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1. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, A, Malik, R., Hachiya, T., Jürgenson, T., Namba, S., Posner, D.C., Kamanu, F.K., Koido, M., Grand, Q. Le, Shi, M., He, Y., Georgakis, M.K., Caro, I., Krebs, K., Liaw, Y.C., Vaura, F.C., Lin, K., Winsvold, B.S., Srinivasasainagendra, V., Parodi, L., Bae, H.J., Chauhan, G., Chong, M.R., Tomppo, L., Akinyemi, R., Roshchupkin, G.V., Habib, N., Jee, Y.H., Thomassen, J.Q., Abedi, V., Cárcel-Márquez, J., Nygaard, M., Leonard, H.L., Yang, C., Yonova-Doing, E., Knol, M.J., Lewis, A.J., Judy, R.L., Ago, T., Amouyel, P., Armstrong, N.D., Bakker, M.K., Bartz, T.M., Bennett, D.A., Bis, J.C., Bordes, C., Børte, S., Cain, A., Ridker, P.M., Cho, K., Chen, Z., Cruchaga, C., Cole, J.W., Jager, P.L., Cid, R. de, Endres, M., Ferreira, L.E., Geerlings, M.I., Gasca, N.C., Gudnason, V., Hata, J., He, J., Heath, A.K., Ho, Y.L., Havulinna, A.S., Hopewell, J.C., Hyacinth, H.I., Inouye, M., Jacob, M.A., Jeon, C.E., Jern, C., Kamouchi, M., Keene, K.L., Kitazono, T., Kittner, S.J., Konuma, T., Kumar, A., Lacaze, P., Launer, L.J., Lee, K.J., Lepik, K., Li, J, Li, L, Manichaikul, A., Markus, H.S., Marston, N.A., Meitinger, T., Mitchell, B.D., Montellano, F.A., Morisaki, T., Mosley, T.H., Nalls, M.A., Nordestgaard, B.G., O'Donnell, M.J., Okada, Y., Onland-Moret, N.C., Ovbiagele, B., Peters, A., Psaty, B.M., Rich, S.S., Tuladhar, A.M., Leeuw, F.E. de, Dichgans, M., Debette, S., Mishra, A, Malik, R., Hachiya, T., Jürgenson, T., Namba, S., Posner, D.C., Kamanu, F.K., Koido, M., Grand, Q. Le, Shi, M., He, Y., Georgakis, M.K., Caro, I., Krebs, K., Liaw, Y.C., Vaura, F.C., Lin, K., Winsvold, B.S., Srinivasasainagendra, V., Parodi, L., Bae, H.J., Chauhan, G., Chong, M.R., Tomppo, L., Akinyemi, R., Roshchupkin, G.V., Habib, N., Jee, Y.H., Thomassen, J.Q., Abedi, V., Cárcel-Márquez, J., Nygaard, M., Leonard, H.L., Yang, C., Yonova-Doing, E., Knol, M.J., Lewis, A.J., Judy, R.L., Ago, T., Amouyel, P., Armstrong, N.D., Bakker, M.K., Bartz, T.M., Bennett, D.A., Bis, J.C., Bordes, C., Børte, S., Cain, A., Ridker, P.M., Cho, K., Chen, Z., Cruchaga, C., Cole, J.W., Jager, P.L., Cid, R. de, Endres, M., Ferreira, L.E., Geerlings, M.I., Gasca, N.C., Gudnason, V., Hata, J., He, J., Heath, A.K., Ho, Y.L., Havulinna, A.S., Hopewell, J.C., Hyacinth, H.I., Inouye, M., Jacob, M.A., Jeon, C.E., Jern, C., Kamouchi, M., Keene, K.L., Kitazono, T., Kittner, S.J., Konuma, T., Kumar, A., Lacaze, P., Launer, L.J., Lee, K.J., Lepik, K., Li, J, Li, L, Manichaikul, A., Markus, H.S., Marston, N.A., Meitinger, T., Mitchell, B.D., Montellano, F.A., Morisaki, T., Mosley, T.H., Nalls, M.A., Nordestgaard, B.G., O'Donnell, M.J., Okada, Y., Onland-Moret, N.C., Ovbiagele, B., Peters, A., Psaty, B.M., Rich, S.S., Tuladhar, A.M., Leeuw, F.E. de, Dichgans, M., and Debette, S.

Abstract

Item does not contain fulltext, Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

2. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment

Author

Haynes, Richard, Jiang, Lixin, Hopewell, Jemma C, Li, Jing, Chen, Fang, Parish, Sarah, Landray, Martin J., Collins, Rory, Armitage, Jane, Collins, R., Armitage, J., Baigent, C., Chen, Z., Landray, M., Chen, Y., Jiang, L., Pedersen, T., Landray, M., Bowman, L., Chen, F., Hill, M., Haynes, R., Knott, C., Rahimi, K., Tobert, J., Sleight, P., Simpson, D., Parish, S., Baxter, A., Lay, M., Bray, C., Wincott, E., Leijenhorst, G., Skattebol, A., Moen, G., Mitchel, Y., Kuznetsova, O., MacMahon, S., Kjekshus, J., Hill, C., Lam, T.H., Sandercock, P., Peto, R., and Hopewell, J.C.

Published
2013
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7. Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelian randomization study

Author

Valdes-Marquez, E., Parish, S., Clarke, R., Stari, T., Worrall, B.B., Hopewell, J.C., and METASTROKE Consortium (Lichtner, P.)

Subjects
Causality, Stroke, Humans, Coronary Disease, Hyperlipidemias, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mendelian Randomization Analysis, Article, Brain Ischemia, Hypolipidemic Agents
Abstract

Objective To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach. Methods We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity. Results A 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32−1.68, p = 1.1 × 10−8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96−1.30, p = 0.14; p for heterogeneity = 2.6 × 10−3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84−1.33, p = 0.64; p for heterogeneity = 8.6 × 10−3) when compared with that for CHD. Conclusions In contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.

Published
2019

8. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, G., Adams, H.H.H., Satizabal, C.L., Bis, J.C., Teumer, A., Sargurupremraj, M., Hofer, E., Trompet, S., Hilal, S., Smith, A.V., Jian, X.Q., Malik, R., Traylor, M., Pulit, S.L., Amouyel, P., Mazoyer, B., Zhu, Y.C., Kaffashian, S., Schilling, S., Beecham, G.W., Montine, T.J., Schellenberg, G.D., Kjartansson, O., Gudnason, V., Knopman, D.S., Griswold, M.E., Windham, B.G., Gottesman, R.F., Mosley, T.H., Schmidt, R., Saba, Y., Schmidt, H., Takeuchi, F., Yamaguchi, S., Nabika, T., Kato, N., Rajan, K.B., Aggarwal, N.T., Jager, P.L. de, Evans, D.A., Psaty, B.M., Rotter, J.I., Rice, K., Lopez, O.L., Liao, J.M., Chen, C., Cheng, C.Y., Wong, T.Y., Ikram, M.K., Lee, S.J. van der, Amin, N., Chouraki, V., DeStefano, A.L., Aparicio, H.J., Romero, J.R., Maillard, P., DeCarli, C., Wardlaw, J.M., Hernandez, M.D.V., Luciano, M., Liewald, D., Deary, I.J., Starr, J.M., Bastin, M.E., Maniega, S.M., Slagboom, P.E., Beekman, M., Deelen, J., Uh, H.W., Lemmens, R., Brodaty, H., Wright, M.J., Ames, D., Boncoraglio, G.B., Hopewell, J.C., Beecham, A.H., Blanton, S.H., Wright, C.B., Sacco, R.L., Wen, W., Thalamuthu, A., Armstrong, N.J., Chong, E., Schofield, P.R., Kwok, J.B., Grond, J. van der, Stott, D.J., Ford, I., Jukema, J.W., Vernooij, M.W., Hofman, A., Uitterlinden, A.G., Lugt, A. van der, Wittfeld, K., Grabe, H.J., Hosten, N., Sarnowski, B. von, Volker, U., Levi, C., Jimenez-Conde, J., Sharma, P., Sudlow, C.L.M., Rosand, J., Woo, D., Cole, J.W., Meschia, J.F., Slowik, A., Thijs, V., Lindgren, A., Melander, O., Grewal, R.P., Rundek, T., Rexrode, K., Rothwell, P.M., Arnett, D.K., Jern, C., Johnson, J.A., Benavente, O.R., Wasssertheil-Smoller, S., Lee, J.M., Wong, Q., Mitchell, B.D., Rich, S.S., McArdle, P.F., Geerlings, M.I., Graaf, Y. van der, Bakker, P.I.W. de, Asselbergs, F.W., Srikanth, V., Thomson, R., McWhirter, R., Moran, C., Callisaya, M., Phan, T., Rutten-Jacobs, L.C.A., Bevan, S., Tzourio, C., Mather, K.A., Sachdev, P.S., Duijn, C.M. van, Worrall, B.B., Dichgans, M., Kittner, S.J., Markus, H.S., Ikram, M.A., Fornage, M., Launer, L.J., Seshadri, S., Longstreth, W.T., Debette, S., Stroke Genetics Network SiGN, ISGC, METASTROKE, ADGC, and CHARGE Consortium

Subjects
Meta-analysis, Mendelian Randomization, Blood Pressure, Polymorphisms, Genome-wide Association, Silent, Insights, Small Vessel Disease, Matter Hyperintensity Volume, Ischemic Stroke, Doenças Cardio e Cérebro-vasculares
Abstract

Collaborators (845): Astrid M. Vicente Free PMC article:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905/ Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. info:eu-repo/semantics/publishedVersion

Published
2019

9. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Author

Aparicio H.J., Del C. Valdes Hernandez M., Luciano M., Liewald D., Deary I.J., Starr J.M., Bastin M.E., Maniega S.M., Slagboom P.E., Beekman M., Deelen J., Uh H.-W., Lemmens R., Brodaty H., Wright M.J., Ames D., Boncoraglio G.B., Hopewell J.C., Beecham A.H., Blanton S.H., Wright C.B., Sacco R.L., Wen W., Thalamuthu A., Armstrong N.J., Chong E., Schofield P.R., Kwok J.B., van der Grond J., Stott D.J., Ford I., Jukema J.W., Vernooij M.W., Hofman A., Uitterlinden A.G., van der Lugt A., Wittfeld K., Grabe H.J., Hosten N., von Sarnowski B., Volker U., Levi C., Jimenez-Conde J., Sharma P., Sudlow C.L.M., Rosand J., Woo D., Cole J.W., Meschia J.F., Slowik A., Thijs V., Lindgren A., Melander O., Grewal R.P., Rundek T., Rexrode K., Rothwell P.M., Arnett D.K., Jern C., Johnson J.A., Benavente O.R., Wasssertheil-Smoller S., Lee J.-M., Wong Q., Mitchell B.D., Rich S.S., McArdle P.F., Geerlings M.I., van der Graaf Y., de Bakker P.I.W., Asselbergs F.W., Srikanth V., Thomson R., McWhirter R., Moran C., Callisaya M., Phan T., Rutten-Jacobs L.C.A., Bevan S., Tzourio C., Mather K.A., Sachdev P.S., van Duijn C.M., Worrall B.B., Dichgans M., Kittner S.J., Markus H.S., Ikram M.A., Fornage M., Launer L.J., Seshadri S., Longstreth W.T., Debette S., Chauhan G., Adams H.H.H., Satizabal C.L., Bis J.C., Teumer A., Sargurupremraj M., Hofer E., Trompet S., Hilal S., Smith A.V., Jian X., Malik R., Traylor M., Pulit S.L., Amouyel P., Mazoyer B., Zhu Y.-C., Kaffashian S., Schilling S., Beecham G.W., Montine T.J., Schellenberg G.D., Kjartansson O., Gudnason V., Knopman D.S., Griswold M.E., Windham B.G., Gottesman R.F., Mosley T.H., Schmidt R., Saba Y., Schmidt H., Takeuchi F., Yamaguchi S., Nabika T., Kato N., Rajan K.B., Aggarwal N.T., De Jager P.L., Evans D.A., Psaty B.M., Rotter J.I., Rice K., Lopez O.L., Liao J., Chen C., Cheng C.-Y., Wong T.Y., Ikram M.K., van der Lee S.J., Amin N., Chouraki V., Destefano A.L., Romero J.R., Maillard P., Decarli C., Wardlaw J.M., Aparicio H.J., Del C. Valdes Hernandez M., Luciano M., Liewald D., Deary I.J., Starr J.M., Bastin M.E., Maniega S.M., Slagboom P.E., Beekman M., Deelen J., Uh H.-W., Lemmens R., Brodaty H., Wright M.J., Ames D., Boncoraglio G.B., Hopewell J.C., Beecham A.H., Blanton S.H., Wright C.B., Sacco R.L., Wen W., Thalamuthu A., Armstrong N.J., Chong E., Schofield P.R., Kwok J.B., van der Grond J., Stott D.J., Ford I., Jukema J.W., Vernooij M.W., Hofman A., Uitterlinden A.G., van der Lugt A., Wittfeld K., Grabe H.J., Hosten N., von Sarnowski B., Volker U., Levi C., Jimenez-Conde J., Sharma P., Sudlow C.L.M., Rosand J., Woo D., Cole J.W., Meschia J.F., Slowik A., Thijs V., Lindgren A., Melander O., Grewal R.P., Rundek T., Rexrode K., Rothwell P.M., Arnett D.K., Jern C., Johnson J.A., Benavente O.R., Wasssertheil-Smoller S., Lee J.-M., Wong Q., Mitchell B.D., Rich S.S., McArdle P.F., Geerlings M.I., van der Graaf Y., de Bakker P.I.W., Asselbergs F.W., Srikanth V., Thomson R., McWhirter R., Moran C., Callisaya M., Phan T., Rutten-Jacobs L.C.A., Bevan S., Tzourio C., Mather K.A., Sachdev P.S., van Duijn C.M., Worrall B.B., Dichgans M., Kittner S.J., Markus H.S., Ikram M.A., Fornage M., Launer L.J., Seshadri S., Longstreth W.T., Debette S., Chauhan G., Adams H.H.H., Satizabal C.L., Bis J.C., Teumer A., Sargurupremraj M., Hofer E., Trompet S., Hilal S., Smith A.V., Jian X., Malik R., Traylor M., Pulit S.L., Amouyel P., Mazoyer B., Zhu Y.-C., Kaffashian S., Schilling S., Beecham G.W., Montine T.J., Schellenberg G.D., Kjartansson O., Gudnason V., Knopman D.S., Griswold M.E., Windham B.G., Gottesman R.F., Mosley T.H., Schmidt R., Saba Y., Schmidt H., Takeuchi F., Yamaguchi S., Nabika T., Kato N., Rajan K.B., Aggarwal N.T., De Jager P.L., Evans D.A., Psaty B.M., Rotter J.I., Rice K., Lopez O.L., Liao J., Chen C., Cheng C.-Y., Wong T.Y., Ikram M.K., van der Lee S.J., Amin N., Chouraki V., Destefano A.L., Romero J.R., Maillard P., Decarli C., and Wardlaw J.M.

Abstract

Objective To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10-8; and LINC00539/ZDHHC20, p = 5.82 x 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 x 10-25; p [SSBI] = 5.23 x 10-14 for hypertension), smoking (p[BI]= 4.4 x 10-10; p [SSBI] = 1.2 x 10 -4), diabetes (p[BI] = 1.7 x 10 -8; p [SSBI] = 2.8 x 10 -3), previous cardiovascular disease (p [BI] = 1.0 x 10-18; p [SSBI] = 2.3 x 10-7), stroke (p [BI] = 3.9 x 10-69; p [SSBI] = 3.2 x 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 x 10-157; p [SSBI] = 3.16 x 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p <= 0.0022), without indication of directional pleiotropy. Conclusion In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significa

Published
2019

11. Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

Author

Malik, R., Traylor, M., Pulit, S.L., Bevan, S., Hopewell, J.C., Holliday, E.G., Zhao, W., Abrantes, P., Amouyel, P., Attia, J.R., Battey, T.W., Berger, K., Boncoraglio, G.B., Chauhan, G., Cheng, Y.C., Chen, W.M., Clarke, R., Cotlarciuc, I., Debette, S., Falcone, G.J., Ferro, J.M., Gamble, D.M., Ilinca, A., Kittner, S.J., Kourkoulis, C.E., Lemmens, R., Levi, C.R., Lichtner, P., Lindgren, A., Liu, J., Meschia, J.F., Mitchell, B.D., Oliveira, S.A., Pera, J., Reiner, A.P., Rothwell, P.M., Sharma, P., Slowik, A., Sudlow, C.L., Tatlisumak, T., Thijs, V., Vicente, A.M., Woo, D., Seshadri, S., Saleheen, D., Rosand, J., Markus, H.S., Worrall, B.B., Dichgans, M., ISGC Analysis Group, METASTROKE collaboration, Wellcome Trust Case Control Consortium 2 (WTCCC2), and NINDS Stroke Genetics Network (SiGN)

Subjects
0301 basic medicine, medicine.medical_specialty, Genome-wide association study, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Doenças Cardio e Cérebro-vasculares, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Internal medicine, ABO blood group system, Genetic variation, Humans, Medicine, Cooperative Behavior, 1000 Genomes Project, Allele frequency, Stroke, Ischemic Stroke, Genetic association, Genetics, business.industry, Genetic Variation, Correction, medicine.disease, 030104 developmental biology, Case-Control Studies, Ischemic stroke, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Erratum in: Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. [Neurology. 2016] Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p , 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency ,5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p , 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

Published
2016

13. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Pattaro, C., Teumer, A., Gorski, M., Chu, A.Y., Li, M., Mijatovic, V., Garnaas, M., Tin, A., Sorice, R., Li, Y., Taliun, D., Olden, M., Foster, M., Yang, Q., Chen, M.-H., Pers, T.H., Johnson, A.D., Ko, Y.-A., Fuchsberger, C., Tayo, B., Nalls, M., Feitosa, M.F., Isaacs, A., Dehghan, A., D'Adamo, P., Adeyemo, A., Dieffenbach, A.K., Zonderman, A.B., Nolte, I.M., Van Der Most, P.J., Wright, A.F., Shuldiner, A.R., Morrison, A.C., Hofman, A., Smith, A.V., Dreisbach, A.W., Franke, A., Uitterlinden, A.G., Metspalu, A., Tonjes, A., Lupo, A., Robino, A., Johansson, Å., Demirkan, A., Kollerits, B., Freedman, B.I., Ponte, B., Oostra, B.A., Paulweber, B., Krämer, B.K., Mitchell, B.D., Buckley, B.M., Peralta, C.A., Hayward, C., Helmer, C., Rotimi, C.N., Shaffer, C.M., Müller, C., Sala, C., Van Duijn, C.M., Saint-Pierre, A., Ackermann, D., Shriner, D., Ruggiero, D., Toniolo, D., Lu, Y., Cusi, D., Czamara, D., Ellinghaus, D., Siscovick, D.S., Ruderfer, D., Gieger, C., Grallert, H., Rochtchina, E., Atkinson, E.J., Holliday, E.G., Boerwinkle, E., Salvi, E., Bottinger, E.P., Murgia, F., Rivadeneira, F., Ernst, F., Kronenberg, F., Hu, F.B., Navis, G.J., Curhan, G.C., Ehret, G.B., Homuth, G., Coassin, S., Thun, G.-A., Pistis, G., Gambaro, G., Malerba, G., Montgomery, G.W., Eiriksdottir, G., Jacobs, G., Li, G., Wichmann, H.-E., Campbell, H., Schmidt, H., Wallaschofski, H., Völzke, H., Brenner, H., Kroemer, H.K., Kramer, H., Lin, H., Leach, I.M., Ford, I., Guessous, I., Rudan, I., Prokopenko, I., Borecki, I., Heid, I.M., Kolcic, I., Persico, I., Jukema, J.W., Wilson, J.F., Felix, J.F., Divers, J., Lambert, J.-C., Stafford, J.M., Gaspoz, J.-M., Smith, J.A., Faul, J.D., Wang, J.J., Ding, J., Hirschhorn, J.N., Attia, J., Whitfield, J.B., Chalmers, J., Viikari, J., Coresh, J., Denny, J.C., Karjalainen, J., Fernandes, J.K., Endlich, K., Butterbach, K., Keene, K.L., Lohman, K., Portas, L., Launer, L.J., Lyytikäinen, L.-P., Yengo, L., Franke, L., Ferrucci, L., Rose, L.M., Kedenko, L., Rao, M., Struchalin, M., Kleber, M.E., Cavalieri, M., Haun, M., Cornelis, M.C., Ciullo, M., Pirastu, M., De Andrade, M., McEvoy, M.A., Woodward, M., Adam, M., Cocca, M., Nauck, M., Imboden, M., Waldenberger, M., Pruijm, M., Metzger, M., Stumvoll, M., Evans, M.K., Sale, M.M., Kähönen, M., Boban, M., Bochud, M., Rheinberger, M., Verweij, N., Bouatia-Naji, N., Martin, N.G., Hastie, N., Probst-Hensch, N., Soranzo, N., Devuyst, O., Raitakari, O., Gottesman, O., Franco, O.H., Polasek, O., Gasparini, P., Munroe, P.B., Ridker, P.M., Mitchell, P., Muntner, P., Meisinger, C., Smit, J.H., Abecasis, G.R., Adair, L.S., Alexander, M., Altshuler, D., Amin, N., Arking, D.E., Arora, P., Aulchenko, Y., Bakker, S.J.L., Bandinelli, S., Barroso, I., Beckmann, J.S., Beilby, J.P., Bergman, R.N., Bergmann, S., Bis, J.C., Boehnke, M., Bonnycastle, L.L., Bornstein, S.R., Bots, M.L., Bragg-Gresham, J.L., Brand, S.-M., Brand, E., Braund, P.S., Brown, M.J., Burton, P.R., Casas, J.P., Caulfield, M.J., Chakravarti, A., Chambers, J.C., Chandak, G.R., Chang, Y.-P.C., Charchar, F.J., Chaturvedi, N., Cho, Y.S., Clarke, R., Collins, F.S., Collins, R., Connell, J.M., Cooper, J.A., Cooper, M.N., Cooper, R.S., Corsi, A.M., Dörr, M., Dahgam, S., Danesh, J., Smith, G.D., Day, I.N.M., Deloukas, P., Denniff, M., Dominiczak, A.F., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, F.G.R., Fox, E.R., Frayling, T.M., Galan, P., Ganesh, S.K., Garcia, M., Gaunt, T.R., Glazer, N.L., Go, M.J., Goel, A., Grässler, J., Grobbee, D.E., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, B.-G., Hardy, R., Hartikainen, A.-L., Heath, S., Heckbert, S.R., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, A.A., Hilton, G., Hingorani, A.D., Hoffman Bolton, J.A., Hopewell, J.C., Howard, P., Humphries, S.E., Hunt, S.C., Hveem, K., Ikram, M.A., Islam, M., Iwai, N., Jarvelin, M.-R., Jackson, A.U., Jafar, T.H., Janipalli, C.S., Johnson, T., Kathiresan, S., Khaw, K.-T., Kim, H.-L., Kinra, S., Kita, Y., Kivimaki, M., Kooner, J.S., Kumar, M.J.K., Kuh, D., Kulkarni, S.R., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, E.G., Langefeld, C.D., Larson, M.G., Lathrop, M., Lawlor, D.A., Lawrence, R.W., Lee, J.-Y., Lee, N.R., Levy, D., Longstreth, W.T., Luan, J., Lucas, G., Ludwig, B., Mangino, M., Mani, K.R., Marmot, M.G., Mattace-Raso, F.U.S., Matullo, G., McArdle, W.L., McKenzie, C.A., Meitinger, T., Melander, O., Meneton, P., Meschia, J.F., Miki, T., Milaneschi, Y., Mohlke, K.L., Mooser, V., Morken, M.A., Morris, R.W., Mosley, T.H., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, K.-D.H., Nilsson, P., Nyberg, F., O'Donnell, C.J., Ogihara, T., Ohkubo, T., Okamura, T., Ong, R.T.-H., Ongen, H., Onland-Moret, N.C., O'Reilly, P.F., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, L.J., Palmer, N.D., Parker, A.N., Peden, J.F., Peltonen, L., Perola, M., Pihur, V., Platou, C.G.P., Plump, A., Prabhakaran, D., Psaty, B.M., Raffel, L.J., Rao, D.C., Rasheed, A., Ricceri, F., Rice, K.M., Rosengren, A., Rotter, J.I., Rudock, M.E., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, N.J., Schwartz, S.M., Schwarz, P.E.H., Scott, L.J., Scott, J., Scuteri, A., Sehmi, J.S., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, N.R.G., Sijbrands, E.J.G., Sim, X., Singleton, A., Sjögren, M., Smith, N.L., Artigas, M.S., Spector, T.D., Staessen, J.A., Stancakova, A., Steinle, N.I., Strachan, D.P., Stringham, H.M., Sun, Y.V., Swift, A.J., Tabara, Y., Tai, E.-S., Talmud, P.J., Taylor, A., Terzic, J., Thelle, D.S., Tobin, M.D., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, C.S.P.M., Umemura, S., Van Der Harst, P., Van Der Schouw, Y.T., Van Gilst, W.H., Vartiainen, E., Vasan, R.S., Veldre, G., Verwoert, G.C., Viigimaa, M., Vinay, D.G., Vineis, P., Voight, B.F., Vollenweider, P., Wagenknecht, L.E., Wain, L.V., Wang, X., Wang, T.J., Wareham, N.J., Watkins, H., Weder, A.B., Whincup, P.H., Wiggins, K.L., Witteman, J.C.M., Wong, A., Wu, Y., Yajnik, C.S., Yao, J., Young, J.H., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, J.H., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, J.-Y., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, S.-C., Wong, T.-Y., Liu, J., Young, T.L., Aung, T., Teo, Y.-Y., Kim, Y.J., Kang, D., Chen, C.-H., Tsai, F.-J., Chang, L.-C., Fann, S.-J.C., Mei, H., Hixson, J.E., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, Y.-T., Tanaka, T., Reilly, M.P., Schunkert, H., Assimes, T.L., Hall, A., Hengstenberg, C., König, I.R., Laaksonen, R., McPherson, R., Thompson, J.R., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, L.A., Halperin, E., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, G.A., Holm, H., Roberts, R., Stewart, A.F.R., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, K.J., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, H.J., Perret, C., Proust, C., Münzel, T.F., Barbalic, M., Chen, I.Y.-D., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, K.D., Volcik, K., Gretarsdottir, S., Gulcher, J.R., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, A.K., Willenborg, C., Böhm, B.O., Dobnig, H., Grammer, T.B., Hoffmann, M.M., Meinitzer, A., Winkelmann, B.R., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, S.B., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, H.H., Devaney, J., Burnett, M.S., Pichard, A.D., Kent, K.M., Satler, L., Lindsay, J.M., Waksman, R., Knouff, C.W., Waterworth, D.M., Walker, M.C., Epstein, S.E., Rader, D.J., Nelson, C.P., Wright, B.J., Balmforth, A.J., Ball, S.G., Loehr, L.R., Rosamond, W.D., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, Y.A., Stricker, B.H., Chang, P.P., Willerson, J.T., Felix, S.B., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R.J., Greiser, K.H., Deckers, J.W., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M.M., Werdan, K., Mitchell, G.F., Arnett, D.K., Gottdiener, J.S., Blettner, M., Friedrich, N., Kovacs, P., Wild, P.S., Froguel, P., Rettig, R., Mägi, R., Biffar, R., Schmidt, R., Middelberg, R.P.S., Carroll, R.J., Penninx, B.W., Scott, R.J., Katz, R., Sedaghat, S., Wild, S.H., Kardia, S.L.R., Ulivi, S., Hwang, S.-J., Enroth, S., Kloiber, S., Trompet, S., Stengel, B., Hancock, S.J., Turner, S.T., Rosas, S.E., Stracke, S., Harris, T.B., Zeller, T., Zemunik, T., Lehtimäki, T., Illig, T., Aspelund, T., Nikopensius, T., Esko, T., Gyllensten, U., Völker, U., Emilsson, V., Vitart, V., Aalto, V., Gudnason, V., Chouraki, V., Chen, W.-M., Igl, W., März, W., Koenig, W., Lieb, W., Loos, R.J.F., Liu, Y., Snieder, H., Pramstaller, P.P., Parsa, A., O'Connell, J.R., Susztak, K., Hamet, P., Tremblay, J., De Boer, I.H., Böger, C.A., Goessling, W., Chasman, D.I., Köttgen, A., Kao, W.H.L., Fox, C.S., UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Pattaro, C., Teumer, A., Gorski, M., Chu, A.Y., Li, M., Mijatovic, V., Garnaas, M., Tin, A., Sorice, R., Li, Y., Taliun, D., Olden, M., Foster, M., Yang, Q., Chen, M.-H., Pers, T.H., Johnson, A.D., Ko, Y.-A., Fuchsberger, C., Tayo, B., Nalls, M., Feitosa, M.F., Isaacs, A., Dehghan, A., D'Adamo, P., Adeyemo, A., Dieffenbach, A.K., Zonderman, A.B., Nolte, I.M., Van Der Most, P.J., Wright, A.F., Shuldiner, A.R., Morrison, A.C., Hofman, A., Smith, A.V., Dreisbach, A.W., Franke, A., Uitterlinden, A.G., Metspalu, A., Tonjes, A., Lupo, A., Robino, A., Johansson, Å., Demirkan, A., Kollerits, B., Freedman, B.I., Ponte, B., Oostra, B.A., Paulweber, B., Krämer, B.K., Mitchell, B.D., Buckley, B.M., Peralta, C.A., Hayward, C., Helmer, C., Rotimi, C.N., Shaffer, C.M., Müller, C., Sala, C., Van Duijn, C.M., Saint-Pierre, A., Ackermann, D., Shriner, D., Ruggiero, D., Toniolo, D., Lu, Y., Cusi, D., Czamara, D., Ellinghaus, D., Siscovick, D.S., Ruderfer, D., Gieger, C., Grallert, H., Rochtchina, E., Atkinson, E.J., Holliday, E.G., Boerwinkle, E., Salvi, E., Bottinger, E.P., Murgia, F., Rivadeneira, F., Ernst, F., Kronenberg, F., Hu, F.B., Navis, G.J., Curhan, G.C., Ehret, G.B., Homuth, G., Coassin, S., Thun, G.-A., Pistis, G., Gambaro, G., Malerba, G., Montgomery, G.W., Eiriksdottir, G., Jacobs, G., Li, G., Wichmann, H.-E., Campbell, H., Schmidt, H., Wallaschofski, H., Völzke, H., Brenner, H., Kroemer, H.K., Kramer, H., Lin, H., Leach, I.M., Ford, I., Guessous, I., Rudan, I., Prokopenko, I., Borecki, I., Heid, I.M., Kolcic, I., Persico, I., Jukema, J.W., Wilson, J.F., Felix, J.F., Divers, J., Lambert, J.-C., Stafford, J.M., Gaspoz, J.-M., Smith, J.A., Faul, J.D., Wang, J.J., Ding, J., Hirschhorn, J.N., Attia, J., Whitfield, J.B., Chalmers, J., Viikari, J., Coresh, J., Denny, J.C., Karjalainen, J., Fernandes, J.K., Endlich, K., Butterbach, K., Keene, K.L., Lohman, K., Portas, L., Launer, L.J., Lyytikäinen, L.-P., Yengo, L., Franke, L., Ferrucci, L., Rose, L.M., Kedenko, L., Rao, M., Struchalin, M., Kleber, M.E., Cavalieri, M., Haun, M., Cornelis, M.C., Ciullo, M., Pirastu, M., De Andrade, M., McEvoy, M.A., Woodward, M., Adam, M., Cocca, M., Nauck, M., Imboden, M., Waldenberger, M., Pruijm, M., Metzger, M., Stumvoll, M., Evans, M.K., Sale, M.M., Kähönen, M., Boban, M., Bochud, M., Rheinberger, M., Verweij, N., Bouatia-Naji, N., Martin, N.G., Hastie, N., Probst-Hensch, N., Soranzo, N., Devuyst, O., Raitakari, O., Gottesman, O., Franco, O.H., Polasek, O., Gasparini, P., Munroe, P.B., Ridker, P.M., Mitchell, P., Muntner, P., Meisinger, C., Smit, J.H., Abecasis, G.R., Adair, L.S., Alexander, M., Altshuler, D., Amin, N., Arking, D.E., Arora, P., Aulchenko, Y., Bakker, S.J.L., Bandinelli, S., Barroso, I., Beckmann, J.S., Beilby, J.P., Bergman, R.N., Bergmann, S., Bis, J.C., Boehnke, M., Bonnycastle, L.L., Bornstein, S.R., Bots, M.L., Bragg-Gresham, J.L., Brand, S.-M., Brand, E., Braund, P.S., Brown, M.J., Burton, P.R., Casas, J.P., Caulfield, M.J., Chakravarti, A., Chambers, J.C., Chandak, G.R., Chang, Y.-P.C., Charchar, F.J., Chaturvedi, N., Cho, Y.S., Clarke, R., Collins, F.S., Collins, R., Connell, J.M., Cooper, J.A., Cooper, M.N., Cooper, R.S., Corsi, A.M., Dörr, M., Dahgam, S., Danesh, J., Smith, G.D., Day, I.N.M., Deloukas, P., Denniff, M., Dominiczak, A.F., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, F.G.R., Fox, E.R., Frayling, T.M., Galan, P., Ganesh, S.K., Garcia, M., Gaunt, T.R., Glazer, N.L., Go, M.J., Goel, A., Grässler, J., Grobbee, D.E., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, B.-G., Hardy, R., Hartikainen, A.-L., Heath, S., Heckbert, S.R., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, A.A., Hilton, G., Hingorani, A.D., Hoffman Bolton, J.A., Hopewell, J.C., Howard, P., Humphries, S.E., Hunt, S.C., Hveem, K., Ikram, M.A., Islam, M., Iwai, N., Jarvelin, M.-R., Jackson, A.U., Jafar, T.H., Janipalli, C.S., Johnson, T., Kathiresan, S., Khaw, K.-T., Kim, H.-L., Kinra, S., Kita, Y., Kivimaki, M., Kooner, J.S., Kumar, M.J.K., Kuh, D., Kulkarni, S.R., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, E.G., Langefeld, C.D., Larson, M.G., Lathrop, M., Lawlor, D.A., Lawrence, R.W., Lee, J.-Y., Lee, N.R., Levy, D., Longstreth, W.T., Luan, J., Lucas, G., Ludwig, B., Mangino, M., Mani, K.R., Marmot, M.G., Mattace-Raso, F.U.S., Matullo, G., McArdle, W.L., McKenzie, C.A., Meitinger, T., Melander, O., Meneton, P., Meschia, J.F., Miki, T., Milaneschi, Y., Mohlke, K.L., Mooser, V., Morken, M.A., Morris, R.W., Mosley, T.H., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, K.-D.H., Nilsson, P., Nyberg, F., O'Donnell, C.J., Ogihara, T., Ohkubo, T., Okamura, T., Ong, R.T.-H., Ongen, H., Onland-Moret, N.C., O'Reilly, P.F., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, L.J., Palmer, N.D., Parker, A.N., Peden, J.F., Peltonen, L., Perola, M., Pihur, V., Platou, C.G.P., Plump, A., Prabhakaran, D., Psaty, B.M., Raffel, L.J., Rao, D.C., Rasheed, A., Ricceri, F., Rice, K.M., Rosengren, A., Rotter, J.I., Rudock, M.E., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, N.J., Schwartz, S.M., Schwarz, P.E.H., Scott, L.J., Scott, J., Scuteri, A., Sehmi, J.S., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, N.R.G., Sijbrands, E.J.G., Sim, X., Singleton, A., Sjögren, M., Smith, N.L., Artigas, M.S., Spector, T.D., Staessen, J.A., Stancakova, A., Steinle, N.I., Strachan, D.P., Stringham, H.M., Sun, Y.V., Swift, A.J., Tabara, Y., Tai, E.-S., Talmud, P.J., Taylor, A., Terzic, J., Thelle, D.S., Tobin, M.D., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, C.S.P.M., Umemura, S., Van Der Harst, P., Van Der Schouw, Y.T., Van Gilst, W.H., Vartiainen, E., Vasan, R.S., Veldre, G., Verwoert, G.C., Viigimaa, M., Vinay, D.G., Vineis, P., Voight, B.F., Vollenweider, P., Wagenknecht, L.E., Wain, L.V., Wang, X., Wang, T.J., Wareham, N.J., Watkins, H., Weder, A.B., Whincup, P.H., Wiggins, K.L., Witteman, J.C.M., Wong, A., Wu, Y., Yajnik, C.S., Yao, J., Young, J.H., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, J.H., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, J.-Y., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, S.-C., Wong, T.-Y., Liu, J., Young, T.L., Aung, T., Teo, Y.-Y., Kim, Y.J., Kang, D., Chen, C.-H., Tsai, F.-J., Chang, L.-C., Fann, S.-J.C., Mei, H., Hixson, J.E., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, Y.-T., Tanaka, T., Reilly, M.P., Schunkert, H., Assimes, T.L., Hall, A., Hengstenberg, C., König, I.R., Laaksonen, R., McPherson, R., Thompson, J.R., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, L.A., Halperin, E., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, G.A., Holm, H., Roberts, R., Stewart, A.F.R., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, K.J., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, H.J., Perret, C., Proust, C., Münzel, T.F., Barbalic, M., Chen, I.Y.-D., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, K.D., Volcik, K., Gretarsdottir, S., Gulcher, J.R., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, A.K., Willenborg, C., Böhm, B.O., Dobnig, H., Grammer, T.B., Hoffmann, M.M., Meinitzer, A., Winkelmann, B.R., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, S.B., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, H.H., Devaney, J., Burnett, M.S., Pichard, A.D., Kent, K.M., Satler, L., Lindsay, J.M., Waksman, R., Knouff, C.W., Waterworth, D.M., Walker, M.C., Epstein, S.E., Rader, D.J., Nelson, C.P., Wright, B.J., Balmforth, A.J., Ball, S.G., Loehr, L.R., Rosamond, W.D., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, Y.A., Stricker, B.H., Chang, P.P., Willerson, J.T., Felix, S.B., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R.J., Greiser, K.H., Deckers, J.W., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M.M., Werdan, K., Mitchell, G.F., Arnett, D.K., Gottdiener, J.S., Blettner, M., Friedrich, N., Kovacs, P., Wild, P.S., Froguel, P., Rettig, R., Mägi, R., Biffar, R., Schmidt, R., Middelberg, R.P.S., Carroll, R.J., Penninx, B.W., Scott, R.J., Katz, R., Sedaghat, S., Wild, S.H., Kardia, S.L.R., Ulivi, S., Hwang, S.-J., Enroth, S., Kloiber, S., Trompet, S., Stengel, B., Hancock, S.J., Turner, S.T., Rosas, S.E., Stracke, S., Harris, T.B., Zeller, T., Zemunik, T., Lehtimäki, T., Illig, T., Aspelund, T., Nikopensius, T., Esko, T., Gyllensten, U., Völker, U., Emilsson, V., Vitart, V., Aalto, V., Gudnason, V., Chouraki, V., Chen, W.-M., Igl, W., März, W., Koenig, W., Lieb, W., Loos, R.J.F., Liu, Y., Snieder, H., Pramstaller, P.P., Parsa, A., O'Connell, J.R., Susztak, K., Hamet, P., Tremblay, J., De Boer, I.H., Böger, C.A., Goessling, W., Chasman, D.I., Köttgen, A., Kao, W.H.L., and Fox, C.S.

Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved.

Published
2016

14. Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease

Author

Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A.D., Teumer, A., Reiner, A.P., Folkersen, L., Basu, S., Rudnicka, A.R., Trompet, S., Malarstig, A., Baumert, J., Bis, J.C., Guo, X.Q., Hottenga, J.J., Shin, S.Y., Lopez, L.M., Lahti, J., Tanaka, T., Yanek, L.R., Oudot-Mellakh, T., Wilson, J.F., Navarro, P., Huffman, J.E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A.F., Kolcic, I., Polasek, O., Wild, S.H., Campbell, H., Curb, J.D., Wallace, R., Liu, S.M., Eaton, C.B., Becker, D.M., Becker, L.C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S.E., Liewald, D.C., Starr, J.M., Williams, F.M.K., Grant, P.J., Spector, T.D., Strawbridge, R.J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A.G., Franco, O.H., Hofman, A., Dongen, J. van, Willemsen, G., Boomsma, D.I., Yao, J., Jenny, N.S., Haritunians, T., McKnight, B., Lumley, T., Taylor, K.D., Rotter, J.I., Psaty, B.M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M.G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K.V., Sanna, S., Schlessinger, D., Stott, D.J., Sattar, N., Buckley, B.M., Rumley, A., Lowe, G.D., McArdle, W.L., Chen, M.H., Tofler, G.H., Song, J., Boerwinkle, E., Folsom, A.R., Rose, L.M., Franco-Cereceda, A., Teichert, M., Ikram, M.A., Mosley, T.H., Bevan, S., Dichgans, M., Rothwell, P.M., Sudlow, C.L.M., Hopewell, J.C., Chambers, J.C., Saleheen, D., Kooner, J.S., Danesh, J., Nelson, C.P., Erdmann, J., Reilly, M.P., Kathiresan, S., Schunkert, H., Morange, P.E., Ferrucci, L., Eriksson, J.G., Jacobs, D., Deary, I.J., Soranzo, N., Witteman, J.C.M., Geus, E.J.C. de, Tracy, R.P., Hayward, C., Koenig, W., Cucca, F., Jukema, J.W., Eriksson, P., Seshadri, S., Markus, H.S., Watkins, H., Samani, N.J., Wallaschofski, H., Smith, N.L., Tregouet, D., Ridker, P.M., Tang, W.H., Strachan, D.P., Hamsten, A., O'Donnell, C.J., VTE Consortium, STROKE Consortium, WTCCC2, CD4 Consortium, CARDIoGRAM Consortium, Epidemiology, Cell biology, Urology, Internal Medicine, Immunology, Radiology & Nuclear Medicine, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes

Subjects
Male, Netherlands Twin Register (NTR), Pathology, Myocardial Infarction, Genome-wide association study, Coronary Artery Disease, Disease, VARIANTS, 030204 cardiovascular system & hematology, Fibrinogen, Genome, 0302 clinical medicine, Risk Factors, Genotype, ARTERY-DISEASE, GENE-EXPRESSION, Aged, 80 and over, Genetics, INDIVIDUAL PARTICIPANT METAANALYSIS, 0303 health sciences, Hispanic or Latino, Venous Thromboembolism, Middle Aged, 3. Good health, Stroke, Meta-analysis, Medical genetics, Female, HEALTH, Cardiology and Cardiovascular Medicine, medicine.drug, Adult, medicine.medical_specialty, cardiovascular diseases, fibrinogen, gene expression, genome-wide association study, Adolescent, Implementation Science [NCEBP 3], Black People, Polymorphism, Single Nucleotide, White People, Young Adult, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Physiology (medical), medicine, Humans, CORONARY-HEART-DISEASE, HEMOSTASIS, Genetic Predisposition to Disease, Aged, 030304 developmental biology, business.industry, Heritability, GENOTYPES, MYOCARDIAL-INFARCTION, Genetic Loci, RISK-FACTORS, business
Abstract

Background— Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion ( Methods and Results— We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant ( P −8 ) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions— We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Published
2013

15. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author

Wain, L.V., Verwoert, G.C., O'Reilly, P.F., Shi, G., Johnson, T., Johnson, A.D., Bochud, M., Rice, K.M., Henneman, P., Smith, A.V., Ehret, G.B., Amin, N., Larson, M.G., Mooser, V., Hadley, D., Dorr, M., Bis, J.C., Aspelund, T., Esko, T., Janssens, A.C.J.W., Zhao, J.H., Heath, S., Laan, M., Fu, J.Y., Pistis, G., Luan, J.A., Arora, P., Lucas, G., Pirastu, N., Pichler, I., Jackson, A.U., Webster, R.J., Zhang, F., Peden, J.F., Schmidt, H., Tanaka, T., Campbell, H., Igl, W., Milaneschi, Y., Hottenga, J.J., Vitart, V., Chasman, D.I., Trompet, S., Bragg-Gresham, J.L., Alizadeh, B.Z., Chambers, J.C., Guo, X.Q., Lehtimaki, T., Kuhnel, B., Lopez, L.M., Polasek, O., Boban, M., Nelson, C.P., Morrison, A.C., Pihur, V., Ganesh, S.K., Hofman, A., Kundu, S., Mattace-Raso, F.U.S., Rivadeneira, F., Sijbrands, E.J.G., Uitterlinden, A.G., Hwang, S.J., Vasan, R.S., Wang, T.J., Bergmann, S., Vollenweider, P., Waeber, G., Laitinen, J., Pouta, A., Zitting, P., McArdle, W.L., Kroemer, H.K., Volker, U., Volzke, H., Glazer, N.L., Taylor, K.D., Harris, T.B., Alavere, H., Haller, T., Keis, A., Tammesoo, M.L., Aulchenko, Y., Barroso, I., Khaw, K.T., Galan, P., Hercberg, S., Lathrop, M., Eyheramendy, S., Org, E., Sober, S., Lu, X.W., Nolte, I.M., Penninx, B.W., Corre, T., Masciullo, C., Sala, C., Groop, L., Voight, B.F., Melander, O., O'Donnell, C.J., Salomaa, V., d'Adamo, A.P., Fabretto, A., Faletra, F., Ulivi, S., Greco, M.F. del, Facheris, M., Collins, F.S., Bergman, R.N., Beilby, J.P., Hung, J., Musk, A.W., Mangino, M., Shin, S.Y., Soranzo, N., Watkins, H., Goel, A., Hamsten, A., Gider, P., Loitfelder, M., Zeginigg, M., Hernandez, D., Najjar, S.S., Navarro, P., Wild, S.H., Corsi, A.M., Singleton, A., Geus, E.J.C. de, Willemsen, G., Parker, A.N., Rose, L.M., Buckley, B., Stott, D., Orru, M., Uda, M., Klauw, M.M. van der, Zhang, W.H., Li, X.Z., Scott, J., Chen, Y.D.I., Burke, G.L., Kahonen, M., Viikari, J., Doring, A., Meitinger, T., Davies, G., Starr, J.M., Emilsson, V., Plump, A., Lindeman, J.H., Hoen, P.A.C. 't, Konig, I.R., Felix, J.F., Clarke, R., Hopewell, J.C., Ongen, H., Breteler, M., Debette, S., DeStefano, A.L., Fornage, M., Mitchell, G.F., Smith, N.L., Holm, H., Stefansson, K., Thorleifsson, G., Thorsteinsdottir, U., Samani, N.J., Preuss, M., Rudan, I., Hayward, C., Deary, I.J., Wichmann, H.E., Raitakari, O.T., Palmas, W., Kooner, J.S., Stolk, R.P., Jukema, J.W., Wright, A.F., Boomsma, D.I., Bandinelli, S., Gyllensten, U.B., Wilson, J.F., Ferrucci, L., Schmidt, R., Farrall, M., Spector, T.D., Palmer, L.J., Tuomilehto, J., Pfeufer, A., Gasparini, P., Siscovick, D., Altshuler, D., Loos, R.J.F., Toniolo, D., Snieder, H., Gieger, C., Meneton, P., Wareham, N.J., Oostra, B.A., Metspalu, A., Launer, L., Rettig, R., Strachan, D.P., Beckmann, J.S., Witteman, J.C.M., Erdmann, J., Dijk, K.W. van, Boerwinkle, E., Boehnke, M., Ridker, P.M., Jarvelin, M.R., Chakravarti, A., Abecasis, G.R., Gudnason, V., Newton-Cheh, C., Levy, D., Munroe, P.B., Psaty, B.M., Caulfield, M.J., Rao, D.C., Tobin, M.D., Elliott, P., Duijn, C.M. van, LifeLines Cohort Study, EchoGen Consortium, AortaGen Consortium, CHARGE Consortium Heart Failure, KidneyGen Consortium, CKDGen Consortium, Cardiogenics Consortium, and CardioGram

Published
2011

16. 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

17. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias

Author

Clarke, R., Bennett, D.A., Parish, S., Verhoef, P., Dotsch-Klerk, M., Lathrop, M., Xu, P., Nordestgaard, B.G., Holm, H., Hopewell, J.C., Saleheen, D., Tanaka, T., Anand, S.S., Chambers, J.C., Kleber, M.E., Ouwehand, W.H., Yamada, Y., Elbers, C.C., Peters, B., Stewart, A.F., Reilly, M.M., Thorand, B., Yusuf, S., Engert, J.C., Assimes, T.L., Kooner, J., Danesh, J., Watkins, H., Samani, N.J., Collins, R., Peto, R., Kluijtmans, L.A.J., et al., Clarke, R., Bennett, D.A., Parish, S., Verhoef, P., Dotsch-Klerk, M., Lathrop, M., Xu, P., Nordestgaard, B.G., Holm, H., Hopewell, J.C., Saleheen, D., Tanaka, T., Anand, S.S., Chambers, J.C., Kleber, M.E., Ouwehand, W.H., Yamada, Y., Elbers, C.C., Peters, B., Stewart, A.F., Reilly, M.M., Thorand, B., Yusuf, S., Engert, J.C., Assimes, T.L., Kooner, J., Danesh, J., Watkins, H., Samani, N.J., Collins, R., Peto, R., Kluijtmans, L.A.J., and et al.

Abstract

Contains fulltext : 108137.pdf (publisher's version ) (Open Access), BACKGROUND: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so "Mendelian randomization" studies using this variant as an instrumental variable could help test causality. METHODS AND FINDINGS: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04-1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09-1.28) in the 72 smaller ones (total 15,498 cases). CONCLUSIONS: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.

Published
2012

18. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author

Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., Wallace, C., Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., and Wallace, C.

Abstract

Contains fulltext : 98050.pdf (publisher's version ) (Open Access), Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in approximately 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other approximately 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular f

Published
2011

19. 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., 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., 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., Luan, J., Makrilakis, K., Manning, A.K., Martinez-Larrad, M.T., Narisu, N., Nastase Mannila, M., Ohrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A.A., Sennblad, B., Silveira, A., Stancakova, A., Stirrups, K., Swift, A.J., Syvanen, A.C., Tuomi, T., Hooft, F. van 't, Walker, M., Weedon, M.N., Xie, W., Zethelius, B., Ongen, H., Malarstig, A., Hopewell, J.C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Ostenson, C.G., Lind, L., Cooper, C.C., Serrano-Rios, M., Ferrannini, E., Forsen, T.J., Clarke, R., Franzosi, M.G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F.S., Laakso, M., Dermitzakis, E.T., Boehnke, M., McCarthy, M.I., Wareham, N.J., Groop, L., Pattou, F., Gloyn, A.L., Dedoussis, G.V., Lyssenko, V., Meigs, J.B., Barroso, I., Watanabe, R.M., Heijer, M. den, Kiemeney, L.A.L.M., et al., 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., 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., 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., Luan, J., Makrilakis, K., Manning, A.K., Martinez-Larrad, M.T., Narisu, N., Nastase Mannila, M., Ohrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A.A., Sennblad, B., Silveira, A., Stancakova, A., Stirrups, K., Swift, A.J., Syvanen, A.C., Tuomi, T., Hooft, F. van 't, Walker, M., Weedon, M.N., Xie, W., Zethelius, B., Ongen, H., Malarstig, A., Hopewell, J.C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Ostenson, C.G., Lind, L., Cooper, C.C., Serrano-Rios, M., Ferrannini, E., Forsen, T.J., Clarke, R., Franzosi, M.G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F.S., Laakso, M., Dermitzakis, E.T., Boehnke, M., McCarthy, M.I., Wareham, N.J., Groop, L., Pattou, F., Gloyn, A.L., Dedoussis, G.V., Lyssenko, V., Meigs, J.B., Barroso, I., Watanabe, R.M., Heijer, M. den, Kiemeney, L.A.L.M., and et al.

Abstract

Contains fulltext : 95931.pdf (publisher's version ) (Closed access), OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-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 approximately 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 x 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 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 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.

Published
2011

20. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Author

International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Ehret, G.B., Munroe, P.B., Rice, K.M., Bochud, M., Johnson, A.D., Chasman, D.I., Smith, A.V., Tobin, M.D., Verwoert, G.C., Hwang, S.J., Pihur, V., Vollenweider, P., O'Reilly, P.F., Amin, N., Bragg-Gresham, J.L., Teumer, A., Glazer, N.L., Launer, L., Zhao, J.H., Aulchenko, Y., Heath, S., Sõber, S., Parsa, A., Luan, J., Arora, P., Dehghan, A., Zhang, F., Lucas, G., Hicks, A.A., Jackson, A.U., Peden, J.F., Tanaka, T., Wild, S.H., Rudan, I., Igl, W., Milaneschi, Y., Parker, A.N., Fava, C., Chambers, J.C., Fox, E.R., Kumari, M., Go, M.J., van der Harst, P., Kao, W.H., Sjögren, M., Vinay, D.G., Alexander, M., Tabara, Y., Shaw-Hawkins, S., Whincup, P.H., Liu, Y., Shi, G., Kuusisto, J., Tayo, B., Seielstad, M., Sim, X., Nguyen, K.D., Lehtimäki, T., Matullo, G., Wu, Y., Gaunt, T.R., Onland-Moret, N.C., Cooper, M.N., Platou, C.G., Org, E., Hardy, R., Dahgam, S., Palmen, J., Vitart, V., Braund, P.S., Kuznetsova, T., Uiterwaal, C.S., Adeyemo, A., Palmas, W., Campbell, H., Ludwig, B., Tomaszewski, M., Tzoulaki, I., Palmer, N.D., Aspelund, T., Garcia, M., Chang, Y.P., O'Connell, J.R., Steinle, N.I., Grobbee, D.E., Arking, D.E., Kardia, S.L., Morrison, A.C., Hernandez, D., Najjar, S., McArdle, W.L., Hadley, D., Brown, M.J., Connell, J.M., Hingorani, A.D., Day, I.N., Lawlor, D.A., Beilby, J.P., Lawrence, R.W., Clarke, R., Hopewell, J.C., Ongen, H., Dreisbach, A.W., Li, Y., Young, J.H., Bis, J.C., Kähönen, M., Viikari, J., Adair, L.S., Lee, N.R., Chen, M.H., Olden, M., Pattaro, C., Bolton, J.A., Köttgen, A., Bergmann, S., Mooser, V., Chaturvedi, N., Frayling, T.M., Islam, M., Jafar, T.H., Erdmann, J., Kulkarni, S.R., Bornstein, S.R., Grässler, J., Groop, L., Voight, B.F., Kettunen, J., Howard, P., Taylor, A., Guarrera, S., Ricceri, F., Emilsson, V., Plump, A., Barroso, I., Khaw, K.T., Weder, A.B., Hunt, S.C., Sun, Y.V., Bergman, R.N., Collins, F.S., Bonnycastle, L.L., Scott, L.J., Stringham, H.M., Peltonen, L., Perola, M., Vartiainen, E., Brand, S.M., Staessen, J.A., Wang, T.J., Burton, P.R., Artigas, M.S., Dong, Y., Snieder, H., Wang, X., Zhu, H., Lohman, K.K., Rudock, M.E., Heckbert, S.R., Smith, N.L., Wiggins, K.L., Doumatey, A., Shriner, D., Veldre, G., Viigimaa, M., Kinra, S., Prabhakaran, D., Tripathy, V., Langefeld, C.D., Rosengren, A., Thelle, D.S., Corsi, A.M., Singleton, A., Forrester, T., Hilton, G., McKenzie, C.A., Salako, T., Iwai, N., Kita, Y., Ogihara, T., Ohkubo, T., Okamura, T., Ueshima, H., Umemura, S., Eyheramendy, S., Meitinger, T., Wichmann, H.E., Cho, Y.S., Kim, H.L., Lee, J.Y., Scott, J., Sehmi, J.S., Zhang, W., Hedblad, B., Nilsson, P., Smith, G.D., Wong, A., Narisu, N., Stančáková, A., Raffel, L.J., Yao, J., Kathiresan, S., O'Donnell, C.J., Schwartz, S.M., Ikram, M.A., Longstreth, W.T., Mosley, T.H., Seshadri, S., Shrine, N.R., Wain, L.V., Morken, M.A., Swift, A.J., Laitinen, J., Prokopenko, I., Zitting, P., Cooper, J.A., Humphries, S.E., Danesh, J., Rasheed, A., Goel, A., Hamsten, A., Watkins, H., Bakker, S.J., van Gilst, W.H., Janipalli, C.S., Mani, K.R., Yajnik, C.S., Hofman, A., Mattace-Raso, F.U., Oostra, B.A., Demirkan, A., Isaacs, A., Rivadeneira, F., Lakatta, E.G., Orru, M., Scuteri, A., Ala-Korpela, M., Kangas, A.J., Lyytikäinen, L.P., Soininen, P., Tukiainen, T., Würtz, P., Ong, R.T., Dörr, M., Kroemer, H.K., Völker, U., Völzke, H., Galan, P., Hercberg, S., Lathrop, M., Zelenika, D., Deloukas, P., Mangino, M., Spector, T.D., Zhai, G., Meschia, J.F., Nalls, M.A., Sharma, P., Terzic, J., Kumar, M.V., Denniff, M., Zukowska-Szczechowska, E., Wagenknecht, L.E., Fowkes, F.G., Charchar, F.J., Schwarz, P.E., Hayward, C., Guo, X., Rotimi, C., Bots, M.L., Brand, E., Samani, N.J., Polasek, O., Talmud, P.J., Nyberg, F., Kuh, D., Laan, M., Hveem, K., Palmer, L.J., van der Schouw, Y.T., Casas, J.P., Mohlke, K.L., Vineis, P., Raitakari, O., Ganesh, S.K., Wong, T.Y., Tai, E.S., Cooper, R.S., Laakso, M., Rao, D.C., Harris, T.B., Morris, R.W., Dominiczak, A.F., Kivimaki, M., Marmot, M.G., Miki, T., Saleheen, D., Chandak, G.R., Coresh, J., Navis, G., Salomaa, V., Han, B.G., Zhu, X., Kooner, J.S., Melander, O., Ridker, P.M., Bandinelli, S., Gyllensten, U.B., Wright, A.F., Wilson, J.F., Ferrucci, L., Farrall, M., Tuomilehto, J., Pramstaller, P.P., Elosua, R., Soranzo, N., Sijbrands, E.J., Altshuler, D., Loos, R.J., Shuldiner, A.R., Gieger, C., Meneton, P., Uitterlinden, A.G., Wareham, N.J., Gudnason, V., Rotter, J.I., Rettig, R., Uda, M., Strachan, D.P., Witteman, J.C., Hartikainen, A.L., Beckmann, J.S., Boerwinkle, E., Vasan, R.S., Boehnke, M., Larson, M.G., Järvelin, M.R., Psaty, B.M., Abecasis, G.R., Chakravarti, A., Elliott, P., van Duijn, C.M., Newton-Cheh, C., Levy, D., Caulfield, M.J., Johnson, T., Tang, H., Knowles, J., Hlatky, M., Fortmann, S., Assimes, T.L., Quertermous, T., Go, A., Iribarren, C., Absher, D., Risch, N., Myers, R., Sidney, S., Ziegler, A., Schillert, A., Bickel, C., Sinning, C., Rupprecht, H.J., Lackner, K., Wild, P., Schnabel, R., Blankenberg, S., Zeller, T., Münzel, T., Perret, C., Cambien, F., Tiret, L., Nicaud, V., Proust, C., Uitterlinden, A., van Duijn, C., Whitteman, J., Cupples, L.A., Demissie-Banjaw, S., Ramachandran, V., Smith, A., Folsom, A., Morrison, A., Chen, I.Y., Bis, J., Volcik, K., Rice, K., Taylor, K.D., Marciante, K., Smith, N., Glazer, N., Heckbert, S., Harris, T., Lumley, T., Kong, A., Thorleifsson, G., Thorgeirsson, G., Holm, H., Gulcher, J.R., Stefansson, K., Andersen, K., Gretarsdottir, S., Thorsteinsdottir, U., Preuss, M., Schreiber, S., König, I.R., Lieb, W., Hengstenberg, C., Schunkert, H., Fischer, M., Grosshennig, A., Medack, A., Stark, K., Linsel-Nitschke, P., Bruse, P., Aherrahrou, Z., Peters, A., Loley, C., Willenborg, C., Nahrstedt, J., Freyer, J., Gulde, S., Doering, A., Meisinger, C., Klopp, N., Illig, T., Meinitzer, A., Tomaschitz, A., Halperin, E., Dobnig, H., Scharnagl, H., Kleber, M., Laaksonen, R., Pilz, S., Grammer, T.B., Stojakovic, T., Renner, W., März, W., Böhm, B.O., Winkelmann, B.R., Winkler, K., Hoffmann, M.M., Siscovick, D.S., Musunuru, K., Barbalic, M., Guiducci, C., Burtt, N., Gabriel, S.B., Stewart, A.F., Wells, G.A., Chen, L., Jarinova, O., Roberts, R., McPherson, R., Dandona, S., Pichard, A.D., Rader, D.J., Devaney, J., Lindsay, J.M., Kent, K.M., Qu, L., Satler, L., Burnett, M.S., Li, M., Reilly, M.P., Wilensky, R., Waksman, R., Epstein, S., Matthai, W., Knouff, C.W., Waterworth, D.M., Hakonarson, H.H., Walker, M.C., Hall, A.S., Balmforth, A.J., Wright, B.J., Nelson, C., Thompson, J.R., Ball, S.G., Felix, J.F., Demissie, S., Loehr, L.R., Rosamond, W.D., Folsom, A.R., Benjamin, E., Aulchenko, Y.S., Haritunians, T., Couper, D., Murabito, J., Wang, Y.A., Stricker, B.H., Gottdiener, J.S., Chang, P.P., Willerson, J.T., Böger, C.A., Fuchsberger, C., Gao, X., Yang, Q., Schmidt, H., Ketkar, S., Paré, G., Atkinson, E.J., Lohman, K., Cornelis, M.C., Probst-Hensch, N.M., Kronenberg, F., Tönjes, A., Eiriksdottir, G., Launer, L.J., Rampersaud, E., Mitchell, B.D., Struchalin, M., Cavalieri, M., Giallauria, F., Metter, J., de Boer, J., Siscovick, D., Zillikens, M.C., Feitosa, M., Province, M., de Andrade, M., Turner, S.T., Wild, P.S., Schnabel, R.B., Wilde, S., Munzel, T.F., Leak, T.S., Koenig, W., Zgaga, L., Zemunik, T., Kolcic, I., Minelli, C., Hu, F.B., Johansson, A., Zaboli, G., Ellinghaus, D., Imboden, M., Nitsch, D., Brandstätter, A., Kollerits, B., Kedenko, L., Mägi, R., Stumvoll, M., Kovacs, P., Boban, M., Campbell, S., Endlich, K., Nauck, M., Badola, S., Curhan, G.C., Franke, A., Rochat, T., Paulweber, B., Wang, W., Schmidt, R., Shlipak, M.G., Borecki, I., Krämer, B.K., Gyllensten, U., Hastie, N., Heid, I.M., Fox, C.S., Felix, S.B., Watzinger, N., Homuth, G., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R.J., Greiser, K.H., Deckers, J.W., Stritzke, J., Lackner, K.J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M.M., Werdan, K., Mitchell, G.F., Arnett, D.K., Blettner, M., Friedrich, N., Benjamin, E.J., Lord, G.M., Gale, D.P., Wass, M.N., Ahmadi, K.R., Beckmann, J., Bilo, H.J., Cook, H.T., Cotlarciuc, I., Davey Smith, G., de Silva, R., Deng, G., Devuyst, O., Dikkeschei, L.D., Dimkovic, N., Dockrell, M., Dominiczak, A., Ebrahim, S., Eggermann, T., Floege, J., Forouhi, N.G., Gansevoort, R.T., Han, X., Homan van der Heide, J.J., Hepkema, B.G., Hernandez-Fuentes, M., Hypponen, E., de Jong, P.E., Kleefstra, N., Lagou, V., Lapsley, M., Luttropp, K., Maréchal, C., Nordfors, L., Penninx, B.W., Perucha, E., Pouta, A., Roderick, P.J., Ruokonen, A., Sanna, S., Schalling, M., Schlessinger, D., Schlieper, G., Seelen, M.A., Smit, J.H., Stenvinkel, P., Sternberg, M.J., Swaminathan, R., Ubink-Veltmaat, L.J., Wallace, C., Waterworth, D., Zerres, K., Waeber, G., Maxwell, P.H., McCarthy, M.I., Jarvelin, M.R., Lightstone, L., International Consortium for Blood 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Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Published
2011

21. ASSOCIATION STUDY OF CORONARY ARTERY DISEASE (CAD) USING HUMANCVD 50K CHIP

Author

Goel, A., primary, Clarke, R., additional, Hopewell, J.C., additional, Kyriakou, T., additional, Heath, S.C., additional, Parish, S., additional, Barlera, S., additional, Franzosi, M.G., additional, Rust, S., additional, Bennett, D., additional, Silveira, A., additional, Malarstig, A., additional, Green, F.R., additional, Lathrop, M., additional, Gigante, B., additional, Leander, K., additional, Faire, U., additional, Seedorf, U., additional, Hamsten, A., additional, Collins, R., additional, Watkins, H., additional, Farrall, M., additional, and Peden, J.F., additional

Published
2009
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