrich, N., Geller, F., Scotland, G., Gillham-Nasenya, I., Gottesman, O., Graff, M., Grodstein, F., Gu, C., Haley, C., Hammond, C.J., Harris, S.E., Harris, T.B., Hastie, N.D., Heard-Costa, N.L., Heikkilä, K., Hocking, L.J., Homuth, G., Hottenga, J.J., Huang, J., Huffman, J.E., Hysi, P.G., Ikram, M.A., Ingelsson, E., Joensuu, A., Johansson, Å., Jousilahti, P., Jukema, J.W., Kähönen, M., Kamatani, Y., Kanoni, S., Kerr, S.M., Khan, N.M., Koellinger, P., Koistinen, H.A., Kooner, M.K., Kubo, M., Kuusisto, J., Lahti, J., Launer, L.J., Lea, R.A., Lehne, B., Lehtimäki, T., Liewald, D.C., Lind, L., Loh, M., Lokki, M.L., London, S.J., Loomis, S.J., Loukola, A., Lu, Y., Lumley, T., Lundqvist, A., Männistö, S., Marques-Vidal, P., Masciullo, C., Matchan, A., Mathias, R.A., Matsuda, K., Meigs, J.B., Meisinger, C., Meitinger, T., Menni, C., Mentch, F.D., Mihailov, E., Milani, L., Montasser, M.E., Montgomery, G.W., Morrison, A., Myers, R.H., Nadukuru, R., Navarro, P., Nelis, M., Nieminen, M.S., Nolte, I.M., O'Connor, G.T., Ogunniyi, A., Padmanabhan, S., Palmas, W.R., Pankow, J.S., Patarcic, I., Pavani, F., Peyser, P.A., Pietilainen, K., Poulter, N., Prokopenko, I., Ralhan, S., Redmond, P., Rich, S.S., Rissanen, H., Robino, A., Rose, L.M., Rose, R., Sala, C., Salako, B., Salomaa, V., Sarin, A.P., Saxena, R., Schmidt, H., Scott, L.J., Scott, W.R., Sennblad, B., Seshadri, S., Sever, P., Shrestha, S., Smith, B.H., Smith, J.A., Soranzo, N., Sotoodehnia, N., Southam, L., Stanton, A.V., Stathopoulou, M.G., Strauch, K., Strawbridge, R.J., Suderman, M.J., Tandon, N., Tang, S.T., Taylor, K.D., Tayo, B.O., Töglhofer, A.M., Tomaszewski, M., T?ernikova N., Tuomilehto, J., Uitterlinden, A.G., Vaidya, D., van Hylckama Vlieg, A., van Setten, J., Vasankari, T., Vedantam, S., Vlachopoulou, E., Vozzi, D., Vuoksimaa, E., Waldenberger, M., Ware, E.B., Wentworth-Shields, W., Whitfield, J.B., Wild, S., Willemsen, G., Yajnik, C.S., Yao, J., Zaza, G., Zhu, X., Salem, R.M., Melbye, M., Bisgaard, H., Samani, N.J., Cusi, D., Mackey, D.A., Cooper, R.S., Froguel, P., Pasterkamp, G., Grant, S.F., Hakonarson, H., Ferrucci, L., Scott, R.A., Morris, A.D., Palmer, C.N., Dedoussis, G., Deloukas, P., Bertram, L., Lindenberger, U., Berndt, S.I., Lindgren, C.M., Timpson, N.J., Tönjes, A., Munroe, P.B., Sørensen, T.I., Rotimi, C.N., Arnett, D.K., Oldehinkel, A.J., Kardia, S.L., Balkau, B., Gambaro, G., Morris, A.P., Eriksson, J.G., Wright, M.J., Martin, N.G., Hunt, S.C., Starr, J.M., Deary, I.J., Griffiths, L.R., Tiemeier, H., Pirastu, N., Kaprio, J., Wareham, N.J., Pérusse, L., Wilson, J.G., Girotto, G., Caulfield, M.J., Raitakari, O., Boomsma, D.I., Gieger, C., van der Harst, P., Hicks, A.A., Kraft, P., Sinisalo, J., Knekt, P., Johannesson, M., Magnusson, P.K., Hamsten, A., Schmidt, R., Borecki, I.B., Vartiainen, E., Becker, D.M., Bharadwaj, D., Mohlke, K.L., Boehnke, M., van Duijn, C.M., Sanghera, D.K., Teumer, A., Zeggini, E., Metspalu, A., Gasparini, P., Ulivi, S., Ober, C., Toniolo, D., Rudan, I., Porteous, D.J., Ciullo, M., Spector, T.D., Hayward, C., Dupuis, J., Loos, R.J., Wright, A.F., Chandak, G.R., Vollenweider, P., Shuldiner, A.R., Ridker, P.M., Rotter, J.I., Sattar, N., Gyllensten, U., North, K.E., Pirastu, M., Psaty, B.M., Weir, D.R., Laakso, M., Gudnason, V., Takahashi, A., Chambers, J.C., Kooner, J.S., Strachan, D.P., Campbell, H., Hirschhorn, J.N., Perola, M., Pola?ek O., Wilson, J.F., BioBank Japan, Project, Joshi, P.K., Esko, T., Mattsson, H., Eklund, N., Gandin, I., Nutile, T., Jackson, A.U., Schurmann, C., Smith, A.V., Zhang, W., Okada, Y., Stančáková, A., Faul, J.D., Zhao, W., Bartz, T.M., Concas, M.P., Franceschini, N., Enroth, S., Vitart, V., Trompet, S., Guo, X., Chasman, D.I., O'Connel, J.R., Corre, T., Nongmaithem, S.S., Chen, Y., Mangino, M., Ruggiero, D., Traglia, M., Farmaki, A.E., Kacprowski, T., Bjonnes, A., van der Spek, A., Wu, Y., Giri, A.K., Yanek, L.R., Wang, L., Hofer, E., Rietveld, C.A., McLeod, O., Cornelis, M.C., Pattaro, C., Verweij, N., Baumbach, C., Abdellaoui, A., Warren, H.R., Vuckovic, D., Mei, H., Bouchard, C., Perry, J.R., Cappellani, S., Mirza, S.S., Benton, M.C., Broeckel, U., Medland, S.E., Lind, P.A., Malerba, G., Drong, A., Yengo, L., Bielak, L.F., Zhi, D., van der Most, P.J., Shriner, D., Mägi, R., Hemani, G., Karaderi, T., Wang, Z., Liu, T., Demuth, I., Zhao, J.H., Meng, W., Lataniotis, L., van der Laan, S.W., Bradfield, J.P., Wood, A.R., Bonnefond, A., Ahluwalia, T.S., Hall, L.M., Salvi, E., Yazar, S., Carstensen, L., de Haan, H.G., Abney, M., Afzal, U., Allison, M.A., Amin, N., Asselbergs, F.W., Bakker, S.J., Barr, R.G., Baumeister, S.E., Benjamin, D.J., Bergmann, S., Boerwinkle, E., Bottinger, E.P., Campbell, A., Chakravarti, A., Chan, Y., Chanock, S.J., Chen, C., Chen, Y.D., Collins, F.S., Connell, J., Correa, A., Cupples, L.A., Smith, G.D., Davies, G., Dörr, M., Ehret, G., Ellis, S.B., Feenstra, B., Feitosa, M.F., Ford, I., Fox, C.S., Frayling, T.M., Friedrich, N., Geller, F., Scotland, G., Gillham-Nasenya, I., Gottesman, O., Graff, M., Grodstein, F., Gu, C., Haley, C., Hammond, C.J., Harris, S.E., Harris, T.B., Hastie, N.D., Heard-Costa, N.L., Heikkilä, K., Hocking, L.J., Homuth, G., Hottenga, J.J., Huang, J., Huffman, J.E., Hysi, P.G., Ikram, M.A., Ingelsson, E., Joensuu, A., Johansson, Å., Jousilahti, P., Jukema, J.W., Kähönen, M., Kamatani, Y., Kanoni, S., Kerr, S.M., Khan, N.M., Koellinger, P., Koistinen, H.A., Kooner, M.K., Kubo, M., Kuusisto, J., Lahti, J., Launer, L.J., Lea, R.A., Lehne, B., Lehtimäki, T., Liewald, D.C., Lind, L., Loh, M., Lokki, M.L., London, S.J., Loomis, S.J., Loukola, A., Lu, Y., Lumley, T., Lundqvist, A., Männistö, S., Marques-Vidal, P., Masciullo, C., Matchan, A., Mathias, R.A., Matsuda, K., Meigs, J.B., Meisinger, C., Meitinger, T., Menni, C., Mentch, F.D., Mihailov, E., Milani, L., Montasser, M.E., Montgomery, G.W., Morrison, A., Myers, R.H., Nadukuru, R., Navarro, P., Nelis, M., Nieminen, M.S., Nolte, I.M., O'Connor, G.T., Ogunniyi, A., Padmanabhan, S., Palmas, W.R., Pankow, J.S., Patarcic, I., Pavani, F., Peyser, P.A., Pietilainen, K., Poulter, N., Prokopenko, I., Ralhan, S., Redmond, P., Rich, S.S., Rissanen, H., Robino, A., Rose, L.M., Rose, R., Sala, C., Salako, B., Salomaa, V., Sarin, A.P., Saxena, R., Schmidt, H., Scott, L.J., Scott, W.R., Sennblad, B., Seshadri, S., Sever, P., Shrestha, S., Smith, B.H., Smith, J.A., Soranzo, N., Sotoodehnia, N., Southam, L., Stanton, A.V., Stathopoulou, M.G., Strauch, K., Strawbridge, R.J., Suderman, M.J., Tandon, N., Tang, S.T., Taylor, K.D., Tayo, B.O., Töglhofer, A.M., Tomaszewski, M., T?ernikova N., Tuomilehto, J., Uitterlinden, A.G., Vaidya, D., van Hylckama Vlieg, A., van Setten, J., Vasankari, T., Vedantam, S., Vlachopoulou, E., Vozzi, D., Vuoksimaa, E., Waldenberger, M., Ware, E.B., Wentworth-Shields, W., Whitfield, J.B., Wild, S., Willemsen, G., Yajnik, C.S., Yao, J., Zaza, G., Zhu, X., Salem, R.M., Melbye, M., Bisgaard, H., Samani, N.J., Cusi, D., Mackey, D.A., Cooper, R.S., Froguel, P., Pasterkamp, G., Grant, S.F., Hakonarson, H., Ferrucci, L., Scott, R.A., Morris, A.D., Palmer, C.N., Dedoussis, G., Deloukas, P., Bertram, L., Lindenberger, U., Berndt, S.I., Lindgren, C.M., Timpson, N.J., Tönjes, A., Munroe, P.B., Sørensen, T.I., Rotimi, C.N., Arnett, D.K., Oldehinkel, A.J., Kardia, S.L., Balkau, B., Gambaro, G., Morris, A.P., Eriksson, J.G., Wright, M.J., Martin, N.G., Hunt, S.C., Starr, J.M., Deary, I.J., Griffiths, L.R., Tiemeier, H., Pirastu, N., Kaprio, J., Wareham, N.J., Pérusse, L., Wilson, J.G., Girotto, G., Caulfield, M.J., Raitakari, O., Boomsma, D.I., Gieger, C., van der Harst, P., Hicks, A.A., Kraft, P., Sinisalo, J., Knekt, P., Johannesson, M., Magnusson, P.K., Hamsten, A., Schmidt, R., Borecki, I.B., Vartiainen, E., Becker, D.M., Bharadwaj, D., Mohlke, K.L., Boehnke, M., van Duijn, C.M., Sanghera, D.K., Teumer, A., Zeggini, E., Metspalu, A., Gasparini, P., Ulivi, S., Ober, C., Toniolo, D., Rudan, I., Porteous, D.J., Ciullo, M., Spector, T.D., Hayward, C., Dupuis, J., Loos, R.J., Wright, A.F., Chandak, G.R., Vollenweider, P., Shuldiner, A.R., Ridker, P.M., Rotter, J.I., Sattar, N., Gyllensten, U., North, K.E., Pirastu, M., Psaty, B.M., Weir, D.R., Laakso, M., Gudnason, V., Takahashi, A., Chambers, J.C., Kooner, J.S., Strachan, D.P., Campbell, H., Hirschhorn, J.N., Perola, M., Pola?ek O., and Wilson, J.F.

Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolu

Published
2015

35. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: A meta-analysis of 50,345 Caucasians

Author

Fretts, A.M. (Amanda M.), Follis, J.L. (Jack ), Nettleton, J.A. (Jennifer ), Lemaitre, R.N. (Rozenn ), Ngwa, J.S., Wojczynski, M.K. (Mary ), Kalafati, I.-P. (Ioanna-Panagiota), Varga, T.V. (Tibor V.), Frazier-Wood, A.C. (Alexis C.), Houston, D.K. (Denise), Lahti, J. (Jari), Ericson, U. (Ulrika), Hooven, E.H. (Edith) van den, Mikkilä, V. (Vera), Kiefte-de Jong, J.C. (Jessica), Mozaffarian, D. (Dariush), Rice, K.M. (Kenneth), Renström, F. (Frida), North, K.E. (Kari), McKeown, N.M. (Nicola ), Feitosa, M.F. (Mary Furlan), Kanoni, S. (Stavroula), Smith, C.E. (Caren), Garcia, M. (Melissa), Tiainen, A.-M. (Anna-Maija), Sonestedt, E. (Emily), Manichaikul, A. (Ani), Rooij, F.J.A. (Frank) van, Dimitriou, M. (Maria), Raitakari, O. (Olli), Pankow, J.S. (James), Djoussé, L. (Luc), Province, M.A. (Mike), Hu, F.B. (Frank), Lai, C.-Q. (Chao-Qiang), Keller, M.F. (Margaux), Perälä, M.-M. (Mia-Maria), Rotter, J.I. (Jerome I.), Hofman, A. (Albert), Graff, M.J. (Maud J.L.), Kähönen, M. (Mika), Mukamal, K. (Kenneth), Johansson, I. (Ingegerd), Ordovas, J.M. (Jose), Liu, Y. (YongMei), Männistö, S. (Satu), Uitterlinden, A.G. (André), Deloukas, P. (Panagiotis), Seppälä, I. (Ilkka), Psaty, B.M. (Bruce), Cupples, L.A. (Adrienne), Borecki, I.B. (Ingrid), Franks, P.W. (Paul W.), Arnett, D.K. (Donna), Nalls, M.A. (Michael), Hagen, K. (Knut), Orho-Melander, M. (Marju), Franco, O.H. (Oscar), Lehtimäki, T. (Terho), Dedoussis, G.V. (George), Meigs, J.B. (James), Siscovick, D.S. (David), Fretts, A.M. (Amanda M.), Follis, J.L. (Jack ), Nettleton, J.A. (Jennifer ), Lemaitre, R.N. (Rozenn ), Ngwa, J.S., Wojczynski, M.K. (Mary ), Kalafati, I.-P. (Ioanna-Panagiota), Varga, T.V. (Tibor V.), Frazier-Wood, A.C. (Alexis C.), Houston, D.K. (Denise), Lahti, J. (Jari), Ericson, U. (Ulrika), Hooven, E.H. (Edith) van den, Mikkilä, V. (Vera), Kiefte-de Jong, J.C. (Jessica), Mozaffarian, D. (Dariush), Rice, K.M. (Kenneth), Renström, F. (Frida), North, K.E. (Kari), McKeown, N.M. (Nicola ), Feitosa, M.F. (Mary Furlan), Kanoni, S. (Stavroula), Smith, C.E. (Caren), Garcia, M. (Melissa), Tiainen, A.-M. (Anna-Maija), Sonestedt, E. (Emily), Manichaikul, A. (Ani), Rooij, F.J.A. (Frank) van, Dimitriou, M. (Maria), Raitakari, O. (Olli), Pankow, J.S. (James), Djoussé, L. (Luc), Province, M.A. (Mike), Hu, F.B. (Frank), Lai, C.-Q. (Chao-Qiang), Keller, M.F. (Margaux), Perälä, M.-M. (Mia-Maria), Rotter, J.I. (Jerome I.), Hofman, A. (Albert), Graff, M.J. (Maud J.L.), Kähönen, M. (Mika), Mukamal, K. (Kenneth), Johansson, I. (Ingegerd), Ordovas, J.M. (Jose), Liu, Y. (YongMei), Männistö, S. (Satu), Uitterlinden, A.G. (André), Deloukas, P. (Panagiotis), Seppälä, I. (Ilkka), Psaty, B.M. (Bruce), Cupples, L.A. (Adrienne), Borecki, I.B. (Ingrid), Franks, P.W. (Paul W.), Arnett, D.K. (Donna), Nalls, M.A. (Michael), Hagen, K. (Knut), Orho-Melander, M. (Marju), Franco, O.H. (Oscar), Lehtimäki, T. (Terho), Dedoussis, G.V. (George), Meigs, J.B. (James), and Siscovick, D.S. (David)

Abstract

Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci k

Published
2015
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36. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, P.K. (Peter), Esko, T. (Tõnu), Mattsson, H. (Hannele), Eklund, N. (Niina), Gandin, I. (Ilaria), Nutile, T., Jackson, A.U. (Anne), Schurmann, C. (Claudia), Smith, A.V. (Davey), Zhang, W. (Weihua), Okada, Y. (Yukinori), Stancáková, A. (Alena), Faul, J.D. (Jessica D.), Zhao, W. (Wei), Bartz, T.M. (Traci M.), Concas, M.P. (Maria Pina), Franceschini, N. (Nora), Enroth, S. (Stefan), Vitart, V. (Veronique), Trompet, S. (Stella), Guo, X. (Xiuqing), Chasman, D.I. (Daniel), O'Connel, J.R. (Jeffrey R.), Corre, T. (Tanguy), Nongmaithem, S.S. (Suraj S.), Chen, Y. (Yuning), Mangino, M. (Massimo), Ruggiero, D., Traglia, M. (Michela), Farmaki, A.-E. (Aliki-Eleni), Kacprowski, T. (Tim), Bjonnes, A. (Andrew), Spek, A. (Ashley) van der, Wu, Y. (Ying), Giri, A.K. (Anil K.), Yanek, L.R. (Lisa), Wang, L. (Lihua), Hofer, E. (Edith), Rietveld, C.A. (Niels), McLeod, O. (Olga), Cornelis, M. (Marilyn), Pattaro, C. (Cristian), Verweij, N. (Niek), Baumbach, C. (Clemens), Abdellaoui, A. (Abdel), Warren, H. (Helen), Vuckovic, D. (Dragana), Mei, H. (Hao), Bouchard, C. (Claude), Perry, J.R.B. (John), Cappellani, S. (Stefania), Mirza, S.S. (Saira), Benton, M.C. (Miles C.), Broeckel, U. (Ulrich), Medland, S.E. (Sarah), Lind, P.A. (Penelope), Malerba, G. (Giovanni), Drong, A. (Alexander), Yengo, L. (Loic), Bielak, L.F. (Lawrence F.), Zhi, D. (Degui), Most, P.J. (Peter) van der, Shriner, D. (Daniel), Mägi, R. (Reedik), Hemani, G., Karaderi, T. (Tugce), Wang, Z. (Zhaoming), Liu, T. (Tian), Demuth, I. (Ilja), Zhao, J.H. (Jing Hua), Meng, W. (Weihua), Lataniotis, L. (Lazaros), Van Der Laan, S.W. (Sander W.), Bradfield, J.P. (Jonathan), Wood, A.R. (Andrew), Bonnefond, A. (Amélie), Ahluwalia, T.S. (Tarunveer Singh), Hall, L.M. (Leanne M.), Salvi, E. (Erika), Yazar, S. (Seyhan), Carstensen, L. (Lisbeth), Haan, H.G. (Hugoline) de, Abney, M. (Mark), Afzal, U. (Uzma), Allison, M.A. (Matthew), Amin, N. (Najaf), Asselbergs, F.W. (Folkert W.), Bakker, S.J.L. (Stephan), Barr, R.G. (Graham), Baumeister, S.E. (Sebastian), Benjamin, D.J. (Daniel J.), Bergmann, S. (Sven), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin P.), Campbell, A. (Archie), Chakravarti, A. (Aravinda), Chan, Y. (Yingleong), Chanock, S.J. (Stephen), Chen, C. (Constance), Chen, Y.-D.I. (Y.-D. Ida), Collins, F.S. (Francis), Connell, J. (John), Correa, A. (Adolfo), Cupples, L.A. (Adrienne), Davies, G. (Gail), Dörr, M. (Marcus), Ehret, G.B. (Georg), Ellis, S.B. (Stephen B.), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Ford, I., Fox, C.S. (Caroline), Frayling, T.M. (Timothy), Friedrich, N. (Nele), Geller, F. (Frank), Scotland, G. (Generation), Gillham-Nasenya, I. (Irina), Gottesman, R.F. (Rebecca), Graff, M.J. (Maud J.L.), Grodstein, F. (Francine), Gu, C. (Charles), Haley, C. (Chris), Hammond, C.J. (Christopher), Harris, S.E. (Sarah), Harris, T.B. (Tamara), Hastie, N. (Nick), Heard-Costa, N.L. (Nancy), Heikkilä, K. (Kauko), Hocking, L.J. (Lynne), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Huffman, J.E. (Jennifer), Hysi, P.G. (Pirro), Ikram, M.A. (Arfan), Ingelsson, E. (Erik), Joensuu, A. (Anni), Johansson, A. (Åsa), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanoni, S. (Stavroula), Kerr, S.M. (Shona), Khan, N.M. (Nazir M.), Koellinger, Ph.D. (Philipp), Koistinen, H.A. (Heikki A.), Kooner, M.K. (Manraj K.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lahti, J. (Jari), Launer, L.J. (Lenore), Lea, R.A. (Rodney A.), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Lind, L. (Lars), Loh, M. (Marie), Lokki, M.L., London, S.J. (Stephanie J.), Loomis, S.J. (Stephanie J.), Loukola, A. (Anu), Lu, Y. (Yingchang), Lumley, T. (Thomas), Lundqvist, A. (Annamari), Männistö, S. (Satu), Marques-Vidal, P. (Pedro), Masciullo, C. (Corrado), Matchan, A. (Angela), Mathias, J. (Jasmine), Matsuda, K. (Koichi), Meigs, J.B. (James), Meisinger, C. (Christa), Meitinger, T. (Thomas), Menni, C. (Cristina), Mentch, F.D. (Frank), Mihailov, E. (Evelin), Milani, L. (Lili), Montasser, M.E. (May E.), Montgomery, G.W. (Grant), Morrison, A.C. (Alanna), Myers, R.H. (Richard), Nadukuru, R. (Rajiv), Navarro, P. (Pau), Nalis, M. (Mari), Nieminen, M.S. (Markku S.), Nolte, I.M. (Ilja M.), O'Connor, G.T. (George), Ogunniyi, A. (Adesola), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Pankow, J.S. (James), Patarcic, I. (Inga), Pavani, F. (Francesca), Peyser, P.A. (Patricia A.), Pietilainen, K.H. (Kirsi Hannele), Poulter, N.R. (Neil), Prokopenko, I. (Inga), Ralhan, S. (Sarju), Redmond, P. (Paul), Rich, S.S. (Stephen S.), Rissanen, H. (Harri), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rose, R.J. (Richard J.), Sala, C. (Cinzia), Salako, B. (Babatunde), Salomaa, V. (Veikko), Sarin, A.-P., Saxena, R. (Richa), Schmidt, R. (Reinhold), Scott, L.J. (Laura), Scott, W.R. (William R.), Sennblad, B. (Bengt), Seshadri, S. (Sudha), Sever, P. (Peter), Shrestha, S. (Smeeta), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Sotoodehnia, N. (Nona), Southam, L. (Lorraine), Stanton, A. (Alice), Stathopoulou, M.G. (Maria G), Strauch, K. (Konstantin), Strawbridge, R.J. (Rona), Suderman, M.J. (Matthew J.), Tandon, N. (Nikhil), Tang, S.-T. (Sian-Tsun), Taylor, K.D. (Kent D.), Tayo, B. (Bamidele), Töglhofer, A.M. (Anna Maria), Tomaszewski, M. (Maciej), Tsernikova, N. (Natalia), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vaidya, D. (Dhananjay), Hylckama Vlieg, A. (Astrid) van, Setten, J. (Jessica) van, Vasankari, T. (Tuula), Vedantam, S. (Sailaja), Vlachopoulou, E. (Efthymia), Vozzi, D. (Diego), Vuoksimaa, E. (Eero), Waldenberger, M. (Melanie), Ware, E.B. (Erin B.), Wentworth-Shields, W. (William), Whitfield, J. (John), Wild, S. (Sarah), Willemsen, G.A.H.M. (Gonneke), Yajnik, C.S. (Chittaranjan S.), Yao, J. (Jie), Zaza, G. (Gianluigi), Zhu, X. (Xiaofeng), Salem, R.M. (Rany), Melbye, M. (Mads), Bisgaard, H. (Hans), Samani, N.J. (Nilesh), Cusi, D. (Daniele), Mackey, D.A. (David A.), Cooper, R.S. (Richard S.), Froguel, P. (Philippe), Pasterkamp, G. (Gerard), Grant, S.F.A. (Struan F.A.), Hakonarson, H. (Hakon), Ferrucci, L. (Luigi), Scott, R.A. (Robert), Morris, A.D. (Andrew), Palmer, C.N.A. (Colin), Dedoussis, G.V. (George V.), Deloukas, P. (Panagiotis), Bertram, L. (Lars), Lindenberger, U. (Ulman), Berndt, S.I. (Sonja), Lindgren, C.M. (Cecilia), Timpson, N.J. (Nicholas), Tönjes, A. (Anke), Munroe, P. (Patricia), Sørensen, T.I.A. (Thorkild I.A.), Rotimi, C. (Charles), Arnett, D.K. (Donna), Oldehinkel, A.J. (Albertine), Kardia, S.L.R. (Sharon), Balkau, B. (Beverley), Gambaro, G. (Giovanni), Morris, A.P. (Andrew), Eriksson, J.G. (Johan G.), Wright, M.J. (Margaret), Martin, N.G. (Nicholas), Hunt, S.C. (Steven), Starr, J.M. (John), Deary, I.J. (Ian), Griffiths, L.R. (Lyn R.), Tiemeier, H.W. (Henning), Pirastu, N. (Nicola), Kaprio, J. (Jaakko), Wareham, N.J. (Nick), Perusse, L. (Louis), Wilson, J.G. (James), Girotto, S., Caulfield, M. (Mark), Raitakari, O.T. (Olli T.), Boomsma, D.I. (Dorret), Gieger, C. (Christian), van der Harst, P., Hicks, A.A. (Andrew), Kraft, P. (Peter), Sinisalo, J. (Juha), Knekt, P., Johannesson, M. (Magnus), Magnusson, P.K.E. (Patrik K. E.), Hamsten, A. (Anders), Borecki, I.B. (Ingrid), Vartiainen, E. (Erkki), Becker, D.M. (Diane), Bharadwaj, D. (Dwaipayan), Mohlke, K.L. (Karen), Boehnke, M. (Michael), Duijn, C.M. (Cornelia) van, Sanghera, D.K. (Dharambir), Teumer, A. (Alexander), Zeggini, E. (Eleftheria), Metspalu, A. (Andres), Gasparini, P. (Paolo), Ulivi, S. (Shelia), Ober, C. (Carole), Toniolo, D. (Daniela), Rudan, I. (Igor), Porteous, D.J. (David J.), Ciullo, M., Spector, T.D. (Timothy), Hayward, C. (Caroline), Dupuis, J. (Josée), Loos, R.J.F. (Ruth), Wright, A. (Alan), Chandak, G.R. (Giriraj), Vollenweider, P. (Peter), Shuldiner, A.R. (Alan), Ridker, P.M. (Paul), Rotter, J.I. (Jerome I.), Sattar, N. (Naveed), Gyllensten, U. (Ulf), North, K.E. (Kari), Pirastu, M. (Mario), Psaty, B.M. (Bruce), Weir, D.R. (David), Laakso, M. (Markku), Gudnason, V. (Vilmundur), Takahashi, A. (Atsushi), Chambers, J.C. (John C.), Kooner, J.S. (Jaspal S.), Strachan, D.P. (David P.), Campbell, H. (Harry), Hirschhorn, J.N. (Joel N.), Perola, M. (Markus), Polasek, O. (Ozren), Wilson, J.F. (James), Joshi, P.K. (Peter), Esko, T. (Tõnu), Mattsson, H. (Hannele), Eklund, N. (Niina), Gandin, I. (Ilaria), Nutile, T., Jackson, A.U. (Anne), Schurmann, C. (Claudia), Smith, A.V. (Davey), Zhang, W. (Weihua), Okada, Y. (Yukinori), Stancáková, A. (Alena), Faul, J.D. (Jessica D.), Zhao, W. (Wei), Bartz, T.M. (Traci M.), Concas, M.P. (Maria Pina), Franceschini, N. (Nora), Enroth, S. (Stefan), Vitart, V. (Veronique), Trompet, S. (Stella), Guo, X. (Xiuqing), Chasman, D.I. (Daniel), O'Connel, J.R. (Jeffrey R.), Corre, T. (Tanguy), Nongmaithem, S.S. (Suraj S.), Chen, Y. (Yuning), Mangino, M. (Massimo), Ruggiero, D., Traglia, M. (Michela), Farmaki, A.-E. (Aliki-Eleni), Kacprowski, T. (Tim), Bjonnes, A. (Andrew), Spek, A. (Ashley) van der, Wu, Y. (Ying), Giri, A.K. (Anil K.), Yanek, L.R. (Lisa), Wang, L. (Lihua), Hofer, E. (Edith), Rietveld, C.A. (Niels), McLeod, O. (Olga), Cornelis, M. (Marilyn), Pattaro, C. (Cristian), Verweij, N. (Niek), Baumbach, C. (Clemens), Abdellaoui, A. (Abdel), Warren, H. (Helen), Vuckovic, D. (Dragana), Mei, H. (Hao), Bouchard, C. (Claude), Perry, J.R.B. (John), Cappellani, S. (Stefania), Mirza, S.S. (Saira), Benton, M.C. (Miles C.), Broeckel, U. (Ulrich), Medland, S.E. (Sarah), Lind, P.A. (Penelope), Malerba, G. (Giovanni), Drong, A. (Alexander), Yengo, L. (Loic), Bielak, L.F. (Lawrence F.), Zhi, D. (Degui), Most, P.J. (Peter) van der, Shriner, D. (Daniel), Mägi, R. (Reedik), Hemani, G., Karaderi, T. (Tugce), Wang, Z. (Zhaoming), Liu, T. (Tian), Demuth, I. (Ilja), Zhao, J.H. (Jing Hua), Meng, W. (Weihua), Lataniotis, L. (Lazaros), Van Der Laan, S.W. (Sander W.), Bradfield, J.P. (Jonathan), Wood, A.R. (Andrew), Bonnefond, A. (Amélie), Ahluwalia, T.S. (Tarunveer Singh), Hall, L.M. (Leanne M.), Salvi, E. (Erika), Yazar, S. (Seyhan), Carstensen, L. (Lisbeth), Haan, H.G. (Hugoline) de, Abney, M. (Mark), Afzal, U. (Uzma), Allison, M.A. (Matthew), Amin, N. (Najaf), Asselbergs, F.W. (Folkert W.), Bakker, S.J.L. (Stephan), Barr, R.G. (Graham), Baumeister, S.E. (Sebastian), Benjamin, D.J. (Daniel J.), Bergmann, S. (Sven), Boerwinkle, E.A. (Eric), Bottinger, E.P. (Erwin P.), Campbell, A. (Archie), Chakravarti, A. (Aravinda), Chan, Y. (Yingleong), Chanock, S.J. (Stephen), Chen, C. (Constance), Chen, Y.-D.I. (Y.-D. Ida), Collins, F.S. (Francis), Connell, J. (John), Correa, A. (Adolfo), Cupples, L.A. (Adrienne), Davies, G. (Gail), Dörr, M. (Marcus), Ehret, G.B. (Georg), Ellis, S.B. (Stephen B.), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Ford, I., Fox, C.S. (Caroline), Frayling, T.M. (Timothy), Friedrich, N. (Nele), Geller, F. (Frank), Scotland, G. (Generation), Gillham-Nasenya, I. (Irina), Gottesman, R.F. (Rebecca), Graff, M.J. (Maud J.L.), Grodstein, F. (Francine), Gu, C. (Charles), Haley, C. (Chris), Hammond, C.J. (Christopher), Harris, S.E. (Sarah), Harris, T.B. (Tamara), Hastie, N. (Nick), Heard-Costa, N.L. (Nancy), Heikkilä, K. (Kauko), Hocking, L.J. (Lynne), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Huffman, J.E. (Jennifer), Hysi, P.G. (Pirro), Ikram, M.A. (Arfan), Ingelsson, E. (Erik), Joensuu, A. (Anni), Johansson, A. (Åsa), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanoni, S. (Stavroula), Kerr, S.M. (Shona), Khan, N.M. (Nazir M.), Koellinger, Ph.D. (Philipp), Koistinen, H.A. (Heikki A.), Kooner, M.K. (Manraj K.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lahti, J. (Jari), Launer, L.J. (Lenore), Lea, R.A. (Rodney A.), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David), Lind, L. (Lars), Loh, M. (Marie), Lokki, M.L., London, S.J. (Stephanie J.), Loomis, S.J. (Stephanie J.), Loukola, A. (Anu), Lu, Y. (Yingchang), Lumley, T. (Thomas), Lundqvist, A. (Annamari), Männistö, S. (Satu), Marques-Vidal, P. (Pedro), Masciullo, C. (Corrado), Matchan, A. (Angela), Mathias, J. (Jasmine), Matsuda, K. (Koichi), Meigs, J.B. (James), Meisinger, C. (Christa), Meitinger, T. (Thomas), Menni, C. (Cristina), Mentch, F.D. (Frank), Mihailov, E. (Evelin), Milani, L. (Lili), Montasser, M.E. (May E.), Montgomery, G.W. (Grant), Morrison, A.C. (Alanna), Myers, R.H. (Richard), Nadukuru, R. (Rajiv), Navarro, P. (Pau), Nalis, M. (Mari), Nieminen, M.S. (Markku S.), Nolte, I.M. (Ilja M.), O'Connor, G.T. (George), Ogunniyi, A. (Adesola), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Pankow, J.S. (James), Patarcic, I. (Inga), Pavani, F. (Francesca), Peyser, P.A. (Patricia A.), Pietilainen, K.H. (Kirsi Hannele), Poulter, N.R. (Neil), Prokopenko, I. (Inga), Ralhan, S. (Sarju), Redmond, P. (Paul), Rich, S.S. (Stephen S.), Rissanen, H. (Harri), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rose, R.J. (Richard J.), Sala, C. (Cinzia), Salako, B. (Babatunde), Salomaa, V. (Veikko), Sarin, A.-P., Saxena, R. (Richa), Schmidt, R. (Reinhold), Scott, L.J. (Laura), Scott, W.R. (William R.), Sennblad, B. (Bengt), Seshadri, S. (Sudha), Sever, P. (Peter), Shrestha, S. (Smeeta), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Sotoodehnia, N. (Nona), Southam, L. (Lorraine), Stanton, A. (Alice), Stathopoulou, M.G. (Maria G), Strauch, K. (Konstantin), Strawbridge, R.J. (Rona), Suderman, M.J. (Matthew J.), Tandon, N. (Nikhil), Tang, S.-T. (Sian-Tsun), Taylor, K.D. (Kent D.), Tayo, B. (Bamidele), Töglhofer, A.M. (Anna Maria), Tomaszewski, M. (Maciej), Tsernikova, N. (Natalia), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vaidya, D. (Dhananjay), Hylckama Vlieg, A. (Astrid) van, Setten, J. (Jessica) van, Vasankari, T. (Tuula), Vedantam, S. (Sailaja), Vlachopoulou, E. (Efthymia), Vozzi, D. (Diego), Vuoksimaa, E. (Eero), Waldenberger, M. (Melanie), Ware, E.B. (Erin B.), Wentworth-Shields, W. (William), Whitfield, J. (John), Wild, S. (Sarah), Willemsen, G.A.H.M. (Gonneke), Yajnik, C.S. (Chittaranjan S.), Yao, J. (Jie), Zaza, G. (Gianluigi), Zhu, X. (Xiaofeng), Salem, R.M. (Rany), Melbye, M. (Mads), Bisgaard, H. (Hans), Samani, N.J. (Nilesh), Cusi, D. (Daniele), Mackey, D.A. (David A.), Cooper, R.S. (Richard S.), Froguel, P. (Philippe), Pasterkamp, G. (Gerard), Grant, S.F.A. (Struan F.A.), Hakonarson, H. (Hakon), Ferrucci, L. (Luigi), Scott, R.A. (Robert), Morris, A.D. (Andrew), Palmer, C.N.A. (Colin), Dedoussis, G.V. (George V.), Deloukas, P. (Panagiotis), Bertram, L. (Lars), Lindenberger, U. (Ulman), Berndt, S.I. (Sonja), Lindgren, C.M. (Cecilia), Timpson, N.J. (Nicholas), Tönjes, A. (Anke), Munroe, P. (Patricia), Sørensen, T.I.A. (Thorkild I.A.), Rotimi, C. (Charles), Arnett, D.K. (Donna), Oldehinkel, A.J. (Albertine), Kardia, S.L.R. (Sharon), Balkau, B. (Beverley), Gambaro, G. (Giovanni), Morris, A.P. (Andrew), Eriksson, J.G. (Johan G.), Wright, M.J. (Margaret), Martin, N.G. (Nicholas), Hunt, S.C. (Steven), Starr, J.M. (John), Deary, I.J. (Ian), Griffiths, L.R. (Lyn R.), Tiemeier, H.W. (Henning), Pirastu, N. (Nicola), Kaprio, J. (Jaakko), Wareham, N.J. (Nick), Perusse, L. (Louis), Wilson, J.G. (James), Girotto, S., Caulfield, M. (Mark), Raitakari, O.T. (Olli T.), Boomsma, D.I. (Dorret), Gieger, C. (Christian), van der Harst, P., Hicks, A.A. (Andrew), Kraft, P. (Peter), Sinisalo, J. (Juha), Knekt, P., Johannesson, M. (Magnus), Magnusson, P.K.E. (Patrik K. E.), Hamsten, A. (Anders), Borecki, I.B. (Ingrid), Vartiainen, E. (Erkki), Becker, D.M. (Diane), Bharadwaj, D. (Dwaipayan), Mohlke, K.L. (Karen), Boehnke, M. (Michael), Duijn, C.M. (Cornelia) van, Sanghera, D.K. (Dharambir), Teumer, A. (Alexander), Zeggini, E. (Eleftheria), Metspalu, A. (Andres), Gasparini, P. (Paolo), Ulivi, S. (Shelia), Ober, C. (Carole), Toniolo, D. (Daniela), Rudan, I. (Igor), Porteous, D.J. (David J.), Ciullo, M., Spector, T.D. (Timothy), Hayward, C. (Caroline), Dupuis, J. (Josée), Loos, R.J.F. (Ruth), Wright, A. (Alan), Chandak, G.R. (Giriraj), Vollenweider, P. (Peter), Shuldiner, A.R. (Alan), Ridker, P.M. (Paul), Rotter, J.I. (Jerome I.), Sattar, N. (Naveed), Gyllensten, U. (Ulf), North, K.E. (Kari), Pirastu, M. (Mario), Psaty, B.M. (Bruce), Weir, D.R. (David), Laakso, M. (Markku), Gudnason, V. (Vilmundur), Takahashi, A. (Atsushi), Chambers, J.C. (John C.), Kooner, J.S. (Jaspal S.), Strachan, D.P. (David P.), Campbell, H. (Harry), Hirschhorn, J.N. (Joel N.), Perola, M. (Markus), Polasek, O. (Ozren), and Wilson, J.F. (James)

Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10-300, 2.1 × 10-6, 2.5 × 10-10 and 1.8 × 10-10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been p

Published
2015
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37. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author

Gaulton, K. (Kyle), Ferreira, T. (Teresa), Lee, Y. (Yeji), Raimondo, A. (Anne), Mägi, R. (Reedik), Reschen, M.E. (Michael E.), Mahajan, A. (Anubha), Locke, A. (Adam), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Scott, R.A. (Robert), Prokopenko, I. (Inga), Scott, L.J. (Laura), Green, T. (Todd), Sparsø, T. (Thomas), Thuillier, D. (Dorothee), Yengo, L. (Loic), Grallert, H. (Harald), Wahl, S. (Simone), Frånberg, M. (Mattias), Strawbridge, R.J. (Rona), Kestler, H. (Hans), Chheda, H. (Himanshu), Eisele, L. (Lewin), Gustafsson, S. (Stefan), Steinthorsdottir, V. (Valgerdur), Thorleifsson, G. (Gudmar), Qi, L. (Lu), Karssen, L.C. (Lennart), Leeuwen, E.M. (Elisa) van, Willems, S.M. (Sara), Li, M. (Man), Chen, H. (Han), Fuchsberger, C. (Christian), Kwan, P. (Phoenix), Ma, C. (Clement), Linderman, M. (Michael), Lu, Y. (Yingchang), Thomsen, S.K. (Soren K.), Rundle, J.K. (Jana K.), Beer, N.L. (Nicola L.), Bunt, M. (Martijn) van de, Chalisey, A. (Anil), Kang, H.M. (Hyun Min), Voight, B.F. (Benjamin), Abecasis, G.R. (Gonçalo), Almgren, P. (Peter), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Blüher, M. (Matthias), Boeing, H. (Heiner), Bonnycastle, L.L. (Lori), Bottinger, E.P. (Erwin P.), Burtt, N.P. (Noël), Carey, J. (Jason), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David J.), Crenshaw, A. (Andrew), Dam, R.M. (Rob) van, Doney, A.S.F. (Alex), Dorkhan, M. (Mozhgan), Edkins, T. (Ted), Eriksson, J.G. (Johan G.), Esko, T. (Tõnu), Eury, E. (Elodie), Fadista, J. (João), Flannick, J. (Jason), Fontanillas, P. (Pierre), Fox, C.S. (Caroline), Franks, P.W. (Paul W.), Gertow, K. (Karl), Gieger, C. (Christian), Gigante, B. (Bruna), Gottesman, R.F. (Rebecca), Grant, G.B. (George), Grarup, N. (Niels), Groves, C.J. (Christopher J.), Hassinen, M. (Maija), Have, C.T. (Christian T.), Herder, C. (Christian), Holmen, O.L. (Oddgeir), Hreidarsson, A.B. (Astradur), Humphries, S.E. (Steve E.), Hunter, D.J. (David J.), Jackson, A.U. (Anne), Jonsson, A. (Anna), Jørgensen, M.E. (Marit E.), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Kerrison, N.D. (Nicola D.), Kinnunen, L. (Leena), Klopp, N. (Norman), Kong, A. (Augustine), Kovacs, P. (Peter), Kraft, P. (Peter), Kravic, J. (Jasmina), Langford, C. (Cordelia), Leander, K. (Karin), Liang, L. (Liming), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia M.), Lindholm, B. (Bengt), Linneberg, A. (Allan), Liu, C.-T. (Ching-Ti), Lobbens, S. (Stéphane), Luan, J. (Jian'fan), Lyssenko, V. (Valeriya), Männistö, S. (Satu), McLeod, O. (Olga), Meyer, J. (Jobst), Mihailov, E. (Evelin), Mirza, G. (Ghazala), Mühleisen, T.W. (Thomas), Müller-Nurasyid, M. (Martina), Navarro, C. (Carmen), Nöthen, M.M. (Markus), Oskolkov, N.N. (Nikolay N.), Owen, K.R. (Katharine), Palli, D. (Domenico), Pechlivanis, S. (Sonali), Peltonen, L. (Leena Johanna), Perry, J.R.B. (John), Platou, C.P. (Carl), Roden, M. (Michael), Ruderfer, D. (Douglas), Rybin, D. (Denis), Van Der Schouw, Y.T. (Yvonne T.), Sennblad, B. (Bengt), Sigurosson, G. (Gunnar), Stancáková, A. (Alena), Steinbach, D., Storm, P. (Petter), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Sun, Q., Thorand, B. (Barbara), Tikkanen, E. (Emmi), Tönjes, A. (Anke), Trakalo, J. (Joseph), Tremoli, E. (Elena), Tuomi, T. (Tiinamaija), Wennauer, R. (Roman), Wiltshire, S. (Steven), Wood, A.R. (Andrew), Zeggini, E. (Eleftheria), Dunham, I. (Ian), Birney, E. (Ewan), Pasquali, L. (Lorenzo), Ferrer, J. (Jorge), Loos, R.J.F. (Ruth), Dupuis, J. (Josée), Florez, J.C. (Jose), Boerwinkle, E.A. (Eric), Pankow, J.S. (James), Duijn, C.M. (Cornelia) van, Sijbrands, E.J.G. (Eric), Meigs, J.B. (James B.), Hu, F.B. (Frank), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Lakka, T.A. (Timo), Rauramaa, R. (Rainer), Stumvoll, M. (Michael), Pedersen, N.L. (Nancy L.), Lind, L. (Lars), Keinanen-Kiukaanniemi, S. (Sirkka), Korpi-Hyövälti, E. (Eeva), Saaristo, T. (Timo), Saltevo, J. (Juha), Kuusisto, J. (Johanna), Laakso, M. (Markku), Metspalu, A. (Andres), Erbel, R. (Raimund), Jöckel, K.-H. (Karl-Heinz), Moebus, S. (Susanne), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Ingelsson, E. (Erik), Boehm, B.O. (Bernhard), Bergman, R.N. (Richard N.), Collins, F.S. (Francis S.), Mohlke, K.L. (Karen L.), Koistinen, H. (Heikki), Tuomilehto, J. (Jaakko), Hveem, K. (Kristian), Njølstad, I. (Inger), Deloukas, P. (Panagiotis), Donnelly, P.J. (Peter J.), Frayling, T.M. (Timothy), Hattersley, A.T. (Andrew), Faire, U. (Ulf) de, Hamsten, A. (Anders), Illig, T. (Thomas), Peters, A. (Annette), Cauchi, S. (Stephane), Sladek, R. (Rob), Froguel, P. (Philippe), Hansen, T. (Torben), Pedersen, O. (Oluf), Morris, A.D. (Andrew), Palmer, C.N.A. (Collin N. A.), Kathiresan, S. (Sekar), Melander, O. (Olle), Nilsson, P.M. (Peter M.), Groop, L. (Leif), Barroso, I.E. (Inês), Langenberg, C. (Claudia), Wareham, N.J. (Nicholas J.), O'Callaghan, C.A. (Christopher A.), Gloyn, A.L. (Anna), Altshuler, D. (David), Boehnke, M. (Michael), Teslovich, T.M. (Tanya M.), McCarthy, M.I. (Mark), Morris, A.P. (Andrew), Gaulton, K. (Kyle), Ferreira, T. (Teresa), Lee, Y. (Yeji), Raimondo, A. (Anne), Mägi, R. (Reedik), Reschen, M.E. (Michael E.), Mahajan, A. (Anubha), Locke, A. (Adam), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Scott, R.A. (Robert), Prokopenko, I. (Inga), Scott, L.J. (Laura), Green, T. (Todd), Sparsø, T. (Thomas), Thuillier, D. (Dorothee), Yengo, L. (Loic), Grallert, H. (Harald), Wahl, S. (Simone), Frånberg, M. (Mattias), Strawbridge, R.J. (Rona), Kestler, H. (Hans), Chheda, H. (Himanshu), Eisele, L. (Lewin), Gustafsson, S. (Stefan), Steinthorsdottir, V. (Valgerdur), Thorleifsson, G. (Gudmar), Qi, L. (Lu), Karssen, L.C. (Lennart), Leeuwen, E.M. (Elisa) van, Willems, S.M. (Sara), Li, M. (Man), Chen, H. (Han), Fuchsberger, C. (Christian), Kwan, P. (Phoenix), Ma, C. (Clement), Linderman, M. (Michael), Lu, Y. (Yingchang), Thomsen, S.K. (Soren K.), Rundle, J.K. (Jana K.), Beer, N.L. (Nicola L.), Bunt, M. (Martijn) van de, Chalisey, A. (Anil), Kang, H.M. (Hyun Min), Voight, B.F. (Benjamin), Abecasis, G.R. (Gonçalo), Almgren, P. (Peter), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Blüher, M. (Matthias), Boeing, H. (Heiner), Bonnycastle, L.L. (Lori), Bottinger, E.P. (Erwin P.), Burtt, N.P. (Noël), Carey, J. (Jason), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David J.), Crenshaw, A. (Andrew), Dam, R.M. (Rob) van, Doney, A.S.F. (Alex), Dorkhan, M. (Mozhgan), Edkins, T. (Ted), Eriksson, J.G. (Johan G.), Esko, T. (Tõnu), Eury, E. (Elodie), Fadista, J. (João), Flannick, J. (Jason), Fontanillas, P. (Pierre), Fox, C.S. (Caroline), Franks, P.W. (Paul W.), Gertow, K. (Karl), Gieger, C. (Christian), Gigante, B. (Bruna), Gottesman, R.F. (Rebecca), Grant, G.B. (George), Grarup, N. (Niels), Groves, C.J. (Christopher J.), Hassinen, M. (Maija), Have, C.T. (Christian T.), Herder, C. (Christian), Holmen, O.L. (Oddgeir), Hreidarsson, A.B. (Astradur), Humphries, S.E. (Steve E.), Hunter, D.J. (David J.), Jackson, A.U. (Anne), Jonsson, A. (Anna), Jørgensen, M.E. (Marit E.), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Kerrison, N.D. (Nicola D.), Kinnunen, L. (Leena), Klopp, N. (Norman), Kong, A. (Augustine), Kovacs, P. (Peter), Kraft, P. (Peter), Kravic, J. (Jasmina), Langford, C. (Cordelia), Leander, K. (Karin), Liang, L. (Liming), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia M.), Lindholm, B. (Bengt), Linneberg, A. (Allan), Liu, C.-T. (Ching-Ti), Lobbens, S. (Stéphane), Luan, J. (Jian'fan), Lyssenko, V. (Valeriya), Männistö, S. (Satu), McLeod, O. (Olga), Meyer, J. (Jobst), Mihailov, E. (Evelin), Mirza, G. (Ghazala), Mühleisen, T.W. (Thomas), Müller-Nurasyid, M. (Martina), Navarro, C. (Carmen), Nöthen, M.M. (Markus), Oskolkov, N.N. (Nikolay N.), Owen, K.R. (Katharine), Palli, D. (Domenico), Pechlivanis, S. (Sonali), Peltonen, L. (Leena Johanna), Perry, J.R.B. (John), Platou, C.P. (Carl), Roden, M. (Michael), Ruderfer, D. (Douglas), Rybin, D. (Denis), Van Der Schouw, Y.T. (Yvonne T.), Sennblad, B. (Bengt), Sigurosson, G. (Gunnar), Stancáková, A. (Alena), Steinbach, D., Storm, P. (Petter), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Sun, Q., Thorand, B. (Barbara), Tikkanen, E. (Emmi), Tönjes, A. (Anke), Trakalo, J. (Joseph), Tremoli, E. (Elena), Tuomi, T. (Tiinamaija), Wennauer, R. (Roman), Wiltshire, S. (Steven), Wood, A.R. (Andrew), Zeggini, E. (Eleftheria), Dunham, I. (Ian), Birney, E. (Ewan), Pasquali, L. (Lorenzo), Ferrer, J. (Jorge), Loos, R.J.F. (Ruth), Dupuis, J. (Josée), Florez, J.C. (Jose), Boerwinkle, E.A. (Eric), Pankow, J.S. (James), Duijn, C.M. (Cornelia) van, Sijbrands, E.J.G. (Eric), Meigs, J.B. (James B.), Hu, F.B. (Frank), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Lakka, T.A. (Timo), Rauramaa, R. (Rainer), Stumvoll, M. (Michael), Pedersen, N.L. (Nancy L.), Lind, L. (Lars), Keinanen-Kiukaanniemi, S. (Sirkka), Korpi-Hyövälti, E. (Eeva), Saaristo, T. (Timo), Saltevo, J. (Juha), Kuusisto, J. (Johanna), Laakso, M. (Markku), Metspalu, A. (Andres), Erbel, R. (Raimund), Jöckel, K.-H. (Karl-Heinz), Moebus, S. (Susanne), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Ingelsson, E. (Erik), Boehm, B.O. (Bernhard), Bergman, R.N. (Richard N.), Collins, F.S. (Francis S.), Mohlke, K.L. (Karen L.), Koistinen, H. (Heikki), Tuomilehto, J. (Jaakko), Hveem, K. (Kristian), Njølstad, I. (Inger), Deloukas, P. (Panagiotis), Donnelly, P.J. (Peter J.), Frayling, T.M. (Timothy), Hattersley, A.T. (Andrew), Faire, U. (Ulf) de, Hamsten, A. (Anders), Illig, T. (Thomas), Peters, A. (Annette), Cauchi, S. (Stephane), Sladek, R. (Rob), Froguel, P. (Philippe), Hansen, T. (Torben), Pedersen, O. (Oluf), Morris, A.D. (Andrew), Palmer, C.N.A. (Collin N. A.), Kathiresan, S. (Sekar), Melander, O. (Olle), Nilsson, P.M. (Peter M.), Groop, L. (Leif), Barroso, I.E. (Inês), Langenberg, C. (Claudia), Wareham, N.J. (Nicholas J.), O'Callaghan, C.A. (Christopher A.), Gloyn, A.L. (Anna), Altshuler, D. (David), Boehnke, M. (Michael), Teslovich, T.M. (Tanya M.), McCarthy, M.I. (Mark), and Morris, A.P. (Andrew)

Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Published
2015
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38. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J. Dupuis, J. Prokopenko, I. Barker, A. Ahlqvist, E. Rybin, D. Petrie, J.R. Travers, M.E. Bouatia-Naji, N. Dimas, A.S. Nica, A.C. Wheeler, E. Chen, H. Voight, B.F. Taneera, J. Kanoni, S. Peden, J.F. Turrini, F. Gustafsson, S. Zabena, C. Almgren, P. Barker, D.J.P. Barnes, D. Dennison, E.M. Eriksson, J.G. Eriksson, P. Eury, E. Folkersen, L. Fox, C.S. Frayling, T.M. Goel, A. Gu, H.F. Horikoshi, M. Isomaa, B. Jackson, A.U. Jameson, K.A. Kajantie, E. Kerr-Conte, J. Kuulasmaa, T. Kuusisto, J. Loos, R.J.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. Dina, C. Welch, R.P. Zeggini, E. Huth, C. Aulchenko, Y.S. Thorleifsson, G. Mcculloch, L.J. Ferreira, T. Grallert, H. Amin, N. Wu, G. Willer, C.J. Raychaudhuri, S. McCarroll, S.A. Hofmann, O.M. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. Bergman, R.N. Cauchi, S. Collins, F.S. Gloyn, A.L. Gyllensten, U. Hansen, T. Hide, W.A. Hitman, G.A. Hofman, A. Hunter, D.J. Hveem, K. Laakso, M. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. Barroso, I. Groop, L. Sladek, R. Thorsteinsdottir, U. Wilson, J.F. Illig, T. Froguel, P. Van Duijn, C.M. Stefansson, K. Altshuler, D. Boehnke, M. McCarthy, M.I. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

Published
2011

39. Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor : The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium

Author

Smith, N.L., Chen, M.H., Dehghan, A., Strachan, D.P., Basu, S., Soranzo, N., Hayward, C., Rudan, Igor, Sabater-Lleal, M., Bis, J.C., de Maat, M.P., Rumley, A., Kong, X., Yang, Q., Williams, F.M., Vitart, V., Campbell, H., Mälarstig, A., Wiggins, K.L., van Duijn, C.M., McArdle, W.L., Pankow, J.S., Johnson, A.D., Silveira, A., McKnight, B., Uitterlinden, A.G., Wellcome Trust Case Control Consortium, Aleksić, N., Meigs, J.B., Peters, A., Koenig, W., Cushman, M., Kathiresan, S., Rotter, J.I., Bovill, E.G., Hofman, A., Boerwinkle, E., Tofler, G.H., Peden, J.F., Psaty, B.M., Leebeek, F., Folsom, A.R., Larson, M.G., Spector, T.D., Wright, A.F., Wilson, J.F., Hamsten, A., Lumley, T., Witteman, J.C., Tang, W., and O'Donnell, C.J.

Subjects
hemic and lymphatic diseases, genome-wide association study, plasma levels, Factor VII, Factor VIII, von Willebrand Factor, genetic loci
Abstract

Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (

Published
2010

40. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Author

Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), Keating, J. (John), Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), and Keating, J. (John)

Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10-7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

Published
2014
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41. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Author

Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), Li, M. (Mingyao), Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), and Li, M. (Mingyao)

Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121-], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Published
2014
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42. Pleiotropic genes for metabolic syndrome and inflammation

Author

Kraja, A. (Aldi), Chasman, D.I. (Daniel), North, K.E. (Kari), Reiner, A. (Alexander), Yanek, L.R. (Lisa), Kilpeläinen, T.O. (Tuomas), Smith, J.A. (Jennifer), Dehghan, A. (Abbas), Dupuis, J. (Josée), Johnson, A.D. (Andrew), Feitosa, M.F. (Mary Furlan), Tekola-Ayele, F. (Fasil), Chu, A.Y. (Audrey), Nolte, I.M. (Ilja), Dastani, Z. (Zari), Morris, A.P. (Andrew), Pendergrass, S.A. (Sarah), Sun, Y.V. (Yan), Ritchie, M.D. (Marylyn), Vaez, A. (Ahmad), Lin, H. (Honghuang), Ligthart, S. (Symen), Marullo, L. (Letizia), Rohde, R. (Rebecca), Shao, Y. (Yaming), Ziegler, M.A. (Mark), Im, K.M. (Kate), Schnabel, R.B. (Renate), Jorgensen, T. (Torben), Jørgensen, M.E. (Marit), Hansen, T. (T.), Pedersen, O. (Oluf), Stolk, R.P. (Ronald), Snieder, H. (Harold), Hofman, A. (Albert), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Ikram, M.A. (Arfan), Richards, J.B. (Brent), Rotimi, C. (Charles), Wilson, J.G. (James), Lange, L.A. (Leslie), Ganesh, S.K. (Santhi), Nalls, M.A. (Michael), Rasmussen-Torvik, L.J. (Laura), Pankow, J.S. (James), Coresh, J. (Josef), Tang, W. (Weihong), Kao, W.-H.L. (Linda), Boerwinkle, E.A. (Eric), Morrison, A.C. (Alanna), Ridker, P.M. (Paul), Becker, D.M. (Diane), Rotter, J.I. (Jerome), Kardia, S.L.R. (Sharon), Loos, R.J.F. (Ruth), Larson, M.G. (Martin), Hsu, Y.-H. (Yi-Hsiang), Province, M.A. (Mike), Tracy, R.P. (Russell), Voight, B.F. (Benjamin), Vaidya, D. (Dhananjay), O'Donnell, C.J. (Christopher), Benjamin, E.J. (Emelia), Alizadeh, B.Z. (Behrooz), Prokopenko, I. (Inga), Meigs, J.B. (James), Borecki, I.B. (Ingrid), Kraja, A. (Aldi), Chasman, D.I. (Daniel), North, K.E. (Kari), Reiner, A. (Alexander), Yanek, L.R. (Lisa), Kilpeläinen, T.O. (Tuomas), Smith, J.A. (Jennifer), Dehghan, A. (Abbas), Dupuis, J. (Josée), Johnson, A.D. (Andrew), Feitosa, M.F. (Mary Furlan), Tekola-Ayele, F. (Fasil), Chu, A.Y. (Audrey), Nolte, I.M. (Ilja), Dastani, Z. (Zari), Morris, A.P. (Andrew), Pendergrass, S.A. (Sarah), Sun, Y.V. (Yan), Ritchie, M.D. (Marylyn), Vaez, A. (Ahmad), Lin, H. (Honghuang), Ligthart, S. (Symen), Marullo, L. (Letizia), Rohde, R. (Rebecca), Shao, Y. (Yaming), Ziegler, M.A. (Mark), Im, K.M. (Kate), Schnabel, R.B. (Renate), Jorgensen, T. (Torben), Jørgensen, M.E. (Marit), Hansen, T. (T.), Pedersen, O. (Oluf), Stolk, R.P. (Ronald), Snieder, H. (Harold), Hofman, A. (Albert), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Ikram, M.A. (Arfan), Richards, J.B. (Brent), Rotimi, C. (Charles), Wilson, J.G. (James), Lange, L.A. (Leslie), Ganesh, S.K. (Santhi), Nalls, M.A. (Michael), Rasmussen-Torvik, L.J. (Laura), Pankow, J.S. (James), Coresh, J. (Josef), Tang, W. (Weihong), Kao, W.-H.L. (Linda), Boerwinkle, E.A. (Eric), Morrison, A.C. (Alanna), Ridker, P.M. (Paul), Becker, D.M. (Diane), Rotter, J.I. (Jerome), Kardia, S.L.R. (Sharon), Loos, R.J.F. (Ruth), Larson, M.G. (Martin), Hsu, Y.-H. (Yi-Hsiang), Province, M.A. (Mike), Tracy, R.P. (Russell), Voight, B.F. (Benjamin), Vaidya, D. (Dhananjay), O'Donnell, C.J. (Christopher), Benjamin, E.J. (Emelia), Alizadeh, B.Z. (Behrooz), Prokopenko, I. (Inga), Meigs, J.B. (James), and Borecki, I.B. (Ingrid)

Abstract

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up

Published
2014
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43. Genetic diversity is a predictor of mortality in humans

Author

Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Davey), Lunetta, K.L. (Kathryn), Nalls, M.A. (Michael), Smith, J.A. (Jennifer A), Tanaka, T. (Toshiko), Davies, G. (Gail), Yu, L. (Lei), Mirza, S.S. (Saira), Teumer, A. (Alexander), Coresh, J. (Josef), Pankow, J.S. (James), Franceschini, N. (Nora), Scaria, A. (Anish), Oshima, J. (Junko), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Li, H. (Hanyue), Karasik, D. (David), Kiel, D.P. (Douglas P.), Garcia, M. (Melissa), Liu, Y. (YongMei), Faul, J.D. (Jessica D.), Kardia, S.L. (Sharon L.r), Zhao, W. (Wei), Ferrucci, L. (Luigi), Allerhand, M.M. (Michael), Liewald, D.C.M. (David), Redmond, P. (Paul), Starr, J.M. (John), Jager, P.L. (Philip) de, Evans, D.A. (Denis), Direk, N. (Nese), Ikram, M.A. (Arfan), Uitterlinden, A.G. (André), Homuth, G. (Georg), Lorbeer, R. (Roberto), Grabe, H.J. (Hans Jörgen), Launer, L.J. (Lenore), Murabito, J. (Joanne), Singleton, A. (Andrew), Weir, D.R. (David), Bandinelli, S. (Stefania), Deary, I.J. (Ian), Bennett, D.A. (David A.), Tiemeier, H.W. (Henning), Kocher, T. (Thomas), Lumley, T. (Thomas), Arking, D.E. (Dan), Bihlmeyer, N.A. (Nathan A.), Brody, J.A. (Jennifer A.), Smith, A.V. (Davey), Lunetta, K.L. (Kathryn), Nalls, M.A. (Michael), Smith, J.A. (Jennifer A), Tanaka, T. (Toshiko), Davies, G. (Gail), Yu, L. (Lei), Mirza, S.S. (Saira), Teumer, A. (Alexander), Coresh, J. (Josef), Pankow, J.S. (James), Franceschini, N. (Nora), Scaria, A. (Anish), Oshima, J. (Junko), Psaty, B.M. (Bruce), Gudnason, V. (Vilmundur), Eiriksdottir, G. (Gudny), Harris, T.B. (Tamara), Li, H. (Hanyue), Karasik, D. (David), Kiel, D.P. (Douglas P.), Garcia, M. (Melissa), Liu, Y. (YongMei), Faul, J.D. (Jessica D.), Kardia, S.L. (Sharon L.r), Zhao, W. (Wei), Ferrucci, L. (Luigi), Allerhand, M.M. (Michael), Liewald, D.C.M. (David), Redmond, P. (Paul), Starr, J.M. (John), Jager, P.L. (Philip) de, Evans, D.A. (Denis), Direk, N. (Nese), Ikram, M.A. (Arfan), Uitterlinden, A.G. (André), Homuth, G. (Georg), Lorbeer, R. (Roberto), Grabe, H.J. (Hans Jörgen), Launer, L.J. (Lenore), Murabito, J. (Joanne), Singleton, A. (Andrew), Weir, D.R. (David), Bandinelli, S. (Stefania), Deary, I.J. (Ian), Bennett, D.A. (David A.), Tiemeier, H.W. (Henning), Kocher, T. (Thomas), Lumley, T. (Thomas), and Arking, D.E. (Dan)

Abstract

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic

Published
2014
Full Text
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44. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, P.K., Esko, T., Mattsson, H., Eklund, N., Gandin, I., Nutile, T., Jackson, A.U., Schurmann, C., Smith, A.V., Zhang, W., Okada, Y., Stančáková, A., Faul, J.D., Zhao, W., Bartz, T.M., Concas, M.P., Franceschini, N., Enroth, S., Vitart, V., Trompet, S., Guo, X., Chasman, D.I., O'Connel, J.R., Corre, T., Nongmaithem, S.S., Chen, Y., Mangino, M., Ruggiero, D., Traglia, M., Farmaki, A.E., Kacprowski, T., Bjonnes, A., van der Spek, A., Wu, Y., Giri, A.K., Yanek, L.R., Wang, L., Hofer, E., Rietveld, C.A., McLeod, O., Cornelis, M.C., Pattaro, C., Verweij, N., Baumbach, C., Abdellaoui, A., Warren, H.R., Vuckovic, D., Mei, H., Bouchard, C., Perry, J.R., Cappellani, S., Mirza, S.S., Benton, M.C., Broeckel, U., Medland, S.E., Lind, P.A., Malerba, G., Drong, A., Yengo, L., Bielak, L.F., Zhi, D., van der Most, P.J., Shriner, D., Mägi, R., Hemani, G., Karaderi, T., Wang, Z., Liu, T., Demuth, I., Zhao, J.H., Meng, W., Lataniotis, L., van der Laan, S.W., Bradfield, J.P., Wood, A.R., Bonnefond, A., Ahluwalia, T.S., Hall, L.M., Salvi, E., Yazar, S., Carstensen, L., de Haan, H.G., Abney, M., Afzal, U., Allison, M.A., Amin, N., Asselbergs, F.W., Bakker, S.J., Barr, R.G., Baumeister, S.E., Benjamin, D.J., Bergmann, S., Boerwinkle, E., Bottinger, E.P., Campbell, A., Chakravarti, A., Chan, Y., Chanock, S.J., Chen, C., Chen, Y.D., Collins, F.S., Connell, J., Correa, A., Cupples, L.A., Smith, G.D., Davies, G., Dörr, M., Ehret, G., Ellis, S.B., Feenstra, B., Feitosa, M.F., Ford, I., Fox, C.S., Frayling, T.M., Friedrich, N., Geller, F., Scotland, G., Gillham-Nasenya, I., Gottesman, O., Graff, M., Grodstein, F., Gu, C., Haley, C., Hammond, C.J., Harris, S.E., Harris, T.B., Hastie, N.D., Heard-Costa, N.L., Heikkilä, K., Hocking, L.J., Homuth, G., Hottenga, J.J., Huang, J., Huffman, J.E., Hysi, P.G., Ikram, M.A., Ingelsson, E., Joensuu, A., Johansson, Å., Jousilahti, P., Jukema, J.W., Kähönen, M., Kamatani, Y., Kanoni, S., Kerr, S.M., Khan, N.M., Koellinger, P., Koistinen, H.A., Kooner, M.K., Kubo, M., Kuusisto, J., Lahti, J., Launer, L.J., Lea, R.A., Lehne, B., Lehtimäki, T., Liewald, D.C., Lind, L., Loh, M., Lokki, M.L., London, S.J., Loomis, S.J., Loukola, A., Lu, Y., Lumley, T., Lundqvist, A., Männistö, S., Marques-Vidal, P., Masciullo, C., Matchan, A., Mathias, R.A., Matsuda, K., Meigs, J.B., Meisinger, C., Meitinger, T., Menni, C., Mentch, F.D., Mihailov, E., Milani, L., Montasser, M.E., Montgomery, G.W., Morrison, A., Myers, R.H., Nadukuru, R., Navarro, P., Nelis, M., Nieminen, M.S., Nolte, I.M., O'Connor, G.T., Ogunniyi, A., Padmanabhan, S., Palmas, W.R., Pankow, J.S., Patarcic, I., Pavani, F., Peyser, P.A., Pietilainen, K., Poulter, N., Prokopenko, I., Ralhan, S., Redmond, P., Rich, S.S., Rissanen, H., Robino, A., Rose, L.M., Rose, R., Sala, C., Salako, B., Salomaa, V., Sarin, A.P., Saxena, R., Schmidt, H., Scott, L.J., Scott, W.R., Sennblad, B., Seshadri, S., Sever, P., Shrestha, S., Smith, B.H., Smith, J.A., Soranzo, N., Sotoodehnia, N., Southam, L., Stanton, A.V., Stathopoulou, M.G., Strauch, K., Strawbridge, R.J., Suderman, M.J., Tandon, N., Tang, S.T., Taylor, K.D., Tayo, B.O., Töglhofer, A.M., Tomaszewski, M., T?ernikova N., Tuomilehto, J., Uitterlinden, A.G., Vaidya, D., van Hylckama Vlieg, A., van Setten, J., Vasankari, T., Vedantam, S., Vlachopoulou, E., Vozzi, D., Vuoksimaa, E., Waldenberger, M., Ware, E.B., Wentworth-Shields, W., Whitfield, J.B., Wild, S., Willemsen, G., Yajnik, C.S., Yao, J., Zaza, G., Zhu, X., BioBank Japan, Project, Salem, R.M., Melbye, M., Bisgaard, H., Samani, N.J., Cusi, D., Mackey, D.A., Cooper, R.S., Froguel, P., Pasterkamp, G., Grant, S.F., Hakonarson, H., Ferrucci, L., Scott, R.A., Morris, A.D., Palmer, C.N., Dedoussis, G., Deloukas, P., Bertram, L., Lindenberger, U., Berndt, S.I., Lindgren, C.M., Timpson, N.J., Tönjes, A., Munroe, P.B., Sørensen, T.I., Rotimi, C.N., Arnett, D.K., Oldehinkel, A.J., Kardia, S.L., Balkau, B., Gambaro, G., Morris, A.P., Eriksson, J.G., Wright, M.J., Martin, N.G., Hunt, S.C., Starr, J.M., Deary, I.J., Griffiths, L.R., Tiemeier, H., Pirastu, N., Kaprio, J., Wareham, N.J., Pérusse, L., Wilson, J.G., Girotto, G., Caulfield, M.J., Raitakari, O., Boomsma, D.I., Gieger, C., van der Harst, P., Hicks, A.A., Kraft, P., Sinisalo, J., Knekt, P., Johannesson, M., Magnusson, P.K., Hamsten, A., Schmidt, R., Borecki, I.B., Vartiainen, E., Becker, D.M., Bharadwaj, D., Mohlke, K.L., Boehnke, M., van Duijn, C.M., Sanghera, D.K., Teumer, A., Zeggini, E., Metspalu, A., Gasparini, P., Ulivi, S., Ober, C., Toniolo, D., Rudan, I., Porteous, D.J., Ciullo, M., Spector, T.D., Hayward, C., Dupuis, J., Loos, R.J., Wright, A.F., Chandak, G.R., Vollenweider, P., Shuldiner, A.R., Ridker, P.M., Rotter, J.I., Sattar, N., Gyllensten, U., North, K.E., Pirastu, M., Psaty, B.M., Weir, D.R., Laakso, M., Gudnason, V., Takahashi, A., Chambers, J.C., Kooner, J.S., Strachan, D.P., Campbell, H., Hirschhorn, J.N., Perola, M., Pola?ek O., Wilson, J.F., Immunology, Medical Microbiology & Infectious Diseases, Erasmus MC other, Medical Informatics, Epidemiology, Pathology, Public Health, Ophthalmology, Internal Medicine, Cardiology, Child and Adolescent Psychiatry / Psychology, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Joshi, Peter K, Esko, Tonu, Mattsson, Hannele, Eklund, Niina, Gandin, Ilaria, Nutile, Teresa, Jackson, Anne U., Schurmann, Claudia, Smith, Albert V., Zhang, Weihua, Okada, Yukinori, Stančáková, Alena, Faul, Jessica D., Zhao, Wei, Bartz, Traci M., Concas, MARIA PINA, Franceschini, Nora, Enroth, Stefan, Vitart, Veronique, Trompet, Stella, Guo, Xiuqing, Chasman, Daniel I., O'Connel, Jeffrey R., Corre, Tanguy, Nongmaithem, Suraj S., Chen, Yuning, Mangino, Massimo, Ruggiero, Daniela, Traglia, Michela, Farmaki, Aliki Eleni, Kacprowski, Tim, Bjonnes, Andrew, Van Der Spek, Ashley, Wu, Ying, Giri, Anil K., Yanek, Lisa R., Wang, Lihua, Hofer, Edith, Rietveld, Cornelius A., Mcleod, Olga, Cornelis, Marilyn C., Pattaro, Cristian, Verweij, Niek, Baumbach, Clemen, Abdellaoui, Abdel, Warren, Helen R., Vuckovic, Dragana, Mei, Hao, Bouchard, Claude, Perry, John R. B., Cappellani, Stefania, Mirza, Saira S., Benton, Miles C., Broeckel, Ulrich, Medland, Sarah E., Lind, Penelope A., Malerba, Giovanni, Drong, Alexander, Yengo, Loic, Bielak, Lawrence F., Zhi, Degui, Van Der Most, Peter J., Shriner, Daniel, Mägi, Reedik, Hemani, Gibran, Karaderi, Tugce, Wang, Zhaoming, Liu, Tian, Demuth, Ilja, Zhao, Jing Hua, Meng, Weihua, Lataniotis, Lazaro, Van Der Laan, Sander W., Bradfield, Jonathan P., Wood, Andrew R., Bonnefond, Amelie, Ahluwalia, Tarunveer S., Hall, Leanne M., Salvi, Erika, Yazar, Seyhan, Carstensen, Lisbeth, De Haan, Hugoline G., Abney, Mark, Afzal, Uzma, Allison, Matthew A., Amin, Najaf, Asselbergs, Folkert W., Bakker, Stephan J. L., Barr, R. Graham, Baumeister, Sebastian E., Benjamin, Daniel J., Bergmann, Sven, Boerwinkle, Eric, Bottinger, Erwin P., Campbell, Archie, Chakravarti, Aravinda, Chan, Yingleong, Chanock, Stephen J., Chen, Constance, Chen, Y. D. Ida, Collins, Francis S., Connell, John, Correa, Adolfo, Cupples, L. Adrienne, Smith, George Davey, Davies, Gail, Dörr, Marcu, Ehret, Georg, Ellis, Stephen B., Feenstra, Bjarke, Feitosa, Mary F., Ford, Ian, Fox, Caroline S., Frayling, Timothy M., Friedrich, Nele, Geller, Frank, Scotland, Generation, Gillham Nasenya, Irina, Gottesman, Omri, Graff, Misa, Grodstein, Francine, Gu, Charle, Haley, Chri, Hammond, Christopher J., Harris, Sarah E., Harris, Tamara B., Hastie, Nicholas D., Heard Costa, Nancy L., Heikkilä, Kauko, Hocking, Lynne J., Homuth, Georg, Hottenga, Jouke Jan, Huang, Jinyan, Huffman, Jennifer E., Hysi, Pirro G., Ikram, M. Arfan, Ingelsson, Erik, Joensuu, Anni, Johansson, Åsa, Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kanoni, Stavroula, Kerr, Shona M., Khan, Nazir M., Koellinger, Philipp, Koistinen, Heikki A., Kooner, Manraj K., Kubo, Michiaki, Kuusisto, Johanna, Lahti, Jari, Launer, Lenore J., Lea, Rodney A., Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C. M., Lind, Lar, Loh, Marie, Lokki, Marja Liisa, London, Stephanie J., Loomis, Stephanie J., Loukola, Anu, Lu, Yingchang, Lumley, Thoma, Lundqvist, Annamari, Männistö, Satu, Marques Vidal, Pedro, Masciullo, Corrado, Matchan, Angela, Mathias, Rasika A., Matsuda, Koichi, Meigs, James B., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Mentch, Frank D., Mihailov, Evelin, Milani, Lili, Montasser, May E., Montgomery, Grant W., Morrison, Alanna, Myers, Richard H., Nadukuru, Rajiv, Navarro, Pau, Nalis, Mari, Nieminen, Markku S., Nolte, Ilja M., O'Connor, George T., Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Pankow, James S., Patarcic, Inga, Pavani, Francesca, Peyser, Patricia A., Pietilainen, Kirsi, Poulter, Neil, Prokopenko, Inga, Ralhan, Sarju, Redmond, Paul, Rich, Stephen S., Rissanen, Harri, Robino, Antonietta, Rose, Lynda M., Rose, Richard, Sala, Cinzia, Salako, Babatunde, Salomaa, Veikko, Sarin, Antti Pekka, Saxena, Richa, Schmidt, Helena, Scott, Laura J., Scott, William R., Sennblad, Bengt, Seshadri, Sudha, Sever, Peter, Shrestha, Smeeta, Smith, Blair H., Smith, Jennifer A., Soranzo, Nicole, Sotoodehnia, Nona, Southam, Lorraine, Stanton, Alice V., Stathopoulou, Maria G., Strauch, Konstantin, Strawbridge, Rona J., Suderman, Matthew J., Tandon, Nikhil, Tang, Sian Tsun, Taylor, Kent D., Tayo, Bamidele O., Töglhofer, Anna Maria, Tomaszewski, Maciej, Tšernikova, Natalia, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vaidya, Dhananjay, Van Hylckama Vlieg, Astrid, Van Setten, Jessica, Vasankari, Tuula, Vedantam, Sailaja, Vlachopoulou, Efthymia, Vozzi, Diego, Vuoksimaa, Eero, Waldenberger, Melanie, Ware, Erin B., Wentworth Shields, William, Whitfield, John B., Wild, Sarah, Willemsen, Gonneke, Yajnik, Chittaranjan S., Yao, Jie, Zaza, Gianluigi, Zhu, Xiaofeng, Salem, Rany M., Melbye, Mad, Bisgaard, Han, Samani, Nilesh J., Cusi, Daniele, Mackey, David A., Cooper, Richard S., Froguel, Philippe, Pasterkamp, Gerard, Grant, Struan F. A., Hakonarson, Hakon, Ferrucci, Luigi, Scott, Robert A., Morris, Andrew D., Palmer, Colin N. A., Dedoussis, George, Deloukas, Pano, Bertram, Lar, Lindenberger, Ulman, Berndt, Sonja I., Lindgren, Cecilia M., Timpson, Nicholas J., Tönjes, Anke, Munroe, Patricia B., Sørensen, Thorkild I. A., Rotimi, Charles N., Arnett, Donna K., Oldehinkel, Albertine J., Kardia, Sharon L. R., Balkau, Beverley, Gambaro, Giovanni, Morris, Andrew P., Eriksson, Johan G., Wright, Margie J., Martin, Nicholas G., Hunt, Steven C., Starr, John M., Deary, Ian J., Griffiths, Lyn R., Tiemeier, Henning, Pirastu, Nicola, Kaprio, Jaakko, Wareham, Nicholas J., Pérusse, Loui, Wilson, James G., Girotto, Giorgia, Caulfield, Mark J., Raitakari, Olli, Boomsma, Dorret I., Gieger, Christian, Van Der Harst, Pim, Hicks, Andrew A., Kraft, Peter, Sinisalo, Juha, Knekt, Paul, Johannesson, Magnu, Magnusson, Patrik K. E., Hamsten, Ander, Schmidt, Reinhold, Borecki, Ingrid B., Vartiainen, Erkki, Becker, Diane M., Bharadwaj, Dwaipayan, Mohlke, Karen L., Boehnke, Michael, Van Duijn, Cornelia M., Sanghera, Dharambir K., Teumer, Alexander, Zeggini, Eleftheria, Metspalu, Andre, Gasparini, Paolo, Ulivi, Sheila, Ober, Carole, Toniolo, Daniela, Rudan, Igor, Porteous, David J., Ciullo, Marina, Spector, Tim D., Hayward, Caroline, Dupuis, Josée, Loos, Ruth J. F., Wright, Alan F., Chandak, Giriraj R., Vollenweider, Peter, Shuldiner, Alan R., Ridker, Paul M., Rotter, Jerome I., Sattar, Naveed, Gyllensten, Ulf, North, Kari E., Pirastu, Mario, Psaty, Bruce M., Weir, David R., Laakso, Markku, Gudnason, Vilmundur, Takahashi, Atsushi, Chambers, John C., Kooner, Jaspal S., Strachan, David P., Campbell, Harry, Hirschhorn, Joel N., Perola, Marku, Polašek, Ozren, Wilson, James F., Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, BioBank Japan, Project, The BioBank Japan Project, Ehret, Georg Benedikt, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), and Cardiovascular Centre (CVC)

Subjects
Male, Netherlands Twin Register (NTR), Blood Pressure, BLOOD-PRESSURE, INTELLIGENCE, Runs of Homozygosity, DISEASE, Homozygosity, Cohort Studies, Cognition, Forced Expiratory Volume, GENETIC-VARIANTS, Inbreeding depression, Settore MED/14 - NEFROLOGIA, Inbreeding, Inbreeding, Evolutionary genetics, Quantitative trait loci, Non-U.S. Gov't, Dominance (genetics), ddc:616, Genetics, ARCHITECTURE, Genome, Multidisciplinary, Body Height/genetics, Research Support, Non-U.S. Gov't, Homozygote, Confounding, heterozygosity, inbreeding, genomics, QUANTITATIVE TRAITS, BioBank Japan Project, Biological Evolution, Multidisciplinary Sciences, Cholesterol, Phenotype, Cholesterol, LDL/genetics, Trait, Science & Technology - Other Topics, Educational Status, Female, Lung Volume Measurements, Human, INBREEDING DEPRESSION, Quantitative trait loci, Blood Pressure/genetics, General Science & Technology, Forced Expiratory Volume/genetics, Lung Volume Measurement, Quantitative trait locus, Biology, Research Support, Evolutionary genetics, Article, LDL, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Journal Article, Humans, Genetic association, Science & Technology, Genome, Human, ta1184, PATHWAYS, Cholesterol, LDL, Body Height, Educational Statu, ASSOCIATION ANALYSIS, Evolutionary biology, Genome, Human/genetics, ta1181, Cohort Studie, Meta-Analysis
Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10-300, 2.1 × 10-6, 2.5 × 10-10 and 1.8 × 10-10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Published
2015
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45. Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes

Author

Yaghootkar, H. (Hanieh), Lamina, C. (Claudia), Scott, R.A. (Robert), Dastani, Z. (Zari), Hivert, M.-F. (Marie-France), Warren, L.L. (Liling), Stancáková, A. (Alena), Buxbaum, S.G. (Sarah), Lyytikäinen, L.-P. (Leo-Pekka), Henneman, P. (Peter), Wu, Y. (Ying), Cheung, C.Y.Y. (Chloe), Pankow, J.S. (James), Jackson, A.U. (Anne), Gustafsson, S. (Stefan), Zhao, J.H. (Jing Hua), Ballantyne, C. (Christie), Xie, W. (Weijia), Bergman, R.N. (Richard), Boehnke, M. (Michael), El Bouazzaoui, F. (Fatiha), Collins, F.S. (Francis), Dunn, S.H. (Sandra), Dupuis, J. (Josée), Forouhi, N.G. (Nita), Gillson, C.J. (Christopher), Hattersley, A.T. (Andrew), Hong, J. (Jaeyoung), Kähönen, M. (Mika), Kuusisto, J. (Johanna), Kedenko, L. (Lyudmyla), Kronenberg, F. (Florian), Doria, A. (Andrea), Assimes, T.L. (Themistocles), Ferrannini, E. (Ele), Hansen, T. (Torben), Hao, K. (Ke), Häring, H. (Hans), Knowles, J.W. (Joshua), Lindgren, C.M. (Cecilia), Nolan, J.J. (John), Paananen, J. (Jussi), Pedersen, O. (Oluf), Quertermous, T. (Thomas), Smith, U. (Ulf), Lehtimäki, T. (Terho), Liu, C.-T. (Ching-Ti), Loos, R.J.F. (Ruth), McCarthy, M.I. (Mark), Morris, A.D. (Andrew), Vasan, R.S. (Ramachandran Srini), Spector, T.D. (Timothy), Teslovich, T.M. (Tanya), Tuomilehto, J. (Jaakko), Willems van Dijk, J.A.P. (Ko), Viikari, J. (Jorma), Zhu, N. (Na), Langenberg, C. (Claudia), Ingelsson, E. (Erik), Semple, R.K. (Robert), Sinaiko, A. (Alan), Palmer, C.N.A. (Colin), Walker, M. (Mark), Lam, K.S.L. (Karen), Paulweber, B. (Bernhard), Mohlke, K.L. (Karen), Duijn, C.M. (Cornelia) van, Raitakari, O. (Olli), Bidulescu, A. (Aurelian), Wareham, N.J. (Nick), Laakso, M. (Markku), Waterworth, D. (Dawn), Lawlor, D.A. (Debbie), Meigs, J.B. (James), Richards, J.B. (Brent), Frayling, T.M. (Timothy), Yaghootkar, H. (Hanieh), Lamina, C. (Claudia), Scott, R.A. (Robert), Dastani, Z. (Zari), Hivert, M.-F. (Marie-France), Warren, L.L. (Liling), Stancáková, A. (Alena), Buxbaum, S.G. (Sarah), Lyytikäinen, L.-P. (Leo-Pekka), Henneman, P. (Peter), Wu, Y. (Ying), Cheung, C.Y.Y. (Chloe), Pankow, J.S. (James), Jackson, A.U. (Anne), Gustafsson, S. (Stefan), Zhao, J.H. (Jing Hua), Ballantyne, C. (Christie), Xie, W. (Weijia), Bergman, R.N. (Richard), Boehnke, M. (Michael), El Bouazzaoui, F. (Fatiha), Collins, F.S. (Francis), Dunn, S.H. (Sandra), Dupuis, J. (Josée), Forouhi, N.G. (Nita), Gillson, C.J. (Christopher), Hattersley, A.T. (Andrew), Hong, J. (Jaeyoung), Kähönen, M. (Mika), Kuusisto, J. (Johanna), Kedenko, L. (Lyudmyla), Kronenberg, F. (Florian), Doria, A. (Andrea), Assimes, T.L. (Themistocles), Ferrannini, E. (Ele), Hansen, T. (Torben), Hao, K. (Ke), Häring, H. (Hans), Knowles, J.W. (Joshua), Lindgren, C.M. (Cecilia), Nolan, J.J. (John), Paananen, J. (Jussi), Pedersen, O. (Oluf), Quertermous, T. (Thomas), Smith, U. (Ulf), Lehtimäki, T. (Terho), Liu, C.-T. (Ching-Ti), Loos, R.J.F. (Ruth), McCarthy, M.I. (Mark), Morris, A.D. (Andrew), Vasan, R.S. (Ramachandran Srini), Spector, T.D. (Timothy), Teslovich, T.M. (Tanya), Tuomilehto, J. (Jaakko), Willems van Dijk, J.A.P. (Ko), Viikari, J. (Jorma), Zhu, N. (Na), Langenberg, C. (Claudia), Ingelsson, E. (Erik), Semple, R.K. (Robert), Sinaiko, A. (Alan), Palmer, C.N.A. (Colin), Walker, M. (Mark), Lam, K.S.L. (Karen), Paulweber, B. (Bernhard), Mohlke, K.L. (Karen), Duijn, C.M. (Cornelia) van, Raitakari, O. (Olli), Bidulescu, A. (Aurelian), Wareham, N.J. (Nick), Laakso, M. (Markku), Waterworth, D. (Dawn), Lawlor, D.A. (Debbie), Meigs, J.B. (James), Richards, J.B. (Brent), and Frayling, T.M. (Timothy)

Abstract

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to te

Published
2013
Full Text
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46. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Author

DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Manning, A.K., Hivert, M.F., Scott, R.A., Grimsby, J.L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C.T., Bielak, L.F., Barnes, D., Cadby, G., Hottenga, J.J., Ingelsson, E., Johnson, T., Kanoni, S., Ladenvall, C., Lagou, V., Lahti, J., Lecoeur, C., Liu, Y., Martinez-Larrad, M.T., Montasser, M.E., Rasmussen-Torvik, L.J., Salo, P., Sattar, N., Shungin, D., Strawbridge, R.J., Tanaka, T., An, P., de Andrade, M., Andrews, J.S., Aspelund, T., Atalay, M., Aulchenko, Y., Bandinelli, S., Beckmann, J.S., Beilby, J.P., Bellis, C., Blangero, J., Boban, M., Boomsma, D.I., Borecki, I.B., Böttcher, Y., Bouchard, C., Brunner, E., Budimir, D., Carlson, O., Clarke, R., Corbatón-Anchuelo, A., Couper, D., de Faire, U., Dedoussis, G.V., Dimitriou, M., Egan, J.M., Eiriksdottir, G., Eriksson, J.G., Eury, E., Ferrucci, L., Ford, I., Forouhi, N.G., Franzosi, M.G., Franks, P.W., Galan, P., de Geus, E., Gigante, B., Glazer, N.L., Goel, A., Gudnason, V., Hallmans, G., Hamsten, A., Hansson, O., Harris, T.B., Hayward, C., Heath, S., Hercberg, S., Hicks, A.A., Hingorani, A., Hui, J., Hung, J., Jarvelin, M.R., Jhun, M.A., Johnson, P.C., Jukema, J.W., Jula, A., Kaprio, J., Kardia, S.L., Keinanen-Kiukaanniemi, S., Kivimaki, M., Kolcic, I., Kovacs, P., Kumari, M., Kyvik, K.O., Lakka, T., Lannfelt, L., Lathrop, G.M., Launer, L.J., Leander, K., Li, G., Lind, L., Lindstrom, J., Lobbens, S., Loos, R.J., Luan, J., Mägi, R., Magnusson, P.K., Marmot, M., Meneton, P., Mooser, V., Miljkovic, I., O'Connell, J., Ong, K.K., Oostra, B.A., Palmer, L.J., Palotie, A., Peden, J.F., Pedersen, N.L., Pehlic, M., Peltonen, L., Penninx, B., Pericic, M., Perola, M., Perusse, L., Peyser, P.A., Polasek, O., Province, M.A., Räikkönen, K., Rauramaa, R., Rehnberg, E., Rice, K., Rotter, J.I., Ruokonen, A., Saaristo, T., Sabater-Lleal, M., Salomaa, V., Savage, D.B., Schwarz, P., Seedorf, U., Sennblad, B., Serrano-Rios, M., Shuldiner, A.R., Sijbrands, E.J., Siscovick, D.S., Smit, J.H., Smith, N.L., Smith, A.V., Stančáková, A., Stirrups, K., Stumvoll, M., Sun, Y.V., Tönjes, A., Trompet, S., Uitterlinden, A.G., Uusitupa, M., Vikström, M., Vitart, V., Vohl, M.C., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Wheeler, E., Widen, E., Wild, S.H., Willems, S.M., Willemsen, G., Witteman, J.C., Wright, A.F., Yaghootkar, H., Zelenika, D., Zemunik, T., Zgaga, L., DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Manning, A.K., Hivert, M.F., Scott, R.A., Grimsby, J.L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C.T., Bielak, L.F., Barnes, D., Cadby, G., Hottenga, J.J., Ingelsson, E., Johnson, T., Kanoni, S., Ladenvall, C., Lagou, V., Lahti, J., Lecoeur, C., Liu, Y., Martinez-Larrad, M.T., Montasser, M.E., Rasmussen-Torvik, L.J., Salo, P., Sattar, N., Shungin, D., Strawbridge, R.J., Tanaka, T., An, P., de Andrade, M., Andrews, J.S., Aspelund, T., Atalay, M., Aulchenko, Y., Bandinelli, S., Beckmann, J.S., Beilby, J.P., Bellis, C., Blangero, J., Boban, M., Boomsma, D.I., Borecki, I.B., Böttcher, Y., Bouchard, C., Brunner, E., Budimir, D., Carlson, O., Clarke, R., Corbatón-Anchuelo, A., Couper, D., de Faire, U., Dedoussis, G.V., Dimitriou, M., Egan, J.M., Eiriksdottir, G., Eriksson, J.G., Eury, E., Ferrucci, L., Ford, I., Forouhi, N.G., Franzosi, M.G., Franks, P.W., Galan, P., de Geus, E., Gigante, B., Glazer, N.L., Goel, A., Gudnason, V., Hallmans, G., Hamsten, A., Hansson, O., Harris, T.B., Hayward, C., Heath, S., Hercberg, S., Hicks, A.A., Hingorani, A., Hui, J., Hung, J., Jarvelin, M.R., Jhun, M.A., Johnson, P.C., Jukema, J.W., Jula, A., Kaprio, J., Kardia, S.L., Keinanen-Kiukaanniemi, S., Kivimaki, M., Kolcic, I., Kovacs, P., Kumari, M., Kyvik, K.O., Lakka, T., Lannfelt, L., Lathrop, G.M., Launer, L.J., Leander, K., Li, G., Lind, L., Lindstrom, J., Lobbens, S., Loos, R.J., Luan, J., Mägi, R., Magnusson, P.K., Marmot, M., Meneton, P., Mooser, V., Miljkovic, I., O'Connell, J., Ong, K.K., Oostra, B.A., Palmer, L.J., Palotie, A., Peden, J.F., Pedersen, N.L., Pehlic, M., Peltonen, L., Penninx, B., Pericic, M., Perola, M., Perusse, L., Peyser, P.A., Polasek, O., Province, M.A., Räikkönen, K., Rauramaa, R., Rehnberg, E., Rice, K., Rotter, J.I., Ruokonen, A., Saaristo, T., Sabater-Lleal, M., Salomaa, V., Savage, D.B., Schwarz, P., Seedorf, U., Sennblad, B., Serrano-Rios, M., Shuldiner, A.R., Sijbrands, E.J., Siscovick, D.S., Smit, J.H., Smith, N.L., Smith, A.V., Stančáková, A., Stirrups, K., Stumvoll, M., Sun, Y.V., Tönjes, A., Trompet, S., Uitterlinden, A.G., Uusitupa, M., Vikström, M., Vitart, V., Vohl, M.C., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Wheeler, E., Widen, E., Wild, S.H., Willems, S.M., Willemsen, G., Witteman, J.C., Wright, A.F., Yaghootkar, H., Zelenika, D., Zemunik, T., and Zgaga, L.

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Published
2012

47. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, 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Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., and Kathiresan, S.

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Published
2012

48. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

Author

Dastani, Z. (Zari), Hivert, M.-F. (Marie-France), Timpson, N.J. (Nicholas), Perry, J.R.B. (John), Yuan, X. (Xin), Scott, R.A. (Robert), Hennemann, P. (Peter), Heid, I.M. (Iris), Kizer, J.R. (Jorge), Lyytikäinen, L.-P. (Leo-Pekka), Fuchsberger, C. (Christian), Tanaka, T. (Toshiko), Morris, A.P. (Andrew), Small, K.S. (Kerrin), Isaacs, A.J. (Aaron), Beekman, M. (Marian), Coassin, S. (Stefan), Lohman, K. (Kurt), Qi, L. (Lu), Kanoni, S. (Stavroula), Pankow, J.S. (James), Uh, H.-W. (Hae-Won), Wu, Y. (Ying), Bidulescu, A. (Aurelian), Rasmussen-Torvik, L.J. (Laura), Greenwood, C.M.T. (Celia), Ladouceur, M. (Martin), Grimsby, J.L. (Jonna), Manning, A.K. (Alisa), Liu, C.-T. (Ching-Ti), Kooner, J.S. (Jaspal), Mooser, V. (Vincent), Vollenweider, P. (Peter), Kapur, K. (Karen), Chambers, J. (John), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Frants, R.R. (Rune), Willems van Dijk, J.A.P. (Ko), Oostra, B.A. (Ben), Willems, S.M. (Sara), Lamina, C. (Claudia), Winkler, T.W. (Thomas), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Brody, J.A. (Jennifer A.), Chen, I. (Ida), Viikari, J. (Jorma), Kähönen, M. (Mika), Pramstaller, P.P. (Peter Paul), Evans, D.M. (David), St Pourcain, B. (Beate), Sattar, N. (Naveed), Wood, A.R. (Andrew), Bandinelli, S. (Stefania), Carlson, O.D. (Olga), Egan, J.M. (Josephine), Böhringer, S. (Stefan), Heemst, D. (Diana) van, Kedenko, L. (Lyudmyla), Kristiansson, K. (Kati), Nuotio, M.-L. (Marja-Liisa), Loo, B.-M. (Britt-Marie), Harris, T.B. (Tamara), Garcia, M. (Melissa), Kanaya, A. (Alka), Haun, M. (Margot), Klopp, N. (Norman), Wichmann, H.E. (Erich), Deloukas, P. (Panagiotis), Katsareli, E. (Efi), Couper, D.J. (David), Duncan, B.B. (Bruce), Kloppenburg, M. (Margreet), Adair, L.S. (Linda), Borja, J.B. (Judith), Wilson, J.G. (James), Musani, S. (Solomon), Guo, X. (Xiuqing), Johnson, T. (Toby), Semple, R.K. (Robert), Teslovich, T.M. (Tanya), Allison, M.A. (Matthew), Redline, S. (Susan), Buxbaum, S.G. (Sarah), Mohlke, K.L. (Karen), Meulenbelt, I. (Ingrid), Ballantyne, C. (Christie), Dedoussis, G.V. (George), Hu, F.B. (Frank), Liu, Y. (YongMei), Paulweber, B. (Bernhard), Spector, T.D. (Timothy), Slagboom, P.E. (Eline), Ferrucci, L. (Luigi), Jula, A. (Antti), Perola, M. (Markus), Raitakari, O.T. (Olli T.), Florez, J.C. (Jose), Salomaa, V. (Veikko), Eriksson, J.G. (Johan), Frayling, T.M. (Timothy), Hicks, A.A. (Andrew), Lehtimäki, T. (Terho), Smith, G.D. (George Davey), Siscovick, D.S. (David), Kronenberg, F. (Florian), Duijn, C.M. (Cornelia) van, Loos, R.J.F. (Ruth), Waterworth, D.M. (Dawn), Meigs, J.B. (James), Dupuis, J. (Josée), Richards, J.B. (Brent), Dastani, Z. (Zari), Hivert, M.-F. (Marie-France), Timpson, N.J. (Nicholas), Perry, J.R.B. (John), Yuan, X. (Xin), Scott, R.A. (Robert), Hennemann, P. (Peter), Heid, I.M. (Iris), Kizer, J.R. (Jorge), Lyytikäinen, L.-P. (Leo-Pekka), Fuchsberger, C. (Christian), Tanaka, T. (Toshiko), Morris, A.P. (Andrew), Small, K.S. (Kerrin), Isaacs, A.J. (Aaron), Beekman, M. (Marian), Coassin, S. (Stefan), Lohman, K. (Kurt), Qi, L. (Lu), Kanoni, S. (Stavroula), Pankow, J.S. (James), Uh, H.-W. (Hae-Won), Wu, Y. (Ying), Bidulescu, A. (Aurelian), Rasmussen-Torvik, L.J. (Laura), Greenwood, C.M.T. (Celia), Ladouceur, M. (Martin), Grimsby, J.L. (Jonna), Manning, A.K. (Alisa), Liu, C.-T. (Ching-Ti), Kooner, J.S. (Jaspal), Mooser, V. (Vincent), Vollenweider, P. (Peter), Kapur, K. (Karen), Chambers, J. (John), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Frants, R.R. (Rune), Willems van Dijk, J.A.P. (Ko), Oostra, B.A. (Ben), Willems, S.M. (Sara), Lamina, C. (Claudia), Winkler, T.W. (Thomas), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Brody, J.A. (Jennifer A.), Chen, I. (Ida), Viikari, J. (Jorma), Kähönen, M. (Mika), Pramstaller, P.P. (Peter Paul), Evans, D.M. (David), St Pourcain, B. (Beate), Sattar, N. (Naveed), Wood, A.R. (Andrew), Bandinelli, S. (Stefania), Carlson, O.D. (Olga), Egan, J.M. (Josephine), Böhringer, S. (Stefan), Heemst, D. (Diana) van, Kedenko, L. (Lyudmyla), Kristiansson, K. (Kati), Nuotio, M.-L. (Marja-Liisa), Loo, B.-M. (Britt-Marie), Harris, T.B. (Tamara), Garcia, M. (Melissa), Kanaya, A. (Alka), Haun, M. (Margot), Klopp, N. (Norman), Wichmann, H.E. (Erich), Deloukas, P. (Panagiotis), Katsareli, E. (Efi), Couper, D.J. (David), Duncan, B.B. (Bruce), Kloppenburg, M. (Margreet), Adair, L.S. (Linda), Borja, J.B. (Judith), Wilson, J.G. (James), Musani, S. (Solomon), Guo, X. (Xiuqing), Johnson, T. (Toby), Semple, R.K. (Robert), Teslovich, T.M. (Tanya), Allison, M.A. (Matthew), Redline, S. (Susan), Buxbaum, S.G. (Sarah), Mohlke, K.L. (Karen), Meulenbelt, I. (Ingrid), Ballantyne, C. (Christie), Dedoussis, G.V. (George), Hu, F.B. (Frank), Liu, Y. (YongMei), Paulweber, B. (Bernhard), Spector, T.D. (Timothy), Slagboom, P.E. (Eline), Ferrucci, L. (Luigi), Jula, A. (Antti), Perola, M. (Markus), Raitakari, O.T. (Olli T.), Florez, J.C. (Jose), Salomaa, V. (Veikko), Eriksson, J.G. (Johan), Frayling, T.M. (Timothy), Hicks, A.A. (Andrew), Lehtimäki, T. (Terho), Smith, G.D. (George Davey), Siscovick, D.S. (David), Kronenberg, F. (Florian), Duijn, C.M. (Cornelia) van, Loos, R.J.F. (Ruth), Waterworth, D.M. (Dawn), Meigs, J.B. (James), Dupuis, J. (Josée), and Richards, J.B. (Brent)

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- choles

Published
2012
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49. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases

Author

Perry, J.R.B. (John), Voight, B.F. (Benjamin), Yengo, L. (Loic), Amin, N. (Najaf), Dupuis, J. (Josée), Ganser, M. (Martha), Grallert, H. (Harald), Navarro, P. (Pau), Li, M. (Man), Qi, L. (Lu), Steinthorsdottir, V. (Valgerdur), Scott, R.A. (Robert), Almgren, P. (Peter), Arking, D.E. (Dan), Aulchenko, Y.S. (Yurii), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Bergman, R.N. (Richard), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Burtt, N.P. (Noël), Campbell, H. (Harry), Charpentier, G. (Guillaume), Collins, F.S. (Francis), Gieger, C. (Christian), Green, T. (Todd), Hadjadj, S. (Samy), Hattersley, A.T. (Andrew), Herder, C. (Christian), Hofman, A. (Albert), Johnson, A.D. (Andrew), Köttgen, A. (Anna), Kraft, P. (Peter), Labrune, Y. (Yann), Langenberg, C. (Claudia), Manning, A.K. (Alisa), Mohlke, K.L. (Karen), Morris, A.P. (Andrew), Oostra, B.A. (Ben), Pankow, J.S. (James), Petersen, A.K., Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Roden, M. (Michael), Rudan, I. (Igor), Rybin, D. (Denis), Scott, L.J. (Laura), Sigurdsson, G. (Gunnar), Sladek, R. (Rob), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vivequin, S. (Sidonie), Weedon, M.N. (Michael), Wright, A.F. (Alan), Hu, F.B. (Frank), Illig, T. (Thomas), Kao, W.H.L. (Wen), Meigs, J.B. (James), Wilson, J.F. (James), Zwart, J-A. (John-Anker), Duijn, C.M. (Cornelia) van, Altshuler, D. (David), Morris, A.D. (Andrew), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Froguel, P. (Philippe), Palmer, C.N.A. (Colin), Wareham, N.J. (Nick), Groop, L. (Leif), Frayling, T.M. (Timothy), Cauchi, S. (Stephane), Perry, J.R.B. (John), Voight, B.F. (Benjamin), Yengo, L. (Loic), Amin, N. (Najaf), Dupuis, J. (Josée), Ganser, M. (Martha), Grallert, H. (Harald), Navarro, P. (Pau), Li, M. (Man), Qi, L. (Lu), Steinthorsdottir, V. (Valgerdur), Scott, R.A. (Robert), Almgren, P. (Peter), Arking, D.E. (Dan), Aulchenko, Y.S. (Yurii), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Bergman, R.N. (Richard), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Burtt, N.P. (Noël), Campbell, H. (Harry), Charpentier, G. (Guillaume), Collins, F.S. (Francis), Gieger, C. (Christian), Green, T. (Todd), Hadjadj, S. (Samy), Hattersley, A.T. (Andrew), Herder, C. (Christian), Hofman, A. (Albert), Johnson, A.D. (Andrew), Köttgen, A. (Anna), Kraft, P. (Peter), Labrune, Y. (Yann), Langenberg, C. (Claudia), Manning, A.K. (Alisa), Mohlke, K.L. (Karen), Morris, A.P. (Andrew), Oostra, B.A. (Ben), Pankow, J.S. (James), Petersen, A.K., Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Roden, M. (Michael), Rudan, I. (Igor), Rybin, D. (Denis), Scott, L.J. (Laura), Sigurdsson, G. (Gunnar), Sladek, R. (Rob), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vivequin, S. (Sidonie), Weedon, M.N. (Michael), Wright, A.F. (Alan), Hu, F.B. (Frank), Illig, T. (Thomas), Kao, W.H.L. (Wen), Meigs, J.B. (James), Wilson, J.F. (James), Zwart, J-A. (John-Anker), Duijn, C.M. (Cornelia) van, Altshuler, D. (David), Morris, A.D. (Andrew), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Froguel, P. (Philippe), Palmer, C.N.A. (Colin), Wareham, N.J. (Nick), Groop, L. (Leif), Frayling, T.M. (Timothy), and Cauchi, S. (Stephane)

Abstract

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10-9, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3×10-8, OR = 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2×10-14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10-16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to t

Published
2012
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50. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Dupuis, J. (Josée), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Soranzo, N. (Nicole), Jackson, A.U. (Anne), Wheeler, E. (Eleanor), Glazer, N.L. (Nicole), Bouatia-Naji, N. (Nabila), Gloyn, A.L. (Anna), Lindgren, C.M. (Cecilia), Mägi, R. (Reedik), Morris, A.P. (Andrew), Randall, J.C. (Joshua), Johnson, T. (Toby), Elliott, P. (Paul), Rybin, D. (Denis), Thorleifsson, G. (Gudmar), Steinthorsdottir, V. (Valgerdur), Henneman, P. (Peter), Grallert, H. (Harald), Dehghan, A. (Abbas), JanHottenga, J. (Jouke), Franklin, C.S. (Christopher), Navarro, P. (Pau), Song, K. (Kijoung), Goel, A. (Anuj), Perry, J.R.B. (John), Egan, J.M. (Josephine), Lajunen, T. (Taina), Grarup, N. (Niels), Sparsø, T. (Thomas), Doney, A.S.F. (Alex), Voight, B.F. (Benjamin), Stringham, H.M. (Heather), Li, M. (Man), Kanoni, S. (Stavroula), Shrader, P. (Peter), Cavalcanti-Proença, C. (Christine), Kumari, M. (Meena), Qi, L. (Lu), Timpson, N.J. (Nicholas), Gieger, C. (Christian), Zabena, C. (Carina), Rocheleau, G. (Ghislain), Ingelsson, E. (Erik), An, P. (Ping), O´Connell, J.R., Luan, J., McCarroll, S.A. (Steven), Payne, F. (Felicity), Roccasecca, R.M., Pattou, F. (François), Sethupathy, P. (Praveen), Ardlie, K.G. (Kristin), Ariyurek, Y. (Yavuz), Balkau, B. (Beverley), Barter, P. (Phil), Beilby, J.P. (John), Ben-Shlomo, Y., Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Bergmann, S.M. (Sven), Bochud, M. (Murielle), Boerwinkle, E.A. (Eric), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borch-Johnsen, K., Böttcher, Y. (Yvonne), Brunner, E. (Eric), Bumpstead, S. (Suzannah), Charpentier, G. (Guillaume), IdaChen, Y. (Yii) der, Chines, P.S. (Peter), Clarke, R., McOin, L.J. (Lachlan), Cooper, M.N. (Matthew), Cornelis, M. (Marilyn), Crawford, G. (Gabe), Crisponi, L. (Laura), Day, I.N.M. (Ian), Geus, E.J.C. (Eco) de, Delplanque, J. (Jerome), Dina, C. (Christian), Erdos, M.R. (Michael), Fedson, A.C. (Annette), Fischer-Rosinsky, A. (Antje), Forouhi, N.G. (Nita), Fox, C.S. (Caroline), Frants, R.R. (Rune), GraziaFranzosi, M. (Maria), Galan, P. (Pilar), Goodarzi, M. (Mark), Graessler, J. (Jürgen), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Gwilliam, R. (Rhian), Gyllensten, U. (Ulf), Hadjadj, S. (Samy), Hallmans, G. (Göran), Hammond, N. (Naomi), Han, X. (Xijing), Hartikainen, A.-L. (Anna-Liisa), Hassanali, N. (Neelam), Hayward, C. (Caroline), Heath, S.C. (Simon), Hercberg, S. (Serge), Herder, C. (Christian), Hicks, A.A. (Andrew), Hillman, D.R. (David), Hingorani, A. (Aroon), Hofman, A. (Albert), Hui, J. (Jennie), Hung, J. (Judy), Isomaa, B. (Bo), Jørgensen, T. (Torben), Jula, A. (Antti), Kaakinen, M. (Marika), Kaprio, J. (Jaakko), AnteroKesaniemi, Y., Kivimaki, M. (Mika), Knight, B. (Beatrice), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyvik, K.O. (Kirsten Ohm), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Bacquer, O.L. (Olivier), Lecoeur, C. (Cécile), Lyssenko, V. (Valeriya), Mahley, R. (Robert), Mangino, M. (Massimo), Manning, A.K. (Alisa), TeresaMartínez-Larrad, M. (María), McAteer, J.B. (Jarred), McCulloch, L.J. (Laura), McPherson, R. (Ruth), Meisinger, C. (Christa), Melzer, D. (David), Meyre, D. (David), Mitchell, B.D. (Braxton), Morken, M.A. (Mario), Mukherjee, S. (Sutapa), Naitza, S. (Silvia), Narisu, N. (Narisu), Neville, M.J. (Matthew), Oostra, B.A. (Ben), Orrù, M. (Marco), Pakyz, R. (Ruth), Palmer, C.N.A. (Colin), Paolisso, G. (Giuseppe), Pattaro, C. (Cristian), Pearson, D. (Daniel), Peden, J. (John), Pedersen, N.L. (Nancy), Perola, M. (Markus), Pfeiffer, A.F.H. (Andreas), Pichler, I. (Irene), Polasek, O. (Ozren), Posthuma, D. (Danielle), Potter, S.C. (Simon), Pouta, A. (Anneli), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Rice, K. (Kenneth), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Roden, M. (Michael), Rolandsson, O. (Olov), Sandbaek, A. (Annelli), Sandhu, M.S. (Manjinder), Sanna, S. (Serena), Sayer, A.A., Scheet, P. (Paul), Scott, L.J. (Laura), Seedorf, U. (Udo), Sharp, S.J. (Stephen), Shields, B.M. (Beverley), Sigursson, G. (Gunnar), Sijbrands, E.J.G. (Eric), Silveira, A. (Angela), Simpson, L. (Laila), Singleton, A. (Andrew), Smith, N.L. (Nicholas), Sovio, U. (Ulla), Swift, A.J. (Amy), Syddall, H. (Holly), Syvänen, A.-C. (Ann-Christine), Tanaka, T. (Toshiko), Thorand, B. (Barbara), Tichet, J. (Jean), Tönjes, A. (Anke), Tuomi, T. (Tiinamaija), Uitterlinden, A.G. (André), Willems van Dijk, J.A.P. (Ko), Hoek, M. (Mandy) van, Varma, D. (Dhiraj), Visvikis-Siest, S. (Sophie), Vitart, V. (Veronique), Vogelzangs, N. (Nicole), Waeber, G. (Gérard), Wagner, P.J. (Peter), Walley, A. (Andrew), BragiWalters, G., Ward, K.L. (Kim), Watkins, H. (Hugh), Weedon, M.N. (Michael), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), GYarnell, J.W. (John), Zeggini, E. (Eleftheria), Zelenika, D. (Diana), Zethelius, B. (Björn), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Borecki, I.B. (Ingrid), Loos, R.J.F. (Ruth), Meneton, P. (Pierre), Magnusson, P.K. (Patrik), Nathan, D.M. (David), Williams, G.H. (Gordon), Hattersley, A.T. (Andrew), Silander, K. (Kaisa), Salomaa, V. (Veikko), Bornstein, S.R. (Stefan), Schwarz, P. (Peter), Spranger, J. (Jürgen), Karpe, F. (Fredrik), Shuldiner, A.R. (Alan), Dedoussis, G.V. (George), Serrano-Ríos, M. (Manuel), Lind, L. (Lars), Palmer, C. (Cameron), Hu, F.B. (Frank), Franks, P.W. (Paul), Ebrahim, S. (Shanil), Marmot, M. (Michael), Kao, W.-H.L. (Linda), Pankow, J.S. (James), Sampson, M.J. (Michael), Kuusisto, J. (Johanna), Laakso, M. (Markku), Hansen, T. (Torben), Pramstaller, P.P. (Peter Paul), Wichmann, H.E. (Erich), Illig, T. (Thomas), Rudan, I. (Igor), Wright, A.F. (Alan), Stumvoll, M. (Michael), Campbell, H. (Harry), Wilson, J.F. (James), Bergman, R.N. (Richard), Buchanan, T.A. (Thomas), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Valle, T.T. (Timo), Altshuler, D. (David), Rotter, J.I. (Jerome), Siscovick, D.S. (David), Penninx, B.W.J.H. (Brenda), Boomsma, D.I. (Dorret), Deloukas, P. (Panagiotis), Spector, T.D. (Timothy), Frayling, T.M. (Timothy), Ferrucci, L. (Luigi), Kong, A. (Augustine), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), Cao, A. (Antonio), Scuteri, A. (Angelo), Schlessinger, D. (David), Uda, M. (Manuela), Ruokonen, A. (Aimo), Jarvelin, M.-R. (Marjo-Riitta), Waterworth, D. (Dawn), Vollenweider, P. (Peter), Peltonen, L. (Leena Johanna), Mooser, V. (Vincent), Abecasis, G.R. (Gonçalo), Wareham, N.J. (Nick), Sladek, R. (Rob), Froguel, P. (Philippe), Meigs, J.B. (James), Groop, L. (Leif), Watanabe, R.M. (Richard), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Florez, J.C. (Jose), Barroso, I.E. (Inês), Dupuis, J. (Josée), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Soranzo, N. (Nicole), Jackson, A.U. (Anne), Wheeler, E. (Eleanor), Glazer, N.L. (Nicole), Bouatia-Naji, N. (Nabila), Gloyn, A.L. (Anna), Lindgren, C.M. (Cecilia), Mägi, R. (Reedik), Morris, A.P. (Andrew), Randall, J.C. (Joshua), Johnson, T. (Toby), Elliott, P. (Paul), Rybin, D. (Denis), Thorleifsson, G. (Gudmar), Steinthorsdottir, V. (Valgerdur), Henneman, P. (Peter), Grallert, H. (Harald), Dehghan, A. (Abbas), JanHottenga, J. (Jouke), Franklin, C.S. (Christopher), Navarro, P. (Pau), Song, K. (Kijoung), Goel, A. (Anuj), Perry, J.R.B. (John), Egan, J.M. (Josephine), Lajunen, T. (Taina), Grarup, N. (Niels), Sparsø, T. (Thomas), Doney, A.S.F. (Alex), Voight, B.F. (Benjamin), Stringham, H.M. (Heather), Li, M. (Man), Kanoni, S. (Stavroula), Shrader, P. (Peter), Cavalcanti-Proença, C. (Christine), Kumari, M. (Meena), Qi, L. (Lu), Timpson, N.J. (Nicholas), Gieger, C. (Christian), Zabena, C. (Carina), Rocheleau, G. (Ghislain), Ingelsson, E. (Erik), An, P. (Ping), O´Connell, J.R., Luan, J., McCarroll, S.A. (Steven), Payne, F. (Felicity), Roccasecca, R.M., Pattou, F. (François), Sethupathy, P. (Praveen), Ardlie, K.G. (Kristin), Ariyurek, Y. (Yavuz), Balkau, B. (Beverley), Barter, P. (Phil), Beilby, J.P. (John), Ben-Shlomo, Y., Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Bergmann, S.M. (Sven), Bochud, M. (Murielle), Boerwinkle, E.A. (Eric), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borch-Johnsen, K., Böttcher, Y. (Yvonne), Brunner, E. (Eric), Bumpstead, S. (Suzannah), Charpentier, G. (Guillaume), IdaChen, Y. (Yii) der, Chines, P.S. (Peter), Clarke, R., McOin, L.J. (Lachlan), Cooper, M.N. (Matthew), Cornelis, M. (Marilyn), Crawford, G. (Gabe), Crisponi, L. (Laura), Day, I.N.M. (Ian), Geus, E.J.C. (Eco) de, Delplanque, J. (Jerome), Dina, C. (Christian), Erdos, M.R. (Michael), Fedson, A.C. (Annette), Fischer-Rosinsky, A. (Antje), Forouhi, N.G. (Nita), Fox, C.S. (Caroline), Frants, R.R. (Rune), GraziaFranzosi, M. (Maria), Galan, P. (Pilar), Goodarzi, M. (Mark), Graessler, J. (Jürgen), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Gwilliam, R. (Rhian), Gyllensten, U. (Ulf), Hadjadj, S. (Samy), Hallmans, G. (Göran), Hammond, N. (Naomi), Han, X. (Xijing), Hartikainen, A.-L. (Anna-Liisa), Hassanali, N. (Neelam), Hayward, C. (Caroline), Heath, S.C. (Simon), Hercberg, S. (Serge), Herder, C. (Christian), Hicks, A.A. (Andrew), Hillman, D.R. (David), Hingorani, A. (Aroon), Hofman, A. (Albert), Hui, J. (Jennie), Hung, J. (Judy), Isomaa, B. (Bo), Jørgensen, T. (Torben), Jula, A. (Antti), Kaakinen, M. (Marika), Kaprio, J. (Jaakko), AnteroKesaniemi, Y., Kivimaki, M. (Mika), Knight, B. (Beatrice), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyvik, K.O. (Kirsten Ohm), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Bacquer, O.L. (Olivier), Lecoeur, C. (Cécile), Lyssenko, V. (Valeriya), Mahley, R. (Robert), Mangino, M. (Massimo), Manning, A.K. (Alisa), TeresaMartínez-Larrad, M. (María), McAteer, J.B. (Jarred), McCulloch, L.J. (Laura), McPherson, R. (Ruth), Meisinger, C. (Christa), Melzer, D. (David), Meyre, D. (David), Mitchell, B.D. (Braxton), Morken, M.A. (Mario), Mukherjee, S. (Sutapa), Naitza, S. (Silvia), Narisu, N. (Narisu), Neville, M.J. (Matthew), Oostra, B.A. (Ben), Orrù, M. (Marco), Pakyz, R. (Ruth), Palmer, C.N.A. (Colin), Paolisso, G. (Giuseppe), Pattaro, C. (Cristian), Pearson, D. (Daniel), Peden, J. (John), Pedersen, N.L. (Nancy), Perola, M. (Markus), Pfeiffer, A.F.H. (Andreas), Pichler, I. (Irene), Polasek, O. (Ozren), Posthuma, D. (Danielle), Potter, S.C. (Simon), Pouta, A. (Anneli), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Rice, K. (Kenneth), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Roden, M. (Michael), Rolandsson, O. (Olov), Sandbaek, A. (Annelli), Sandhu, M.S. (Manjinder), Sanna, S. (Serena), Sayer, A.A., Scheet, P. (Paul), Scott, L.J. (Laura), Seedorf, U. (Udo), Sharp, S.J. (Stephen), Shields, B.M. (Beverley), Sigursson, G. (Gunnar), Sijbrands, E.J.G. (Eric), Silveira, A. (Angela), Simpson, L. (Laila), Singleton, A. (Andrew), Smith, N.L. (Nicholas), Sovio, U. (Ulla), Swift, A.J. (Amy), Syddall, H. (Holly), Syvänen, A.-C. (Ann-Christine), Tanaka, T. (Toshiko), Thorand, B. (Barbara), Tichet, J. (Jean), Tönjes, A. (Anke), Tuomi, T. (Tiinamaija), Uitterlinden, A.G. (André), Willems van Dijk, J.A.P. (Ko), Hoek, M. (Mandy) van, Varma, D. (Dhiraj), Visvikis-Siest, S. (Sophie), Vitart, V. (Veronique), Vogelzangs, N. (Nicole), Waeber, G. (Gérard), Wagner, P.J. (Peter), Walley, A. (Andrew), BragiWalters, G., Ward, K.L. (Kim), Watkins, H. (Hugh), Weedon, M.N. (Michael), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), GYarnell, J.W. (John), Zeggini, E. (Eleftheria), Zelenika, D. (Diana), Zethelius, B. (Björn), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Borecki, I.B. (Ingrid), Loos, R.J.F. (Ruth), Meneton, P. (Pierre), Magnusson, P.K. (Patrik), Nathan, D.M. (David), Williams, G.H. (Gordon), Hattersley, A.T. (Andrew), Silander, K. (Kaisa), Salomaa, V. (Veikko), Bornstein, S.R. (Stefan), Schwarz, P. (Peter), Spranger, J. (Jürgen), Karpe, F. (Fredrik), Shuldiner, A.R. (Alan), Dedoussis, G.V. (George), Serrano-Ríos, M. (Manuel), Lind, L. (Lars), Palmer, C. (Cameron), Hu, F.B. (Frank), Franks, P.W. (Paul), Ebrahim, S. (Shanil), Marmot, M. (Michael), Kao, W.-H.L. (Linda), Pankow, J.S. (James), Sampson, M.J. (Michael), Kuusisto, J. (Johanna), Laakso, M. (Markku), Hansen, T. (Torben), Pramstaller, P.P. (Peter Paul), Wichmann, H.E. (Erich), Illig, T. (Thomas), Rudan, I. (Igor), Wright, A.F. (Alan), Stumvoll, M. (Michael), Campbell, H. (Harry), Wilson, J.F. (James), Bergman, R.N. (Richard), Buchanan, T.A. (Thomas), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Valle, T.T. (Timo), Altshuler, D. (David), Rotter, J.I. (Jerome), Siscovick, D.S. (David), Penninx, B.W.J.H. (Brenda), Boomsma, D.I. (Dorret), Deloukas, P. (Panagiotis), Spector, T.D. (Timothy), Frayling, T.M. (Timothy), Ferrucci, L. (Luigi), Kong, A. (Augustine), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), Cao, A. (Antonio), Scuteri, A. (Angelo), Schlessinger, D. (David), Uda, M. (Manuela), Ruokonen, A. (Aimo), Jarvelin, M.-R. (Marjo-Riitta), Waterworth, D. (Dawn), Vollenweider, P. (Peter), Peltonen, L. (Leena Johanna), Mooser, V. (Vincent), Abecasis, G.R. (Gonçalo), Wareham, N.J. (Nick), Sladek, R. (Rob), Froguel, P. (Philippe), Meigs, J.B. (James), Groop, L. (Leif), Watanabe, R.M. (Richard), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Florez, J.C. (Jose), and Barroso, I.E. (Inês)

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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