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1. Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

Author: Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, Chambers, JC, Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, and Chambers, JC
Abstract: South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
Published: 2022

2. Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

Author: Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, Chambers, JC, Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, and Chambers, JC
Published: 2022

3. Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Author: Patel, RS, Schmidt, AF, Tragante, V, McCubrey, RO, Holmes, MV, Howe, LJ, Direk, K, Åkerblom, A, Leander, K, Virani, SS, Kaminski, KA, Muehlschlegel, JD, Dubé, M-P, Allayee, H, Almgren, P, Alver, M, Baranova, EV, Behlouli, H, Boeckx, B, Braund, PS, Breitling, LP, Delgado, G, Duarte, NE, Dufresne, L, Eriksson, N, Foco, L, Gijsberts, CM, Gong, Y, Hartiala, J, Heydarpour, M, Hubacek, JA, Kleber, M, Kofink, D, Kuukasjärvi, P, Lee, V-V, Leiherer, A, Lenzini, PA, Levin, D, Lyytikäinen, L-P, Martinelli, N, Mons, U, Nelson, CP, Nikus, K, Pilbrow, AP, Ploski, R, Sun, YV, Tanck, MWT, Tang, WHW, Trompet, S, Van Der Laan, SW, Van Setten, J, Vilmundarson, RO, Anselmi, C, Vlachopoulou, E, Boerwinkle, E, Briguori, C, Carlquist, JF, Carruthers, KF, Casu, G, Deanfield, J, Deloukas, P, Dudbridge, F, Fitzpatrick, N, Gigante, B, James, S, Lokki, M-L, Lotufo, PA, Marziliano, N, Mordi, IR, Muhlestein, JB, Newton-Cheh, C, Pitha, J, Saely, CH, Samman-Tahhan, A, Sandesara, PB, Teren, A, Timmis, A, Van De Werf, F, Wauters, E, Wilde, AAM, Ford, I, Stott, DJ, Algra, A, Andreassi, MG, Ardissino, D, Arsenault, BJ, Ballantyne, CM, Bergmeijer, TO, Bezzina, CR, Body, SC, Bogaty, P, De Borst, GJ, Brenner, H, Burkhardt, R, Carpeggiani, C, Condorelli, G, Cooper-Dehoff, RM, Cresci, S, De Faire, U, Doughty, RN, Drexel, H, Engert, JC, Fox, KAA, Girelli, D, Hagström, E, Hazen, SL, Held, C, Hemingway, H, Hoefer, IE, Hovingh, GK, Johnson, JA, De Jong, PA, Jukema, JW, Kaczor, MP, Kähönen, M, Kettner, J, Kiliszek, M, Klungel, OH, Lagerqvist, B, Lambrechts, D, Laurikka, JO, Lehtimäki, T, Lindholm, D, Mahmoodi, BK, Der Zee, AH, McPherson, R, Melander, O, Metspalu, A, Pepinski, W, Olivieri, O, Opolski, G, Palmer, CN, Pasterkamp, G, Pepine, CJ, Pereira, AC, Pilote, L, Quyyumi, AA, Richards, AM, Sanak, M, Scholz, M, Siegbahn, A, Sinisalo, J, Smith, JG, Spertus, JA, Stewart, AFR, Szczeklik, W, Szpakowicz, A, Berg, JM, Thanassoulis, G, Thiery, J, Van Der Graaf, Y, Visseren, FLJ, Waltenberger, J, Van Der Harst, P, Tardif, J-C, Sattar, N, Lang, CC, Paré, G, Brophy, JM, Anderson, JL, März, W, Wallentin, L, Cameron, VA, Horne, BD, Samani, NJ, Hingorani, AD, and Asselbergs, FW
Subjects: Male, Myocardial Infarction, genetic risk factor, Coronary Artery Disease, Middle Aged, Article, chromosome 9p21, Gene Frequency, Risk Factors, Case-Control Studies, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, cardiovascular diseases, Chromosomes, Human, Pair 9, secondary prevention
Abstract: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
Published: 2019

4. ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels

Author: Zwarts, KY, Clee, SM, Zwinderman, AH, Engert, JC, Singaraja, R, Loubser, O, James, E, Roomp, K, Hudson, TJ, Jukema, JW, Kastelein, JJP, and Hayden, MR
Published: 2002

5. Association of Triglyceride-Related Genetic Variants With Mitral Annular Calcification

Author: Afshar, M, Luk, K, Do, R, Dufresnse, L, Owens, DS, Harris, TB, Peloso, GM, Kerr, KF, Wong, Q, Smith, AV, Budoff, MJ, Rotter, JI, Cupples, LA, Rich, SS, Engert, JC, Gudnason, V, O'Donnell, CJ, Post, WS, Thanassoulis, G, and Worki, CHARGEEC
Subjects: lipids, mitral valve, prevention, single nucleotide polymorphism, Mendelian randomization
Published: 2017
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6. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author: Butterworth, As, Braund, Ps, Farrall, M, Hardwick, Rj, Saleheen, D, Peden, Jf, Soranzo, N, Chambers, Jc, Sivapalaratnam, S, Kleber, Me, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, Tl, Ball, Sg, Balmforth, Aj, Barnes, Ta, Basart, H, Baumert, J, Bezzina, Cr, Boerwinkle, E, Boehm, Bo, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Cupples, La, de Jong JS, Diemert, P, Ejebe, K, Elbers, Cc, Elliott, P, Fornage, M, Franzosi, Mg, Frossard, P, Garner, S, Goel, A, Goodall, Ah, Hengstenberg, C, Hunt, Se, Kastelein, Jj, Klungel, Oh, Klüter, H, Koch, K, König, Ir, Kooner, As, Laaksonen, R, Lathrop, M, Li, M, Liu, K, Mcpherson, R, Musameh, Md, Musani, S, Nelson, Cp, O'Donnell, Cj, Ongen, H, Papanicolaou, G, Peters, A, Peters, Bj, Potter, S, Psaty, Bm, Qu, L, Rader, Dj, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, Js, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, Rs, Wilde, Aa, Willenborg, C, Winkelmann, Br, Zaidi, M, Zhang, W, Ziegler, A, de Bakker PI, Koenig, W, Mätz, W, Trip, Md, Reilly, Mp, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, As, Kooner, Js, Thompson, Sg, Thompson, Jr, Deloukas, P, Ouwehand, Wh, Watkins, H, Danesh, J, Samani, Nj, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, Lr, Henriques, Jp, Koch, Kt, de Winter RJ, Alings, M, Allaart, Cf, Gorgels, Ap, Verheugt, Fw, Mueller, M, Meisinger, C, Derohannessian, S, Mehta, Nn, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, Jc, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Silveira, A, Söderholm, B, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, Ml, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater Lleal, M, Sennblad, B, Strawbridge, R, Öhrvik, J, Zaman, Ks, Mallick, Nh, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, Jl, Ardissino, D, Becker, Lc, Becker, Dm, Berger, K, Bis, Jc, Boekholdt, Sm, Brown, Mj, Burnett, Ms, Buysschaert, I, Carlquist, Jf, Chen, L, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari NE, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, S, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Tennstedt, S, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Musunuru, K, Nahrstaedt, J, Nöthen, Mm, Olivieri, Oliviero, Peyvandi, F, Patel, Rs, Patterson, Cc, Quyyumi, Aa, Rallidis, Ls, Roosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Smith, Av, Smith, Tb, Snoep, Jd, Spertus, Ja, Stefansson, K, Stirrups, K, Stoll, M, Tang, Wh, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Awells, G, Wichmann, He, Witteman, Jc, Wright, Bj, Ye, S, Quertermous, T, März, W, Blankenberg, S, Roberts, R, Onland Moret NC, van Setten, J, Verschuren, Wm, Boer, Jm, Wijmenga, C, Hofker, Mh, Maitland van der Zee AH, de Boer, A, Grobbee, De, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd Jones, H, Lugauer, I, Lundmark, P, Moore, Js, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, Ac, Wallace, C., Cardiologie, RS: CAPHRI School for Public Health and Primary Care, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Pulmonology, and Medical Research Council (MRC)
Subjects: Male, Cancer Research, Candidate gene, Epidemiology, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, GENETICS & HEREDITY, Genetics (clinical), Genetics, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Middle Aged, 3. Good health, CYP17A1, Genetic Epidemiology, Genome-wide association, Myocardial-infarction, Susceptibility loci, Risk, Atherosclerosis, Metanalysis, Lipoprotein, Medicine, Female, Life Sciences & Biomedicine, Research Article, Asian Continental Ancestry Group, Adult, SUSCEPTIBILITY LOCI, lcsh:QH426-470, European Continental Ancestry Group, Biology, Polymorphism, Single Nucleotide, coronary artery disease, genetics, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, Genetic variation, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Molecular Biology, Gene, METAANALYSIS, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Cardiovascular Disease Epidemiology, Alleles, 030304 developmental biology, Aged, 0604 Genetics, Science & Technology, Case-control study, Genetic Variation, Human Genetics, Odds ratio, large-scale gene analysis, lcsh:Genetics, LIPOPROTEIN, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Case-Control Studies, Genetics of Disease, IBC 50K CAD Consortium, Developmental Biology, Genome-Wide Association Study
Abstract: 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 ∼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, Author Summary Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the 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) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.
Published: 2016

7. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease

Author: Markku S. Nieminen, Engert Jc, Anders Hamsten, Mark I. McCarthy, Khan Shah Zaman, Nilesh J. Samani, Silvia Pietri, Nadeem Hayat Mallick, Robert Clarke, Anna Helgadottir, John C. Chambers, Peter Sleight, Lasse Folkersen, Simon C. Potter, Fazal-ur-Rehman Memon, Gonçalo R. Abecasis, Shapour Jalilzadeh, Louise Bowman, Anders Mälarstig, Abdus Samad, Veikko Salomaa, John F. Peden, Juha Sinisalo, Jane Armitage, Asif Rasheed, Simona Barlera, Eirini V. Theodoraki, Suthesh Sivapalaratnam, Halit Ongen, Alison Offer, Theodosios Kyriakou, Hugh Watkins, John J.P. Kastelein, Philippe Froguel, Emma Gray, Tim D. Spector, Panos Deloukas, Mai-Lis Hellénius, Anders Gabrielsen, Martin Farrall, Jemma C. Hopewell, Mark Lathrop, Nicole Soranzo, Nabeel Ahmed, Bruna Gigante, Roberto Marchioli, Muhammad Azhar, Danish Saleheen, Salim Yusuf, Simon Heath, Anders Franco-Cereceda, Ulf de Faire, James Scott, Ann-Christine Syvänen, Marc Delepine, Maria Samuel, John Öhrvik, M. Ishaq, Fiona Green, Leena Peltonen, Paul Elliott, Moazzam Zaidi, Gerd Assmann, Rhian Gwilliam, Gianni Tognoni, Nabi Shah, John Danesh, Jorg Hager, Weihua Zhang, Mark J. Caulfield, Jaspal S. Kooner, Angad S. Kooner, Suzannah Bumpstead, Richard Peto, Francesca Gori, Maria Grazia Franzosi, Anuj Goel, Sarah E. Hunt, Karin Leander, Ferdinand M. van't Hooft, Angela Silveira, Rory Collins, Samuli Ripatti, Muhammed Murtaza, Pamela Linksted, Per Eriksson, George V. Dedoussis, Sarah Edkins, Sonia S. Anand, Philippe M. Frossard, Tomas Axelsson, Ali Raza Gardezi, Peter Donnelly, Mieke D. Trip, Sarah Parish, Stephan Rust, Udo Seedorf, Gunnar O Olsson, Kathy Stirrups, Rona J. Strawbridge, Joban Sehmi, Derrick A Bennett, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology
Subjects: Adult, Male, South asia, Quantitative Trait Loci, ADAMTS7 Protein, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, White People, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Genotype, Genetics, Medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Myocardial infarction, Genotyping, Genetics (clinical), 030304 developmental biology, Genetic association, Aged, Oligonucleotide Array Sequence Analysis, Platelet-Derived Growth Factor, 0303 health sciences, Lymphokines, business.industry, Heritability, Middle Aged, Sterol Esterase, medicine.disease, ADAM Proteins, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Imputation (genetics), Genome-Wide Association Study, Transcription Factors
Abstract: Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI) by 10% to 30%. The authors state that these loci explain only a small proportion of the predicted genetic risk and that all of the current loci for CAD and MI by GWAS have been discovered in European populations. The authors hypothesized that discovery of new susceptibility loci of smaller effect sizes would be aided by conducting much larger studies in addition to an emphasis on early-onset CAD and clearly defined clinical end points. Therefore, they assembled the Coronary Artery Disease (C4D) Genetics Consortium.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 4 large GWAS of CAD, 2 of European ancestry (PROCARDIS and HPS) and 2 of South Asian ancestry (PROMIS and LOLLIPOP), with ≈575 000 genotyped single-nucleotide polymorphisms (SNPs) in a discovery data set comprising 15 420 individuals with CAD (cases) (8424 Europeans and 6996 South Asians) and 15 062 control subjects. They observed little evidence for ancestry-specific associations, supporting the use of combined analyses. Furthermore, the authors state that because all individuals were genotyped on the same platform (whole-genome Illumina BeadChips), a meta-analysis of actual genotypes rather than imputed data enabled analysis of low-frequency variants (1% to 5%), which have been excluded from GWAS either because of sample size or because imputation has been required to combine data from different genotyping platforms. After the meta-analysis, they selected 59 SNPs from 50 loci that showed potential new associations from the meta-analysis of the European and South Asian studies (41 SNPs; P
Published: 2016

8. The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression

Author: Margarita Rivera, Wang X, Dipika Desai, Zoltán Kutalik, Hertzel C. Gerstein, Sven Bergmann, Waeber G, Zainab Samaan, Martin Preisig, Tanguy Corre, Sonia S. Anand, Changchun Xie, Mohan, Ian W. Craig, Guillaume Paré, Liu L, Peter Vollenweider, Engert Jc, Lehana Thabane, Salim Yusuf, David Meyre, Rafael Diaz, Xiaohe Zhang, and Sarah Cohen-Woods
Subjects: Male, medicine.medical_specialty, Candidate gene, Genotype, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Polymorphism, Single Nucleotide, FTO gene, Cellular and Molecular Neuroscience, Internal medicine, Genetic model, Humans, Medicine, Genetic Predisposition to Disease, Obesity, Molecular Biology, Depression (differential diagnoses), Depressive Disorder, Major, Depression, business.industry, Proteins, nutritional and metabolic diseases, Odds ratio, Middle Aged, medicine.disease, Psychiatry and Mental health, Phenotype, Endocrinology, Female, Metabolic syndrome, business
Abstract: Candidate gene and genome-wide association studies have not identified common variants, which are reliably associated with depression. The recent identification of obesity predisposing genes that are highly expressed in the brain raises the possibility of their genetic contribution to depression. As variation in the intron 1 of the fat mass- and obesity-associated (FTO) gene contributes to polygenic obesity, we assessed the possibility that FTO gene may contribute to depression in a cross-sectional multi-ethnic sample of 6561 depression cases and 21,932 controls selected from the EpiDREAM, INTERHEART, DeCC (depression case-control study) and Cohorte Lausannoise (CoLaus) studies. Major depression was defined according to DSM IV diagnostic criteria. Association analyses were performed under the additive genetic model. A meta-analysis of the four studies showed a significant inverse association between the obesity risk FTO rs9939609 A variant and depression (odds ratio=0.92 (0.89, 0.97), P=3 × 10(-4)) adjusted for age, sex, ethnicity/population structure and body-mass index (BMI) with no significant between-study heterogeneity (I(2)=0%, P=0.63). The FTO rs9939609 A variant was also associated with increased BMI in the four studies (β 0.30 (0.08, 0.51), P=0.0064) adjusted for age, sex and ethnicity/population structure. In conclusion, we provide the first evidence that the FTO rs9939609 A variant may be associated with a lower risk of depression independently of its effect on BMI. This study highlights the potential importance of obesity predisposing genes on depression.
Published: 2012
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9. Hypothesis-based analysis of gene-gene interactions and risk of myocardial infarction

Author: Lucas G1, Lluís-Ganella C, Subirana I, Musameh MD, Gonzalez JR, Nelson CP, Sentí M, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Schwartz SM, Siscovick D, O'Donnell CJ, Melander O, Salomaa V, Purcell S, Altshuler D, Samani NJ, Kathiresan S, Elosua R, Voight BF, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, Peltonen L, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Yee J, Friedlander Y, Marrugat J, Lucas G, Sala J, Ramos R, Meigs JB, Williams G, Nathan DM, MacRae CA, Havulinna AS, Berglund G, Deloukas P, Donnelly P, Farrall M, Gough SC, Hall AS, Hattersley AT, Hill AV, Kwiatkowski DP, Mathew CG, McCarthy MI, Ouwehand WH, Parkes M, Pembrey M, Rahman N, Stratton MR, Todd JA, Worthington J, Burton PR, Clayton DG, Cardon LR, Craddock N, Duncanson A, Barrett JC, Davison D, Easton D, Evans D, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Ball SG, Balmforth AJ, Barrett JH, Bishop D, Iles MM, Maqbool A, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Cardo LR, Cardin NJ, Ferreira T, Pereira-Gale J, Hallgrimsdottir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Lucas, G1, Lluís-Ganella, C, Subirana, I, Musameh, Md, Gonzalez, Jr, Nelson, Cp, Sentí, M, Myocardial Infarction Genetics, Consortium, Wellcome Trust Case Control, Consortium, Schwartz, Sm, Siscovick, D, O'Donnell, Cj, Melander, O, Salomaa, V, Purcell, S, Altshuler, D, Samani, Nj, Kathiresan, S, Elosua, R, Voight, Bf, Musunuru, K, Ardissino, D, Mannucci, Pm, Anand, S, Engert, Jc, Schunkert, H, Erdmann, J, Reilly, Mp, Rader, Dj, Morgan, T, Spertus, Ja, Stoll, M, Girelli, D, Mckeown, Pp, Patterson, Cc, Peltonen, L, Merlini, Pa, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, G, Galli, M, Ribichini, F, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Yee, J, Friedlander, Y, Marrugat, J, Lucas, G, Sala, J, Ramos, R, Meigs, Jb, Williams, G, Nathan, Dm, Macrae, Ca, Havulinna, A, Berglund, G, Deloukas, P, Donnelly, P, Farrall, M, Gough, Sc, Hall, A, Hattersley, At, Hill, Av, Kwiatkowski, Dp, Mathew, Cg, Mccarthy, Mi, Ouwehand, Wh, Parkes, M, Pembrey, M, Rahman, N, Stratton, Mr, Todd, Ja, Worthington, J, Burton, Pr, Clayton, Dg, Cardon, Lr, Craddock, N, Duncanson, A, Barrett, Jc, Davison, D, Easton, D, Evans, D, Leung, Ht, Marchini, Jl, Morris, Ap, Spencer, Cc, Tobin, Md, Attwood, Ap, Boorman, Jp, Cant, B, Everson, U, Hussey, Jm, Jolley, Jd, Knight, A, Koch, K, Meech, E, Nutland, S, Prowse, Cv, Stevens, He, Taylor, Nc, Walters, Gr, Walker, Nm, Watkins, Na, Winzer, T, Jones, Rw, Mcardle, Wl, Ring, Sm, Strachan, Dp, Ball, Sg, Balmforth, Aj, Barrett, Jh, Bishop, D, Iles, Mm, Maqbool, A, Braund, P, Dixon, Rj, Mangino, M, Stevens, S, Thompson, Jr, Bumpstead, Sj, Chaney, A, Downes, K, Ghori, Mj, Gwilliam, R, Hunt, Se, Inouye, M, Keniry, A, King, E, Mcginnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Widden, C, Cardo, Lr, Cardin, Nj, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, Ib, Howie, Bn, Su, Z, Teo, Yy, and Vukcevic, D
Subjects: Heredity, Epidemiology, Myocardial Infarction, lcsh:Medicine, Genome-wide association study, Coronary Artery Disease, Cardiovascular, Logistic regression, Risk Factors, Cardiac and Cardiovascular Systems, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, Medicine (all), 030305 genetics & heredity, Genomics, Genetic Epidemiology, Medicine, Research Article, Human, Risk, Genotype, Genotypes, Reproducibility of Result, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genome Analysis Tools, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Risk factor, Allele frequency, Genetic Association Studies, 030304 developmental biology, Genetic association, Biochemistry, Genetics and Molecular Biology (all), Complex Traits, Risk Factor, lcsh:R, Reproducibility of Results, Human Genetics, Epistasis, Genetic, Odds ratio, Genetic epidemiology, Agricultural and Biological Sciences (all), Genetics of Disease, Epistasis, Genetic Polymorphism, Infart de miocardi -- Epidemiologia, lcsh:Q, Population Genetics, Genome-Wide Association Study
Abstract: The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3–2.0, depending on allele frequency and interaction model).
Published: 2012
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10. Association of low-density lipoprotein cholesterol - Related genetic variants with aortic valve calcium and incident aortic stenosis

Author: Smith, JG, Luk, K, Schulz, CA, Engert, JC, Do, R, Hindy, G, Rukh, G, Dufresne, L, Almgren, P, Owens, DS, Harris, TB, Peloso, GM, Kerr, KF, Wong, Q, Smith, AV, Budoff, MJ, Rotter, JI, Cupples, LA, Rich, S, Kathiresan, S, Orho-Melander, M, Gudnason, V, O'Donnell, CJ, Post, WS, and Thanassoulis, G
Abstract: IMPORTANCE Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. Copyright 2014 American Medical Association. All rights reserved.OBJECTIVE To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease.DESIGN, SETTING, AND PARTICIPANTS Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28 461).MAIN OUTCOMES AND MEASURES Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.RESULTS The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P =.02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P =.007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P=.02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P =.03) and aortic stenosis (P =.009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P =.02).CONCLUSIONS AND RELEVANCE Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.
Published: 2014
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11. Erratum: Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height ((The American Journal of Human Genetics (2010) 88 (6-18))

Author: Lanktree, MB, Guo, Y, Murtaza, M, Glessner, JT, Bailey, SD, Onland-Moret, NC, Lettre, G, Ongen, H, Rajagopalan, R, Johnson, T, Shen, H, Nelson, CP, Klopp, N, Baumert, J, Padmanabhan, S, Pankratz, N, Pankow, JS, Shah, S, Taylor, K, Barnard, J, Peters, BJ, Maloney, CM, Lobmeyer, MT, Stanton, A, Zafarmand, MH, Romaine, SPR, Mehta, A, Van Iperen, EPA, Gong, Y, Price, TS, Smith, EN, Kim, CE, Li, YR, Asselbergs, FW, Atwood, LD, Bailey, KM, Bhatt, D, Bauer, F, Behr, ER, Bhangale, T, Boer, JMA, Boehm, BO, Bradfield, JP, Brown, M, Braund, PS, Burton, PR, Carty, C, Chandrupatla, HR, Chen, W, Connell, J, Dalgeorgou, C, De Boer, A, Drenos, F, Elbers, CC, Fang, JC, Fox, CS, Frackelton, EC, Fuchs, B, Furlong, CE, Gibson, Q, Gieger, C, Goel, A, Grobbee, DE, Hastie, C, Howard, PJ, Huang, G-H, Johnson, WC, Li, Q, Kleber, ME, Klein, BEK, Klein, R, Kooperberg, C, Ky, B, Lacroix, A, Lanken, P, Lathrop, M, Li, M, Marshall, V, Melander, O, Mentch, FD, Meyer, NJ, Monda, KL, Montpetit, A, Murugesan, G, Nakayama, K, Nondahl, D, Onipinla, A, Rafelt, S, Newhouse, SJ, Otieno, FG, Patel, SR, Putt, ME, Rodriguez, S, Safa, RN, Sawyer, DB, Schreiner, PJ, Simpson, C, Sivapalaratnam, S, Srinivasan, SR, Suver, C, Swergold, G, Sweitzer, NK, Thomas, KA, Thorand, B, Timpson, NJ, Tischfield, S, Tobin, M, Tomaszewski, M, Verschuren, WMM, Wallace, C, Winkelmann, B, Zhang, H, Zheng, D, Zhang, L, Zmuda, JM, Clarke, R, Balmforth, AJ, Danesh, J, Day, IN, Schork, NJ, De Bakker, PIW, Delles, C, Duggan, D, Hingorani, AD, Hirschhorn, JN, Hofker, MH, Humphries, SE, Kivimaki, M, Lawlor, DA, Kottke-Marchant, K, Mega, JL, Mitchell, BD, Morrow, DA, Palmen, J, Redline, S, Shields, DC, Shuldiner, AR, Sleiman, PM, Smith, GD, Farrall, M, Jamshidi, Y, Christiani, DC, Casas, JP, Hall, AS, Doevendans, PA, Christie, JD, Berenson, GS, Murray, SS, Illig, T, Dorn, GW, Cappola, TP, Boerwinkle, E, Sever, P, Rader, DJ, Reilly, MP, Caulfield, M, Talmud, PJ, Topol, E, Engert, JC, Wang, K, Dominiczak, A, Hamsten, A, Curtis, SP, Silverstein, RL, Lange, LA, Sabatine, MS, Trip, M, Saleheen, D, Peden, JF, Cruickshanks, KJ, März, W, O'Connell, JR, Klungel, OH, Wijmenga, C, Maitland-Van Der Zee, AH, Schadt, EE, Johnson, JA, Jarvik, GP, Papanicolaou, GJ, Grant, SFA, Munroe, PB, North, KE, Samani, NJ, Koenig, W, Gaunt, TR, Anand, SS, Van Der Schouw, YT, Soranzo, N, Fitzgerald, GA, Reiner, A, Hegele, RA, Hakonarson, H, and Keating, BJ
Published: 2012

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

Author: Holm, H, Thorsteinsdottir, U, Gretarsdottir, S, Gulcher, Jr, Thorgeirsson, G, Andersen, K, Stefansson, K, Parish, S, Bennett, Da, Clarke, R, Peto, R, Sleight, P, Collins, R, Hopewell, Jc, Watkins, H, Saleheen, D, Danesh, J, Rasheed, A, Zaidi, M, Frossard, P, Shah, N, Samuel, M, Tanaka, T, Ozaki, K, Sato, H, Sakata, Y, Komuro, I, Anand, Ss, Yusuf, S, Engert, Jc, Chambers, J, Kooner, J, Armitage, J, Samani, Nj, Braund, Ps, Nelson, Cp, Hall, As, Balmforth, A, Ball, Sg, Kleber, Me, Hoffmann, Mm, März, Wa, Bugert, P, Winkelmann, B, Böhm, Bo, Ouwehand, Wh, Sivapalaratnam, S, Kastelein, Jj, Trip, Md, Bezzina, Cr, Ouwehand, W, Yamada, Y, Elbers, Cc, Onland Moret NC, Bauer, F, van der Schouw YT, Verschuren, Wm, de Boer JM, Wijmenga, C, Hofker, Mh, de Bakker PI, Peters, Bj, Maitland van der Zee AH, de Boer, A, Klungel, Oh, Grobbee, De, Stewart, Af, Roberts, R, Mcpherson, R, Chen, L, Wells, Ga, Reilly, Mm, Li, M, Qu, I, Rader, Dj, Thorand, B, Illig, T, Peters, A, Koenig, W, Assimes, Tl, Fortmann, S, Iribarren, C, Abbate, R, Marcucci, R, Anderson, Jl, Zebrack, Js, Ardissino, D, Merlini, Fm, Bonomi, Ab, Ashfield Watt PA, Clark, Ze, van Bockxmeer FM, Brownrigg, L, Kooner, Js, Ferrer Antunes, C, Palmeiro, A, Fernandez Arcas, N, Reyes Engel, A, Folsom, Ar, Fowkes, Fg, Lee, Aj, Gaziano, Jm, Gemmati, D, Scapoli, Gl, Genest, J, Rozen, R, Girelli, Domenico, Corrocher, Roberto, Rossi, Gb, Meleady, R, Graham, Im, Gulec, S, Hopkins, Pn, Inbal, A, Selighson, U, Jukema, Jw, Litynsky, P, Kluijtmans, La, Kozich, V, Janosikova, B, Ma, J, Stampfer, Mj, Malinow, Mr, Meisel, C, Stangl, K, Morita, H, Nagai, R, Nakai, K, Nordestgaard, Bg, Zacho, J, Rimm, Eb, Schwartz, Sm, Siscovick, Ds, Silberberg, Js, Szczeklik, A, Domagala, Bt, Tanis, Bc, Rosendaal, Fm, Thogersen, Am, Nilsson, Tk, Todesco, L, Tokgozoglu, Sl, Tsai, My, Hanson, Nq, Verhoeff, Bj, Yamakawa Kobayashi, K, Hamaguchi, H., Medical Research Council (MRC), Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Pulmonology, and Other departments
Subjects: Homocysteine, coronary heart disease, methylene tetrahydrofolate reductase, Coronary Disease, FOLIC-ACID, 030204 cardiovascular system & hematology, PLACEBO-CONTROLLED TRIAL, Gastroenterology, Methylenetetrahydrofolate reductase gene, Placebo-controlled trial, Cardiovascular-disease, Mendelian randomization, Myocardial-infarction, Vascular-disease, Common mutation, B vitamins, Folic-acid, Ethnic-groups, chemistry.chemical_compound, MTHFR, risk factors, publication bias, GWA, genome-wide association, meta-analysis, 0302 clinical medicine, Polymorphism (computer science), 030212 general & internal medicine, Myocardial infarction, 11 Medical and Health Sciences, Genetics, biology, VASCULAR-DISEASE, General Medicine, ETHNIC-GROUPS, 3. Good health, CARDIOVASCULAR-DISEASE, Meta-analysis, MENDELIAN RANDOMIZATION, Medicine, MTHFR Studies Collaborative Group, Life Sciences & Biomedicine, Research Article, medicine.medical_specialty, Genotype, METHYLENETETRAHYDROFOLATE REDUCTASE GENE, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Medicine, General & Internal, Folic Acid, Bias, Internal medicine, General & Internal Medicine, medicine, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Science & Technology, Polymorphism, Genetic, business.industry, Case-control study, Odds ratio, Publication bias, medicine.disease, COMMON MUTATION, chemistry, MYOCARDIAL-INFARCTION, Methylenetetrahydrofolate reductase, biology.protein, B VITAMINS, business
Abstract: Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease., 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, Editors' Summary Background Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits (atherosclerotic plaques) coat the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant restriction of the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and sometimes fatal heart attacks. Many established risk factors for CHD, including smoking, physical inactivity, being overweight, and eating a fat-rich diet, can be modified by lifestyle changes. Another possible modifiable risk factor for CHD is a high blood level of the amino acid homocysteine. Methylene tetrahydofolate reductase, which is encoded by the MTHFR gene, uses folate to break down and remove homocysteine so fortification of cereals with folate can reduce population homocysteine blood levels. Pooled results from prospective observational studies that have looked for an association between homocysteine levels and later development of CHD suggest that the reduction in homocysteine levels that can be achieved by folate supplementation is associated with an 11% lower CHD risk. Why Was This Study Done? Prospective observational studies cannot prove that high homocysteine levels cause CHD because of confounding, the potential presence of other unknown shared characteristics that really cause CHD. However, an approach called “Mendelian randomization” can test whether high blood homocysteine causes CHD. A common genetic variant of the MTHFR gene—the C677T polymorphism—reduces MTHFR efficiency so TT homozygotes (individuals in whom both copies of the MTHFR gene have the nucleotide thymine at position 677; the human genome contains two copies of most genes) have 25% higher blood homocysteine levels than CC homozygotes. In meta-analyses (statistical pooling of the results of several studies) of published Mendelian randomized studies, TT homozygotes have a higher CHD risk than CC homozygotes. Because gene variants are inherited randomly, they are not subject to confounding, so this result suggests that high blood homocysteine causes CHD. But what if only Mendelian randomization studies that found an association have been published? Such publication bias would affect this aggregate result. Here, the researchers investigate the association of the MTHFR C677T polymorphism with CHD in unpublished datasets that have analyzed this polymorphism incidentally during other genetic studies. What Did the Researchers Do and Find? The researchers obtained 19 unpublished datasets that contained data on the MTHFR C677T polymorphism in thousands of people with and without CHD. Meta-analysis of these datasets indicates that the excess CHD risk in TT homozygotes compared to CC homozygotes was 2% (much lower than predicted from the prospective observational studies), a nonsignificant difference (that is, it could have occurred by chance). When the probable folate status of the study populations (based on when national folic acid fortification legislation came into effect) was taken into account, there was still no evidence that TT homozygotes had an excess CHD risk. By contrast, in an updated meta-analysis of 86 published studies of the association of the polymorphism with CHD, the excess CHD risk in TT homozygotes compared to CC homozygotes was 15%. Finally, in a meta-analysis of randomized trials on the use of vitamin B supplements for homocysteine reduction, folate supplementation had no significant effect on the 5-year incidence of CHD. What Do These Findings Mean? These analyses of unpublished datasets are consistent with lifelong moderate elevation of homocysteine levels having no significant effect on CHD risk. In other words, these findings indicate that circulating homocysteine levels within the normal range are not causally related to CHD risk. The meta-analysis of the randomized trials of folate supplementation also supports this conclusion. So why is there a discrepancy between these findings and those of meta-analyses of published Mendelian randomization studies? The discrepancy is too large to be dismissed as a chance finding, suggest the researchers, but could be the result of publication bias—some studies might have been prioritized for publication because of the positive nature of their results whereas the unpublished datasets used in this study would not have been affected by any failure to publish null results. Overall, these findings reveal a serious example of publication bias and argue against the use of folate supplements as a means of reducing CHD risk. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001177. The American Heart Association provides information about CHD and tips on keeping the heart healthy; it also provides information on homocysteine, folic acid, and CHD, general information on supplements and heart health, and personal stories about CHD The UK National Health Service Choices website provides information about CHD, including personal stories about CHD Information is available from the British Heart Foundation on heart disease and keeping the heart healthy The US National Heart Lung and Blood Institute also provides information on CHD (in English and Spanish) MedlinePlus provides links to many other sources of information on CHD (in English and Spanish) Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Published: 2012

13. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Author: Wensley, F, Gao, P, Burgess, S, Kaptoge, S, Di Angelantonio, E, Shah, T, Engert, JC, Clarke, R, Davey-Smith, G, Nordestgaard, BG, Saleheen, D, Samani, NJ, Sandhu, M, Anand, S, Pepys, MB, Smeeth, L, Whittaker, J, Casas, JP, Thompson, SG, Hingorani, AD, Danesh, J, Eiriksdottir, G, Harris, TB, Launer, LJ, Gudnason, V, Folsom, AR, Andrews, G, Ballantyne, CM, Hall, AS, Braund, PS, Balmforth, AJ, Whincup, PH, Morris, R, Lawlor, DA, Lowe, GDO, Timpson, N, Ebrahim, S, Ben-Shlomo, Y, Tybjaerg-Hansen, A, Zacho, J, Brown, M, Ricketts, SL, Ashford, S, Lange, L, Reiner, A, Cushman, M, Tracy, R, Wu, C, Ge, J, Zou, Y, Sun, A, Hung, J, McQuillan, B, Thompson, P, Beilby, J, Warrington, N, Palmer, LJ, Wanner, C, Drechsler, C, Hoffmann, MM, Fowkes, FGR, Tzoulaki, I, Kumari, M, Miller, M, Marmot, M, Onland-Moret, C, van der Schouw, YT, Boer, JM, Wijmenga, C, Khaw, K-T, Vasan, RS, Schnabel, RB, Yamamoto, JF, Benjamin, EJ, Schunkert, H, Erdmann, J, Koenig, IR, Hengstenberg, C, Chiodini, B, Franzosi, MG, Pietri, S, Gori, F, Rudock, M, Liu, Y, Lohman, K, Humphries, SE, Hamsten, A, Norman, PE, Hankey, GJ, Jamrozik, K, Rimm, EB, Pai, JK, Psaty, BM, Heckbert, SR, Bis, JC, Yusuf, S, Xie, C, Collins, R, Bennett, D, Kooner, J, Chambers, J, Elliott, P, Maerz, W, Kleber, ME, Boehm, BO, Winkelmann, BR, Melander, O, Berglund, G, Koenig, W, Thorand, B, Baumert, J, Peters, A, Manson, J, Cooper, JA, Talmud, PJ, Ladenvall, P, Johansson, L, Jansson, J-H, Hallmans, G, Reilly, MP, Qu, L, Li, M, Rader, DJ, Watkins, H, Hopewell, J, Frossard, P, Sattar, N, Robertson, M, Shepherd, J, Schaefer, E, Hofman, A, Witteman, JCM, Kardys, I, Dehghan, A, de Faire, U, Bennet, A, Gigante, B, Leander, K, Peters, B, Maitland-van der Zee, AH, de Boer, A, Klungel, O, Greenland, P, Dai, J, Liu, S, Brunner, E, Kivimaki, M, O'Reilly, D, Ford, I, Packard, CJ, Dis, CRPCH, CIHDS, CC, CUPID, C, Medical Research Council (MRC), University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Pulmonology, and Coronel Institute of Occupational Health
Subjects: Male, Coronary Disease, Bioinformatics, Gene Frequency, MARKERS, Polymorphism (computer science), Risk Factors, Myocardial infarction, Prospective Studies, Prospective cohort study, General Environmental Science, Genetics, RISK, biology, General Engineering, Mendelian Randomization Analysis, General Medicine, Middle Aged, C-Reactive Protein, 1117 Public Health And Health Services, CARDIOVASCULAR-DISEASE, Meta-analysis, symbols, Female, Life Sciences & Biomedicine, Ischaemic Heart Disease, Polymorphism, Single Nucleotide, Molecular Genetics, symbols.namesake, Medicine, General & Internal, INFLAMMATION, Drugs: Cardiovascular System, General & Internal Medicine, medicine, INSTRUMENTAL VARIABLES, Humans, C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC), Allele frequency, METAANALYSIS, POLYMORPHISMS, Science & Technology, business.industry, Research, C-reactive protein, medicine.disease, GENE, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Mendelian inheritance, biology.protein, General Earth and Planetary Sciences, business
Abstract: Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P
Published: 2011

14. 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, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract: OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-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 × 10−4), improved β-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.
Published: 2011
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15. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author: Schunkert, H, König, Ir, Kathiresan, S, Reilly, Mp, Assimes, Tl, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Balmforth, Aj, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Boerwinkle, E, Braund, Ps, Brown, Mj, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, Mokhtari, Ne, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Kastelein, Jj, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Laaksonen, R, Lambrechts, D, Leander, K, Lettre, G, Li, M, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peters, A, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Soranzo, N, Spertus, Ja, Stark, K, Stirrups, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Thorleifsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Witteman, Jc, Wright, Bj, Ye, S, Zeller, T, Ziegler, A, Cambien, F, Goodall, Ah, Cupples, La, Quertermous, T, März, W, Hengstenberg, C, Blankenberg, S, Ouwehand, Wh, Hall, As, Deloukas, P, Thompson, Jr, Stefansson, K, Roberts, R, Thorsteinsdottir, U, O'Donnell, Cj, Mcpherson, R, Erdmann, J, the CARDIoGRAM Consortium, Samani, N. J., Epidemiology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine
Subjects: Adult, Male, Multifunction cardiogram, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Genetic determinism, artery disease, Article, Coronary artery disease, Gene Frequency, SDG 3 - Good Health and Well-being, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Allele, Genotyping, Allele frequency, coronary, Alleles, Genetics (clinical), Aged, Genetic association, business.industry, Case-control study, Middle Aged, medicine.disease, coronary artery disease, Large-scale association analysis, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract: 1. The CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics. 2011;43:333–338. ### Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants that are associated with risk of coronary artery disease (CAD) and myocardial infarction (MI). The authors state that the current loci discovered in CAD and MI GWAS explain only a small fraction of the heritability of this complex disease. The authors hypothesized that a larger study would provide more power to discover common variants with modest effect sizes. Therefore, they formed the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium, which consisted of data from 14 GWAS of CAD and MI.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 14 GWAS of CAD comprising 22 233 cases and 64 762 control subjects, all of European ancestry. CAD was defined angiographically in a subset (n=7364) and by history in the entire sample. Presence of MI ranged from 48.1% to 100% of each cohort. After the meta-analysis, they genotyped the lead single-nucleotide polymorphisms (SNPs) within the most promising (defined a priori as P 90% power to detect effect sizes observed in the GWAS meta-analysis. Finally, to understand potential mechanisms and intermediate pathways by which novel loci may mediate risk, the authors interrogated 3 genome-wide studies that also assessed gene expression in multiple tissues, using human cell lines, a genome-wide map of allelic expression imbalance, and other human disease traits. ### Principal Findings The analysis of approximately 135 000 individuals more than doubled the number of loci with CAD association, yielding 13 previously unidentified loci and confirming at …
Published: 2011

16. Defining the role of common variation in the genomic and biological architecture of adult human height.

Author: Genomics (eMEMERGEGE) Consortium, MIGen Consortium, PAGEGE Consortium, LifeLines Cohort Study, Electronic Medical, Records, McCarty, CA., Starren, J., Peissig, P., Berg, R., Rasmussen, L., Linneman, J., Miller, A., Choudary, V., Chen, L., Waudby, C., Kitchner, T., Reeser, J., Fost, N., Ritchie, M., Wilke, RA., Chisholm, RL., Avila, PC., Greenland, P., Hayes, M., Kho, A., Kibbe, WA., Lemke, AA., Lowe, WL., Smith, ME., Wolf, WA., Pacheco, JA., Thompson, WK., Humowiecki, J., Law, M., Chute, C., Kullo, I., Koenig, B., de Andrade, M., Bielinski, S., Pathak, J., Savova, G., Wu, J., Henriksen, J., Ding, K., Hart, L., Palbicki, J., Larson, EB., Newton, K., Ludman, E., Spangler, L., Hart, G., Carrell, D., Jarvik, G., Crane, P., Burke, W., Fullerton, SM., Trinidad, SB., Carlson, C., Hutchinson, F., McDavid, A., Roden, DM., Clayton, E., Haines, JL., Masys, DR., Churchill, LR., Cornfield, D., Crawford, D., Darbar, D., Denny, JC., Malin, BA., Ritchie, MD., Schildcrout, JS., Xu, H., Ramirez, AH., Basford, M., Pulley, J., Alizadeh, B., de Boer RA., Boezen, HM., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, HL., van der Klauw MM., Navis, G., Ormel, J., Postma, DS., Rosmalen, JG., Slaets, JP., Snieder, H., Stolk, RP., Wolffenbuttel, BH., Wijmenga, C., Kathiresan, S., Voight, BF., Purcell, S., Musunuru, K., Ardissino, D., Mannucci, PM., Anand, S., Engert, JC., Samani, NJ., Schunkert, H., Erdmann, J., Reilly, MP., Rader, DJ., Morgan, T., Spertus, JA., Stoll, M., Girelli, D., McKeown, PP., Patterson, CC., Siscovick, DS., O'Donnell, CJ., Elosua, R., Peltonen, L., Salomaa, V., Schwartz, SM., Melander, O., Altshuler, D., Merlini, PA., Berzuini, C., Bernardinelli, L., Peyvandi, F., Tubaro, M., Celli, P., Ferrario, M., Fetiveau, R., Marziliano, N., Casari, G., Galli, M., Ribichini, F., Rossi, M., Bernardi, F., Zonzin, P., Piazza, A., Yee, J., Friedlander, Y., Marrugat, J., Lucas, G., Subirana, I., Sala, J., Ramos, R., Meigs, JB., Williams, G., Nathan, DM., MacRae, CA., Havulinna, AS., Berglund, G., Voight, B., Hirschhorn, JN., Asselta, R., Duga, S., Spreafico, M., Daly, MJ., Nemesh, J., Korn, JM., McCarroll, SA., Surti, A., Guiducci, C., Gianniny, L., Mirel, D., Parkin, M., Burtt, N., Gabriel, SB., Thompson, JR., Braund, PS., Wright, BJ., Balmforth, AJ., Ball, SG., Hall, AS., Schunkert, I., Linsel-Nitschke, P., Lieb, W., Ziegler, A., König, IR., Hengstenberg, C., Fischer, M., Stark, K., Grosshennig, A., Preuss, M., Wichmann, HE., Schreiber, S., Ouwehand, W., Deloukas, P., Scholz, M., Cambien, F., Goodall, A., Li, M., Chen, Z., Wilensky, R., Matthai, W., Qasim, A., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Mooser, V., Epstein, SE., Scheffold, T., Berger, K., Huge, A., Martinelli, N., Olivieri, O., Corrocher, R., König, I., Hólm, H., Thorleifsson, G., Thorsteinsdottir, U., Stefansson, K., Do, R., Xie, C., Siscovick, D., Matise, T., Buyske, S., Higashio, J., Williams, R., Nato, A., Ambite, JL., Deelman, E., Manolio, T., Hindorff, L., North, KE., Heiss, G., Taylor, K., Franceschini, N., Avery, C., Graff, M., Lin, D., Quibrera, M., Cochran, B., Kao, L., Umans, J., Cole, S., MacCluer, J., Person, S., Pankow, J., Gross, M., Boerwinkle, E., Fornage, M., Durda, P., Jenny, N., Patsy, B., Arnold, A., Buzkova, P., Haines, J., Murdock, D., Glenn, K., Brown-Gentry, K., Thornton-Wells, T., Dumitrescu, L., Jeff, J., Bush, WS., Mitchell, SL., Goodloe, R., Wilson, S., Boston, J., Malinowski, J., Restrepo, N., Oetjens, M., Fowke, J., Zheng, W., Spencer, K., Pendergrass, S., Le Marchand£££Loïc£££ L., Wilkens, L., Park, L., Tiirikainen, M., Kolonel, L., Lim, U., Cheng, I., Wang, H., Shohet, R., Haiman, C., Stram, D., Henderson, B., Monroe, K., Schumacher, F., Kooperberg, C., Peters, U., Anderson, G., Prentice, R., LaCroix, A., Wu, C., Carty, C., Gong, J., Rosse, S., Young, A., Haessler, J., Kocarnik, J., Lin, Y., Jackson, R., Duggan, D., Kuller, L., Wood, A.R., Esko, T., Yang, J., Vedantam, S., Pers, T.H., Gustafsson, S., Chu, A.Y., Estrada, K., Luan, J., Kutalik, Z., Amin, N., Buchkovich, M.L., Croteau-Chonka, D.C., Day, F.R., Duan, Y., Fall, T., Fehrmann, R., Ferreira, T., Jackson, A.U., Karjalainen, J., Lo, K.S., Locke, A.E., Mägi, R., Mihailov, E., Porcu, E., Randall, J.C., Scherag, A., Vinkhuyzen, A.A., Westra, H.J., Winkler, T.W., Workalemahu, T., Zhao, J.H., Absher, D., Albrecht, E., Anderson, D., Baron, J., Beekman, M., Demirkan, A., Ehret, G.B., Feenstra, B., Feitosa, M.F., Fischer, K., Fraser, R.M., Goel, A., Justice, A.E., Kanoni, S., Kleber, M.E., Kristiansson, K., Lotay, V., Lui, J.C., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Nalls, M.A., Nyholt, D.R., Palmer, C.D., Pasko, D., Pechlivanis, S., Prokopenko, I., Ried, J.S., Ripke, S., Shungin, D., Stancáková, A., Strawbridge, R.J., Sung, Y.J., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S.W., van Setten, J., Van Vliet-Ostaptchouk, J.V., Wang, Z., Yengo, L., Zhang, W., Afzal, U., Arnlöv, J., Arscott, G.M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A.J., Berne, C., Blüher, M., Bolton, J.L., Böttcher, Y., Boyd, H.A., Buckley, B.M., Caspersen, I.H., Chines, P.S., Clarke, R., Claudi-Boehm, S., Cooper, M., Daw, E.W., De Jong, P.A., Deelen, J., Delgado, G., Denny, J.C., Dhonukshe-Rutten, R., Dimitriou, M., Doney, A.S., Dörr, M., Eklund, N., Eury, E., Folkersen, L., Garcia, M.E., Geller, F., Giedraitis, V., Go, A.S., Grallert, H., Grammer, T.B., Gräßler, J., Grönberg, H., de Groot, L.C., Groves, C.J., Hall, P., Haller, T., Hallmans, G., Hannemann, A., Hartman, C.A., Hassinen, M., Hayward, C., Heard-Costa, N.L., Helmer, Q., Hemani, G., Henders, A.K., Hillege, H.L., Hlatky, M.A., Hoffmann, W., Hoffmann, P., Holmen, O., Houwing-Duistermaat, J.J., Illig, T., Isaacs, A., James, A.L., Johansen, B., Johansson, Å., Jolley, J., Juliusdottir, T., Junttila, J., Kho, A.N., Kinnunen, L., Klopp, N., Kocher, T., Kratzer, W., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Lu, Y., Lyssenko, V., Magnusson, P.K., Mahajan, A., Maillard, M., McArdle, W.L., McKenzie, C.A., McLachlan, S., McLaren, P.J., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, K.L., Morken, M.A., Müller, G., Müller-Nurasyid, M., Musk, A.W., Narisu, N., Nauck, M., Nolte, I.M., Nöthen, M.M., Oozageer, L., Pilz, S., Rayner, N.W., Renstrom, F., Robertson, N.R., Rose, L.M., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F.R., Scott, R.A., Sehmi, J., Seufferlein, T., Shi, J., Silventoinen, K., Smit, J.H., Smith, A.V., Smolonska, J., Stanton, A.V., Stirrups, K., Stott, D.J., Stringham, H.M., Sundström, J., Swertz, M.A., Syvänen, A.C., Tayo, B.O., Tyrer, J.P., van Dijk, S., van Schoor, N.M., van der Velde, N., van Heemst, D., van Oort, F.V., Vermeulen, S.H., Verweij, N., Vonk, J.M., Waite, L.L., Waldenberger, M., Wennauer, R., Wilkens, L.R., Willenborg, C., Wilsgaard, T., Wojczynski, M.K., Wong, A., Wright, A.F., Zhang, Q., Arveiler, D., Bakker, S.J., Beilby, J., Bergman, R.N., Bergmann, S., Biffar, R., Blangero, J., Boomsma, D.I., Bornstein, S.R., Bovet, P., Brambilla, P., Brown, M.J., Campbell, H., Caulfield, M.J., Chakravarti, A., Collins, R., Collins, F.S., Crawford, D.C., Cupples, L.A., Danesh, J., de Faire, U., den Ruijter, H.M., Erbel, R., Eriksson, J.G., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N.G., Forrester, T., Gansevoort, R.T., Gejman, P.V., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, D.W., Hall, A.S., Harris, T.B., Hattersley, A.T., Heath, A.C., Hicks, A.A., Hindorff, L.A., Hingorani, A.D., Hofman, A., Hovingh, G.K., Humphries, S.E., Hunt, S.C., Hypponen, E., Jacobs, K.B., Jarvelin, M.R., Jousilahti, P., Jula, A.M., Kaprio, J., Kastelein, J.J., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, S.M., Kiemeney, L.A., Kooner, J.S., Koskinen, S., Kovacs, P., Kraja, A.T., Kumari, M., Kuusisto, J., Lakka, T.A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, P.A., Männistö, S., Manunta, P., Marette, A., Matise, T.C., McKnight, B., Meitinger, T., Moll, F.L., Montgomery, G.W., Morris, A.D., Morris, A.P., Murray, J.C., Nelis, M., Ohlsson, C., Oldehinkel, A.J., Ong, K.K., Ouwehand, W.H., Pasterkamp, G., Peters, A., Pramstaller, P.P., Price, J.F., Qi, L., Raitakari, O.T., Rankinen, T., Rao, D.C., Rice, T.K., Rudan, I., Samani, N.J., Saramies, J., Sarzynski, M.A., Schwarz, P.E., Sebert, S., Sever, P., Shuldiner, A.R., Sinisalo, J., Steinthorsdottir, V., Stolk, R.P., Tardif, J.C., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M.C., Amouyel, P., Asselbergs, F.W., Assimes, T.L., Bochud, M., Boehm, B.O., Bottinger, E.P., Bouchard, C., Cauchi, S., Chambers, J.C., Chanock, S.J., Cooper, R.S., de Bakker, P.I., Dedoussis, G., Ferrucci, L., Franks, P.W., Froguel, P., Groop, L.C., Haiman, C.A., Hamsten, A., Hayes, M.G., Hui, J., Hunter, D.J., Hveem, K., Jukema, J.W., Kaplan, R.C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N.G., März, W., Melbye, M., Moebus, S., Munroe, P.B., Njølstad, I., Oostra, B.A., Palmer, C.N., Pedersen, N.L., Perola, M., Pérusse, L., Powell, J.E., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, P.M., Rivadeneira, F., Rotter, J.I., Saaristo, T.E., Saleheen, D., Schlessinger, D., Slagboom, P.E., Spector, T.D., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., Völzke, H., Walker, M., Wareham, N.J., Watkins, H., Wichmann, H.E., Wilson, J.F., Zanen, P., Heid, I.M., Lindgren, C.M., Mohlke, K.L., Speliotes, E.K., Barroso, I., Fox, C.S., North, K.E., Strachan, D.P., Beckmann, J.S., Berndt, S.I., Boehnke, M., Borecki, I.B., McCarthy, M.I., Metspalu, A., Uitterlinden, A.G., van Duijn, C.M., Willer, C.J., Price, A.L., Lettre, G., Loos, R.J., Weedon, M.N., Ingelsson, E., O'Connell, J.R., Abecasis, G.R., Chasman, D.I., Goddard, M.E., Visscher, P.M., Hirschhorn, J.N., Frayling, T.M., Genomics (eMEMERGEGE) Consortium, MIGen Consortium, PAGEGE Consortium, LifeLines Cohort Study, Electronic Medical, Records, McCarty, CA., Starren, J., Peissig, P., Berg, R., Rasmussen, L., Linneman, J., Miller, A., Choudary, V., Chen, L., Waudby, C., Kitchner, T., Reeser, J., Fost, N., Ritchie, M., Wilke, RA., Chisholm, RL., Avila, PC., Greenland, P., Hayes, M., Kho, A., Kibbe, WA., Lemke, AA., Lowe, WL., Smith, ME., Wolf, WA., Pacheco, JA., Thompson, WK., Humowiecki, J., Law, M., Chute, C., Kullo, I., Koenig, B., de Andrade, M., Bielinski, S., Pathak, J., Savova, G., Wu, J., Henriksen, J., Ding, K., Hart, L., Palbicki, J., Larson, EB., Newton, K., Ludman, E., Spangler, L., Hart, G., Carrell, D., Jarvik, G., Crane, P., Burke, W., Fullerton, SM., Trinidad, SB., Carlson, C., Hutchinson, F., McDavid, A., Roden, DM., Clayton, E., Haines, JL., Masys, DR., Churchill, LR., Cornfield, D., Crawford, D., Darbar, D., Denny, JC., Malin, BA., Ritchie, MD., Schildcrout, JS., Xu, H., Ramirez, AH., Basford, M., Pulley, J., Alizadeh, B., de Boer RA., Boezen, HM., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, HL., van der Klauw MM., Navis, G., Ormel, J., Postma, DS., Rosmalen, JG., Slaets, JP., Snieder, H., Stolk, RP., Wolffenbuttel, BH., Wijmenga, C., Kathiresan, S., Voight, BF., Purcell, S., Musunuru, K., Ardissino, D., Mannucci, PM., Anand, S., Engert, JC., Samani, NJ., Schunkert, H., Erdmann, J., Reilly, MP., Rader, DJ., Morgan, T., Spertus, JA., Stoll, M., Girelli, D., McKeown, PP., Patterson, CC., Siscovick, DS., O'Donnell, CJ., Elosua, R., Peltonen, L., Salomaa, V., Schwartz, SM., Melander, O., Altshuler, D., Merlini, PA., Berzuini, C., Bernardinelli, L., Peyvandi, F., Tubaro, M., Celli, P., Ferrario, M., Fetiveau, R., Marziliano, N., Casari, G., Galli, M., Ribichini, F., Rossi, M., Bernardi, F., Zonzin, P., Piazza, A., Yee, J., Friedlander, Y., Marrugat, J., Lucas, G., Subirana, I., Sala, J., Ramos, R., Meigs, JB., Williams, G., Nathan, DM., MacRae, CA., Havulinna, AS., Berglund, G., Voight, B., Hirschhorn, JN., Asselta, R., Duga, S., Spreafico, M., Daly, MJ., Nemesh, J., Korn, JM., McCarroll, SA., Surti, A., Guiducci, C., Gianniny, L., Mirel, D., Parkin, M., Burtt, N., Gabriel, SB., Thompson, JR., Braund, PS., Wright, BJ., Balmforth, AJ., Ball, SG., Hall, AS., Schunkert, I., Linsel-Nitschke, P., Lieb, W., Ziegler, A., König, IR., Hengstenberg, C., Fischer, M., Stark, K., Grosshennig, A., Preuss, M., Wichmann, HE., Schreiber, S., Ouwehand, W., Deloukas, P., Scholz, M., Cambien, F., Goodall, A., Li, M., Chen, Z., Wilensky, R., Matthai, W., Qasim, A., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Mooser, V., Epstein, SE., Scheffold, T., Berger, K., Huge, A., Martinelli, N., Olivieri, O., Corrocher, R., König, I., Hólm, H., Thorleifsson, G., Thorsteinsdottir, U., Stefansson, K., Do, R., Xie, C., Siscovick, D., Matise, T., Buyske, S., Higashio, J., Williams, R., Nato, A., Ambite, JL., Deelman, E., Manolio, T., Hindorff, L., North, KE., Heiss, G., Taylor, K., Franceschini, N., Avery, C., Graff, M., Lin, D., Quibrera, M., Cochran, B., Kao, L., Umans, J., Cole, S., MacCluer, J., Person, S., Pankow, J., Gross, M., Boerwinkle, E., Fornage, M., Durda, P., Jenny, N., Patsy, B., Arnold, A., Buzkova, P., Haines, J., Murdock, D., Glenn, K., Brown-Gentry, K., Thornton-Wells, T., Dumitrescu, L., Jeff, J., Bush, WS., Mitchell, SL., Goodloe, R., Wilson, S., Boston, J., Malinowski, J., Restrepo, N., Oetjens, M., Fowke, J., Zheng, W., Spencer, K., Pendergrass, S., Le Marchand£££Loïc£££ L., Wilkens, L., Park, L., Tiirikainen, M., Kolonel, L., Lim, U., Cheng, I., Wang, H., Shohet, R., Haiman, C., Stram, D., Henderson, B., Monroe, K., Schumacher, F., Kooperberg, C., Peters, U., Anderson, G., Prentice, R., LaCroix, A., Wu, C., Carty, C., Gong, J., Rosse, S., Young, A., Haessler, J., Kocarnik, J., Lin, Y., Jackson, R., Duggan, D., Kuller, L., Wood, A.R., Esko, T., Yang, J., Vedantam, S., Pers, T.H., Gustafsson, S., Chu, A.Y., Estrada, K., Luan, J., Kutalik, Z., Amin, N., Buchkovich, M.L., Croteau-Chonka, D.C., Day, F.R., Duan, Y., Fall, T., Fehrmann, R., Ferreira, T., Jackson, A.U., Karjalainen, J., Lo, K.S., Locke, A.E., Mägi, R., Mihailov, E., Porcu, E., Randall, J.C., Scherag, A., Vinkhuyzen, A.A., Westra, H.J., Winkler, T.W., Workalemahu, T., Zhao, J.H., Absher, D., Albrecht, E., Anderson, D., Baron, J., Beekman, M., Demirkan, A., Ehret, G.B., Feenstra, B., Feitosa, M.F., Fischer, K., Fraser, R.M., Goel, A., Justice, A.E., Kanoni, S., Kleber, M.E., Kristiansson, K., Lotay, V., Lui, J.C., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Nalls, M.A., Nyholt, D.R., Palmer, C.D., Pasko, D., Pechlivanis, S., Prokopenko, I., Ried, J.S., Ripke, S., Shungin, D., Stancáková, A., Strawbridge, R.J., Sung, Y.J., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S.W., van Setten, J., Van Vliet-Ostaptchouk, J.V., Wang, Z., Yengo, L., Zhang, W., Afzal, U., Arnlöv, J., Arscott, G.M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A.J., Berne, C., Blüher, M., Bolton, J.L., Böttcher, Y., Boyd, H.A., Buckley, B.M., Caspersen, I.H., Chines, P.S., Clarke, R., Claudi-Boehm, S., Cooper, M., Daw, E.W., De Jong, P.A., Deelen, J., Delgado, G., Denny, J.C., Dhonukshe-Rutten, R., Dimitriou, M., Doney, A.S., Dörr, M., Eklund, N., Eury, E., Folkersen, L., Garcia, M.E., Geller, F., Giedraitis, V., Go, A.S., Grallert, H., Grammer, T.B., Gräßler, J., Grönberg, H., de Groot, L.C., Groves, C.J., Hall, P., Haller, T., Hallmans, G., Hannemann, A., Hartman, C.A., Hassinen, M., Hayward, C., Heard-Costa, N.L., Helmer, Q., Hemani, G., Henders, A.K., Hillege, H.L., Hlatky, M.A., Hoffmann, W., Hoffmann, P., Holmen, O., Houwing-Duistermaat, J.J., Illig, T., Isaacs, A., James, A.L., Johansen, B., Johansson, Å., Jolley, J., Juliusdottir, T., Junttila, J., Kho, A.N., Kinnunen, L., Klopp, N., Kocher, T., Kratzer, W., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Lu, Y., Lyssenko, V., Magnusson, P.K., Mahajan, A., Maillard, M., McArdle, W.L., McKenzie, C.A., McLachlan, S., McLaren, P.J., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, K.L., Morken, M.A., Müller, G., Müller-Nurasyid, M., Musk, A.W., Narisu, N., Nauck, M., Nolte, I.M., Nöthen, M.M., Oozageer, L., Pilz, S., Rayner, N.W., Renstrom, F., Robertson, N.R., Rose, L.M., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F.R., Scott, R.A., Sehmi, J., Seufferlein, T., Shi, J., Silventoinen, K., Smit, J.H., Smith, A.V., Smolonska, J., Stanton, A.V., Stirrups, K., Stott, D.J., Stringham, H.M., Sundström, J., Swertz, M.A., Syvänen, A.C., Tayo, B.O., Tyrer, J.P., van Dijk, S., van Schoor, N.M., van der Velde, N., van Heemst, D., van Oort, F.V., Vermeulen, S.H., Verweij, N., Vonk, J.M., Waite, L.L., Waldenberger, M., Wennauer, R., Wilkens, L.R., Willenborg, C., Wilsgaard, T., Wojczynski, M.K., Wong, A., Wright, A.F., Zhang, Q., Arveiler, D., Bakker, S.J., Beilby, J., Bergman, R.N., Bergmann, S., Biffar, R., Blangero, J., Boomsma, D.I., Bornstein, S.R., Bovet, P., Brambilla, P., Brown, M.J., Campbell, H., Caulfield, M.J., Chakravarti, A., Collins, R., Collins, F.S., Crawford, D.C., Cupples, L.A., Danesh, J., de Faire, U., den Ruijter, H.M., Erbel, R., Eriksson, J.G., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N.G., Forrester, T., Gansevoort, R.T., Gejman, P.V., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, D.W., Hall, A.S., Harris, T.B., Hattersley, A.T., Heath, A.C., Hicks, A.A., Hindorff, L.A., Hingorani, A.D., Hofman, A., Hovingh, G.K., Humphries, S.E., Hunt, S.C., Hypponen, E., Jacobs, K.B., Jarvelin, M.R., Jousilahti, P., Jula, A.M., Kaprio, J., Kastelein, J.J., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, S.M., Kiemeney, L.A., Kooner, J.S., Koskinen, S., Kovacs, P., Kraja, A.T., Kumari, M., Kuusisto, J., Lakka, T.A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, P.A., Männistö, S., Manunta, P., Marette, A., Matise, T.C., McKnight, B., Meitinger, T., Moll, F.L., Montgomery, G.W., Morris, A.D., Morris, A.P., Murray, J.C., Nelis, M., Ohlsson, C., Oldehinkel, A.J., Ong, K.K., Ouwehand, W.H., Pasterkamp, G., Peters, A., Pramstaller, P.P., Price, J.F., Qi, L., Raitakari, O.T., Rankinen, T., Rao, D.C., Rice, T.K., Rudan, I., Samani, N.J., Saramies, J., Sarzynski, M.A., Schwarz, P.E., Sebert, S., Sever, P., Shuldiner, A.R., Sinisalo, J., Steinthorsdottir, V., Stolk, R.P., Tardif, J.C., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M.C., Amouyel, P., Asselbergs, F.W., Assimes, T.L., Bochud, M., Boehm, B.O., Bottinger, E.P., Bouchard, C., Cauchi, S., Chambers, J.C., Chanock, S.J., Cooper, R.S., de Bakker, P.I., Dedoussis, G., Ferrucci, L., Franks, P.W., Froguel, P., Groop, L.C., Haiman, C.A., Hamsten, A., Hayes, M.G., Hui, J., Hunter, D.J., Hveem, K., Jukema, J.W., Kaplan, R.C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N.G., März, W., Melbye, M., Moebus, S., Munroe, P.B., Njølstad, I., Oostra, B.A., Palmer, C.N., Pedersen, N.L., Perola, M., Pérusse, L., Powell, J.E., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, P.M., Rivadeneira, F., Rotter, J.I., Saaristo, T.E., Saleheen, D., Schlessinger, D., Slagboom, P.E., Spector, T.D., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., Völzke, H., Walker, M., Wareham, N.J., Watkins, H., Wichmann, H.E., Wilson, J.F., Zanen, P., Heid, I.M., Lindgren, C.M., Mohlke, K.L., Speliotes, E.K., Barroso, I., Fox, C.S., North, K.E., Strachan, D.P., Beckmann, J.S., Berndt, S.I., Boehnke, M., Borecki, I.B., McCarthy, M.I., Metspalu, A., Uitterlinden, A.G., van Duijn, C.M., Willer, C.J., Price, A.L., Lettre, G., Loos, R.J., Weedon, M.N., Ingelsson, E., O'Connell, J.R., Abecasis, G.R., Chasman, D.I., Goddard, M.E., Visscher, P.M., Hirschhorn, J.N., and Frayling, T.M.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Published: 2014

17. Lack of association between type 2 diabetes and major depression: epidemiologic and genetic evidence in a multiethnic population

Author: Sophiya Garasia, David Meyre, Sonia S. Anand, Rafael Diaz, Engert Jc, Viswanathan Mohan, Hertzel C. Gerstein, and Zainab Samaan
Subjects: Adult, Blood Glucose, Male, medicine.medical_specialty, endocrine system diseases, Adolescent, Type 2 diabetes, Comorbidity, Polymorphism, Single Nucleotide, Impaired glucose tolerance, Cohort Studies, Cellular and Molecular Neuroscience, Young Adult, Risk Factors, Diabetes mellitus, Internal medicine, medicine, Ethnicity, Humans, Genetic Predisposition to Disease, Longitudinal Studies, Major depressive episode, Biological Psychiatry, Depression (differential diagnoses), Aged, Aged, 80 and over, Depressive Disorder, Major, business.industry, nutritional and metabolic diseases, Middle Aged, medicine.disease, Impaired fasting glucose, Psychiatry and Mental health, Endocrinology, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Original Article, Female, medicine.symptom, business, Body mass index, Cohort study
Abstract: The positive association between depression and type 2 diabetes (T2D) has been controversial, and little is known about the molecular determinants linking these disorders. Here we investigated the association between T2D and depression at the clinical and genetic level in a multiethnic cohort. We studied 17 404 individuals from EpiDREAM (3209 depression cases and 14 195 controls) who were at risk for T2D and had both phenotypic and genotypic information available at baseline. The glycemic status was determined using the 2003 American Diabetes Association criteria and an oral glucose tolerance test. Major depressive episode during the previous 12 months was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria. Twenty single-nucleotide polymorphisms (SNPs) previously associated with T2D were genotyped using the cardiovascular gene-centric 50-K SNP array and were analyzed separately and in combination using an unweighted genotype score (GS). Multivariate logistic regression models adjusted for age, sex, ethnicity and body mass index were performed. Newly diagnosed impaired fasting glucose (IFG)/impaired glucose tolerance (IGT), T2D and dysglycemia status were not associated with major depression (0.30⩽P⩽0.65). Twelve out of twenty SNPs and the GS were associated with IFG/IGT, T2D and/or dysglycemia status (6.0 × 10−35⩽P⩽0.048). In contrast, the 20 SNPs and GS were not associated with depression (P⩾0.09). Our cross-sectional data do not support an association between T2D and depression at the clinical and genetic level in a multiethnic population at risk for T2D.
Published: 2015

18. Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway

Author: Do, R, primary, Kiss, RS, additional, Gaudet, D, additional, and Engert, JC, additional
Published: 2009
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19. Genetics of high-density lipoproteins.

Author: Dastani Z, Engert JC, Genest J, and Marcil M
Published: 2006
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20. The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study.

Author: Do R, Xie C, Zhang X, Männistö S, Harald K, Islam S, Bailey SD, Rangarajan S, McQueen MJ, Diaz R, Lisheng L, Wang X, Silander K, Peltonen L, Yusuf S, Salomaa V, Engert JC, Anand SS, INTERHEART investigators, and Do, Ron
Abstract: Background: One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.Methods and Findings: We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10(-8)≤p≤5.21×10(-7)). A significant interaction (p = 4.0×10(-4)) was observed between rs2383206 and a factor-analysis-derived "prudent" diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10(-7)), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10(-3)) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10(-4), and HR = 1.35, p = 4.1×10(-3), respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10(-9)) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).Conclusions: The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits. Please see later in the article for the Editors' Summary. [ABSTRACT FROM AUTHOR]
Published: 2011
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21. Parental History and Myocardial Infarction Risk Across the World The INTERHEART Study.

Author: Chow CK, Islam S, Bautista L, Rumboldt Z, Yusufali A, Xie C, Anand SS, Engert JC, Rangarajan S, and Yusuf S
Published: 2011
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22. Defining the role of common variation in the genomic and biological architecture of adult human height

Author: Wood, Ar, Esko, T, Yang, J, Vedantam, S, Pers, Th, Gustafsson, S, Chu, Ay, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, Ml, Croteau Chonka DC, Day, Fr, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, Au, Karjalainen, J, Lo, Ks, Locke, Ae, Mägi, R, Mihailov, E, Porcu, E, Randall, Jc, Scherag, A, Vinkhuyzen, Aa, Westra, Hj, Winkler, Tw, Workalemahu, T, Zhao, Jh, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, Gb, Feenstra, B, Feitosa, Mf, Fischer, K, Fraser, Rm, Goel, A, Gong, J, Justice, Ae, Kanoni, S, Kleber, Me, Kristiansson, K, Lim, U, Lotay, V, Lui, Jc, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, Ma, Nyholt, Dr, Palmer, Cd, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, Js, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, Rj, Sung, Yj, Tanaka, T, Teumer, A, Trompet, S, van der Laan SW, van Setten, J, Van Vliet Ostaptchouk JV, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Arnlöv, J, Arscott, Gm, Bandinelli, S, Barrett, A, Bellis, C, Bennett, Aj, Berne, C, Blüher, M, Bolton, Jl, Böttcher, Y, Boyd, Ha, Bruinenberg, M, Buckley, Bm, Buyske, S, Caspersen, Ih, Chines, Ps, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, Ew, De Jong PA, Deelen, J, Delgado, G, Denny, Jc, Dhonukshe Rutten, R, Dimitriou, M, Doney, As, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, Me, Geller, F, Giedraitis, V, Go, As, Grallert, H, Grammer, Tb, Gräßler, J, Grönberg, H, de Groot LC, Groves, Cj, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hannemann, A, Hartman, Ca, Hassinen, M, Hayward, C, Heard Costa NL, Helmer, Q, Hemani, G, Henders, Ak, Hillege, Hl, Hlatky, Ma, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat JJ, Illig, T, Isaacs, A, James, Al, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, An, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, Pk, Mahajan, A, Maillard, M, Mcardle, Wl, Mckenzie, Ca, Mclachlan, S, Mclaren, Pj, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, Kl, Morken, Ma, Müller, G, Müller Nurasyid, M, Musk, Aw, Narisu, N, Nauck, M, Nolte, Im, Nöthen, Mm, Oozageer, L, Pilz, S, Rayner, Nw, Renstrom, F, Robertson, Nr, Rose, Lm, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, Fr, Schunkert, H, Scott, Ra, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, Jh, Smith, Av, Smolonska, J, Stanton, Av, Stirrups, K, Stott, Dj, Stringham, Hm, Sundström, J, Swertz, Ma, Syvänen, Ac, Tayo, Bo, Thorleifsson, G, Tyrer, Jp, van Dijk, S, van Schoor NM, van der Velde, N, van Heemst, D, van Oort FV, Vermeulen, Sh, Verweij, N, Vonk, Jm, Waite, Ll, Waldenberger, M, Wennauer, R, Wilkens, Lr, Willenborg, C, Wilsgaard, T, Wojczynski, Mk, Wong, A, Wright, Af, Zhang, Q, Arveiler, D, Bakker, Sj, Beilby, J, Bergman, Rn, Bergmann, S, Biffar, R, Blangero, J, Boomsma, Di, Bornstein, Sr, Bovet, P, Brambilla, P, Brown, Mj, Campbell, H, Caulfield, Mj, Chakravarti, A, Collins, R, Collins, Fs, Crawford, Dc, Cupples, La, Danesh, J, de Faire, U, den Ruijter HM, Erbel, R, Erdmann, J, Eriksson, Jg, Farrall, M, Ferrannini, Eleuterio, Ferrières, J, Ford, I, Forouhi, Ng, Forrester, T, Gansevoort, Rt, Gejman, Pv, Gieger, C, Golay, A, Gottesman, O, Gudnason, V, Gyllensten, U, Haas, Dw, Hall, As, Harris, Tb, Hattersley, At, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hindorff, La, Hingorani, Ad, Hofman, A, Hovingh, Gk, Humphries, Se, Hunt, Sc, Hypponen, E, Jacobs, Kb, Jarvelin, Mr, Jousilahti, P, Jula, Am, Kaprio, J, Kastelein, Jj, Kayser, M, Kee, F, Keinanen Kiukaanniemi SM, Kiemeney, La, Kooner, Js, Kooperberg, C, Koskinen, S, Kovacs, P, Kraja, At, Kumari, M, Kuusisto, J, Lakka, Ta, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lupoli, S, Madden, Pa, Männistö, S, Manunta, P, Marette, A, Matise, Tc, Mcknight, B, Meitinger, T, Moll, Fl, Montgomery, Gw, Morris, Ad, Morris, Ap, Murray, Jc, Nelis, M, Ohlsson, C, Oldehinkel, Aj, Ong, Kk, Ouwehand, Wh, Pasterkamp, G, Peters, A, Pramstaller, Pp, Price, Jf, Qi, L, Raitakari, Ot, Rankinen, T, Rao, Dc, Rice, Tk, Ritchie, M, Rudan, I, Salomaa, V, Samani, Nj, Saramies, J, Sarzynski, Ma, Schwarz, Pe, Sebert, S, Sever, P, Shuldiner, Ar, Sinisalo, J, Steinthorsdottir, V, Stolk, Rp, Tardif, Jc, Tönjes, A, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, Mc, Electronic Medical Records, Genomics, Consortium, Migen, Consortium, Pagege, Consortium, LifeLines Cohort Study, Amouyel, P, Asselbergs, Fw, Assimes, Tl, Bochud, M, Boehm, Bo, Boerwinkle, E, Bottinger, Ep, Bouchard, C, Cauchi, S, Chambers, Jc, Chanock, Sj, Cooper, Rs, de Bakker PI, Dedoussis, G, Ferrucci, L, Franks, Pw, Froguel, P, Groop, Lc, Haiman, Ca, Hamsten, A, Hayes, Mg, Hui, J, Hunter, Dj, Hveem, K, Jukema, Jw, Kaplan, Rc, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, Ng, März, W, Melbye, M, Moebus, S, Munroe, Pb, Njølstad, I, Oostra, Ba, Palmer, Cn, Pedersen, Nl, Perola, M, Pérusse, L, Peters, U, Powell, Je, Power, C, Quertermous, T, Rauramaa, R, Reinmaa, E, Ridker, Pm, Rivadeneira, F, Rotter, Ji, Saaristo, Te, Saleheen, D, Schlessinger, D, Slagboom, Pe, Snieder, H, Spector, Td, Strauch, K, Stumvoll, M, Tuomilehto, J, Uusitupa, M, van der Harst, P, Völzke, H, Walker, M, Wareham, Nj, Watkins, H, Wichmann, He, Wilson, Jf, Zanen, P, Deloukas, P, Heid, Im, Lindgren, Cm, Mohlke, Kl, Speliotes, Ek, Thorsteinsdottir, U, Barroso, I, Fox, Cs, North, Ke, Strachan, Dp, Beckmann, Js, Berndt, Si, Boehnke, M, Borecki, Ib, Mccarthy, Mi, Metspalu, A, Stefansson, K, Uitterlinden, Ag, van Duijn CM, Franke, L, Willer, Cj, Price, Al, Lettre, G, Loos, Rj, Weedon, Mn, Ingelsson, E, O'Connell, Jr, Abecasis, Gr, Chasman, Di, Goddard, Me, Visscher, Pm, Hirschhorn, Jn, Frayling, T. M., Isotope Research, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Ehret, Georg Benedikt, Wood, A, Esko, T, Yang, J, Vedantam, S, Pers, T, Gustafsson, S, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, A, Karjalainen, J, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Westra, H, Winkler, T, Workalemahu, T, Zhao, J, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Fraser, R, Goel, A, Gong, J, Justice, A, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Lui, J, Mangino, M, Leach, I, Medina Gomez, C, Nalls, M, Nyholt, D, Palmer, C, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, J, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, Van Der Laan, S, Van Setten, J, Van Vliet Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Bolton, J, Böttcher, Y, Boyd, H, Bruinenberg, M, Buckley, B, Buyske, S, Caspersen, I, Chines, P, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, E, De Jong, P, Deelen, J, Delgado, G, Denny, J, Dhonukshe Rutten, R, Dimitriou, M, Doney, A, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, M, Geller, F, Giedraitis, V, Go, A, Grallert, H, Grammer, T, Gräßler, J, Grönberg, H, De Groot, L, Groves, C, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hannemann, A, Hartman, C, Hassinen, M, Hayward, C, Heard Costa, N, Helmer, Q, Hemani, G, Henders, A, Hillege, H, Hlatky, M, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat, J, Illig, T, Isaacs, A, James, A, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, A, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, P, Mahajan, A, Maillard, M, Mcardle, W, Mckenzie, C, Mclachlan, S, Mclaren, P, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, K, Morken, M, Müller, G, Müller Nurasyid, M, Musk, A, Narisu, N, Nauck, M, Nolte, I, Nöthen, M, Oozageer, L, Pilz, S, Rayner, N, Renstrom, F, Robertson, N, Rose, L, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Schunkert, H, Scott, R, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, J, Smith, A, 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Henderson, B., Monroe, K., Schumacher, F., Kooperberg, C., Peters, U., Anderson, G., Prentice, R., LaCroix, A., Wu, C., Carty, C., Gong, J., Rosse, S., Young, A., Haessler, J., Kocarnik, J., Lin, Y., Jackson, R., Duggan, D., Kuller, L., Psychiatry, Epidemiology and Data Science, EMGO - Lifestyle, overweight and diabetes, Wood, Ar, Pers, Th, Chu, Ay, Buchkovich, Ml, CROTEAU CHONKA, Dc, Day, Fr, Jackson, Au, Locke, Ae, Randall, Jc, Vinkhuyzen, Aa, Westra, Hj, Winkler, Tw, Zhao, Jh, Ehret, Gb, Feitosa, Mf, Fraser, Rm, Justice, Ae, Kleber, Me, Lui, Jc, MATEO LEACH, I, MEDINA GOMEZ, C, Nalls, Ma, Nyholt, Dr, Palmer, Cd, Strawbridge, Rj, Sung, Yj, VAN DER LAAN, Sw, VAN SETTEN, J, VAN VLIET OSTAPTCHOUK, Jv, Arnlöv, J, Arscott, Gm, Bennett, Aj, Bolton, Jl, Boyd, Ha, Buckley, Bm, Caspersen, Ih, CLAUDI BOEHM, S, Daw, Ew, DE JONG, Pa, Denny, Jc, DHONUKSHE RUTTEN, R, Garcia, Me, Grammer, Tb, DE GROOT, Lc, Groves, Cj, Hartman, Ca, HEARD COSTA, Nl, Henders, Ak, Hillege, Hl, Hlatky, Ma, HOUWING 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Fl, Montgomery, Gw, Morris, Ad, Morris, Ap, Murray, Jc, Oldehinkel, Aj, Ong, Kk, Ouwehand, Wh, Pramstaller, Pp, Price, Jf, Raitakari, Ot, Rao, Dc, Rice, Tk, Samani, Nj, Sarzynski, Ma, Schwarz, Pe, Shuldiner, Ar, Stolk, Rp, Tardif, Jc, Vohl, Mc, ELECTRONIC MEDICAL RECORDS AND GENOMICS, Consortium, Migen, Consortium, Page, Consortium, LIFELINES COHORT, Study, Asselbergs, Fw, Assimes, Tl, Boehm, Bo, Bottinger, Ep, Chambers, Jc, Chanock, Sj, DE BAKKER, Pi, Franks, Pw, Groop, Lc, Haiman, Ca, Hayes, Mg, Hunter, Dj, Jukema, Jw, Kaplan, Rc, Martin, Ng, Munroe, Pb, Oostra, Ba, Palmer, Cn, Pedersen, Nl, Powell, Je, Ridker, Pm, Rotter, Ji, Saaristo, Te, Slagboom, Pe, Spector, Td, VAN DER HARST, P, Wareham, Nj, Wichmann, He, Wilson, Jf, Heid, Im, Lindgren, Cm, Mohlke, Kl, Speliotes, Ek, North, Ke, Strachan, Dp, Berndt, Si, Borecki, Ib, Mccarthy, Mi, Uitterlinden, Ag, VAN DUIJN, Cm, Willer, Cj, Price, Al, Loos, Rj, Weedon, Mn, O'Connell, Jr, Abecasis, Gr, Chasman, Di, Goddard, Me, Visscher, Pm, Hirschhorn, Jn, Frayling, Tm, Epidemiology, Surgery, Public Health, Internal Medicine, Erasmus MC other, Genetic Identification, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Biological Psychology, AIMMS, Functional Genomics, EMGO+ - Lifestyle, Overweight and Diabetes, Wood, AR, Vadantam, S, Hypponen, Elina, Frayling, TM, Wood A.R., Esko T., Yang J., Vedantam S., Pers T.H., Gustafsson S., Chu A.Y., Estrada K., Luan J., Kutalik Z., Amin N., Buchkovich M.L., Croteau-Chonka D.C., Day F.R., Duan Y., Fall T., Fehrmann R., Ferreira T., Jackson A.U., Karjalainen J., Lo K.S., Locke A.E., Magi R., Mihailov E., Porcu E., Randall J.C., Scherag A., Vinkhuyzen A.A.E., Westra H.-J., Winkler T.W., Workalemahu T., Zhao J.H., Absher D., Albrecht E., Anderson D., Baron J., Beekman M., Demirkan A., Ehret G.B., Feenstra B., Feitosa M.F., Fischer K., Fraser R.M., Goel A., Gong J., Justice A.E., Kanoni S., Kleber M.E., Kristiansson K., Lim U., Lotay V., Lui J.C., Mangino M., Leach I.M., Medina-Gomez C., Nalls M.A., Nyholt D.R., Palmer C.D., Pasko D., Pechlivanis S., Prokopenko I., Ried J.S., Ripke S., Shungin D., Stancakova A., Strawbridge R.J., Sung Y.J., Tanaka T., Teumer A., Trompet S., Van Der Laan S.W., Van Setten J., Van Vliet-Ostaptchouk J.V., Wang Z., Yengo L., Zhang W., Afzal U., Arnlov J., Arscott G.M., Bandinelli S., Barrett A., Bellis C., Bennett A.J., Berne C., Bluher M., Bolton J.L., Bottcher Y., Boyd H.A., Bruinenberg M., Buckley B.M., Buyske S., Caspersen I.H., Chines P.S., Clarke R., Claudi-Boehm S., Cooper M., Daw E.W., De Jong P.A., Deelen J., Delgado G., Denny J.C., Dhonukshe-Rutten R., Dimitriou M., Doney A.S.F., Dorr M., Eklund N., Eury E., Folkersen L., Garcia M.E., Geller F., Giedraitis V., Go A.S., Grallert H., Grammer T.B., Grassler J., Gronberg H., De Groot L.C.P.G.M., Groves C.J., Haessler J., Hall P., Haller T., Hallmans G., Hannemann A., Hartman C.A., Hassinen M., Hayward C., Heard-Costa N.L., Helmer Q., Hemani G., Henders A.K., Hillege 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Price A.L., Lettre G., Loos R.J.F., Weedon M.N., Ingelsson E., O'Connell J.R., Abecasis G.R., Chasman D.I., Goddard M.E., Visscher P.M., Hirschhorn J.N., and Frayling T.M.
Subjects: Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Electronic Medical Records and Genomics (eMEMERGEGE) Consortium, Medizin, Genome-wide association study, Adult, Analysis of Variance, Body Height/genetics, European Continental Ancestry Group/genetics, Genetic Variation/genetics, Genetics, Population, Genome-Wide Association Study/methods, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics, heritability, 0302 clinical medicine, Genome-wide, SNPS, snps, Genetics & Heredity, ddc:616, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, variants, GENETIC-VARIATION, Biological Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], body height, genetic-variation, Life Sciences & Biomedicine, Single Nucleotide/genetics, Human, European Continental Ancestry Group, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, NO, complex traits, 03 medical and health sciences, Genetic variation, heritability, adult, height, Polymorphism, Human height, PAGEGE Consortium, education, Gene, VLAG, 030304 developmental biology, Global Nutrition, Wereldvoeding, genome-wide association study, Science & Technology, Whites, Oligonucleotide Array Sequence Analysi, MUTATIONS, COMPLEX TRAITS, ta1184, Klinisk medicin, population genetics, Genetic Variation, Heritability, ta3121, mutations, Genetic architecture, Body Height, genetic variation, MIGen Consortium, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Clinical Medicine, 030217 neurology & neurosurgery, height, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract: Item does not contain fulltext Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Published: 2014
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23. Genetic studies of body mass index yield new insights for obesity biology

Author: Locke, Adam E, Kahali, Bratati, Croteau-Chonka, Damien C, Doney, Alex S F, He, Bing, Heikkilä, Outi, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne, Rosengård-Bärlund, Milla, Eklund, Niina, Saraheimo, Markku, Sarti, Cinzia, Söderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M, Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Estrada, Karol, Wadén, Johan, Gill, Geoffrey V, Prior, Sarah, Guiducci, Candace, Mirel, Daniel B, Taylor, Andrew, Hosseini, Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Eury, Elodie, Ladenvall, Claes, Alhenc-Gelas, François, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Folkersen, Lasse, Möllsten, Anna, Cimponeriu, Dan, Mihai, Ioana, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L, Nelson, Robert G, Kretzler, Matthias, Fraser, Ross M, Colhoun, Helen M, Panduru, Nicolae Mircea, Gu, Harvest F, Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B, Garcia, Melissa E, Waggott, Daryl, Paterson, Andrew D, Savage, David A, Bain, Stephen C, Martin, Finian, Hirschhorn, Joel N, Godson, Catherine, Florez, Jose C, Groop, Per-Henrik, Maxwell, Alexander P, Geller, Frank, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Giedraitis, Vilmantas, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Y, Demirkan, Ayşe, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Gigante, Bruna, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Esko, Tonu, Go, Alan S, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K E, Mangino, Massimo, Golay, Alain, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Goodall, Alison H, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Gordon, Scott D, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Gorski, Mathias, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doring, Angela, Elliott, Paul, Grabe, Hans-Jörgen, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, 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EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Eriksson, J., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Peacock, M., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., van Meurs JB., Weedon, MN., Wichmann, H., Young, L., Bierut, LJ., Boyd, HA., Econs, MJ., Van T'Hooft, Ferdinand M., Njølstad, Inger, Abecasis, Gonçalo R., Barroso, Inɥ, The MIGEN Consortium, Investigator, Casari, GIORGIO NEVIO, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Landsteiner Laboratory, Clinical Haematology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life 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Mangino, M, Leach, I, Medina-Gomez, C, Medland, S, Nalls, M, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Shungin, D, Stancakova, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, van der Laan, S, van Setten, J, Van Vliet-Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Isaacs, A, Albrecht, E, Arnlov, J, Arscott, G, Attwood, A, Bandinelli, S, Barrett, A, Bas, I, Bellis, C, Bennett, A, Berne, C, Blagieva, R, Bluher, M, Bohringer, S, Bonnycastle, L, Bottcher, Y, Boyd, H, Bruinenberg, M, Caspersen, I, Chen, Y, Clarke, R, Daw, E, de Craen, A, Delgado, G, Dimitriou, M, Doney, A, Eklund, N, Estrada, K, Eury, E, Folkersen, L, Fraser, R, Garcia, M, Geller, F, Giedraitis, V, Gigante, B, Go, A, Golay, A, Goodall, A, Gordon, S, Gorski, M, Grabe, H, Grallert, H, Grammer, T, Grassler, J, Gronberg, H, Groves, C, Gusto, G, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heard-Costa, N, Helmer, Q, Hengstenberg, C, Holmen, O, Hottenga, J, James, A, Jeff, J, Johansson, A, Jolley, J, Juliusdottir, T, Kinnunen, L, Koenig, W, Koskenvuo, M, Kratzer, W, Laitinen, J, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindstrom, J, Lo, K, Lobbens, S, Lorbeer, R, Lu, Y, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Mclachlan, S, Menni, C, Merger, S, Mihailov, E, Milani, L, Moayyeri, A, Monda, K, Morken, M, Mulas, A, Muller, G, Muller-Nurasyid, M, Musk, A, Nagaraja, R, Nothen, M, Nolte, I, Pilz, S, Rayner, N, Renstrom, F, Rettig, R, Ried, J, Ripke, S, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Scott, W, Seufferlein, T, Shi, J, Smith, A, Smolonska, J, Stanton, A, Steinthorsdottir, V, Stirrups, K, Stringham, H, Sundstrom, J, Swertz, M, Swift, A, Syvanen, A, Tan, S, Tayo, B, Thorand, B, Thorleifsson, G, Tyrer, J, Uh, H, Vandenput, L, Verhulst, F, Vermeulen, S, Verweij, N, Vonk, J, Waite, L, Warren, H, Waterworth, D, Weedon, M, Wilkens, L, Willenborg, C, Wilsgaard, T, Wojczynski, M, Wong, A, Wright, A, Zhang, Q, Brennan, E, Choi, M, Dastani, Z, Drong, A, Eriksson, P, Franco-Cereceda, A, Gadin, J, Gharavi, A, Goddard, M, Handsaker, R, Huang, J, Karpe, F, Kathiresan, S, Keildson, S, Kiryluk, K, Kubo, M, Lee, J, Liang, L, Lifton, R, Ma, B, Mccarroll, S, Mcknight, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Okada, Y, Perry, J, Dorajoo, R, Reinmaa, E, Salem, R, Sandholm, N, Scott, R, Stolk, L, Takahashi, A, Van't Hooft, F, Vinkhuyzen, A, Westra, H, Zheng, W, Zondervan, K, Heath, A, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Bovet, P, Campbell, H, Caulfield, M, Cesana, G, Chakravarti, A, Chasman, D, Chines, P, Collins, F, Crawford, D, Cupples, L, Cusi, D, Danesh, J, de Faire, U, Den Ruijter, H, Dominiczak, A, Erbel, R, Erdmann, J, Eriksson, J, Farrall, M, Felix, S, Ferrannini, E, Ferrieres, J, Ford, I, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gejman, P, Gieger, C, Gottesman, O, Gudnason, V, Gyllensten, U, Hall, A, Harris, T, Hattersley, A, Hicks, A, Hindorff, L, Hingorani, A, Hofman, A, Homuth, G, Hovingh, G, Humphries, S, Hunt, S, Hypponen, E, Illig, T, Jacobs, K, Jarvelin, M, Jockel, K, Johansen, B, Jousilahti, P, Jukema, J, Jula, A, Kaprio, J, Kastelein, J, Keinanen-Kiukaanniemi, S, Kiemeney, L, Knekt, P, Kooner, J, Kooperberg, C, Kovacs, P, Kraja, A, Kumari, M, Kuusisto, J, Lakka, T, Langenberg, C, Marchand, L, Lehtimaki, T, Lyssenko, V, Mannisto, S, Marette, A, Matise, T, Mckenzie, C, Mcknight, B, Moll, F, Morris, A, Murray, J, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Madden, P, Pasterkamp, G, Peden, J, Peters, A, Postma, D, Pramstaller, P, Price, J, Qi, L, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ridker, P, Rioux, J, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schunkert, H, Schwarz, P, Sever, P, Shuldiner, A, Sinisalo, J, Stolk, R, Strauch, K, Tonjes, A, Tregouet, D, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, M, Volker, U, Waeber, G, Willemsen, G, 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Mccarthy, M, Visscher, P, Scherag, A, Willer, C, Boehnke, M, Mohlke, K, Lindgren, C, Beckmann, J, Barroso, I, North, K, Ingelsson, E, Hirschhorn, J, Loos, R, Speliotes, E, Thompson, J, Goldstein, B, Konig, I, Cazier, J, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Lundmark, P, Lyytikainen, L, Rafelt, S, Tikkanen, E, Van Zuydam, N, Voight, B, Ziegler, A, Altshuler, D, Balmforth, A, Braund, P, Burgdorf, C, Claudi-Boehm, S, Cox, D, Do, R, El Mokhtari, N, Fontanillas, P, Hager, J, Han, B, Kang, H, Kessler, T, Knowles, J, Kolovou, G, Langford, C, Lokki, M, Lundmark, A, Meisinger, C, Melander, O, Maouche, S, Nikus, K, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schafer, A, Sivananthan, M, Song, C, Stewart, A, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Tsun-Po, Y, Basart, H, Brambilla, P, Cambien, F, Cupples, A, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Gauguier, D, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kahonen, M, Kee, F, Kim, H, 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Kroemer, H, Nauck, M, Stracke, S, Volzke, H, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, J, Ruggiero, D, Bergmann, S, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Robino, A, Giulianini, F, Kramer, B, Portas, L, Buckley, B, Adam, M, Thun, G, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, S, Vollenweider, P, Gasparini, P, Pirastu, M, Probst-Hensch, N, Kronenberg, F, Toniolo, D, Coresh, J, Schmidt, R, Siscovick, D, Kardia, S, Curhan, G, Franke, A, Parsa, A, Goessling, W, Kao, W, de Boer, I, Peralta, C, Akylbekova, E, Kramer, H, Arking, D, Franceschini, N, Egan, J, Hernandez, D, Townsend, R, Lumley, T, Psaty, B, Kestenbaum, B, Haritunians, T, Mooser, V, Florez, J, Meigs, J, Lu, X, Leak, T, Aasarod, K, Skorpen, F, Baumert, J, Devuyst, O, Mychaleckyj, J, Kedenko, L, Coassin, S, Hallan, S, Navis, G, Shlipak, M, Bull, S, Paterson, A, Rotter, J, Dreisbach, A, Anderson, C, Guo, Q, Henders, A, Lambert, A, Lee, S, Kraft, P, Kennedy, S, Macgregor, S, Missmer, S, Painter, J, Roseman, F, Treloar, S, Wallace, L, Forsblom, C, Isakova, T, Mckay, G, Williams, W, Sadlier, D, Makinen, V, Swan, E, Boright, A, Ahlqvist, E, Keller, B, Huang, H, Ahola, A, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkila, O, Hietala, K, Kyto, J, Lahermo, P, Lehto, M, Osterholm, A, Parkkonen, M, Pitkaniemi, J, Rosengard-Barlund, M, Saraheimo, M, Sarti, C, Soderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, L, Tikkanen, H, Tolonen, N, Tryggvason, K, Waden, J, Gill, G, Prior, S, Guiducci, C, Mirel, D, Taylor, A, Hosseini, M, Parving, H, Rossing, P, Tarnow, L, Ladenvall, C, Alhenc-Gelas, F, Lefebvre, P, Rigalleau, V, Roussel, R, Maestroni, A, Maestroni, S, Falhammar, H, Gu, T, Mollsten, A, Cimponeriu, D, Mihai, I, Mota, M, Mota, E, Serafinceanu, C, Stavarachi, M, Hanson, R, Nelson, R, Kretzler, M, Panduru, N, Gu, H, Brismar, K, Zerbini, G, Hadjadj, S, Marre, M, Lajer, M, Waggott, D, Savage, D, Bain, S, Martin, F, Godson, C, Groop, P, Maxwell, A, Sengupta, S, Peloso, G, Ganna, A, Mora, S, Chang, H, Den Hertog, H, Donnelly, L, Freitag, D, Gurdasani, D, Heikkila, K, Johnson, T, Kaakinen, M, Kettunen, J, Li, X, Montasser, M, Petersen, A, Saxena, R, Service, S, Sidore, C, Surakka, I, Teslovich, T, Van den Herik, E, Volcik, K, Wu, Y, Asiki, G, Been, L, Burnett, M, Elliott, P, Eyjolfsson, G, Goodarzi, M, Gravito, M, Hartikainen, A, Hung, Y, Jones, M, Kaleebu, P, Khaw, K, Kim, E, Komulainen, P, Lin, S, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Ruokonen, A, Seeley, J, Silander, K, Tiret, L, van Pelt, L, Wainwright, N, Wijmenga, C, Young, E, Bennett, F, Boomsma, D, Burnier, M, Feranil, A, Freimer, N, Hsiung, C, Kesaniemi, A, Koudstaal, P, Krauss, R, Kyvik, K, Meneton, P, Moilanen, L, Sanghera, D, Sheu, W, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Rich, S, Johnson, L, Larson, M, Levy, D, Newton-Cheh, C, O'Reilly, P, Palmas, W, Rice, K, Snider, H, Tobin, M, Verwoert, G, Pihur, V, Heath, S, Sober, S, Arora, P, Zhang, F, Lucas, G, Milaneschi, Y, Parker, A, Fava, C, Fox, E, Go, M, Sjogren, M, Vinay, D, Alexander, M, Tabara, Y, Shaw-Hawkins, S, Whincup, P, Shi, G, Seielstad, M, Sim, X, Nguyen, K, Matullo, G, Gaunt, T, Onland-Moret, N, Cooper, M, Platou, C, Org, E, Hardy, R, Dahgam, S, Palmen, J, Kuznetsova, T, Uiterwaal, C, Adeyemo, A, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, N, Chang, Y, Steinle, N, Grobbee, D, Morrison, A, Najjar, S, Hadley, D, Brown, M, Connell, J, Day, I, Lawlor, D, Lawrence, R, Ongen, H, Li, Y, Young, J, Bis, J, Chaturvedi, N, Islam, M, Jafar, T, Kulkarni, S, Howard, P, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Weder, A, Sun, Y, Scott, L, Peltonen, L, Vartiainen, E, Brand, S, Staessen, J, Wang, T, Burton, P, Artigas, M, Dong, Y, Wang, X, Zhu, H, Rudock, M, Heckbert, S, Smith, N, Wiggins, K, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, C, Rosengren, A, Thelle, D, Corsi, A, Singleton, A, Hilton, G, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Cho, Y, Scott, J, Sehmi, J, Hedblad, B, Nilsson, P, Smith, G, Raffel, L, Yao, J, Schwartz, S, Ikram, M, W, L, Mosley, T, Seshadri, S, Shrine, N, Wain, L, Zitting, P, Cooper, J, van Gilst, W, Janipalli, C, Mani, K, Yajnik, C, Mattace-Raso, F, Lakatta, E, Orru, M, Scuteri, A, Ala-Korpela, M, Kangas, A, Soininen, P, Tukiainen, T, Wurtz, P, Ong, R, Dorr, M, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Zhai, G, Meschia, J, Sharma, P, Terzic, J, Kumar, M, Denniff, M, Zukowska-Szczechowska, E, Wagenknecht, L, Fowkes, F, Charchar, F, Guo, X, Rotimi, C, Bots, M, Brand, E, Talmud, P, Nyberg, F, Laan, M, Palmer, L, van der Schouw, Y, Casas, J, Vineis, P, Ganesh, S, Wong, T, Tai, E, Morris, R, Marmot, M, Miki, T, Chandak, G, Zhu, X, Elosua, R, Soranzo, N, Sijbrands, E, Uda, M, Vasan, R, Alizadeh, B, de Boer, R, Boezen, H, Hillege, H, van der Klauw, M, Ormel, J, Rosmalen, J, Slaets, J, Lagou, V, Welch, R, Wheeler, E, Rehnberg, E, Rasmussen-Torvik, L, Lecoeur, C, Johnson, P, Sennblad, B, Salo, P, Timpson, N, Evans, D, St Pourcain, B, Bielak, L, Horikoshi, M, Navarro, P, Raychaudhuri, S, Chen, H, Rybin, D, Willems, S, Song, K, An, P, Marullo, L, Jansen, H, Pankow, J, Edkins, S, Varga, T, Oksa, H, Antonella, M, Kong, A, Herder, C, Antti, J, Small, K, Miljkovic, I, Atalay, M, Kiess, W, Smit, J, Campbell, S, Fowkes, G, Rathmann, W, Maerz, W, Watanabe, R, de Geus, E, Penninx, B, Toenjes, A, Peyser, P, Korner, A, Dupuis, J, Cucca, F, Balkau, B, Bouatia-Naji, N, Purcell, S, Musunuru, K, Ardissino, D, Mannucci, P, Anand, S, Engert, J, Morgan, T, Spertus, J, Stoll, M, Girelli, D, Mckeown, P, Patterson, C, Merlini, P, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Fetiveau, R, Marziliano, N, Casari, G, Galli, M, Ribichini, F, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Yee, J, Friedlander, Y, Marrugat, J, Subirana, I, Sala, J, Ramos, R, Williams, G, Nathan, D, Macrae, C, Berglund, G, Asselta, R, Duga, S, Spreafico, M, Daly, M, Nemesh, J, Korn, J, Surti, A, Gianniny, L, Parkin, M, Burtt, N, Gabriel, S, Wright, B, Ball, S, Schunkert, I, Linsel-Nitschke, P, Lieb, W, Fischer, M, Grosshennig, A, Preuss, M, Scholz, M, Chen, Z, Wilensky, R, Matthai, W, Qasim, A, Hakonarson, H, Devaney, J, Pichard, A, Kent, K, Satler, L, Lindsay, J, Waksman, R, Knouff, C, Scheffold, T, Berger, K, Huge, A, Martinelli, N, Olivieri, O, Corrocher, R, Xie, C, Ahmadi, K, Ainali, C, Bataille, V, Bell, J, Buil, A, Dermitzakis, E, Dimas, A, Durbin, R, Glass, D, Hassanali, N, Ingle, C, Knowles, D, Krestyaninova, M, Lowe, C, Meduri, E, Di Meglio, P, Montgomery, S, Nestle, F, Nica, A, Nisbet, J, O'Rahilly, S, Parts, L, Potter, S, Sekowska, M, Shin, S, Surdulescu, G, Travers, M, Tsaprouni, L, Tsoka, S, Wilk, A, Yang, T, Higashio, J, Williams, R, Nato, A, Ambite, J, Deelman, E, Manolio, T, Heiss, G, Taylor, K, Avery, C, Graff, M, Lin, D, Quibrera, M, Cochran, B, Kao, L, Umans, J, Cole, S, Maccluer, J, Person, S, Gross, M, Fornage, M, Durda, P, Jenny, N, Patsy, B, Arnold, A, Buzkova, P, Haines, J, Murdock, D, Glenn, K, Brown-Gentry, K, Thornton-Wells, T, Dumitrescu, L, Bush, W, Mitchell, S, Goodloe, R, Wilson, S, Boston, J, Malinowski, J, Restrepo, N, Oetjens, M, Fowke, J, Spencer, K, Pendergrass, S, Le Marchand, L, Park, L, Tiirikainen, M, Kolonel, L, Cheng, I, Wang, H, Shohet, R, Stram, D, Henderson, B, Monroe, K, Anderson, G, Carlson, C, Prentice, R, Lacroix, A, Wu, C, Carty, C, Rosse, S, Young, A, Kocarnik, J, Lin, Y, Jackson, R, Duggan, D, Kuller, L, He, C, Sulem, P, Barbalic, M, Broer, L, Byrne, E, Gudbjartsson, D, Mcardle, P, Porcu, E, van Wingerden, S, Zhuang, W, Lauc, L, Broekmans, F, Burri, A, Chen, C, Corre, T, Coviello, A, D'Adamo, P, Davies, G, Deary, I, Ebrahim, S, Fauser, B, Ferreli, L, Folsom, A, Hankinson, S, Hass, M, Janssens, A, Karasik, D, Keyzer, J, Kiel, D, Lahti, J, Lai, S, Laisk, T, Laven, J, Liu, J, Lopez, L, Louwers, Y, Marongiu, M, Klaric, I, Masciullo, C, Melzer, D, Newman, A, Pare, G, Peeters, P, Pop, V, Raikkonen, K, Salumets, A, Stacey, S, Starr, J, Stathopoulou, M, Styrkarsdottir, U, Tenesa, A, Tryggvadottir, L, Tsui, K, van Dam, R, van Gils, C, van Nierop, P, Vink, J, Voorhuis, M, Widen, E, Wijnands-Van Gent, C, Yerges-Armstrong, L, Zgaga, L, Zygmunt, M, Buring, J, Crisponi, L, Demerath, E, Streeten, E, Murray, A, Visser, J, Lunetta, K, Elks, C, Cousminer, D, Koller, D, Lin, P, Smith, E, Warrington, N, Alavere, H, Berenson, G, Blackburn, H, Busonero, F, Chen, W, Couper, D, Easton, D, Foroud, T, Kilpelainen, T, Li, S, Murray, S, Ness, A, Northstone, K, Peacock, M, Pennell, C, Pharoah, P, Rafnar, T, Rice, J, Ring, S, Schork, N, Segre, A, Sovio, U, Srinivasan, S, Tammesoo, M, van Meurs, J, Young, L, Bierut, L, Econs, M, The ADIPOGen Consortium, The AGEN-BMI Working Group, The CARDIOGRAMplusC4D Consortium, The CKDGen Consortium, The GLGC, The ICBP, The MAGIC Investigators, The MuTHER Consortium, The MIGen Consortium, The PAGE Consortium, The ReproGen Consortium, The GENIE Consortium, The International Endogene Consortium, Berndt, Sonja I, Justice, Anne E, Hyppönen, Elina Tuulikki, Epidemiology and Data Science, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
Subjects: Male, LOCI, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Body Mass Index, Insulin Secretion, Insulin, Age Factor, Adiposity, ddc:616, Adipogenesis, Genetic Predisposition to Disease/genetics, Synapse, 3. Good health, Continental Population Group, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], GENOME-WIDE ASSOCIATIONPROVIDES INSIGHTSGLYCEMIC TRAITSLOCIMETAANALYSISVARIANTSINDIVIDUALSHIPPOCAMPALARCHITECTURETOPIRAMATE, ddc:500, Adipogenesis/genetics, Single Nucleotide/genetics, Age Factors, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Glutamic Acid, Humans, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses, Genome-Wide Association Study, Multidisciplinary, genetics [Adiposity], Human, Socio-culturale, genetics [Energy Metabolism], ta3111, genetic, body mass index, obesity, SDG 3 - Good Health and Well-being, GLYCEMIC TRAITS, genetics [Continental Population Groups], Genetic variability, Polymorphism, GENOME-WIDE ASSOCIATION, genetics [Adipogenesis], METAANALYSIS, Genetic association, Adipogenesi, genetics [Quantitative Trait Loci], ta1184, metabolism [Glutamic Acid], ta1182, PATHWAYS, metabolism [Synapses], ta3121, medicine.disease, metabolism [Insulin], Adiposity/genetics, Clinical Medicine, Quantitative Trait Loci/genetics, Body mass index, HUMAN HEIGHT, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Synapses/metabolism, Medizin, Obesity/genetics, Bioinformatics, genetic basis, Obesity/metabolism, genetics [Obesity], body mass index (BMI), genetics [Genetic Predisposition to Disease], ethnology [Europe], 2. Zero hunger, Genetics, ARCHITECTURE, Genetics of obesity, Medicine (all), Single Nucleotide, Polymorphism, Single Nucleotide/genetics, Insulin/metabolism/secretion, Glutamic Acid/metabolism, genetics [Polymorphism, Single Nucleotide], EXPRESSION, Insulin/metabolism, PROVIDES INSIGHTS, genetics [Racial Groups], Biology, Obesity/genetics/metabolism, Europe/ethnology, metabolism [Obesity], Mendelian randomization, medicine, Energy Metabolism/genetics, body mass, genetic analysis, obesity, Klinisk medicin
Abstract: Item does not contain fulltext Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Published: 2015
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24. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

Author: Myocardial Infarction Genetics, The complete list, Sekar, Kathiresan, Voight, Benjamin F., Shaun, Purcell, Kiran, Musunuru, Diego, Ardissino, Mannucci, Pier M., Sonia, Anand, Engert, James C., Samani, Nilesh J., Heribert, Schunkert, Jeanette, Erdmann, Reilly, Muredach P., Rader, Daniel J., Thomas, Morgan, Spertus, John A., Monika, Stoll, Girelli, Domenico, Mckeown, Pascal P., Patterson, Chris C., Siscovick, David S., O'Donnell, Christopher J., Roberto, Elosua, Leena, Peltonen, Veikko, Salomaa, Schwartz, Stephen M., Olle, Melander, David, Altshuler, Thrombosis Italian Atherosclerosis, Vascular Biology Study, Pier Angelica Merlini, Carlo, Berzuini, Luisa, Bernardinelli, Flora, Peyvandi, Marco, Tubaro, Patrizia, Celli, Maurizio, Ferrario, Raffaela, Fetiveau, Nicola, Marziliano, Giorgio, Casari, Michele, Galli, Ribichini, Flavio Luciano, Marco, Rossi, Francesco, Bernardi, Pietro, Zonzin, Alberto, Piazza, Heart Attack Risk, Jean, Yee, Yechiel, Friedlander, Registre Gironi del, Jaume, Marrugat, Gavin, Lucas, Isaac, Subirana, Joan, Sala, Rafael, Ramos, Massachusetts General Hospital, Meigs, James B., Gordon, Williams, Nathan, David M., Macrae, Calum A., F. I. N., Havulinna, Aki S., Malmo, Diet, Cancer, Study, Goran, Berglund, Stage, 1 data, Hirschhorn, Joel N., Rosanna, Asselta, Stefano, Duga, Marta, Spreafico, Daly, Mark J., Copy number variant, James, Nemesh, Korn, Joshua M., Mccarroll, Steven A., Stage, 1 phenotype, Stage, 1 genome wide, Aarti, Surti, Candace, Guiducci, Lauren, Gianniny, Daniel, Mirel, Melissa, Parkin, Noel, Burtt, Gabriel, Stacey B., Replication, Studies, Thompson, John R., Braund, Peter S., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Hall, Alistair S., Wellcome Trust Case, German MI Family, Patrick Linsel Nitschke, Wolfgang, Lieb, Andreas, Ziegler, König, Inke R., Christian, Hengstenberg, Marcus, Fischer, Klaus, Stark, Anika, Grosshennig, Michael, Preuss, Erich Wichmann, H., Stefan, Schreiber, Cardiogenics, Willem, Ouwehand, Panos, Deloukas, Michael, Scholz, Francois, Cambien, C. a. r. d. i. o. g. e. n. i. c. s., P. e. n. n. C. A. T., Mingyao, Li, Zhen, Chen, Robert, Wilensky, William, Matthai, Atif, Qasim, Hakonarson, Hakon H., Joe, Devaney, Mary Susan Burnett, Pichard, Augusto D., Kent, Kenneth M., Lowell, Satler, Lindsay, Joseph M., Ron, Waksman, Epstein, Stephen E., Acute Myocardial Infarction, Thomas, Scheffold, Klaus, Berger, Andreas, Huge, Verona Heart Study, Domenico, Girelli, Martinelli, Nicola, Olivieri, Oliviero, Corrocher, Roberto, Mid America Heart Institute, Irish Family Study, d. e. C. O. D., Hilma, Hólm, Gudmar, Thorleifsson, Unnur, Thorsteinsdottir, Kari, Stefansson, I. N. T., Ron, Do, Changchun, Xie, Gen, M. I., David, Siscovick, Kathiresan, S, Altschuler, D, Anand, S, Ardissino, D, Asselta, R, Ball, Sg, Balmforth, Aj, Berger, K, Berglund, G, Bernardi, F, Bernardinelli, L, Berzuini, C, Braund, P, Burnett, M, Burtt, N, Cambien, F, Casari, GIORGIO NEVIO, Celli, P, Chen, Z, Corrocher, R, Daly, Mj, Deloukas, P, Devaney, J, Do, R, Duga, S, Elosua, R, Engert, Jc, Epstein, Se, Erdmann, J, Ferrario, M, Fetiveau, R, Fischer, M, Friedlander, Y, Gabriel, Sb, Galli, M, Gianniny, L, Girelli, D, Grosshennig, A, Guiducci, C, Hakonarson, Hh, Hall, A, Havulinna, A, Hengstenberg, C, Hirschhorn, Jn, Holm, H, Huge, A, Kent, Km, Konig, Ir, Korn, Jm, Li, M, Lieb, W, Lindsay, Jm, Linsel Nitschke, P, Lucas, G, Macrae, Ca, Mannucci, Pm, Marrugat, J, Martinelli, N, Marziliano, N, Matthai, W, Mccarroll, Sa, Mckeown, Pp, Meigs, Jb, Melander, O, Merlini, Pa, Mirel, D, Morgan, T, Musunuru, K, Nathan, Dm, Nemesh, J, O'Donnell, Cj, Olivieri, O, Ouwehand, W, Parkin, M, Patterson, Cc, Peltonen, L, Peyvandi, F, Piazza, A, Pichard, Ad, Preuss, M, Purcell, S, Qasim, A, Rader, Dj, Ramos, R, Reilly, Mp, Ribichini, F, Rossi, M, Sala, J, Salomaa, V, Samani, Nj, Satler, L, Scheffold, T, Scholz, M, Schreiber, S, Schunkert, H, Schwartz, Sm, Siscovick, D, Spertus, Ja, Spreafico, M, Stark, K, Stefansson, K, Stoll, M, Subirana, I, Surti, A, Thompson, Jr, Thorleifsson, G, Thorsteinsdottir, U, Tubaro, M, Voight, Bf, Waksman, R, Wichmann, He, Wilensky, R, Williams, G, Wright, Bj, Xie, C, Yee, J, Ziegler, A, and Zonzin, P.
Subjects: Adult, Male, copy number variants (CNVs), Gene Dosage, Myocardial Infarction, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Bioinformatics, association study, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, myocardial infarction with single, Gene Frequency, Risk Factors, Genetics cardiovascular diseases, genome-wide association, single nucleotide polymorphisms (SNPs), association with early-onset myocardial infarction, Genetics, Humans, Genetic Predisposition to Disease, Copy-number variation, Age of Onset, Gene, Allele frequency, 030304 developmental biology, 0303 health sciences, myocardial infarction, SNPs, Genome-wide association, nucleotide polymorphisms, Middle Aged, Genetic epidemiology, Case-Control Studies, Mutation, Female, Age of onset, Algorithms, Genome-Wide Association Study
Abstract: We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1, 2, 3, 4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.
Published: 2009

25. Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.

Author: Trenkwalder T, Maj C, Al-Kassou B, Debiec R, Doppler SA, Musameh MD, Nelson CP, Dasmeh P, Grover S, Knoll K, Naamanka J, Mordi IR, Braund PS, Dreßen M, Lahm H, Wirth F, Baldus S, Kelm M, von Scheidt M, Krefting J, Ellinghaus D, Small AM, Peloso GM, Natarajan P, Thanassoulis G, Engert JC, Dufresne L, Franke A, Görg S, Laudes M, Nowak-Göttl U, Vaht M, Metspalu A, Stoll M, Berger K, Pellegrini C, Kastrati A, Hengstenberg C, Lang CC, Kessler T, Hovatta I, Nickenig G, Nöthen MM, Krane M, Schunkert H, Samani NJ, Schumacher J, Kals M, Reigo A, Teder-Laving M, Gehlen J, Webb TR, Giel AS, Koebbe LL, Feirer N, Billmann M, Srinivasan S, Zimmer S, Palmer CNA, Li L, Yang C, Borisov O, Adam M, Veulemans V, Joner M, and Xhepa E
Abstract: Importance: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD., Objective: To identify genetic risk loci and cardiovascular risk factors with AS-specific associations., Design, Setting, and Participants: This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023., Exposures: Genetic variants., Main Outcomes and Measures: Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts., Results: A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development., Conclusions and Relevance: This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.
Published: 2024
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26. Plasma Proteomic Biomarkers of Aortic Stenosis: A Mendelian Randomization Study.

Author: Yang TY, Small AM, Dufresne L, Peloso GM, Natarajan P, Engert JC, and Thanassoulis G
Subjects: Humans, Female, Male, Aortic Valve Stenosis blood, Aortic Valve Stenosis genetics, Aortic Valve Stenosis diagnosis, Mendelian Randomization Analysis, Biomarkers blood, Proteomics methods
Abstract: Competing Interests: Funding Support and Author Disclosures This study has been funded by the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation of Canada (HSFC), the National Institutes of Health, and the U.S. Department of Veterans Affairs. Dr Natarajan has received research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; has received personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; has held scientific advisory board membership for Esperion Therapeutics, Preciseli, and TenSixteen Bio; has served as a scientific cofounder of TenSixteen Bio; has held equity in MyOme, Preciseli, and TenSixteen Bio; and has disclosed spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Dr Thanassoulis has received consulting fees from Ionis Pharmaceuticals; and has participated in advisory boards for Amgen, Sanofi, Novartis, HLS Therapeutics, and Silence. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Published: 2024
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27. Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Author: Debban CL, Ambalavanan A, Ghosh A, Li Z, Buschur KL, Ma Y, George E, Pistenmaa C, Bertoni AG, Oelsner EC, Michos ED, Moraes TJ, Jacobs DR Jr, Christenson S, Bhatt SP, Kaner RJ, Simons E, Turvey SE, Vameghestahbanati M, Engert JC, Kirby M, Bourbeau J, Tan WC, Gabriel SB, Gupta N, Woodruff PG, Subbarao P, Ortega VE, Bleecker ER, Meyers DA, Rich SS, Hoffman EA, Barr RG, Cho MH, Bossé Y, Duan Q, Manichaikul A, and Smith BM
Abstract: Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP , DSP , and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.
Published: 2024
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28. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Author: Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Melloni GEM, Kanoni S, Rayner NW, Bocher O, Arruda AL, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee JJ, Pan I, Taliun D, Parra EJ, Chai JF, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak SH, Long J, Sun M, Tong L, Chen WM, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Thangam M, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Hakaste L, Han S, Hattersley AT, Herder C, Horikoshi M, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kamanu FK, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitinger T, Melander O, Metspalu A, Mo H, Morris AD, Moura FA, Nadler JL, Nalls MA, Nayak U, Ntalla I, Okada Y, Orozco L, Patel SR, Patil S, Pei P, Pereira MA, Peters A, Pirie FJ, Polikowsky HG, Porneala B, Prasad G, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sandow K, Sankareswaran A, Sattar N, Schönherr S, Shahriar M, Shen B, Shi J, Shin DM, Shojima N, Smith JA, So WY, Stančáková A, Steinthorsdottir V, Stilp AM, Strauch K, Taylor KD, Thorand B, Thorsteinsdottir U, Tomlinson B, Tran TC, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Wacher-Rodarte N, Wheeler E, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamamoto K, Yoon K, Yu C, Yuan JM, Yusuf S, Zawistowski M, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Fornage M, Hanis CL, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Yokota M, Kardia SLR, Peyser PA, Pankow JS, Engert JC, Bonnefond A, Froguel P, Wilson JG, Sheu WHH, Wu JY, Hayes MG, Ma RCW, Wong TY, Mook-Kanamori DO, Tuomi T, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, Chen YI, Rich SS, McKean-Cowdin R, Grallert H, Cheng CY, Ghanbari M, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Bowden DW, Palmer CNA, Kooner JS, Kooperberg C, Liu S, North KE, Saleheen D, Hansen T, Pedersen O, Wareham NJ, Lee J, Kim BJ, Millwood IY, Walters RG, Stefansson K, Ahlqvist E, Goodarzi MO, Mohlke KL, Langenberg C, Haiman CA, Loos RJF, Florez JC, Rader DJ, Ritchie MD, Zöllner S, Mägi R, Marston NA, Ruff CT, van Heel DA, Finer S, Denny JC, Yamauchi T, Kadowaki T, Chambers JC, Ng MCY, Sim X, Below JE, Tsao PS, Chang KM, McCarthy MI, Meigs JB, Mahajan A, Spracklen CN, Mercader JM, Boehnke M, Rotter JI, Vujkovic M, Voight BF, Morris AP, and Zeggini E
Subjects: Humans, Adipocytes metabolism, Chromatin genetics, Chromatin metabolism, Coronary Artery Disease complications, Coronary Artery Disease genetics, Diabetic Nephropathies complications, Diabetic Nephropathies genetics, Endothelial Cells metabolism, Enteroendocrine Cells, Epigenomics, Islets of Langerhans metabolism, Multifactorial Inheritance genetics, Peripheral Arterial Disease complications, Peripheral Arterial Disease genetics, Single-Cell Analysis, Diabetes Mellitus, Type 2 classification, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 pathology, Diabetes Mellitus, Type 2 physiopathology, Disease Progression, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
Abstract: Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often specific to cell type 3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10 -8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores 5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., (© 2024. The Author(s).)
Published: 2024
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29. Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis.

Author: Shelbaya K, Arthur V, Yang Y, Dorbala P, Buckley L, Claggett B, Skali H, Dufresne L, Yang TY, Engert JC, Thanassoulis G, Floyd J, Austin TR, Bortnick A, Kizer J, Freitas RCC, Singh SA, Aikawa E, Hoogeveen RC, Ballantyne C, Yu B, Coresh J, Blaha MJ, Matsushita K, and Shah AM
Subjects: Humans, Middle Aged, Aged, Aged, 80 and over, Matrix Metalloproteinase 12, Risk Factors, Aortic Valve diagnostic imaging, Biomarkers, Proteomics, Aortic Valve Stenosis, Aortic Valve pathology, Calcinosis
Abstract: Background: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms., Objectives: The aim of this study was to discover novel biomarkers with potentially causal associations with AS., Methods: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue., Results: Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis., Conclusions: These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services, under contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I. This study was also supported by NIH/NHLBI grants R01HL135008, R01HL143224, R01HL150342, R01HL148218, R01HL160025, and K24HL152008 to Dr Shah; R01HL136592 to Drs Matsushita and Blaha; R01HL141917 and R01 HL147095 to Dr Aikawa; K23HL146982 to Dr Bortnick; R01HL144483 to Dr Austin; R01HL142599 and R01HL149706 to Dr Floyd; R01HL128550 to Dr Thanassoulis; and K23HL150311, ASN/KidneyCure Carl W. Gottschalk Research Scholar Grant, and BWH Khoury Innovation Fund to Dr Buckley. Dr Thanassoulis is a Chercheur Boursier Clinicien—Senior from the Fonds de Recherche du Québec—Santé and holds operating grants from the Heart and Stroke Foundation of Canada. Drs Thanassoulis and Engert hold an operating grant from the Canadian Institutes for Health Research. Dr Skali has received consulting fees from Astellas; and has received research support from ABT Associates. Dr Thanassoulis has received consulting fees or participated in advisory boards or speakers bureau for Ionis Pharmaceuticals, Amgen, Sanofi, Novartis, HLS Therapeutics, New Amsterdam, and Silence. Dr Bortnick was the site principal investigator for a clinical trial by CSL-Behring; has received an unrestricted educational grant to her institution from Zoll; and has received a modest honorarium from ClearView Healthcare, outside the present work. Dr Kizer has stock ownership in Abbott, Bristol Myers Squibb, Johnson & Johnson, Medtronic, Merck, and Pfizer. Dr Aikawa is a Scientific Advisory Board member for Elastrin Therapeutics. Dr Hoogeveen has received consulting fees and research funds from Denka Seiken through Baylor College of Medicine, outside the present work. Dr Coresh is a member of the SomaLogic Scientific Advisory Board. Dr Blaha has Advisory Board membership for Novartis, Novo Nordisk, Bayer, Roche, Merck, Vectura, Boehringer Ingelheim, 89BioConsulting, Kowa, and Scene Health. Dr Matsushita has received honoraria from Fukuda Denshi and Kowa, outside the present work. Dr Shah has received consulting fees from Philips Ultrasound; and has received research funds from Novartis through Brigham and Women’s Hospital. The funders had no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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30. Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease.

Author: Rogers MA, Bartoli-Leonard F, Zheng KH, Small AM, Chen HY, Clift CL, Asano T, Kuraoka S, Blaser MC, Perez KA, Natarajan P, Yeang C, Stroes ESG, Tsimikas S, Engert JC, Thanassoulis G, O'Donnell CJ, Aikawa M, Singh SA, and Aikawa E
Subjects: Humans, Aortic Valve metabolism, Lipoprotein(a), Risk Factors, Aortic Valve Disease metabolism, Aortic Valve Stenosis drug therapy, Aortic Valve Stenosis genetics, Atherosclerosis metabolism, Calcinosis, Heart Valve Diseases drug therapy, Heart Valve Diseases genetics, Heart Valve Diseases complications
Abstract: Background: High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein-targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake., Methods: Here, unbiased ligand-receptor capture mass spectrometry was used to identify MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor/cofactor involved in Lp(a) uptake., Results: Reducing MFSD5 expression by a computationally identified small molecule or small interfering RNA suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. MFSD5 variants were associated with aortic stenosis ( P =0.027 after multiple hypothesis testing) with evidence suggestive of an interaction with plasma Lp(a) levels., Conclusions: MFSD5 knockdown suppressing human valvular cell Lp(a) uptake and calcification, along with meta-analysis of MFSD5 variants associating with aortic stenosis, supports further preclinical assessment of MFSD5 in cardiovascular diseases, the leading cause of death worldwide., Competing Interests: Disclosures Dr O’Donnell is employed by Novartis Institutes for Biomedical Research. Dr Rogers is employed by Intellia Therapeutics, but completed all work related to this study before this employment, while employed by Brigham and Women’s Hospital. Dr Natarajan reports grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, Novartis, and TenSixteen Bio, equity in geneXwell, TenSixteen Bio, and Zizi, co-founder of TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. Dr E. Aikawa is on an advisory board for Elastrin Therapeutics Inc. Dr Thanassoulis has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen and Sanofi. The authors declare no other conflicts of interests.
Published: 2024
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31. P2RX7 gene knockout or antagonism reduces angiotensin II-induced hypertension, vascular injury and immune cell activation.

Author: Shokoples BG, Berillo O, Comeau K, Chen HY, Higaki A, Caillon A, Ferreira NS, Engert JC, Thanassoulis G, Paradis P, and Schiffrin EL
Subjects: Humans, Mice, Male, Animals, Angiotensin II pharmacology, Gene Knockout Techniques, T-Lymphocytes, Mice, Knockout, Mice, Inbred C57BL, Receptors, Purinergic P2X7 genetics, Vascular System Injuries, Hypertension chemically induced, Hypertension genetics
Abstract: Objective: Extracellular ATP is elevated in hypertensive mice and humans and may trigger immune activation through the purinergic receptor P2X7 (P2RX7) causing interleukin-1β production and T-cell activation and memory T-cell development. Furthermore, P2RX7 single nucleotide polymorphisms (SNP) are associated with hypertension. We hypothesized that P2RX7 activation contributes to hypertension and cardiovascular injury by promoting immune activation., Methods: Male wild-type and P2rx7-/- mice were infused or not with angiotensin II (AngII) for 14 days. A second group of AngII-infused wild-type mice were co-infused with the P2RX7 antagonist AZ10606120 or vehicle. BP was monitored by telemetry. Cardiac and mesenteric artery function and remodeling were assessed using ultrasound and pressure myography, respectively. T cells were profiled in thoracic aorta/perivascular adipose tissue by flow cytometry. Associations between SNPs within 50 kb of P2RX7 transcription, and BP or hypertension were modeled in 384 653 UK Biobank participants., Results: P2rx7 inactivation attenuated AngII-induced SBP elevation, and mesenteric artery dysfunction and remodeling. This was associated with decreased perivascular infiltration of activated and effector memory T-cell subsets. Surprisingly, P2rx7 knockout exaggerated AngII-induced cardiac dysfunction and remodeling. Treatment with a P2RX7 antagonist reduced BP elevation, preserved mesenteric artery function and reduced activated and effector memory T cell perivascular infiltration without adversely affecting cardiac function and remodeling in AngII-infused mice. Three P2RX7 SNPs were associated with increased odds of DBP elevation., Conclusion: P2RX7 may represent a target for attenuating BP elevation and associated vascular damage by decreasing immune activation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
Published: 2023
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32. Hypertension, brain imaging phenotypes, and cognitive impairment: lessons from Mendelian randomization.

Author: Schiffrin EL and Engert JC
Subjects: Humans, Blood Pressure, Mendelian Randomization Analysis, Phenotype, Brain diagnostic imaging, Neuroimaging, Hypertension genetics, Cognitive Dysfunction
Abstract: Competing Interests: Conflict of interest None declared.
Published: 2023
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33. Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

Author: Yu Chen H, Dina C, Small AM, Shaffer CM, Levinson RT, Helgadóttir A, Capoulade R, Munter HM, Martinsson A, Cairns BJ, Trudsø LC, Hoekstra M, Burr HA, Marsh TW, Damrauer SM, Dufresne L, Le Scouarnec S, Messika-Zeitoun D, Ranatunga DK, Whitmer RA, Bonnefond A, Sveinbjornsson G, Daníelsen R, Arnar DO, Thorgeirsson G, Thorsteinsdottir U, Gudbjartsson DF, Hólm H, Ghouse J, Olesen MS, Christensen AH, Mikkelsen S, Jacobsen RL, Dowsett J, Pedersen OBV, Erikstrup C, Ostrowski SR, O'Donnell CJ, Budoff MJ, Gudnason V, Post WS, Rotter JI, Lathrop M, Bundgaard H, Johansson B, Ljungberg J, Näslund U, Le Tourneau T, Smith JG, Wells QS, Söderberg S, Stefánsson K, Schott JJ, Rader DJ, Clarke R, Engert JC, and Thanassoulis G
Subjects: Humans, Genome-Wide Association Study methods, Adiposity genetics, Genetic Predisposition to Disease, Obesity, Risk Factors, Inflammation, Apolipoproteins genetics, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide genetics, Aortic Valve Stenosis genetics, Dyslipidemias complications, Dyslipidemias genetics
Abstract: Aims: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS., Methods and Results: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS., Conclusion: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies., Competing Interests: Conflict of interest Scott M. Damrauer receives research support (to the University of Pennsylvania) from RenalytixAI and personal fees from Caico Ibs, both outside the scope of the present work. SMD is also named as a co-inventor on a government-owned US Patent application related to the use of genetic risk prediction for venous thromboembolic disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. SMD is named as a co-inventor on a Government-owned US Patent application related to the use of PDE3B inhibition for preventing cardiovascular disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. Stefan Söderberg has received speaker honoraria and consulting fees from Actelion Ltd. George Thanassoulis has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen, Sanofi, Novartis, HLS Therapeutics and Silence. Morten Salling Olesen has received 5.000.000 dkrfra Sundhedsdonationer.Journalnr. 2022-0243. David O. Arnar has received travel support from Pfizer to attend the ESC 2022 Scientific Meeting in Barcelona and has stock options in Sidekick Health Digital Therapeutics. Henning Bundgaard has received lecture fees from Amgen, MSD, Sanofi-Avensis, BMS and grants from NordForsk, Innovation Fond, Denmark, The Capital Regions Research Foundation. Alex Hoerby Christensen—Novo Nordisk Foundation NNF20OC0065799. Romaine Capoulade has received an Honorarium for one lecture from Novartis. Robert Clarke has received support from BAYER (China Kadoorie Biobank). Unnur Thorsteinsdottir’s research is funded by deCODE genetics/Amgen. Daniel F. Gudbjartsson receives funds from deCODE Genetics/Amgen. Until 1 June 2022, Gudmundur Thorgeirsson was a part time employee of deCode Genetics that is owned by Amgen. Hilma Holm is an employee of deCODE genetics/Amgen Inc. Anna Helgadottir is an employee of deCODE genetics/Amgen Inc., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Published: 2023
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34. Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

Author: Gollmann-Tepeköylü C, Graber M, Hirsch J, Mair S, Naschberger A, Pölzl L, Nägele F, Kirchmair E, Degenhart G, Demetz E, Hilbe R, Chen HY, Engert JC, Böhm A, Franz N, Lobenwein D, Lener D, Fuchs C, Weihs A, Töchterle S, Vogel GF, Schweiger V, Eder J, Pietschmann P, Seifert M, Kronenberg F, Coassin S, Blumer M, Hackl H, Meyer D, Feuchtner G, Kirchmair R, Troppmair J, Krane M, Weiss G, Tsimikas S, Thanassoulis G, Grimm M, Rupp B, Huber LA, Zhang SY, Casanova JL, Tancevski I, and Holfeld J
Subjects: Adult, Animals, Humans, Mice, Aortic Valve pathology, Biglycan metabolism, Cells, Cultured, Toll-Like Receptor 3 genetics, Toll-Like Receptor 3 metabolism, Zebrafish, Aortic Valve Stenosis pathology, Calcinosis metabolism
Abstract: Background: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling., Methods: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan ( Bgn ), Tlr3 , and IFN-α/β receptor alpha chain ( Ifnar1 )-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans., Results: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn -/- , Tlr3 -/- , and Ifnar1 -/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans., Conclusions: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD., Competing Interests: Disclosures None.
Published: 2023
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35. Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Author: Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Rayner NW, Bocher O, Arruda ALSV, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee JJ, Pan I, Taliun D, Parra EJ, Chai JF, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak SH, Long J, Sun M, Tong L, Chen WM, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Han S, Hattersley AT, Herder C, Horikoshi M, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Lithgart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitinger T, Metspalu A, Mo H, Morris AD, Nadler JL, Nalls MA, Nayak U, Ntalla I, Okada Y, Orozco L, Patel SR, Patil S, Pei P, Pereira MA, Peters A, Pirie FJ, Polikowsky HG, Porneala B, Prasad G, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sandow K, Sankareswaran A, Sattar N, Schönherr S, Shahriar M, Shen B, Shi J, Shin DM, Shojima N, Smith JA, So WY, Stančáková A, Steinthorsdottir V, Stilp AM, Strauch K, Taylor KD, Thorand B, Thorsteinsdottir U, Tomlinson B, Tran TC, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Wacher-Rodarte N, Wheeler E, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamamoto K, Yoon K, Yu C, Yuan JM, Yusuf S, Zawistowski M, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Fornage M, Hanis CL, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Yokota M, Kardia SLR, Peyser PA, Pankow JS, Engert JC, Bonnefond A, Froguel P, Wilson JG, Sheu WHH, Wu JY, Hayes MG, Ma RCW, Wong TY, Mook-Kanamori DO, Tuomi T, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, Chen YI, Rich SS, McKean-Cowdin R, Grallert H, Cheng CY, Ghanbari M, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Bowden DW, Palmer CNA, Kooner JS, Kooperberg C, Liu S, North KE, Saleheen D, Hansen T, Pedersen O, Wareham NJ, Lee J, Kim BJ, Millwood IY, Walters RG, Stefansson K, Goodarzi MO, Mohlke KL, Langenberg C, Haiman CA, Loos RJF, Florez JC, Rader DJ, Ritchie MD, Zöllner S, Mägi R, Denny JC, Yamauchi T, Kadowaki T, Chambers JC, Ng MCY, Sim X, Below JE, Tsao PS, Chang KM, McCarthy MI, Meigs JB, Mahajan A, Spracklen CN, Mercader JM, Boehnke M, Rotter JI, Vujkovic M, Voight BF, Morris AP, and Zeggini E
Abstract: Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance ( P <5×10 -8 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care., Competing Interests: R.A.S. is now an employee of GlaxoSmithKline. G.T. is an employee of deCODE genetics/Amgen Inc. A.S.B. reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron and Sanofi. J.Danesh serves on scientific advisory boards for AstraZeneca, Novartis, and UK Biobank, and has received multiple grants from academic, charitable and industry sources outside of the submitted work. L.S.E. is now an employee of Bristol Myers Squibb. J.S.F. has consulted for Shionogi Inc. T.M.F. has consulted for Sanofi, Boehringer Ingelheim, and received funding from GlaxoSmithKline. H.C.G. holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care; reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Roche, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, Sanofi, Kowa and Hanmi.lth Institute Chair in Diabetes Research and Care; reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Janssen, Sanofi, and Kowa. M.Ingelsson is a paid consultant to BioArctic AB. R.L.-G. is a part-time consultant of Metabolon Inc. A.E.L. is now an employee of Regeneron Genetics Center LLC and holds shares in Regeneron Pharmaceuticals. M.A.N. currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc. S.R.P. has received grant funding from Bayer Pharmaceuticals, Philips Respironics and Respicardia. N.Sattar has consulted for or been on speakers bureau for Abbott, Amgen, Astrazeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Novartis, Novo Nordisk, Sanofi and Pfizer and has received grant funding from Astrazeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics. V.S. is now an employee of deCODE genetics/Amgen Inc. A.M.S. receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. U.T. is an employee of deCODE genetics/Amgen Inc. E.Ingelsson is now an employee of GlaxoSmithKline. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. R.C.W.M. reports research funding from AstraZeneca, Bayer, Novo Nordisk, Pfizer, Tricida Inc. and Sanofi, and has consulted for or received speakers fees from AstraZeneca, Bayer, Boehringer Ingelheim, all of which have been donated to the Chinese University of Hong Kong to support diabetes research. D.O.M.-K. is a part-time clinical research consultant for Metabolon Inc. S.Liu reports consulting payments and honoraria or promises of the same for scientific presentations or reviews at numerous venues, including but not limited to Barilla, by-Health Inc, Ausa Pharmed Co.LTD, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital and Academy of Medical Sciences, Consulting member for Novo Nordisk, Inc; member of the Data Safety and Monitoring Board for a trial of pulmonary hypertension in diabetes patients at Massachusetts General Hospital; receives royalties from UpToDate; receives an honorarium from the American Society for Nutrition for his duties as Associate Editor. K.Stefansson is an employee of deCODE genetics/Amgen Inc. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda; and is now an employee of Genentech and a holder of Roche stock. J.B.M. is an Academic Associate for Quest Diagnostics R&D. A.Mahajan is an employee of Genentech, and a holder of Roche stock.
Published: 2023
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36. Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity.

Author: Iqbal F, Schlotter F, Becker-Greene D, Lupieri A, Goettsch C, Hutcheson JD, Rogers MA, Itoh S, Halu A, Lee LH, Blaser MC, Mlynarchik AK, Hagita S, Kuraoka S, Chen HY, Engert JC, Passos LSA, Jha PK, Osborn EA, Jaffer FA, Body SC, Robson SC, Thanassoulis G, Aikawa M, Singh SA, Sonawane AR, and Aikawa E
Subjects: Humans, Animals, Mice, Aortic Valve pathology, Constriction, Pathologic, Cells, Cultured, Fibrosis, Aortic Valve Stenosis genetics, Calcinosis metabolism
Abstract: Aims: Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored., Methods and Results: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype., Conclusion: Sortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD., Competing Interests: Conflict of interest: E.A. has participated in advisory board for Elastrin Therapeutics; G.T. has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen and Sanofi., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Published: 2023
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37. Interplay of Atherogenic Particle Number and Particle Size and the Risk of Coronary Heart Disease.

Author: Pencina KM, Pencina MJ, Lawler PR, Engert JC, Dufresne L, Ridker PM, Thanassoulis G, Mora S, and Sniderman AD
Subjects: Humans, Female, Cholesterol, LDL, Particle Size, Apolipoproteins B, Cholesterol, Risk Factors, Cholesterol, HDL, Coronary Disease epidemiology, Coronary Disease etiology
Abstract: Background: We examined the interplay of apolipoprotein B (apoB) and LDL particle size, approximated by the LDL-cholesterol (LDL-C)/apoB ratio, on the risk of new-onset coronary heart disease (CHD)., Methods: Participants without cardiovascular disease from the UK Biobank (UKB; n = 308 182), the Women's Health Study (WHS; n = 26 204), and the Framingham Heart Study (FHS; n = 2839) were included. Multivariable Cox models were used to assess the relationship between apoB and LDL-C/apoB ratio and incidence of CHD (14 994 events). Our analyses were adjusted for age, sex (except WHS), HDL-cholesterol (HDL-C), systolic blood pressure, antihypertensive treatment, diabetes, and smoking., Results: In all 3 studies, there was a strong positive correlation between apoB and LDL-C (correlation coefficients r = 0.80 or higher) and a weak inverse correlation of apoB with LDL-C/apoB ratio (-0.28 ≤ r ≤ -0.14). For all 3 cohorts, CHD risk was higher for higher levels of apoB. Upon multivariable adjustment, the association between apoB and new-onset CHD remained robust and statistically significant in all 3 cohorts with hazard ratios per 1 SD (95% CI): 1.24 (1.22-1.27), 1.33 (1.20-1.47), and 1.24 (1.09-1.42) for UKB, WHS, and FHS, respectively. However, the association between LDL-C/apoB and CHD was statistically significant only in the FHS cohort: 0.78 (0.64-0.94)., Conclusions: Our analysis confirms that apoB is a strong risk factor for CHD. However, given the null association in 2 of the 3 studies, we cannot confirm that cholesterol-depleted LDL particles are substantially more atherogenic than cholesterol-replete particles. These results lend further support to routine measurement of apoB in clinical care., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Published: 2023
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38. Sex Differences in Clopidogrel Effects Among Young Patients With Acute Coronary Syndrome: A Role for Genetics?

Author: Kaur A, Dreyer RP, Marsh TW, Thanassoulis G, Raparelli V, D'Onofrio G, Engert JC, and Pilote L
Abstract: Background: Poorer health outcomes experienced by young women with acute coronary syndrome may be related to sex differences in the safety and efficacy of antiplatelet agents, such as clopidogrel. Polymorphisms in drug metabolism enzyme (cytochrome P450 [ CYP ] family) genes are independent factors for the variability in response to clopidogrel. However, a sex-specific impact of genetics to explain worse clinical outcomes in women has not been explored extensively. Therefore, our objective was to determine whether an interaction of sex with CYP variants occurs among users of clopidogrel, and if so, its impact on 1-year adverse clinical outcomes., Methods: We used data from a combined cohort of 2272 patients (median age 49 years; 56% female) hospitalized for acute coronary syndrome. We examined interactions between sex and CYP variants among clopidogrel users at admission and discharge to assess associations with 1-year readmission due to cardiac events., Results: The case-only analysis of 177 participants on clopidogrel at the time of presentation showed that the risk of an atherothrombotic event was greater in female carriers of the CYP2C9∗3 loss-of-function allele (odds ratio = 3.77, 95% confidence interval = 1.54-9.24). The results of the multivariable logistic regression model for users of clopidogrel at discharge (n = 1733) indicated that women had significantly higher risk of atherothrombotic readmissions at 1 year (odds ratio = 1.55, 95% confidence interval = 1.16-2.07), compared to the risk for men, but the loss-of-function alleles, either individually or through a genetic risk score, were not associated with 1-year readmissions., Conclusion: This study highlights the need for an improved understanding of the role of sex-by-gene interactions in causing sex differences in drug metabolism., (© 2022 The Authors.)
Published: 2022
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39. Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

Author: Loh M, Zhang W, Ng HK, Schmid K, Lamri A, Tong L, Ahmad M, Lee JJ, Ng MCY, Petty LE, Spracklen CN, Takeuchi F, Islam MT, Jasmine F, Kasturiratne A, Kibriya M, Mohlke KL, Paré G, Prasad G, Shahriar M, Chee ML, de Silva HJ, Engert JC, Gerstein HC, Mani KR, Sabanayagam C, Vujkovic M, Wickremasinghe AR, Wong TY, Yajnik CS, Yusuf S, Ahsan H, Bharadwaj D, Anand SS, Below JE, Boehnke M, Bowden DW, Chandak GR, Cheng CY, Kato N, Mahajan A, Sim X, McCarthy MI, Morris AP, Kooner JS, Saleheen D, and Chambers JC
Published: 2022
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40. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.

Author: Mahajan A, Spracklen CN, Zhang W, Ng MCY, Petty LE, Kitajima H, Yu GZ, Rüeger S, Speidel L, Kim YJ, Horikoshi M, Mercader JM, Taliun D, Moon S, Kwak SH, Robertson NR, Rayner NW, Loh M, Kim BJ, Chiou J, Miguel-Escalada I, Della Briotta Parolo P, Lin K, Bragg F, Preuss MH, Takeuchi F, Nano J, Guo X, Lamri A, Nakatochi M, Scott RA, Lee JJ, Huerta-Chagoya A, Graff M, Chai JF, Parra EJ, Yao J, Bielak LF, Tabara Y, Hai Y, Steinthorsdottir V, Cook JP, Kals M, Grarup N, Schmidt EM, Pan I, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Long J, Sun M, Tong L, Chen WM, Ahmad M, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Lecoeur C, Prins BP, Nicolas A, Yanek LR, Chen G, Jensen RA, Tajuddin S, Kabagambe EK, An P, Xiang AH, Choi HS, Cade BE, Tan J, Flanagan J, Abaitua F, Adair LS, Adeyemo A, Aguilar-Salinas CA, Akiyama M, Anand SS, Bertoni A, Bian Z, Bork-Jensen J, Brandslund I, Brody JA, Brummett CM, Buchanan TA, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Fornage M, Franco OH, Frayling TM, Freedman BI, Fuchsberger C, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Goodarzi MO, Gordon-Larsen P, Gorkin D, Gross M, Guo Y, Hackinger S, Han S, Hattersley AT, Herder C, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen ME, Jørgensen T, Kamatani Y, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kohara K, Kriebel J, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lyssenko V, Mamakou V, Mani KR, Meitinger T, Metspalu A, Morris AD, Nadkarni GN, Nadler JL, Nalls MA, Nayak U, Nongmaithem SS, Ntalla I, Okada Y, Orozco L, Patel SR, Pereira MA, Peters A, Pirie FJ, Porneala B, Prasad G, Preissl S, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sander M, Sandow K, Sattar N, Schönherr S, Schurmann C, Shahriar M, Shi J, Shin DM, Shriner D, Smith JA, So WY, Stančáková A, Stilp AM, Strauch K, Suzuki K, Takahashi A, Taylor KD, Thorand B, Thorleifsson G, Thorsteinsdottir U, Tomlinson B, Torres JM, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Vujkovic M, Wacher-Rodarte N, Wheeler E, Whitsel EA, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamauchi T, Yengo L, Yoon K, Yu C, Yuan JM, Yusuf S, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Hanis CL, Peyser PA, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Zeggini E, Yokota M, Rich SS, Kooperberg C, Pankow JS, Engert JC, Chen YI, Froguel P, Wilson JG, Sheu WHH, Kardia SLR, Wu JY, Hayes MG, Ma RCW, Wong TY, Groop L, Mook-Kanamori DO, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, McKean-Cowdin R, Grallert H, Cheng CY, Bottinger EP, Dehghan A, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Palmer CNA, Liu S, Abecasis G, Kooner JS, Loos RJF, North KE, Haiman CA, Florez JC, Saleheen D, Hansen T, Pedersen O, Mägi R, Langenberg C, Wareham NJ, Maeda S, Kadowaki T, Lee J, Millwood IY, Walters RG, Stefansson K, Myers SR, Ferrer J, Gaulton KJ, Meigs JB, Mohlke KL, Gloyn AL, Bowden DW, Below JE, Chambers JC, Sim X, Boehnke M, Rotter JI, McCarthy MI, and Morris AP
Subjects: Ethnicity, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide genetics, Risk Factors, Diabetes Mellitus, Type 2 epidemiology, Genome-Wide Association Study
Abstract: We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10 -9 ), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2022
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41. Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

Author: Loh M, Zhang W, Ng HK, Schmid K, Lamri A, Tong L, Ahmad M, Lee JJ, Ng MCY, Petty LE, Spracklen CN, Takeuchi F, Islam MT, Jasmine F, Kasturiratne A, Kibriya M, Mohlke KL, Paré G, Prasad G, Shahriar M, Chee ML, de Silva HJ, Engert JC, Gerstein HC, Mani KR, Sabanayagam C, Vujkovic M, Wickremasinghe AR, Wong TY, Yajnik CS, Yusuf S, Ahsan H, Bharadwaj D, Anand SS, Below JE, Boehnke M, Bowden DW, Chandak GR, Cheng CY, Kato N, Mahajan A, Sim X, McCarthy MI, Morris AP, Kooner JS, Saleheen D, and Chambers JC
Subjects: Asian People genetics, Case-Control Studies, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics, Genome-Wide Association Study
Abstract: South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (n eff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10 -8 to 5.2 × 10 -12 ), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations., (© 2022. The Author(s).)
Published: 2022
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42. Utility of Genetically Predicted Lp(a) (Lipoprotein [a]) and ApoB Levels for Cardiovascular Risk Assessment.

Author: Wu H, Luan J, Forgetta V, Engert JC, Thanassoulis G, Mooser V, Wareham NJ, Langenberg C, and Richards JB
Subjects: Aged, Female, Humans, Male, Middle Aged, Prospective Studies, Risk Assessment, Apolipoprotein B-100 blood, Apolipoprotein B-100 genetics, Atherosclerosis blood, Atherosclerosis genetics, Lipoprotein(a) blood, Lipoprotein(a) genetics
Abstract: Background: Current lipid guidelines suggest measurement of Lp(a) (lipoprotein[a]) and ApoB (apolipoprotein B) for atherosclerotic cardiovascular disease risk assessment. Polygenic risk scores (PRSs) for Lp(a) and ApoB may identify individuals unlikely to have elevated Lp(a) or ApoB and thus reduce such suggested testing., Methods: PRSs were developed using least absolute shrinkage and selection operator regression among 273 222 and 356 958 UK Biobank participants of white British ancestry for Lp(a) and ApoB, respectively, and validated in separate sets of 60 771 UK Biobank and 15 050 European Prospective Investigation into Cancer and Nutrition-Norfolk participants. We then assessed the proportion of participants who, based on these PRSs, were unlikely to benefit from Lp(a) or ApoB measurements, according to current lipid guidelines., Results: In the UK Biobank and European Prospective Investigation into Cancer and Nutrition-Norfolk cohorts, the area under the receiver operating curve for the PRS-predicted Lp(a) and ApoB to identify individuals with elevated Lp(a) and ApoB was at least 0.91 (95% CI, 0.90-0.92) and 0.74 (95% CI, 0.73-0.75), respectively. The Lp(a) PRS and measured Lp(a) showed comparable association with atherosclerotic cardiovascular disease incidence, whereas the ApoB PRS was in general less predictive of atherosclerotic cardiovascular disease risk than measured ApoB. In the context of the European Society of Cardiology/European Atherosclerosis Society lipid guidelines, at a 95% sensitivity to identify individuals with elevated Lp(a) and ApoB levels, at least 54% of Lp(a) and 24% of ApoB testing could be reduced by prescreening with a PRS while maintaining a low false-negative rate., Conclusions: A substantial proportion of suggested testing for elevated Lp(a) and a modest proportion of testing for elevated ApoB could potentially be reduced by prescreening individuals with PRSs.
Published: 2021
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43. Drugs for Prevention and Treatment of Aortic Stenosis: How Close Are We?

Author: Afshar M, Yazdan-Ashoori S, Engert JC, and Thanassoulis G
Subjects: Aortic Valve metabolism, Disease Progression, Drugs, Investigational pharmacology, Genetic Therapy methods, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Aortic Valve pathology, Aortic Valve Stenosis etiology, Aortic Valve Stenosis metabolism, Aortic Valve Stenosis prevention & control, Aortic Valve Stenosis therapy, Calcinosis etiology, Calcinosis metabolism, Calcinosis prevention & control, Calcinosis therapy, Medication Therapy Management trends
Abstract: Aortic stenosis is one of the most common cardiovascular diseases in the world. Extensive work on the underlying pathophysiology responsible for calcific aortic valve disease and its progression to aortic stenosis has described a complex process involving inflammation, lipid deposition, mineralisation, and genetic factors such as elevated lipoprotein(a). With the advancement of gene silencing technology and development of novel therapeutic agents, we may now be closer than ever to having medical therapies that prevent, or at least slow the progression of aortic stenosis. In this review, we highlight the pathophysiology and risk factors of calcific aortic valve disease, along with current, potential, and emerging novel medical therapies. We also provide potential explanations for the failure of statin trials and suggest new avenues for research and new randomised trials in this area., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)
Published: 2021
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44. Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels-Brief Report.

Author: Hoekstra M, Chen HY, Rong J, Dufresne L, Yao J, Guo X, Tsai MY, Tsimikas S, Post WS, Vasan RS, Rotter JI, Larson MG, Thanassoulis G, and Engert JC
Subjects: Aged, Aged, 80 and over, Biomarkers blood, Cardiovascular Diseases epidemiology, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Disease Risk Factors, Humans, Male, Middle Aged, Phenotype, Risk Assessment, Cardiovascular Diseases blood, Cardiovascular Diseases genetics, Genetic Loci, Genetic Variation, Lipoprotein(a) blood, beta 2-Glycoprotein I genetics
Abstract: Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P ≤5×10 -8 ). In addition to validating previous associations at LPA , APOE , and CETP , we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; P =2.8×10 -13 ) and demonstrated a stronger effect after adjustment for variation at the LPA locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; P =3.8×10 -42 ). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; P =0.0071)., Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.
Published: 2021
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45. Risks of Incident Cardiovascular Disease Associated With Concomitant Elevations in Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-The Framingham Heart Study.

Author: Afshar M, Rong J, Zhan Y, Chen HY, Engert JC, Sniderman AD, Larson MG, Vasan RS, and Thanassoulis G
Subjects: Age Factors, Cardiovascular Diseases blood, Cardiovascular Diseases epidemiology, Female, Humans, Incidence, Longitudinal Studies, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Sex Factors, Cardiovascular Diseases etiology, Cholesterol, LDL blood, Lipoprotein(a) blood
Abstract: Background Elevated lipoprotein(a) is a well-established risk factor for atherosclerotic vascular disease but is not measured in routine clinical care. Screening of high lipoprotein(a) in individuals with moderate elevations of low-density lipoprotein cholesterol (LDL-C) may identify individuals at high risk of cardiovascular disease. Methods and Results We examined 2606 Framingham Offspring participants (median age, 54 years; 45% men) prospectively with a median follow-up of 15 years (n=392 incident cardiovascular events). Individuals with higher (≥100 nmol/L) versus lower lipoprotein(a) were divided into groups based on LDL-C <135 mg/dL versus ≥135 mg/dL. In Cox models, after adjustment for known risk factors, high lipoprotein(a) (≥100 nmol/L) and LDL-C ≥135 mg/dL were each significant predictors of cardiovascular disease (LDL-C ≥135 mg/dL: hazard ratio [HR], 1.34; 95% CI, 1.09-1.64; P =0.006; high lipoprotein (a): HR, 1.31; 95% CI, 1.03-1.66; P =0.026). Across the groups of high/low lipoprotein (a) and LDL-C ≥135 mg/dL or <135 mg/dL, the absolute cardiovascular disease risks at 15 years were 22.6% (high lipoprotein(a)/LDL-C ≥135 mg/dL, n=248), 17.3% (low lipoprotein(a)/LDL-C ≥135 mg/dL, n=758), 12.7% (high lipoprotein(a)/LDL-C <135 mg/dL, n=275) and 11.5% (low lipoprotein(a)/LDL-C <135 mg/dL, n=1328, reference group). Among individuals with LDL-C ≥135 mg/dL, those with high lipoprotein(a) had a 43% higher risk (HR, 1.43; 95% CI, 1.05-1.97; P =0.02). Presence of high lipoprotein(a) with moderate LDL-C levels (135-159 mg/dL) yielded absolute risks equivalent to those with LDL-C ≥160 mg/dL (23.5%, 95% CI, 17.4%-31.3%; and 20.7%, 95% CI, 16.8%-25.3%, respectively). Conclusions Concomitant elevation of LDL-C ≥135 mg/dL and lipoprotein(a) ≥100 nmol/L is associated with a high absolute risk of incident cardiovascular disease. lipoprotein(a) measurement in individuals with moderate elevations in LDL-C, who do not otherwise meet criteria for statins, may identify individuals at high cardiovascular risk.
Published: 2020
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46. Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans.

Author: Perrot N, Thériault S, Rigade S, Chen HY, Dina C, Martinsson A, Boekholdt SM, Capoulade R, Le Tourneau T, Messika-Zeitoun D, Engert JC, Wareham NJ, Clavel MA, Pibarot P, Smith JG, Schott JJ, Mathieu P, Bossé Y, Thanassoulis G, and Arsenault BJ
Subjects: Aged, Aged, 80 and over, Aortic Valve enzymology, Aortic Valve Stenosis blood, Aortic Valve Stenosis diagnosis, Aortic Valve Stenosis genetics, Biomarkers blood, Calcinosis blood, Calcinosis diagnosis, Calcinosis genetics, Case-Control Studies, Europe, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Meta-Analysis as Topic, Phenotype, Risk Assessment, Risk Factors, Up-Regulation, 1-Alkyl-2-acetylglycerophosphocholine Esterase blood, 1-Alkyl-2-acetylglycerophosphocholine Esterase genetics, Aortic Valve pathology, Aortic Valve Stenosis enzymology, Calcinosis enzymology, Polymorphism, Single Nucleotide
Abstract: Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans., Methods and Results: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351)., Conclusions: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS., Competing Interests: Competing interests: BA has received research funding from Pfizer, Merck and Ionis Pharmaceuticals and is a consultant for Novartis. PM is a consultant for Casebia Therapeutics., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2020
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47. Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis.

Author: Perrot N, Valerio V, Moschetta D, Boekholdt SM, Dina C, Chen HY, Abner E, Martinsson A, Manikpurage HD, Rigade S, Capoulade R, Mass E, Clavel MA, Le Tourneau T, Messika-Zeitoun D, Wareham NJ, Engert JC, Polvani G, Pibarot P, Esko T, Smith JG, Mathieu P, Thanassoulis G, Schott JJ, Bossé Y, Camera M, Thériault S, Poggio P, and Arsenault BJ
Abstract: The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation., (© 2020 The Authors.)
Published: 2020
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48. Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis.

Author: Chen HY, Cairns BJ, Small AM, Burr HA, Ambikkumar A, Martinsson A, Thériault S, Munter HM, Steffen B, Zhang R, Levinson RT, Shaffer CM, Rong J, Sonestedt E, Dufresne L, Ljungberg J, Näslund U, Johansson B, Ranatunga DK, Whitmer RA, Budoff MJ, Nguyen A, Vasan RS, Larson MG, Harris WS, Damrauer SM, Stark KD, Boekholdt SM, Wareham NJ, Pibarot P, Arsenault BJ, Mathieu P, Gudnason V, O'Donnell CJ, Rotter JI, Tsai MY, Post WS, Clarke R, Söderberg S, Bossé Y, Wells QS, Smith JG, Rader DJ, Lathrop M, Engert JC, and Thanassoulis G
Subjects: Aged, Alleles, Aortic Valve Stenosis metabolism, Case-Control Studies, Delta-5 Fatty Acid Desaturase, Fatty Acid Desaturases metabolism, Fatty Acids, Unsaturated metabolism, Female, Genome-Wide Association Study, Humans, Male, Aortic Valve Stenosis genetics, DNA genetics, Fatty Acid Desaturases genetics, Fatty Acids, Unsaturated genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
Abstract: Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets., Objective: To identify novel genetic loci and pathways associated with AS., Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019., Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples., Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography., Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4])., Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.
Published: 2020
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49. Periodontitis and hypertension: causally linked by immune mechanisms.

Author: Schiffrin EL and Engert JC
Subjects: Humans, Mendelian Randomization Analysis, Hypertension, Periodontitis
Published: 2019
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50. Genetic Variation in LPA, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification.

Author: Perrot N, Thériault S, Dina C, Chen HY, Boekholdt SM, Rigade S, Després AA, Poulin A, Capoulade R, Le Tourneau T, Messika-Zeitoun D, Trottier M, Tessier M, Guimond J, Nadeau M, Engert JC, Khaw KT, Wareham NJ, Dweck MR, Mathieu P, Pibarot P, Schott JJ, Thanassoulis G, Clavel MA, Bossé Y, and Arsenault BJ
Subjects: Aged, Female, Humans, Male, Clinical Trials as Topic, Coronary Artery Disease genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Pedigree, Prospective Studies, Risk Factors, Case-Control Studies, Multicenter Studies as Topic, Aortic Valve pathology, Aortic Valve Stenosis genetics, Calcinosis genetics, Lipoprotein(a) genetics
Abstract: Importance: Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown., Objective: To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lp[a]) levels showed evidence of aortic valve microcalcification., Design, Setting, and Participants: This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018., Exposures: Case-control studies., Main Outcomes and Measures: Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography., Results: This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41 100 controls with CAD, 2069 individuals with CAVS without CAD, and 380 075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio [OR], 1.35 [95% CI, 1.10-1.66]; P = .003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 [95% CI, 1.20-1.42]; P < .001) and without CAD (OR, 1.33 [95% CI, 1.14-1.55]; P < .001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 [49%]) than control participants (3 of 23 [13%]; P = .006)., Conclusions and Relevance: In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS.
Published: 2019
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