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

Author: Dastani, Z. (Zari), Hivert, M.-F. (Marie-France), Timpson, N.J. (Nicholas), Perry, J.R.B. (John), Yuan, X. (Xin), Scott, R.A. (Robert), Hennemann, P. (Peter), Heid, I.M. (Iris), Kizer, J.R. (Jorge), Lyytikäinen, L.-P. (Leo-Pekka), Fuchsberger, C. (Christian), Tanaka, T. (Toshiko), Morris, A.P. (Andrew), Small, K.S. (Kerrin), Isaacs, A.J. (Aaron), Beekman, M. (Marian), Coassin, S. (Stefan), Lohman, K. (Kurt), Qi, L. (Lu), Kanoni, S. (Stavroula), Pankow, J.S. (James), Uh, H.-W. (Hae-Won), Wu, Y. (Ying), Bidulescu, A. (Aurelian), Rasmussen-Torvik, L.J. (Laura), Greenwood, C.M.T. (Celia), Ladouceur, M. (Martin), Grimsby, J.L. (Jonna), Manning, A.K. (Alisa), Liu, C.-T. (Ching-Ti), Kooner, J.S. (Jaspal), Mooser, V. (Vincent), Vollenweider, P. (Peter), Kapur, K. (Karen), Chambers, J. (John), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Frants, R.R. (Rune), Willems van Dijk, J.A.P. (Ko), Oostra, B.A. (Ben), Willems, S.M. (Sara), Lamina, C. (Claudia), Winkler, T.W. (Thomas), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Brody, J.A. (Jennifer A.), Chen, I. (Ida), Viikari, J. (Jorma), Kähönen, M. (Mika), Pramstaller, P.P. (Peter Paul), Evans, D.M. (David), St Pourcain, B. (Beate), Sattar, N. (Naveed), Wood, A.R. (Andrew), Bandinelli, S. (Stefania), Carlson, O.D. (Olga), Egan, J.M. (Josephine), Böhringer, S. (Stefan), Heemst, D. (Diana) van, Kedenko, L. (Lyudmyla), Kristiansson, K. (Kati), Nuotio, M.-L. (Marja-Liisa), Loo, B.-M. (Britt-Marie), Harris, T.B. (Tamara), Garcia, M. (Melissa), Kanaya, A. (Alka), Haun, M. (Margot), Klopp, N. (Norman), Wichmann, H.E. (Erich), Deloukas, P. (Panagiotis), Katsareli, E. (Efi), Couper, D.J. (David), Duncan, B.B. (Bruce), Kloppenburg, M. (Margreet), Adair, L.S. (Linda), Borja, J.B. (Judith), Wilson, J.G. (James), Musani, S. (Solomon), Guo, X. (Xiuqing), Johnson, T. (Toby), Semple, R.K. (Robert), Teslovich, T.M. (Tanya), Allison, M.A. (Matthew), Redline, S. (Susan), Buxbaum, S.G. (Sarah), Mohlke, K.L. (Karen), Meulenbelt, I. (Ingrid), Ballantyne, C. (Christie), Dedoussis, G.V. (George), Hu, F.B. (Frank), Liu, Y. (YongMei), Paulweber, B. (Bernhard), Spector, T.D. (Timothy), Slagboom, P.E. (Eline), Ferrucci, L. (Luigi), Jula, A. (Antti), Perola, M. (Markus), Raitakari, O.T. (Olli T.), Florez, J.C. (Jose), Salomaa, V. (Veikko), Eriksson, J.G. (Johan), Frayling, T.M. (Timothy), Hicks, A.A. (Andrew), Lehtimäki, T. (Terho), Smith, G.D. (George Davey), Siscovick, D.S. (David), Kronenberg, F. (Florian), Duijn, C.M. (Cornelia) van, Loos, R.J.F. (Ruth), Waterworth, D.M. (Dawn), Meigs, J.B. (James), Dupuis, J. (Josée), Richards, J.B. (Brent), Dastani, Z. (Zari), Hivert, M.-F. (Marie-France), Timpson, N.J. (Nicholas), Perry, J.R.B. (John), Yuan, X. (Xin), Scott, R.A. (Robert), Hennemann, P. (Peter), Heid, I.M. (Iris), Kizer, J.R. (Jorge), Lyytikäinen, L.-P. (Leo-Pekka), Fuchsberger, C. (Christian), Tanaka, T. (Toshiko), Morris, A.P. (Andrew), Small, K.S. (Kerrin), Isaacs, A.J. (Aaron), Beekman, M. (Marian), Coassin, S. (Stefan), Lohman, K. (Kurt), Qi, L. (Lu), Kanoni, S. (Stavroula), Pankow, J.S. (James), Uh, H.-W. (Hae-Won), Wu, Y. (Ying), Bidulescu, A. (Aurelian), Rasmussen-Torvik, L.J. (Laura), Greenwood, C.M.T. (Celia), Ladouceur, M. (Martin), Grimsby, J.L. (Jonna), Manning, A.K. (Alisa), Liu, C.-T. (Ching-Ti), Kooner, J.S. (Jaspal), Mooser, V. (Vincent), Vollenweider, P. (Peter), Kapur, K. (Karen), Chambers, J. (John), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Frants, R.R. (Rune), Willems van Dijk, J.A.P. (Ko), Oostra, B.A. (Ben), Willems, S.M. (Sara), Lamina, C. (Claudia), Winkler, T.W. (Thomas), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Brody, J.A. (Jennifer A.), Chen, I. (Ida), Viikari, J. (Jorma), Kähönen, M. (Mika), Pramstaller, P.P. (Peter Paul), Evans, D.M. (David), St Pourcain, B. (Beate), Sattar, N. (Naveed), Wood, A.R. (Andrew), Bandinelli, S. (Stefania), Carlson, O.D. (Olga), Egan, J.M. (Josephine), Böhringer, S. (Stefan), Heemst, D. (Diana) van, Kedenko, L. (Lyudmyla), Kristiansson, K. (Kati), Nuotio, M.-L. (Marja-Liisa), Loo, B.-M. (Britt-Marie), Harris, T.B. (Tamara), Garcia, M. (Melissa), Kanaya, A. (Alka), Haun, M. (Margot), Klopp, N. (Norman), Wichmann, H.E. (Erich), Deloukas, P. (Panagiotis), Katsareli, E. (Efi), Couper, D.J. (David), Duncan, B.B. (Bruce), Kloppenburg, M. (Margreet), Adair, L.S. (Linda), Borja, J.B. (Judith), Wilson, J.G. (James), Musani, S. (Solomon), Guo, X. (Xiuqing), Johnson, T. (Toby), Semple, R.K. (Robert), Teslovich, T.M. (Tanya), Allison, M.A. (Matthew), Redline, S. (Susan), Buxbaum, S.G. (Sarah), Mohlke, K.L. (Karen), Meulenbelt, I. (Ingrid), Ballantyne, C. (Christie), Dedoussis, G.V. (George), Hu, F.B. (Frank), Liu, Y. (YongMei), Paulweber, B. (Bernhard), Spector, T.D. (Timothy), Slagboom, P.E. (Eline), Ferrucci, L. (Luigi), Jula, A. (Antti), Perola, M. (Markus), Raitakari, O.T. (Olli T.), Florez, J.C. (Jose), Salomaa, V. (Veikko), Eriksson, J.G. (Johan), Frayling, T.M. (Timothy), Hicks, A.A. (Andrew), Lehtimäki, T. (Terho), Smith, G.D. (George Davey), Siscovick, D.S. (David), Kronenberg, F. (Florian), Duijn, C.M. (Cornelia) van, Loos, R.J.F. (Ruth), Waterworth, D.M. (Dawn), Meigs, J.B. (James), Dupuis, J. (Josée), and Richards, J.B. (Brent)
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- choles
Published: 2012
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52. Nucleotide excision DNA repair is associated with age-related vascular dysfunction

Author: Durik, M. (Matej), Kavousi, M. (Maryam), Pluijm, I. (Ingrid) van der, Isaacs, A.J. (Aaron), Cheng, C. (Caroline), Verdonk, K. (Koen), Loot, A.E. (Annemarieke), Oeseburg, H. (Hisko), Bhaggoe, U.M. (Usha), Leijten, F.P.J. (Frank), Veghel, R. (Richard) van, Vries, R. (René) de, Rudež, G. (Goran), Brandt, R.M.C. (Renata), Ridwan, R.Y. (Yanto), Deel, E.D. (Elza) van, Boer, M. (Martine) de, Tempel, D. (Dennie), Fleming, I. (Ingrid), Mitchell, G.F. (Gary), Verwoert, G.C. (Germaine), Tarasov, K.V. (Kirill), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duckers, H.J. (Henricus), Duijn, C.M. (Cornelia) van, Oostra, B.A. (Ben), Witteman, J.C.M. (Jacqueline), Duncker, D.J.G.M. (Dirk), Danser, A.H.J. (Jan), Hoeijmakers, J.H.J. (Jan), Roks, A.J.M. (Anton), Durik, M. (Matej), Kavousi, M. (Maryam), Pluijm, I. (Ingrid) van der, Isaacs, A.J. (Aaron), Cheng, C. (Caroline), Verdonk, K. (Koen), Loot, A.E. (Annemarieke), Oeseburg, H. (Hisko), Bhaggoe, U.M. (Usha), Leijten, F.P.J. (Frank), Veghel, R. (Richard) van, Vries, R. (René) de, Rudež, G. (Goran), Brandt, R.M.C. (Renata), Ridwan, R.Y. (Yanto), Deel, E.D. (Elza) van, Boer, M. (Martine) de, Tempel, D. (Dennie), Fleming, I. (Ingrid), Mitchell, G.F. (Gary), Verwoert, G.C. (Germaine), Tarasov, K.V. (Kirill), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duckers, H.J. (Henricus), Duijn, C.M. (Cornelia) van, Oostra, B.A. (Ben), Witteman, J.C.M. (Jacqueline), Duncker, D.J.G.M. (Dirk), Danser, A.H.J. (Jan), Hoeijmakers, J.H.J. (Jan), and Roks, A.J.M. (Anton)
Abstract: Background: Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. Methods and Results: In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1 and Xpd mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1 mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1 mice, age-related endothelium-dependent vasodilator dysfunction in Xpd animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity. ConclusionS: Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
Published: 2012
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53. Genome-wide association and functional follow-up reveals new loci for kidney function

Author: Pattaro, C. (Cristian), Köttgen, A. (Anna), Teumer, A. (Alexander), Böger, C.A. (Carsten), Fuchsberger, C. (Christian), Olden, M. (Matthias), Chen, M-H. (Ming-Huei), Li, M. (Man), Gao, X. (Xiaoyi), Gorski, M. (Mathias), Yang, Q. (Qiong Fang), O'Seaghdha, C.M. (Conall), Glazer, N.L. (Nicole), Isaacs, A.J. (Aaron), Liu, C.-T. (Ching-Ti), Smith, A.V. (Albert Vernon), O´Connell, J.R., Struchalin, M.V. (Maksim), Tanaka, T. (Toshiko), Johnson, A.D. (Andrew), Feitosa, M.F. (Mary Furlan), Hwang, S.J., Lohman, K. (Kurt), Cornelis, M. (Marilyn), Johansson, A. (Åsa), Tönjes, A. (Anke), Dehghan, A. (Abbas), Chouraki, V. (Vincent), Holliday, E.G. (Elizabeth), Sorice, R., Kutalik, Z. (Zoltán), Lehtimäki, T. (Terho), Esko, T. (Tõnu), Ulivi, S. (Shelia), Trompet, S. (Stella), Imboden, M. (Medea), Kollerits, B. (Barbara), Pistis, G. (Giorgio), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Aspelund, T. (Thor), Eiriksdottir, G. (Gudny), Mitchell, B.D. (Braxton), Boerwinkle, E.A. (Eric), Schmidt, R. (Reinhold), Cavalieri, M. (Margherita), Hu, F.B. (Frank), Demirkan, A. (Ayşe), Oostra, B.A. (Ben), Andrade, M. (Mariza) de, Andrews, J.S. (Jeanette), Koenig, W. (Wolfgang), Illig, T. (Thomas), Döring, A. (Angela), Wichmann, H.E. (Erich), Kolcic, I. (Ivana), Zemunik, T. (Tatijana), Boban, M. (Mladen), Igl, W. (Wilmar), Zaboli, G. (Ghazal), Wild, S.H. (Sarah), Wright, A.F. (Alan), Campbell, H. (Harry), Biffar, R. (Reiner), Ernst, F.D.J. (Florian), Homuth, G. (Georg), Kroemer, H.K. (Heyo), Nauck, M. (Matthias), Kovacs, P. (Peter), Stumvoll, M. (Michael), Mägi, R. (Reedik), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Aulchenko, Y.S. (Yurii), Polasek, O. (Ozren), Hastie, N. (Nick), Vitart, V. (Veronique), Wang, J.J. (Jie Jin), Bergmann, S.M. (Sven), Kähönen, M. (Mika), Viikari, J. (Jorma), Province, M.A. (Mike), Ketkar, S. (Shamika), Doney, A.S.F. (Alex), Ford, I. (Ian), Buckley, B.M. (Brendan M.), Paulweber, B. (Bernhard), Haun, M. (Margot), Sala, C. (Cinzia), Ciullo, M., Vollenweider, P. (Peter), Raitakari, O. (Olli), Metspalu, A. (Andres), Palmer, C.N.A. (Colin), Gasparini, P. (Paolo), Jukema, J.W. (Jan Wouter), Kronenberg, F. (Florian), Toniolo, D. (Daniela), Gudnason, V. (Vilmundur), Shuldiner, A.R. (Alan), Coresh, J. (Josef), Ferrucci, L. (Luigi), Siscovick, D.S. (David), Tikka-Kleemola, P. (Päivi), Borecki, I.B. (Ingrid), Kardia, S.L.R. (Sharon), Curhan, G.C. (Gary), Rudan, I. (Igor), Gyllensten, U. (Ulf), Wilson, J.F. (James), Franke, A. (Andre), Pramstaller, P.P. (Peter Paul), Rettig, R. (Rainer), Prokopenko, I. (Inga), Witteman, J.C.M. (Jacqueline), Hayward, C. (Caroline), Ridker, P.M. (Paul), Parsa, A. (Afshin), Bochud, M. (Murielle), Heid, I.M. (Iris), Goessling, W. (Wolfram), Chasman, D.I. (Daniel), Kao, W.H.L. (Wen), Fox, C.S. (Caroline), Pattaro, C. (Cristian), Köttgen, A. (Anna), Teumer, A. (Alexander), Böger, C.A. (Carsten), Fuchsberger, C. (Christian), Olden, M. (Matthias), Chen, M-H. (Ming-Huei), Li, M. (Man), Gao, X. (Xiaoyi), Gorski, M. (Mathias), Yang, Q. (Qiong Fang), O'Seaghdha, C.M. (Conall), Glazer, N.L. (Nicole), Isaacs, A.J. (Aaron), Liu, C.-T. (Ching-Ti), Smith, A.V. (Albert Vernon), O´Connell, J.R., Struchalin, M.V. (Maksim), Tanaka, T. (Toshiko), Johnson, A.D. (Andrew), Feitosa, M.F. (Mary Furlan), Hwang, S.J., Lohman, K. (Kurt), Cornelis, M. (Marilyn), Johansson, A. (Åsa), Tönjes, A. (Anke), Dehghan, A. (Abbas), Chouraki, V. (Vincent), Holliday, E.G. (Elizabeth), Sorice, R., Kutalik, Z. (Zoltán), Lehtimäki, T. (Terho), Esko, T. (Tõnu), Ulivi, S. (Shelia), Trompet, S. (Stella), Imboden, M. (Medea), Kollerits, B. (Barbara), Pistis, G. (Giorgio), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Aspelund, T. (Thor), Eiriksdottir, G. (Gudny), Mitchell, B.D. (Braxton), Boerwinkle, E.A. (Eric), Schmidt, R. (Reinhold), Cavalieri, M. (Margherita), Hu, F.B. (Frank), Demirkan, A. (Ayşe), Oostra, B.A. (Ben), Andrade, M. (Mariza) de, Andrews, J.S. (Jeanette), Koenig, W. (Wolfgang), Illig, T. (Thomas), Döring, A. (Angela), Wichmann, H.E. (Erich), Kolcic, I. (Ivana), Zemunik, T. (Tatijana), Boban, M. (Mladen), Igl, W. (Wilmar), Zaboli, G. (Ghazal), Wild, S.H. (Sarah), Wright, A.F. (Alan), Campbell, H. (Harry), Biffar, R. (Reiner), Ernst, F.D.J. (Florian), Homuth, G. (Georg), Kroemer, H.K. (Heyo), Nauck, M. (Matthias), Kovacs, P. (Peter), Stumvoll, M. (Michael), Mägi, R. (Reedik), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Aulchenko, Y.S. (Yurii), Polasek, O. (Ozren), Hastie, N. (Nick), Vitart, V. (Veronique), Wang, J.J. (Jie Jin), Bergmann, S.M. (Sven), Kähönen, M. (Mika), Viikari, J. (Jorma), Province, M.A. (Mike), Ketkar, S. (Shamika), Doney, A.S.F. (Alex), Ford, I. (Ian), Buckley, B.M. (Brendan M.), Paulweber, B. (Bernhard), Haun, M. (Margot), Sala, C. (Cinzia), Ciullo, M., Vollenweider, P. (Peter), Raitakari, O. (Olli), Metspalu, A. (Andres), Palmer, C.N.A. (Colin), Gasparini, P. (Paolo), Jukema, J.W. (Jan Wouter), Kronenberg, F. (Florian), Toniolo, D. (Daniela), Gudnason, V. (Vilmundur), Shuldiner, A.R. (Alan), Coresh, J. (Josef), Ferrucci, L. (Luigi), Siscovick, D.S. (David), Tikka-Kleemola, P. (Päivi), Borecki, I.B. (Ingrid), Kardia, S.L.R. (Sharon), Curhan, G.C. (Gary), Rudan, I. (Igor), Gyllensten, U. (Ulf), Wilson, J.F. (James), Franke, A. (Andre), Pramstaller, P.P. (Peter Paul), Rettig, R. (Rainer), Prokopenko, I. (Inga), Witteman, J.C.M. (Jacqueline), Hayward, C. (Caroline), Ridker, P.M. (Paul), Parsa, A. (Afshin), Bochud, M. (Murielle), Heid, I.M. (Iris), Goessling, W. (Wolfram), Chasman, D.I. (Daniel), Kao, W.H.L. (Wen), and Fox, C.S. (Caroline)
Abstract: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Published: 2012
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54. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations

Author: Demirkan, A. (Ayşe), Duijn, C.M. (Cornelia) van, Ugocsai, P. (Peter), Isaacs, A.J. (Aaron), Pramstaller, P.P. (Peter Paul), Liebisch, G. (Gerhard), Wilson, J.F. (James), Johansson, A. (Åsa), Rudan, I. (Igor), Aulchenko, Y.S. (Yurii), Kirichenko, A.V. (Anatoly), Janssens, A.C.J.W. (Cécile), Jansen, R.C. (Ritsert), Gnewuch, C. (Carsten), Domingues, I. (Inês), Pattaro, C. (Cristian), Wild, S.H. (Sarah), Jonasson, I. (Inger), Polasek, O. (Ozren), Zorkoltseva, I.V. (Irina), Hofman, A. (Albert), Karssen, L.C. (Lennart), Struchalin, M.V. (Maksim), Floyd, J. (Jamie), Igl, W. (Wilmar), Biloglav, Z. (Zrinka), Broer, L. (Linda), Pfeufer, A. (Arne), Pichler, I. (Irene), Campbell, S. (Susan), Zaboli, G. (Ghazal), Kolcic, I. (Ivana), Rivadeneira Ramirez, F. (Fernando), Huffman, J.E. (Jennifer), Hastie, N. (Nick), Uitterlinden, A.G. (André), Franke, L. (Lude), Franklin, C.S. (Christopher), Vitart, V. (Veronique), Nelson, C.P. (Christopher P.), Preuss, M. (Michael), Bis, J.C. (Joshua), O'Donnell, C.J. (Christopher), Franceschini, N. (Nora), Witteman, J.C.M. (Jacqueline), Axenovich, T.I. (Tatiana), Oostra, B.A. (Ben), Meitinger, T. (Thomas), Hicks, A.A. (Andrew), Hayward, C. (Caroline), Wright, A.F. (Alan), Gyllensten, U. (Ulf), Campbell, H. (Harry), Schmitz, G. (Gerd), Demirkan, A. (Ayşe), Duijn, C.M. (Cornelia) van, Ugocsai, P. (Peter), Isaacs, A.J. (Aaron), Pramstaller, P.P. (Peter Paul), Liebisch, G. (Gerhard), Wilson, J.F. (James), Johansson, A. (Åsa), Rudan, I. (Igor), Aulchenko, Y.S. (Yurii), Kirichenko, A.V. (Anatoly), Janssens, A.C.J.W. (Cécile), Jansen, R.C. (Ritsert), Gnewuch, C. (Carsten), Domingues, I. (Inês), Pattaro, C. (Cristian), Wild, S.H. (Sarah), Jonasson, I. (Inger), Polasek, O. (Ozren), Zorkoltseva, I.V. (Irina), Hofman, A. (Albert), Karssen, L.C. (Lennart), Struchalin, M.V. (Maksim), Floyd, J. (Jamie), Igl, W. (Wilmar), Biloglav, Z. (Zrinka), Broer, L. (Linda), Pfeufer, A. (Arne), Pichler, I. (Irene), Campbell, S. (Susan), Zaboli, G. (Ghazal), Kolcic, I. (Ivana), Rivadeneira Ramirez, F. (Fernando), Huffman, J.E. (Jennifer), Hastie, N. (Nick), Uitterlinden, A.G. (André), Franke, L. (Lude), Franklin, C.S. (Christopher), Vitart, V. (Veronique), Nelson, C.P. (Christopher P.), Preuss, M. (Michael), Bis, J.C. (Joshua), O'Donnell, C.J. (Christopher), Franceschini, N. (Nora), Witteman, J.C.M. (Jacqueline), Axenovich, T.I. (Tatiana), Oostra, B.A. (Ben), Meitinger, T. (Thomas), Hicks, A.A. (Andrew), Hayward, C. (Caroline), Wright, A.F. (Alan), Gyllensten, U. (Ulf), Campbell, H. (Harry), and Schmitz, G. (Gerd)
Abstract: Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10 -204) and 10 loci for sphingolipids (smallest P-value = 3.10×10 -57). After a correction for multiple comparisons (P-value&2.2×10 -9), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nin
Published: 2012
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55. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author: Ehret, G.B. (Georg), Munroe, P. (Patricia), Rice, K.M. (Kenneth), Bochud, M. (Murielle), Johnson, A.D. (Andrew), Chasman, D.I. (Daniel), Smith, A.V. (Albert Vernon), Tobin, M.D. (Martin), Verwoert, G.C. (Germaine), Hwang, S.J., Pihur, V. (Vasyl), Vollenweider, P. (Peter), O'Reilly, P.F. (Paul), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Teumer, A. (Alexander), Glazer, N.L. (Nicole), Launer, L.J. (Lenore), Zhao, J.H. (Jing Hua), Aulchenko, Y.S. (Yurii), Heath, S.C. (Simon), Sõber, S. (Siim), Parsa, A. (Afshin), Luan, J., Arora, P. (Pankaj), Dehghan, A. (Abbas), Zhang, F. (Feng), Lucas, G. (Gavin), Hicks, A.A. (Andrew), Jackson, A.U. (Anne), Peden, J. (John), Tanaka, T. (Toshiko), Wild, S.H. (Sarah), Rudan, I. (Igor), Igl, W. (Wilmar), Milaneschi, Y. (Yuri), Parker, A.N. (Alex), Fava, C. (Cristiano), Chambers, J.C. (John), Fox, E.R. (Ervin), Kumari, M. (Meena), Jin Go, M. (Min), Harst, P. (Pim) van der, Kao, W.-H.L. (Wen-Hong Linda), Sjögren, M. (Marketa), Vinay, D.G., Alexander, M. (Myriam), Tabara, Y. (Yasuharu), Shaw-Hawkins, S. (Sue), Whincup, P.H. (Peter), Liu, Y. (YongMei), Shi, G. (Gang), Kuusisto, J. (Johanna), Tayo, B. (Bamidele), Seielstad, M. (Mark), Sim, X. (Xueling), Hoang Nguyen, K.-D., Lehtimäki, T. (Terho), Matullo, G. (Giuseppe), Wu, Y. (Ying), Gaunt, T.R. (Tom), Onland-Moret, N.C. (Charlotte), Cooper, M.N. (Matthew), Platou, C. (Carl), Org, E. (Elin), Hardy, R. (Rebecca), Dahgam, S. (Santosh), Palmen, J. (Jutta), Vitart, V. (Veronique), Braund, P.S. (Peter), Kuznetsova, T. (Tatiana), Uiterwaal, C.S.P.M. (Cuno), Adeyemo, A. (Adebowale), Palmas, W. (Walter), Campbell, H. (Harry), Ludwig, B. (Barbara), Tomaszewski, M., Tzoulaki, I., Palmer, N.D. (Nicholette), Aspelund, T. (Thor), Garcia, M. (Melissa), Chang, Y.-P.C. (Yen-Pei), O´Connell, J.R., Steinle, N.I. (Nanette), Grobbee, D.E. (Diederick), Arking, D.E. (Dan), Kardia, S.L. (Sharon), Morrison, A.C. (Alanna), Hernandez, D.G. (Dena), Najjar, S.S. (Samer), McArdle, W.L. (Wendy), Hadley, D. (David), Brown, M.J. (Morris), Connell, J. (John), Hingorani, A. (Aroon), Day, I.N.M. (Ian), Lawlor, D.A. (Debbie), Beilby, J.P. (John), Lawrence, R.W. (Robert), Clarke, R., Hopewell, J., Ongen, H. (Halit), Dreisbach, A.W. (Albert), Li, Y. (Yali), Hunter Young, J., Bis, J.C. (Joshua), Kähönen, M. (Mika), Viikari, J. (Jorma), Lee, N.R. (Nanette), Chen, M-H. (Ming-Huei), Olden, M. (Matthias), Pattaro, C. (Cristian), Hoffman Bolton, J.A. (Judith), Köttgen, A. (Anna), Bergmann, S.M. (Sven), Mooser, V. (Vincent), Chaturvedi, N. (Nish), Frayling, T.M. (Timothy), Islam, M. (Muhammad), Jafar, T.H. (Tazeen), Kulkarni, S.R. (Smita), Bornstein, S.R. (Stefan), Gräßler, J. (Jürgen), Groop, L. (Leif), Voight, B.F. (Benjamin), Kettunen, J. (Johannes), Howard, P. (Philip), Taylor, A. (Andrew), Guarrera, S. (Simonetta), Ricceri, F. (Fulvio), Emilsson, V. (Valur), Plump, A.S. (Andrew), Khaw, K-T. (Kay-Tee), Weder, A.B. (Alan), Hunt, S.C. (Steven), Sun, Y.V. (Yan), Bergman, R.N. (Richard), Collins, F.S. (Francis), Bonnycastle, L.L. (Lori), Scott, L.J. (Laura), Stringham, H.M. (Heather), Peltonen, L. (Leena Johanna), Perola, M. (Markus), Vartiainen, E. (Erkki), Brand, S.-M., Staessen, J.A. (Jan), Wang, Y.A. (Ying), Burton, P.R. (Paul), Soler Artigas, M. (Maria), Dong, Y. (Yanbin), Snieder, H. (Harold), Zhu, H. (Haidong), Lohman, K. (Kurt), Rudock, M.E. (Megan), Heckbert, S.R. (Susan), Wiggins, K.L. (Kerri), Doumatey, A. (Ayo), Shriner, D. (Daniel), Veldre, G. (Gudrun), Viigimaa, M. (Margus), Kinra, S. (Sanjay), Prabhakaran, D. (Dorairaj), Tripathy, V. (Vikal), Langefeld, C.D. (Carl), Rosengren, A. (Annika), Thelle, D.S. (Dag), Corsi, A.M. (Anna Maria), Singleton, A. (Andrew), Forrester, T. (Terrence), Hilton, G. (Gina), McKenzie, C.A. (Colin), Salako, T. (Tunde), Iwai, N. (Naoharu), Kita, Y. (Yoshikuni), Ogihara, T. (Toshio), Ohkubo, T. (Takayoshi), Okamura, T. (Tomonori), Ueshima, H. (Hirotsugu), Umemura, S. (Satoshi), Eyheramendy, S. (Susana), Meitinger, T. (Thomas), Wichmann, H.E. (Heinz Erich), Shin Cho, Y. (Yoon), Kim, H.-L., Sehmi, J.S. (Joban), Hedblad, B. (Bo), Nilsson, P. (Peter), Davey-Smith, G. (George), Wong, A. (Andrew), Narisu, N. (Narisu), Stancáková, A. (Alena), Raffel, L.J. (Leslie), Yao, J. (Jie), Kathiresan, S. (Sekar), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Ikram, M.A. (Arfan), Longstreth Jr, W.T., Mosley, T.H. (Thomas), Seshadri, S. (Sudha), Shrine, N.R.G. (Nick), Wain, L.V. (Louise), Morken, M.A. (Mario), Swift, A.J. (Amy), Laitinen, J. (Jaana), Prokopenko, I. (Inga), Zitting, P. (Paavo), Humphries, S.E. (Steve), Danesh, J. (John), Rasheed, A. (Asif), Goel, A. (Anuj), Hamsten, A. (Anders), Watkins, H. (Hugh), Gilst, W.H. (Wiek) van, Janipalli, C.S. (Charles), Radha Mani, K., Yajnik, C. (Chittaranjan), Hofman, A. (Albert), Mattace Raso, F.U.S. (Francesco), Oostra, B.A. (Ben), Demirkan, A. (Ayşe), Isaacs, A.J. (Aaron), Rivadeneira Ramirez, F. (Fernando), Lakatta, E. (Edward), Orrù, M. (Marco), Scuteri, A. (Angelo), Ala-Korpela, M. (Mika), Kangas, A.J. (Antti), Lyytikäinen, L.-P. (Leo-Pekka), Soininen, P. (Pasi), Tukiainen, T. (Taru), Würtz, P. (Peter), Twee-Hee Ong, R. (Rick), Dörr, M. (Marcus), Kroemer, H.K. (Heyo), Völker, U. (Uwe), Völzke, H. (Henry), Galan, P. (Pilar), Hercberg, S. (Serge), Lathrop, G.M. (Mark), Zelenika, D. (Diana), Deloukas, P. (Panagiotis), Mangino, M. (Massimo), Spector, T.D. (Timothy), Zhai, G. (Guangju), Meschia, J.F. (James F.), Nalls, M.A. (Michael), Sharma, P. (Pankaj), Terzic, J. (Janos), Kranthi Kumar, M.V., Denniff, M. (Matthew), Zukowska-Szczechowska, E. (Ewa), Wagenknecht, L.E. (Lynne), Fowkes, F.G.R. (Gerald), Charchar, F.J. (Fadi), Schwarz, P.E.H. (Peter), Hayward, C. (Caroline), Guo, X. (Xiuqing), Rotimi, C. (Charles), Bots, M.L. (Michiel), Samani, N.J. (Nilesh), Polasek, O. (Ozren), Talmud, P.J. (Philippa), Nyberg, F. (Fredrik), Kuh, D. (Diana), Laan, M. (Maris), Hveem, K. (Kristian), Schouw, Y.T. (Yvonne) van der, Casas, J.P. (Juan), Mohlke, K.L. (Karen), Vineis, P. (Paolo), Raitakari, O. (Olli), Ganesh, S.K. (Santhi), Shyong Tai, E., Laakso, M. (Markku), Rao, D.C. (Dabeeru C.), Harris, T.B. (Tamara), Morris, R.W. (Richard), Dominiczak, A. (Anna), Kivimaki, M. (Mika), Marmot, M. (Michael), Miki, T. (Tetsuro), Saleheen, D., Chandak, G.R. (Giriraj), Coresh, J. (Josef), Navis, G. (Gerjan), Salomaa, V. (Veikko), Han, B.-G., Kooner, J.S. (Jaspal), Melander, O. (Olle), Ridker, P.M. (Paul), Bandinelli, S. (Stefania), Gyllensten, U. (Ulf), Wright, A.F. (Alan), Wilson, J.F. (James), Ferrucci, L. (Luigi), Farrall, M. (Martin), Tuomilehto, J. (Jaakko), Pramstaller, P.P. (Peter Paul), Elosua, R. (Roberto), Soranzo, N. (Nicole), Sijbrands, E.J.G. (Eric), Altshuler, D. (David), Loos, R.J.F. (Ruth), Shuldiner, A.R. (Alan), Gieger, C. (Christian), Meneton, P. (Pierre), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Gudnason, V. (Vilmundur), Rotter, J.I. (Jerome), Rettig, R. (Rainer), Uda, M. (Manuela), Strachan, D.P. (David), Witteman, J.C.M. (Jacqueline), Hartikainen, A.L., Beckmann, J.S. (Jacques), Boerwinkle, E.A. (Eric), Erdmann, J. (Jeanette), Vasan, R.S. (Ramachandran Srini), Boehnke, M. (Michael), Larson, M.G. (Martin), Järvelin, M.R., Psaty, B.M. (Bruce), Tikka-Kleemola, P. (Päivi), Newton-Cheh, C. (Christopher), Elliott, P. (Paul), Levy, D. (Daniel), Caulfield, M. (Mark), Abecasis, G.R. (Gonçalo), Adair, L.S. (Linda), Bakker, S.J.L. (Stephan), Barroso, I.E. (Inês), Ehret, G.B. (Georg), Munroe, P. (Patricia), Rice, K.M. (Kenneth), Bochud, M. (Murielle), Johnson, A.D. (Andrew), Chasman, D.I. (Daniel), Smith, A.V. (Albert Vernon), Tobin, M.D. (Martin), Verwoert, G.C. (Germaine), Hwang, S.J., Pihur, V. (Vasyl), Vollenweider, P. (Peter), O'Reilly, P.F. (Paul), Amin, N. (Najaf), Bragg-Gresham, J.L. (Jennifer L.), Teumer, A. (Alexander), Glazer, N.L. (Nicole), Launer, L.J. (Lenore), Zhao, J.H. (Jing Hua), Aulchenko, Y.S. (Yurii), Heath, S.C. (Simon), Sõber, S. (Siim), Parsa, A. (Afshin), Luan, J., Arora, P. (Pankaj), Dehghan, A. (Abbas), Zhang, F. (Feng), Lucas, G. (Gavin), Hicks, A.A. (Andrew), Jackson, A.U. (Anne), Peden, J. (John), Tanaka, T. (Toshiko), Wild, S.H. (Sarah), Rudan, I. (Igor), Igl, W. (Wilmar), Milaneschi, Y. (Yuri), Parker, A.N. (Alex), Fava, C. (Cristiano), Chambers, J.C. (John), Fox, E.R. (Ervin), Kumari, M. (Meena), Jin Go, M. (Min), Harst, P. (Pim) van der, Kao, W.-H.L. (Wen-Hong Linda), Sjögren, M. (Marketa), Vinay, D.G., Alexander, M. (Myriam), Tabara, Y. (Yasuharu), Shaw-Hawkins, S. (Sue), Whincup, P.H. (Peter), Liu, Y. (YongMei), Shi, G. (Gang), Kuusisto, J. (Johanna), Tayo, B. (Bamidele), Seielstad, M. (Mark), Sim, X. (Xueling), Hoang Nguyen, K.-D., Lehtimäki, T. (Terho), Matullo, G. (Giuseppe), Wu, Y. (Ying), Gaunt, T.R. (Tom), Onland-Moret, N.C. (Charlotte), Cooper, M.N. (Matthew), Platou, C. (Carl), Org, E. (Elin), Hardy, R. (Rebecca), Dahgam, S. (Santosh), Palmen, J. (Jutta), Vitart, V. (Veronique), Braund, P.S. (Peter), Kuznetsova, T. (Tatiana), Uiterwaal, C.S.P.M. (Cuno), Adeyemo, A. (Adebowale), Palmas, W. (Walter), Campbell, H. (Harry), Ludwig, B. (Barbara), Tomaszewski, M., Tzoulaki, I., Palmer, N.D. (Nicholette), Aspelund, T. (Thor), Garcia, M. (Melissa), Chang, Y.-P.C. (Yen-Pei), O´Connell, J.R., Steinle, N.I. (Nanette), Grobbee, D.E. (Diederick), Arking, D.E. (Dan), Kardia, S.L. (Sharon), Morrison, A.C. (Alanna), Hernandez, D.G. (Dena), Najjar, S.S. (Samer), McArdle, W.L. (Wendy), Hadley, D. (David), Brown, M.J. (Morris), Connell, J. (John), Hingorani, A. (Aroon), Day, I.N.M. (Ian), Lawlor, D.A. (Debbie), Beilby, J.P. (John), Lawrence, R.W. (Robert), Clarke, R., Hopewell, J., Ongen, H. (Halit), Dreisbach, A.W. (Albert), Li, Y. (Yali), Hunter Young, J., Bis, J.C. (Joshua), Kähönen, M. (Mika), Viikari, J. (Jorma), Lee, N.R. (Nanette), Chen, M-H. (Ming-Huei), Olden, M. (Matthias), Pattaro, C. (Cristian), Hoffman Bolton, J.A. (Judith), Köttgen, A. (Anna), Bergmann, S.M. (Sven), Mooser, V. (Vincent), Chaturvedi, N. (Nish), Frayling, T.M. (Timothy), Islam, M. (Muhammad), Jafar, T.H. (Tazeen), Kulkarni, S.R. (Smita), Bornstein, S.R. (Stefan), Gräßler, J. (Jürgen), Groop, L. (Leif), Voight, B.F. (Benjamin), Kettunen, J. (Johannes), Howard, P. (Philip), Taylor, A. (Andrew), Guarrera, S. (Simonetta), Ricceri, F. (Fulvio), Emilsson, V. (Valur), Plump, A.S. (Andrew), Khaw, K-T. (Kay-Tee), Weder, A.B. (Alan), Hunt, S.C. (Steven), Sun, Y.V. (Yan), Bergman, R.N. (Richard), Collins, F.S. (Francis), Bonnycastle, L.L. (Lori), Scott, L.J. (Laura), Stringham, H.M. (Heather), Peltonen, L. (Leena Johanna), Perola, M. (Markus), Vartiainen, E. (Erkki), Brand, S.-M., Staessen, J.A. (Jan), Wang, Y.A. (Ying), Burton, P.R. (Paul), Soler Artigas, M. (Maria), Dong, Y. (Yanbin), Snieder, H. (Harold), Zhu, H. (Haidong), Lohman, K. (Kurt), Rudock, M.E. (Megan), Heckbert, S.R. (Susan), Wiggins, K.L. (Kerri), Doumatey, A. (Ayo), Shriner, D. (Daniel), Veldre, G. (Gudrun), Viigimaa, M. (Margus), Kinra, S. (Sanjay), Prabhakaran, D. (Dorairaj), Tripathy, V. (Vikal), Langefeld, C.D. (Carl), Rosengren, A. (Annika), Thelle, D.S. (Dag), Corsi, A.M. (Anna Maria), Singleton, A. (Andrew), Forrester, T. (Terrence), Hilton, G. (Gina), McKenzie, C.A. (Colin), Salako, T. (Tunde), Iwai, N. (Naoharu), Kita, Y. (Yoshikuni), Ogihara, T. (Toshio), Ohkubo, T. (Takayoshi), Okamura, T. (Tomonori), Ueshima, H. (Hirotsugu), Umemura, S. (Satoshi), Eyheramendy, S. (Susana), Meitinger, T. (Thomas), Wichmann, H.E. (Heinz Erich), Shin Cho, Y. (Yoon), Kim, H.-L., Sehmi, J.S. (Joban), Hedblad, B. (Bo), Nilsson, P. (Peter), Davey-Smith, G. (George), Wong, A. (Andrew), Narisu, N. (Narisu), Stancáková, A. (Alena), Raffel, L.J. (Leslie), Yao, J. (Jie), Kathiresan, S. (Sekar), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Ikram, M.A. (Arfan), Longstreth Jr, W.T., Mosley, T.H. (Thomas), Seshadri, S. (Sudha), Shrine, N.R.G. (Nick), Wain, L.V. (Louise), Morken, M.A. (Mario), Swift, A.J. (Amy), Laitinen, J. (Jaana), Prokopenko, I. (Inga), Zitting, P. (Paavo), Humphries, S.E. (Steve), Danesh, J. (John), Rasheed, A. (Asif), Goel, A. (Anuj), Hamsten, A. (Anders), Watkins, H. (Hugh), Gilst, W.H. (Wiek) van, Janipalli, C.S. (Charles), Radha Mani, K., Yajnik, C. (Chittaranjan), Hofman, A. (Albert), Mattace Raso, F.U.S. (Francesco), Oostra, B.A. (Ben), Demirkan, A. (Ayşe), Isaacs, A.J. (Aaron), Rivadeneira Ramirez, F. (Fernando), Lakatta, E. (Edward), Orrù, M. (Marco), Scuteri, A. (Angelo), Ala-Korpela, M. (Mika), Kangas, A.J. (Antti), Lyytikäinen, L.-P. (Leo-Pekka), Soininen, P. (Pasi), Tukiainen, T. (Taru), Würtz, P. (Peter), Twee-Hee Ong, R. (Rick), Dörr, M. (Marcus), Kroemer, H.K. (Heyo), Völker, U. (Uwe), Völzke, H. (Henry), Galan, P. (Pilar), Hercberg, S. (Serge), Lathrop, G.M. (Mark), Zelenika, D. (Diana), Deloukas, P. (Panagiotis), Mangino, M. (Massimo), Spector, T.D. (Timothy), Zhai, G. (Guangju), Meschia, J.F. (James F.), Nalls, M.A. (Michael), Sharma, P. (Pankaj), Terzic, J. (Janos), Kranthi Kumar, M.V., Denniff, M. (Matthew), Zukowska-Szczechowska, E. (Ewa), Wagenknecht, L.E. (Lynne), Fowkes, F.G.R. (Gerald), Charchar, F.J. (Fadi), Schwarz, P.E.H. (Peter), Hayward, C. (Caroline), Guo, X. (Xiuqing), Rotimi, C. (Charles), Bots, M.L. (Michiel), Samani, N.J. (Nilesh), Polasek, O. (Ozren), Talmud, P.J. (Philippa), Nyberg, F. (Fredrik), Kuh, D. (Diana), Laan, M. (Maris), Hveem, K. (Kristian), Schouw, Y.T. (Yvonne) van der, Casas, J.P. (Juan), Mohlke, K.L. (Karen), Vineis, P. (Paolo), Raitakari, O. (Olli), Ganesh, S.K. (Santhi), Shyong Tai, E., Laakso, M. (Markku), Rao, D.C. (Dabeeru C.), Harris, T.B. (Tamara), Morris, R.W. (Richard), Dominiczak, A. (Anna), Kivimaki, M. (Mika), Marmot, M. (Michael), Miki, T. (Tetsuro), Saleheen, D., Chandak, G.R. (Giriraj), Coresh, J. (Josef), Navis, G. (Gerjan), Salomaa, V. (Veikko), Han, B.-G., Kooner, J.S. (Jaspal), Melander, O. (Olle), Ridker, P.M. (Paul), Bandinelli, S. (Stefania), Gyllensten, U. (Ulf), Wright, A.F. (Alan), Wilson, J.F. (James), Ferrucci, L. (Luigi), Farrall, M. (Martin), Tuomilehto, J. (Jaakko), Pramstaller, P.P. (Peter Paul), Elosua, R. (Roberto), Soranzo, N. (Nicole), Sijbrands, E.J.G. (Eric), Altshuler, D. (David), Loos, R.J.F. (Ruth), Shuldiner, A.R. (Alan), Gieger, C. (Christian), Meneton, P. (Pierre), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Gudnason, V. (Vilmundur), Rotter, J.I. (Jerome), Rettig, R. (Rainer), Uda, M. (Manuela), Strachan, D.P. (David), Witteman, J.C.M. (Jacqueline), Hartikainen, A.L., Beckmann, J.S. (Jacques), Boerwinkle, E.A. (Eric), Erdmann, J. (Jeanette), Vasan, R.S. (Ramachandran Srini), Boehnke, M. (Michael), Larson, M.G. (Martin), Järvelin, M.R., Psaty, B.M. (Bruce), Tikka-Kleemola, P. (Päivi), Newton-Cheh, C. (Christopher), Elliott, P. (Paul), Levy, D. (Daniel), Caulfield, M. (Mark), Abecasis, G.R. (Gonçalo), Adair, L.S. (Linda), Bakker, S.J.L. (Stephan), and Barroso, I.E. (Inês)
Abstract: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140mmg Hg systolic blood pressure ≥90mmg Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3 GUCY1B3, NPR3 C5orf23, ADM, FURIN FES, GOSR2, GNAS EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 geno
Published: 2011
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56. A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol

Author: Surakka, I. (Ida), Isaacs, A.J. (Aaron), Karssen, L.C. (Lennart), Laurila, P.-P.P., Middelberg, R.P.S. (Rita), Tikkanen, E. (Emmi), Ried, J.S. (Janina), Lamina, C. (Claudia), Mangino, M. (Massimo), Igl, W. (Wilmar), Hottenga, J.J. (Jouke Jan), Lagou, V. (Vasiliki), Harst, P. (Pim) van der, Leach, I.M. (Irene Mateo), Esko, T. (Tõnu), Kutalik, Z. (Zoltán), Wainwright, N.W. (Nicholas), Struchalin, M.V. (Maksim), Sarin, A.-P., Kangas, A.J. (Antti), Viikari, J. (Jorma), Perola, M. (Markus), Rantanen, T. (Taina), Petersen, A.K., Soininen, P. (Pasi), Johansson, A. (Åsa), Soranzo, N. (Nicole), Heath, A.C. (Andrew), Papamarkou, T. (Theodore), Prokopenko, I. (Inga), Tönjes, A. (Anke), Kronenberg, F. (Florian), Döring, A. (Angela), Rivadeneira Ramirez, F. (Fernando), Montgomery, G.W. (Grant), Whitfield, J.B. (John), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Freimer, N.B. (Nelson), Willemsen, G.A.H.M. (Gonneke), Geus, E.J.C. (Eco) de, Palotie, A. (Aarno), Sandhu, M.S. (Manj), Waterworth, D. (Dawn), Metspalu, A. (Andres), Stumvoll, M. (Michael), Uitterlinden, A.G. (André), Jula, A. (Antti), Navis, G. (Gerjan), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.R. (Bruce), Taskinen, M.-R., Ala-Korpela, M. (Mika), Kaprio, J. (Jaakko), Kyvik, K.O. (Kirsten Ohm), Boomsma, D.I. (Dorret), Pedersen, N.L. (Nancy), Gyllensten, U. (Ulf), Wilson, J.F. (James), Rudan, I. (Igor), Campbell, H. (Harry), Pramstaller, P.P. (Peter Paul), Spector, T.D. (Timothy), Witteman, J.C.M. (Jacqueline), Eriksson, J.G. (Johan), Salomaa, V. (Veikko), Oostra, B.A. (Ben), Raitakari, O. (Olli), Wichmann, H.E. (Heinz Erich), Gieger, C. (Christian), Järvelin, M.R., Martin, N.G. (Nicholas), Hofman, A. (Albert), McCarthy, M.I. (Mark), Aulchenko, Y.S. (Yurii), Peltonen, L. (Leena Johanna), Tikka-Kleemola, P. (Päivi), Ripatti, S. (Samuli), Surakka, I. (Ida), Isaacs, A.J. (Aaron), Karssen, L.C. (Lennart), Laurila, P.-P.P., Middelberg, R.P.S. (Rita), Tikkanen, E. (Emmi), Ried, J.S. (Janina), Lamina, C. (Claudia), Mangino, M. (Massimo), Igl, W. (Wilmar), Hottenga, J.J. (Jouke Jan), Lagou, V. (Vasiliki), Harst, P. (Pim) van der, Leach, I.M. (Irene Mateo), Esko, T. (Tõnu), Kutalik, Z. (Zoltán), Wainwright, N.W. (Nicholas), Struchalin, M.V. (Maksim), Sarin, A.-P., Kangas, A.J. (Antti), Viikari, J. (Jorma), Perola, M. (Markus), Rantanen, T. (Taina), Petersen, A.K., Soininen, P. (Pasi), Johansson, A. (Åsa), Soranzo, N. (Nicole), Heath, A.C. (Andrew), Papamarkou, T. (Theodore), Prokopenko, I. (Inga), Tönjes, A. (Anke), Kronenberg, F. (Florian), Döring, A. (Angela), Rivadeneira Ramirez, F. (Fernando), Montgomery, G.W. (Grant), Whitfield, J.B. (John), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Freimer, N.B. (Nelson), Willemsen, G.A.H.M. (Gonneke), Geus, E.J.C. (Eco) de, Palotie, A. (Aarno), Sandhu, M.S. (Manj), Waterworth, D. (Dawn), Metspalu, A. (Andres), Stumvoll, M. (Michael), Uitterlinden, A.G. (André), Jula, A. (Antti), Navis, G. (Gerjan), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.R. (Bruce), Taskinen, M.-R., Ala-Korpela, M. (Mika), Kaprio, J. (Jaakko), Kyvik, K.O. (Kirsten Ohm), Boomsma, D.I. (Dorret), Pedersen, N.L. (Nancy), Gyllensten, U. (Ulf), Wilson, J.F. (James), Rudan, I. (Igor), Campbell, H. (Harry), Pramstaller, P.P. (Peter Paul), Spector, T.D. (Timothy), Witteman, J.C.M. (Jacqueline), Eriksson, J.G. (Johan), Salomaa, V. (Veikko), Oostra, B.A. (Ben), Raitakari, O. (Olli), Wichmann, H.E. (Heinz Erich), Gieger, C. (Christian), Järvelin, M.R., Martin, N.G. (Nicholas), Hofman, A. (Albert), McCarthy, M.I. (Mark), Aulchenko, Y.S. (Yurii), Peltonen, L. (Leena Johanna), Tikka-Kleemola, P. (Päivi), and Ripatti, S. (Samuli)
Abstract: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ~25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10-9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Published: 2011
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57. Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Author: Bis, J.C. (Joshua), Kavousi, M. (Maryam), Franceschini, N. (Nora), Isaacs, A.J. (Aaron), Abecasis, G.R. (Gonçalo), Schminke, U. (Ulf), Post, W.S. (Wendy S.), Smith, A.V. (Albert Vernon), Cupples, L.A. (Adrienne), Markus, H.S. (Hugh S.), Schmidt, R. (Reinhold), Huffman, J.E. (Jennifer), Lehtimäki, T. (Terho), Baumert, J. (Jens), Münzel, T. (Thomas), Heckbert, S.R. (Susan), Dehghan, A. (Abbas), North, K.E. (Kari), Oostra, B.A. (Ben), Bevan, S. (Steve), Stoegerer, E.M. (Eva Maria), Hayward, C. (Caroline), Raitakari, O. (Olli), Meisinger, C. (Christa), Schillert, A. (Arne), Sanna, S. (Serena), Völzke, H. (Henry), Cheng, Y.C. (Yu Ching), Thorsson, B. (Bolli), Fox, C.S. (Caroline), Rice, K. (Kenneth), Rivadeneira Ramirez, F. (Fernando), Nambi, V. (Vijay), Halperin, E. (Eran), Petrovic, K. (Katja), Peltonen, L. (Leena Johanna), Wichmann, H.E. (Heinz Erich), Schnabel, R.B. (Renate), Dörr, M. (Marcus), Parsa, A. (Afshin), Aspelund, T. (Thor), Demissie, S. (Serkalem), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Taylor, K.D. (Kent), Uitterlinden, A.G. (André), Couper, D.J. (David), Sitzer, M. (Matthias), Kähönen, M. (Mika), Illig, T. (Thomas), Wild, P.S. (Philipp), Orrù, M. (Marco), Lüdemann, J. (Jan), Shuldiner, A.R. (Alan), Eiriksdottir, G. (Gudny), White, C.C. (Charles), Rotter, J.I. (Jerome), Hofman, A. (Albert), Seissler, J. (Jochen), Zeller, T. (Tanja), Usala, G., Ernst, F.D.J. (Florian), Launer, L.J. (Lenore), D'Agostino, R.B. (Ralph), O'Leary, D.H. (Daniel H.), Ballantyne, C. (Christie), Thiery, J.P. (Joachim), Ziegler, A. (Andreas), Lakatta, E. (Edward), Chilukoti, R.K. (Ravi Kumar), Harris, T.B. (Tamara), Wolf, P.A. (Philip), Psaty, B.M. (Bruce), Polak, J.F. (Joseph F.), Rathmann, W. (Wolfgang), Uda, M. (Manuela), Boerwinkle, E.A. (Eric), Klopp, N. (Norman), Wilson, J.F. (James), Viikari, J. (Jorma), Koenig, W. (Wolfgang), Blankenberg, S. (Stefan), Newman, A.B. (Anne), Witteman, J.C.M. (Jacqueline), Li, X. (Xia), Heiss, G. (Gerardo), Duijn, C.M. (Cornelia) van, Scuteri, A. (Angelo), Homuth, G. (Georg), Mitchell, B.D. (Braxton), Gudnason, V. (Vilmundur), O'Donnell, C.J. (Christopher), Bis, J.C. (Joshua), Kavousi, M. (Maryam), Franceschini, N. (Nora), Isaacs, A.J. (Aaron), Abecasis, G.R. (Gonçalo), Schminke, U. (Ulf), Post, W.S. (Wendy S.), Smith, A.V. (Albert Vernon), Cupples, L.A. (Adrienne), Markus, H.S. (Hugh S.), Schmidt, R. (Reinhold), Huffman, J.E. (Jennifer), Lehtimäki, T. (Terho), Baumert, J. (Jens), Münzel, T. (Thomas), Heckbert, S.R. (Susan), Dehghan, A. (Abbas), North, K.E. (Kari), Oostra, B.A. (Ben), Bevan, S. (Steve), Stoegerer, E.M. (Eva Maria), Hayward, C. (Caroline), Raitakari, O. (Olli), Meisinger, C. (Christa), Schillert, A. (Arne), Sanna, S. (Serena), Völzke, H. (Henry), Cheng, Y.C. (Yu Ching), Thorsson, B. (Bolli), Fox, C.S. (Caroline), Rice, K. (Kenneth), Rivadeneira Ramirez, F. (Fernando), Nambi, V. (Vijay), Halperin, E. (Eran), Petrovic, K. (Katja), Peltonen, L. (Leena Johanna), Wichmann, H.E. (Heinz Erich), Schnabel, R.B. (Renate), Dörr, M. (Marcus), Parsa, A. (Afshin), Aspelund, T. (Thor), Demissie, S. (Serkalem), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Taylor, K.D. (Kent), Uitterlinden, A.G. (André), Couper, D.J. (David), Sitzer, M. (Matthias), Kähönen, M. (Mika), Illig, T. (Thomas), Wild, P.S. (Philipp), Orrù, M. (Marco), Lüdemann, J. (Jan), Shuldiner, A.R. (Alan), Eiriksdottir, G. (Gudny), White, C.C. (Charles), Rotter, J.I. (Jerome), Hofman, A. (Albert), Seissler, J. (Jochen), Zeller, T. (Tanja), Usala, G., Ernst, F.D.J. (Florian), Launer, L.J. (Lenore), D'Agostino, R.B. (Ralph), O'Leary, D.H. (Daniel H.), Ballantyne, C. (Christie), Thiery, J.P. (Joachim), Ziegler, A. (Andreas), Lakatta, E. (Edward), Chilukoti, R.K. (Ravi Kumar), Harris, T.B. (Tamara), Wolf, P.A. (Philip), Psaty, B.M. (Bruce), Polak, J.F. (Joseph F.), Rathmann, W. (Wolfgang), Uda, M. (Manuela), Boerwinkle, E.A. (Eric), Klopp, N. (Norman), Wilson, J.F. (James), Viikari, J. (Jorma), Koenig, W. (Wolfgang), Blankenberg, S. (Stefan), Newman, A.B. (Anne), Witteman, J.C.M. (Jacqueline), Li, X. (Xia), Heiss, G. (Gerardo), Duijn, C.M. (Cornelia) van, Scuteri, A. (Angelo), Homuth, G. (Georg), Mitchell, B.D. (Braxton), Gudnason, V. (Vilmundur), and O'Donnell, C.J. (Christopher)
Abstract: Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
Published: 2011
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58. Genetic architecture of circulating lipid levels

Author: Demirkan, A. (Ayşe), Amin, N. (Najaf), Isaacs, A.J. (Aaron), Järvelin, M.R., Whitfield, J.B. (John), Wichmann, H.E. (Heinz Erich), Kyvik, K.O. (Kirsten Ohm), Rudan, I. (Igor), Gieger, C. (Christian), Hicks, A.A. (Andrew), Johansson, A. (Åsa), Hottenga, J.J. (Jouke Jan), Smith, J.J. (Johannes), Wild, S.H. (Sarah), Pedersen, N.L. (Nancy), Willemsen, G.A.H.M. (Gonneke), Mangino, M. (Massimo), Hayward, C. (Caroline), Uitterlinden, A.G. (André), Hofman, A. (Albert), Witteman, J.C.M. (Jacqueline), Montgomery, G.W. (Grant), Pietilainen, K.H. (Kirsi Hannele), Rantanen, T. (Taina), Kaprio, J. (Jaakko), Döring, A. (Angela), Pramstaller, P.P. (Peter Paul), Gyllensten, U. (Ulf), Geus, E.J.C. (Eco) de, Penninx, B.W.J.H. (Brenda), Wilson, J.F. (James), Rivadeneria, F. (Fernando), Magnusson, P.K. (Patrik), Boomsma, D.I. (Dorret), Spector, T.D. (Timothy), Campbell, H. (Harry), Hoehne, B. (Birgit), Martin, N.G. (Nicholas), Oostra, B.A. (Ben), McCarthy, M.I. (Mark), Peltonen-Palotie, L. (Leena), Aulchenko, Y.S. (Yurii), Visscher, P.M. (Peter), Ripatti, S. (Samuli), Janssens, A.C.J.W. (Cécile), Tikka-Kleemola, P. (Päivi), Demirkan, A. (Ayşe), Amin, N. (Najaf), Isaacs, A.J. (Aaron), Järvelin, M.R., Whitfield, J.B. (John), Wichmann, H.E. (Heinz Erich), Kyvik, K.O. (Kirsten Ohm), Rudan, I. (Igor), Gieger, C. (Christian), Hicks, A.A. (Andrew), Johansson, A. (Åsa), Hottenga, J.J. (Jouke Jan), Smith, J.J. (Johannes), Wild, S.H. (Sarah), Pedersen, N.L. (Nancy), Willemsen, G.A.H.M. (Gonneke), Mangino, M. (Massimo), Hayward, C. (Caroline), Uitterlinden, A.G. (André), Hofman, A. (Albert), Witteman, J.C.M. (Jacqueline), Montgomery, G.W. (Grant), Pietilainen, K.H. (Kirsi Hannele), Rantanen, T. (Taina), Kaprio, J. (Jaakko), Döring, A. (Angela), Pramstaller, P.P. (Peter Paul), Gyllensten, U. (Ulf), Geus, E.J.C. (Eco) de, Penninx, B.W.J.H. (Brenda), Wilson, J.F. (James), Rivadeneria, F. (Fernando), Magnusson, P.K. (Patrik), Boomsma, D.I. (Dorret), Spector, T.D. (Timothy), Campbell, H. (Harry), Hoehne, B. (Birgit), Martin, N.G. (Nicholas), Oostra, B.A. (Ben), McCarthy, M.I. (Mark), Peltonen-Palotie, L. (Leena), Aulchenko, Y.S. (Yurii), Visscher, P.M. (Peter), Ripatti, S. (Samuli), Janssens, A.C.J.W. (Cécile), and Tikka-Kleemola, P. (Päivi)
Abstract: Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
Published: 2011
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59. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14

Author: Solouki, A.M. (Abbas), Verhoeven, V.J.M. (Virginie), Duijn, C.M. (Cornelia) van, Verkerk, A.J.H.M. (Annemieke), Ikram, M.K. (Kamran), Hysi, P.G. (Pirro), Despriet, D.D.G. (Dominique), Koolwijk, L.M.E. (Leonieke) van, Ho, L. (Lintje), Ramdas, W.D. (Wishal), Czudowska, M.A. (Monika), Kuijpers, R.W.A.M. (Robert), Amin, N. (Najaf), Struchalin, M.V. (Maksim), Aulchenko, Y.S. (Yurii), Rij, G. (Gabriel) van, Riemslag, F.C.C. (Frans), Young, T.L. (Terry), Mackey, D.A. (David), Spector, T.D. (Timothy), Gorgels, T.G.M.F. (Theo), Willemse-Assink, J.J.M. (Jacqueline), Isaacs, A.J. (Aaron), Kramer, R. (Rogier), Swagemakers, S.M.A. (Sigrid), Bergen, A.A.B. (Arthur), Oosterhout, A.A.L.J. (Andrew) van, Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Hammond, C.J. (Christopher), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Solouki, A.M. (Abbas), Verhoeven, V.J.M. (Virginie), Duijn, C.M. (Cornelia) van, Verkerk, A.J.H.M. (Annemieke), Ikram, M.K. (Kamran), Hysi, P.G. (Pirro), Despriet, D.D.G. (Dominique), Koolwijk, L.M.E. (Leonieke) van, Ho, L. (Lintje), Ramdas, W.D. (Wishal), Czudowska, M.A. (Monika), Kuijpers, R.W.A.M. (Robert), Amin, N. (Najaf), Struchalin, M.V. (Maksim), Aulchenko, Y.S. (Yurii), Rij, G. (Gabriel) van, Riemslag, F.C.C. (Frans), Young, T.L. (Terry), Mackey, D.A. (David), Spector, T.D. (Timothy), Gorgels, T.G.M.F. (Theo), Willemse-Assink, J.J.M. (Jacqueline), Isaacs, A.J. (Aaron), Kramer, R. (Rogier), Swagemakers, S.M.A. (Sigrid), Bergen, A.A.B. (Arthur), Oosterhout, A.A.L.J. (Andrew) van, Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Jong, P.T.V.M. (Paulus) de, Hammond, C.J. (Christopher), Vingerling, J.R. (Hans), and Klaver, C.C.W. (Caroline)
Abstract: Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.
Published: 2010
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60. Linkage and genome-wide association analysis of obesity-related phenotypes: Association of weight with the MGAT1 gene

Author: Johansson, A. (Åsa), Marroni, F. (Fabio), Hayward, C. (Caroline), Franklin, C.S. (Christopher), Kirichenko, A.V. (Anatoly), Jonasson, I. (Inger), Hicks, A.A. (Andrew), Vitart, V. (Veronique), Isaacs, A.J. (Aaron), Axenovich, T.I. (Tatiana), Campbell, S. (Susan), Floyd, J. (Jamie), Hastie, N. (Nick), Knott, S. (Sara), Lauc, G. (Gordan), Pichler, I. (Irene), Rotim, K. (Kresimir), Wild, S.H. (Sarah), Zorkoltseva, I.V. (Irina), Wilson, J.F. (James), Rudan, I. (Igor), Pattaro, C. (Cristian), Pramstaller, P.P. (Peter Paul), Oostra, B.A. (Ben), Wright, A.F. (Alan), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), Gyllensten, U. (Ulf), Johansson, A. (Åsa), Marroni, F. (Fabio), Hayward, C. (Caroline), Franklin, C.S. (Christopher), Kirichenko, A.V. (Anatoly), Jonasson, I. (Inger), Hicks, A.A. (Andrew), Vitart, V. (Veronique), Isaacs, A.J. (Aaron), Axenovich, T.I. (Tatiana), Campbell, S. (Susan), Floyd, J. (Jamie), Hastie, N. (Nick), Knott, S. (Sara), Lauc, G. (Gordan), Pichler, I. (Irene), Rotim, K. (Kresimir), Wild, S.H. (Sarah), Zorkoltseva, I.V. (Irina), Wilson, J.F. (James), Rudan, I. (Igor), Pattaro, C. (Cristian), Pramstaller, P.P. (Peter Paul), Oostra, B.A. (Ben), Wright, A.F. (Alan), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), and Gyllensten, U. (Ulf)
Abstract: As major risk-factors for diabetes and cardiovascular diseases, the genetic contribution to obesity-related traits has been of interest for decades. Recently, a limited number of common genetic variants, which have replicated in different populations, have been identified. One approach to increase the statistical power in genetic mapping studies is to focus on populations with increased levels of linkage disequilibrium (LD) and reduced genetic diversity. We have performed joint linkage and genome-wide association analyses for weight and BMI in 3,448 (linkage) and 3,925 (association) partly overlapping healthy individuals from five European populations. A total of four chromosomal regions (two for weight and two for BMI) showed suggestive linkage (lod >2.69) either in one of the populations or in the joint data. At the genome-wide level (nominal P <1.6 × 10 7, Bonferroni-adjusted P 0.05) one single-nucleotide polymorphism (SNP) (rs12517906) (nominal P = 7.3 × 10-8) was associated with weight, whereas none with BMI. The SNP associated with weight is located close to MGAT1. The monoacylglycerol acyltransferase (MGAT) enzyme family is known to be involved in dietary fat absorption. There was no overlap between the linkage regions and the associated SNPs. Our results show that genetic effects influencing weight and BMI are shared across diverse European populations, even though some of these populations have experienced recent population bottlenecks and/or been affected by genetic drift. The analysis enabled us to identify a new candidate gene, MGAT1, associated with weight in women.
Published: 2010
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61. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

Author: Sofat, R. (Reecha), Hingorani, A. (Aroon), Smeeth, L. (Liam), Humphries, S.E. (Steve), Talmud, P.J., Cooper, J. (Jim), Shah, T. (Tina), Sandhu, M.S. (Manjinder), Ricketts, S.L. (Sally), Boekholdt, S.M. (Matthijs), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Kumari, M. (Meena), Kivimaki, M. (Mika), Marmot, M. (Michael), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Dullaart, R.P.F. (Robin), Navis, G. (Gerjan), Veldhuisen, D.J. (Dirk) van, Gilst, W.H. (Wiek) van, Thompson, J.F. (John), McCaskie, P. (Pamela), Palmer, C. (Cameron), Arca, M. (Marcello), Quagliarini, F. (Fabiana), Gaudio, C. (Carlo), Cambien, F. (François), Nicaud, V., Poirer, O. (Odette), Gudnason, V. (Vilmundur), Isaacs, A.J. (Aaron), Witteman, J.C.M. (Jacqueline), Tikka-Kleemola, P. (Päivi), Pencina, M. (Michael), Vasan, R.S. (Ramachandran Srini), D'Agostino, R.B. (Ralph), Ordovas, J.M. (Jose), Li, T.Y. (Tricia), Kakko, S. (Sakari), Kauma, H. (Heikki), Savolainen, M.J. (Markku), Kesäniemi, Y.A. (Antero), Sandhofer, A. (Anton), Paulweber, B. (Bernhard), Sorli, J.V. (Jose), Goto, A. (Akimoto), Yokoyama, S. (Shinji), Okumura, K. (Kenji), Horne, B.D. (Benjamin), Packard, C. (Chris), Freeman, D. (Dilys), Ford, I. (Ian), Sattar, N. (Naveed), McCormack, V. (Valerie), Lawlor, D.A. (Debbie), Ebrahim, S. (Shanil), Smith, A.V. (Davey), Kastelein, J.J.P. (John), Deanfield, J. (John), Casas, J.P. (Juan), Sofat, R. (Reecha), Hingorani, A. (Aroon), Smeeth, L. (Liam), Humphries, S.E. (Steve), Talmud, P.J., Cooper, J. (Jim), Shah, T. (Tina), Sandhu, M.S. (Manjinder), Ricketts, S.L. (Sally), Boekholdt, S.M. (Matthijs), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Kumari, M. (Meena), Kivimaki, M. (Mika), Marmot, M. (Michael), Asselbergs, F.W. (Folkert), Harst, P. (Pim) van der, Dullaart, R.P.F. (Robin), Navis, G. (Gerjan), Veldhuisen, D.J. (Dirk) van, Gilst, W.H. (Wiek) van, Thompson, J.F. (John), McCaskie, P. (Pamela), Palmer, C. (Cameron), Arca, M. (Marcello), Quagliarini, F. (Fabiana), Gaudio, C. (Carlo), Cambien, F. (François), Nicaud, V., Poirer, O. (Odette), Gudnason, V. (Vilmundur), Isaacs, A.J. (Aaron), Witteman, J.C.M. (Jacqueline), Tikka-Kleemola, P. (Päivi), Pencina, M. (Michael), Vasan, R.S. (Ramachandran Srini), D'Agostino, R.B. (Ralph), Ordovas, J.M. (Jose), Li, T.Y. (Tricia), Kakko, S. (Sakari), Kauma, H. (Heikki), Savolainen, M.J. (Markku), Kesäniemi, Y.A. (Antero), Sandhofer, A. (Anton), Paulweber, B. (Bernhard), Sorli, J.V. (Jose), Goto, A. (Akimoto), Yokoyama, S. (Shinji), Okumura, K. (Kenji), Horne, B.D. (Benjamin), Packard, C. (Chris), Freeman, D. (Dilys), Ford, I. (Ian), Sattar, N. (Naveed), McCormack, V. (Valerie), Lawlor, D.A. (Debbie), Ebrahim, S. (Shanil), Smith, A.V. (Davey), Kastelein, J.J.P. (John), Deanfield, J. (John), and Casas, J.P. (Juan)
Abstract: Background: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI-0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI-0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action
Published: 2010
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62. A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level

Author: Pattaro, C. (Cristian), Grandi, A. (Alessandro) de, Vitart, V. (Veronique), Hayward, C. (Caroline), Franke, A. (Andre), Aulchenko, Y.S. (Yurii), Johansson, A. (Åsa), Wild, S.H. (Sarah), Melville, S.A. (Scott), Isaacs, A.J. (Aaron), Polasek, O. (Ozren), Ellinghaus, D. (David), Kolcic, I. (Ivana), Nöthlings, U. (Ute), Zgaga, L. (Lina), Zemunik, T. (Tatijana), Gnewuch, C. (Carsten), Schreiber, S. (Stefan), Campbell, S. (Susan), Hastie, N. (Nick), Boban, M. (Mladen), Meitinger, T. (Thomas), Oostra, B.A. (Ben), Riegler, P. (Peter), Minelli, C. (Cosetta), Wright, A.F. (Alan), Campbell, H. (Harry), Duijn, C.M. (Cornelia) van, Gyllensten, U. (Ulf), Wilson, J.F. (James), Krawczak, M. (Michael), Rudan, I. (Igor), Pramstaller, P.P. (Peter Paul), Pattaro, C. (Cristian), Grandi, A. (Alessandro) de, Vitart, V. (Veronique), Hayward, C. (Caroline), Franke, A. (Andre), Aulchenko, Y.S. (Yurii), Johansson, A. (Åsa), Wild, S.H. (Sarah), Melville, S.A. (Scott), Isaacs, A.J. (Aaron), Polasek, O. (Ozren), Ellinghaus, D. (David), Kolcic, I. (Ivana), Nöthlings, U. (Ute), Zgaga, L. (Lina), Zemunik, T. (Tatijana), Gnewuch, C. (Carsten), Schreiber, S. (Stefan), Campbell, S. (Susan), Hastie, N. (Nick), Boban, M. (Mladen), Meitinger, T. (Thomas), Oostra, B.A. (Ben), Riegler, P. (Peter), Minelli, C. (Cosetta), Wright, A.F. (Alan), Campbell, H. (Harry), Duijn, C.M. (Cornelia) van, Gyllensten, U. (Ulf), Wilson, J.F. (James), Krawczak, M. (Michael), Rudan, I. (Igor), and Pramstaller, P.P. (Peter Paul)
Abstract: Background: Serum creatinine (SCR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in SCR level is explicable by genetic factors.Methods: We performed a meta-analysis of genome-wide association studies of SCR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence f
Published: 2010
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63. Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease

Author: Brugts, J.J. (Jasper), Isaacs, A.J. (Aaron), Boersma, H. (Eric), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Remme, W.J. (Willem), Bertrand, M.E. (Michel), Ninomiya, T. (T.), Ceconi, C. (Claudio), Chalmers, J. (John), MacmMahon, S. (Stephen), Fox, K.M. (Kim), Ferrari, R. (Roberto), Witteman, J.C.M. (Jacqueline), Danser, A.H.J. (Jan), Simoons, M.L. (Maarten), Maat, M.P.M. (Moniek) de, Brugts, J.J. (Jasper), Isaacs, A.J. (Aaron), Boersma, H. (Eric), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Remme, W.J. (Willem), Bertrand, M.E. (Michel), Ninomiya, T. (T.), Ceconi, C. (Claudio), Chalmers, J. (John), MacmMahon, S. (Stephen), Fox, K.M. (Kim), Ferrari, R. (Roberto), Witteman, J.C.M. (Jacqueline), Danser, A.H.J. (Jan), Simoons, M.L. (Maarten), and Maat, M.P.M. (Moniek) de
Abstract: Aims The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors. Methods and resultsIn 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5 of the patients [hazard ratio (HR) 0.67; 95 confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5 (HR 1.26; 95 CI 0.97-1.67) with a trend towards a harmful effec
Published: 2010
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64. Biological, clinical and population relevance of 95 loci for blood lipids

Author: Teslovich, T.M. (Tanya), Musunuru, K. (Kiran), Smith, A.V. (Albert Vernon), Edmondson, A.C. (Andrew), Stylianou, I.M. (Ioannis), Koseki, M. (Masahiro), Pirruccello, J.P. (James), Ripatti, S. (Samuli), Chasman, D.I. (Daniel), Willer, C.J. (Cristen), Johansen, C.T. (Christopher), Fouchier, S.W. (Sigrid), Isaacs, A.J. (Aaron), Peloso, G.M. (Gina), Barbalic, M. (maja), Ricketts, S.L. (Sally), Bis, J.C. (Joshua), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), Feitosa, M.F. (Mary Furlan), Chambers, J. (John), Orho-Melander, M. (Marju), Melander, O. (Olle), Johnson, T. (Toby), Li, X. (Xiaohui), Guo, X. (Xiuqing), Shin Cho, Y. (Yoon), Jin Go, M. (Min), Jin Kim, Y. (Young), Lee, J.Y. (Jong Young), Park, T. (Taesung), Kim, Y-J. (Yong-Jin), Sim, X. (Xueling), Twee-Hee Ong, R. (Rick), Croteau-Chonka, D.C. (Damien), Lange, L.A. (Leslie), Song, K. (Kijoung), Zhao, J.H. (Jing Hua), Yuan, X. (Xin), Luan, J., Lamina, C. (Claudia), Ziegler, A. (Andreas), Zhang, W. (Weibo), Zee, R.Y.L. (Robert), Wright, A.F. (Alan), Witteman, J.C.M. (Jacqueline), Wilson, J.F. (James), Willemsen, G.A.H.M. (Gonneke), Wichmann, H.E. (Heinz Erich), Whitfield, J. (John), Waterworth, D. (Dawn), Wareham, N.J. (Nick), Waeber, G. (Gérard), Vollenweider, P. (Peter), Voight, B.F. (Benjamin), Vitart, V. (Veronique), Uitterlinden, A.G. (André), Uda, M. (Manuela), Tuomilehto, J. (Jaakko), Thompson, J.R. (John), Tanaka, T. (Toshiko), Surakka, I. (Ida), Stringham, H.M. (Heather), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Smit, J.H. (Johannes), Sinisalo, J. (Juha), Silander, K. (Kaisa), Sijbrands, E.J.G. (Eric), Scuteri, A. (Angelo), Scott, J. (James), Schlessinger, D. (David), Sanna, S. (Serena), Salomaa, V. (Veikko), Saharinen, J. (Juha), Sabatti, C. (Chiara), Ruokonen, A. (Aimo), Rudan, I. (Igor), Rose, L.M. (Lynda), Roberts, R. (Robert), Rieder, M. (Mark), Psaty, B.M. (Bruce), Pramstaller, P.P. (Peter Paul), Pichler, I. (Irene), Perola, M. (Markus), Penninx, B.W.J.H. (Brenda), Pedersen, N.L. (Nancy), Pattaro, C. (Cristian), Parker, A.N. (Alex), Pare, G. (Guillaume), Oostra, B.A. (Ben), Nieminen, M.S. (Markku), Nickerson, D.A. (Deborah), Montgomery, G.W. (Grant), Meitinger, T. (Thomas), McPherson, R. (Ruth), McCarthy, M.I. (Mark), McArdle, W.L. (Wendy), Masson, D. (David), Martin, N.G. (Nicholas), Marroni, F. (Fabio), Mangino, M. (Massimo), Magnusson, P.K. (Patrik), Lucas, G. (Gavin), Luben, R.N. (Robert), Loos, R.J.F. (Ruth), Lokki, M.L., Lettre, G. (Guillaume), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lakatta, E. (Edward), Laaksonen, R. (Reijo), Kyvik, K.O. (Kirsten Ohm), Kronenberg, F. (Florian), König, I.R. (Inke), Khaw, K-T. (Kay-Tee), Kaprio, J. (Jaakko), Kaplan, R.C. (Robert), Johansson, A. (Åsa), Jarvelin, M.-R. (Marjo-Riitta), Cecile, A. (A.), Ingelsson, E. (Erik), Igl, W. (Wilmar), Hovingh, G.K. (Kees), Hottenga, J.J. (Jouke Jan), Hofman, A. (Albert), Hicks, A.A. (Andrew), Hengstenberg, C. (Christian), Heid, I.M. (Iris), Hayward, C. (Caroline), Havulinna, A.S. (Aki), Hastie, N. (Nick), Harris, T.B. (Tamara), Haritunians, T. (Talin), Hall, A.S. (Alistair), Gyllensten, U. (Ulf), Guiducci, C. (Candace), Groop, L. (Leif), Gonzalez, E. (Elena), Gieger, C. (Christian), Freimer, N.B. (Nelson), Ferrucci, L. (Luigi), Erdmann, J. (Jeanette), Elliott, P. (Paul), Ejebe, K.G. (Kenechi), Döring, A. (Angela), Dominiczak, A. (Anna), Demissie, S. (Serkalem), Deloukas, P. (Panagiotis), Geus, E.J.C. (Eco) de, Faire, U. (Ulf) de, Crawford, G. (Gabe), Collins, F.S. (Francis), Chen, C. (Chao), Caulfield, M. (Mark), Campbell, H. (Harry), Burtt, N.P. (Noël), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Boekholdt, S.M. (Matthijs), Bergman, R.N. (Richard), Barroso, I.E. (Inês), Bandinelli, S. (Stefania), Ballantyne, C. (Christie), Assimes, T.L. (Themistocles), Quertermous, T. (Thomas), Altshuler, D. (David), Seielstad, M. (Mark), Wong, T.Y. (Tien Yin), Tai, E.S. (Shyong), Feranil, A.B. (Alan), Kuzawa, C.W. (Christopher), Adair, L.S. (Linda), Taylor, H.A. (Herman), Borecki, I.B. (Ingrid), Gabriel, S.B. (Stacey), Holm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Gudnason, V. (Vilmundur), Krauss, R.M. (Ronald), Mohlke, K.L. (Karen), Ordovas, J.M. (Jose), Munroe, P. (Patricia), Kooner, J.S. (Jaspal), Tall, A.R. (Alan), Hegele, R.A. (Robert), Kastelein, J.J.P. (John), Schadt, E.E. (Eric), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Strachan, D.P. (David), Mooser, V. (Vincent), Zwart, J-A. (John-Anker), Reilly, M.P. (Muredach), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Cupples, L.A. (Adrienne), Sandhu, M.S. (Manjinder), Ridker, P.M. (Paul), Rader, D.J. (Daniel), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Kathiresan, S. (Sekar), O'Donnell, C.J. (Christopher), Teslovich, T.M. (Tanya), Musunuru, K. (Kiran), Smith, A.V. (Albert Vernon), Edmondson, A.C. (Andrew), Stylianou, I.M. (Ioannis), Koseki, M. (Masahiro), Pirruccello, J.P. (James), Ripatti, S. (Samuli), Chasman, D.I. (Daniel), Willer, C.J. (Cristen), Johansen, C.T. (Christopher), Fouchier, S.W. (Sigrid), Isaacs, A.J. (Aaron), Peloso, G.M. (Gina), Barbalic, M. (maja), Ricketts, S.L. (Sally), Bis, J.C. (Joshua), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), Feitosa, M.F. (Mary Furlan), Chambers, J. (John), Orho-Melander, M. (Marju), Melander, O. (Olle), Johnson, T. (Toby), Li, X. (Xiaohui), Guo, X. (Xiuqing), Shin Cho, Y. (Yoon), Jin Go, M. (Min), Jin Kim, Y. (Young), Lee, J.Y. (Jong Young), Park, T. (Taesung), Kim, Y-J. (Yong-Jin), Sim, X. (Xueling), Twee-Hee Ong, R. (Rick), Croteau-Chonka, D.C. (Damien), Lange, L.A. (Leslie), Song, K. (Kijoung), Zhao, J.H. (Jing Hua), Yuan, X. (Xin), Luan, J., Lamina, C. (Claudia), Ziegler, A. (Andreas), Zhang, W. (Weibo), Zee, R.Y.L. (Robert), Wright, A.F. (Alan), Witteman, J.C.M. (Jacqueline), Wilson, J.F. (James), Willemsen, G.A.H.M. (Gonneke), Wichmann, H.E. (Heinz Erich), Whitfield, J. (John), Waterworth, D. (Dawn), Wareham, N.J. (Nick), Waeber, G. (Gérard), Vollenweider, P. (Peter), Voight, B.F. (Benjamin), Vitart, V. (Veronique), Uitterlinden, A.G. (André), Uda, M. (Manuela), Tuomilehto, J. (Jaakko), Thompson, J.R. (John), Tanaka, T. (Toshiko), Surakka, I. (Ida), Stringham, H.M. (Heather), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Smit, J.H. (Johannes), Sinisalo, J. (Juha), Silander, K. (Kaisa), Sijbrands, E.J.G. (Eric), Scuteri, A. (Angelo), Scott, J. (James), Schlessinger, D. (David), Sanna, S. (Serena), Salomaa, V. (Veikko), Saharinen, J. (Juha), Sabatti, C. (Chiara), Ruokonen, A. (Aimo), Rudan, I. (Igor), Rose, L.M. (Lynda), Roberts, R. (Robert), Rieder, M. (Mark), Psaty, B.M. (Bruce), Pramstaller, P.P. (Peter Paul), Pichler, I. (Irene), Perola, M. (Markus), Penninx, B.W.J.H. (Brenda), Pedersen, N.L. (Nancy), Pattaro, C. (Cristian), Parker, A.N. (Alex), Pare, G. (Guillaume), Oostra, B.A. (Ben), Nieminen, M.S. (Markku), Nickerson, D.A. (Deborah), Montgomery, G.W. (Grant), Meitinger, T. (Thomas), McPherson, R. (Ruth), McCarthy, M.I. (Mark), McArdle, W.L. (Wendy), Masson, D. (David), Martin, N.G. (Nicholas), Marroni, F. (Fabio), Mangino, M. (Massimo), Magnusson, P.K. (Patrik), Lucas, G. (Gavin), Luben, R.N. (Robert), Loos, R.J.F. (Ruth), Lokki, M.L., Lettre, G. (Guillaume), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lakatta, E. (Edward), Laaksonen, R. (Reijo), Kyvik, K.O. (Kirsten Ohm), Kronenberg, F. (Florian), König, I.R. (Inke), Khaw, K-T. (Kay-Tee), Kaprio, J. (Jaakko), Kaplan, R.C. (Robert), Johansson, A. (Åsa), Jarvelin, M.-R. (Marjo-Riitta), Cecile, A. (A.), Ingelsson, E. (Erik), Igl, W. (Wilmar), Hovingh, G.K. (Kees), Hottenga, J.J. (Jouke Jan), Hofman, A. (Albert), Hicks, A.A. (Andrew), Hengstenberg, C. (Christian), Heid, I.M. (Iris), Hayward, C. (Caroline), Havulinna, A.S. (Aki), Hastie, N. (Nick), Harris, T.B. (Tamara), Haritunians, T. (Talin), Hall, A.S. (Alistair), Gyllensten, U. (Ulf), Guiducci, C. (Candace), Groop, L. (Leif), Gonzalez, E. (Elena), Gieger, C. (Christian), Freimer, N.B. (Nelson), Ferrucci, L. (Luigi), Erdmann, J. (Jeanette), Elliott, P. (Paul), Ejebe, K.G. (Kenechi), Döring, A. (Angela), Dominiczak, A. (Anna), Demissie, S. (Serkalem), Deloukas, P. (Panagiotis), Geus, E.J.C. (Eco) de, Faire, U. (Ulf) de, Crawford, G. (Gabe), Collins, F.S. (Francis), Chen, C. (Chao), Caulfield, M. (Mark), Campbell, H. (Harry), Burtt, N.P. (Noël), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Boekholdt, S.M. (Matthijs), Bergman, R.N. (Richard), Barroso, I.E. (Inês), Bandinelli, S. (Stefania), Ballantyne, C. (Christie), Assimes, T.L. (Themistocles), Quertermous, T. (Thomas), Altshuler, D. (David), Seielstad, M. (Mark), Wong, T.Y. (Tien Yin), Tai, E.S. (Shyong), Feranil, A.B. (Alan), Kuzawa, C.W. (Christopher), Adair, L.S. (Linda), Taylor, H.A. (Herman), Borecki, I.B. (Ingrid), Gabriel, S.B. (Stacey), Holm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Gudnason, V. (Vilmundur), Krauss, R.M. (Ronald), Mohlke, K.L. (Karen), Ordovas, J.M. (Jose), Munroe, P. (Patricia), Kooner, J.S. (Jaspal), Tall, A.R. (Alan), Hegele, R.A. (Robert), Kastelein, J.J.P. (John), Schadt, E.E. (Eric), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Strachan, D.P. (David), Mooser, V. (Vincent), Zwart, J-A. (John-Anker), Reilly, M.P. (Muredach), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Cupples, L.A. (Adrienne), Sandhu, M.S. (Manjinder), Ridker, P.M. (Paul), Rader, D.J. (Daniel), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Kathiresan, S. (Sekar), and O'Donnell, C.J. (Christopher)
Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<-10-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Published: 2010
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65. A genome-wide association study of optic disc parameters

Author: Ramdas, W.D. (Wishal), Koolwijk, L.M.E. (Leonieke) van, Ikram, M.K. (Kamran), Jansonius, N.M. (Nomdo), Jong, P.T.V.M. (Paulus) de, Bergen, A.A.B. (Arthur), Isaacs, A.J. (Aaron), Amin, N. (Najaf), Aulchenko, Y.S. (Yurii), Wolfs, R.C.W. (Roger), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hysi, P.G. (Pirro), Hammond, C.J. (Christopher), Lemij, H.G. (Hans), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Duijn, C.M. (Cornelia) van, Ramdas, W.D. (Wishal), Koolwijk, L.M.E. (Leonieke) van, Ikram, M.K. (Kamran), Jansonius, N.M. (Nomdo), Jong, P.T.V.M. (Paulus) de, Bergen, A.A.B. (Arthur), Isaacs, A.J. (Aaron), Amin, N. (Najaf), Aulchenko, Y.S. (Yurii), Wolfs, R.C.W. (Roger), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hysi, P.G. (Pirro), Hammond, C.J. (Christopher), Lemij, H.G. (Hans), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), and Duijn, C.M. (Cornelia) van
Abstract: The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p =6.72*10-19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p=2.67*10-33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p =6.15*10-11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p=2.93*10-10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N=3,612), and the TwinsUK cohort (N=843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin. © 2010 Ramdas et al.
Published: 2010
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66. Genome-wide association analysis identifies multiple loci related to resting heart rate

Author: Eijgelsheim, M. (Mark), Newton-Cheh, C. (Christopher), Sotoodehnia, N. (Nona), Bakker, P.I.W. (Paul) de, Müller, M. (Martina), Morrison, A.C. (Alanna), Smith, A.V. (Albert Vernon), Isaacs, A.J. (Aaron), Sanna, S. (Serena), Dörr, M. (Marcus), Navarro, P. (Pau), Fuchsberger, C. (Christian), Nolte, I.M. (Ilja), Geus, E.J.C. (Eco) de, Estrada Gil, K. (Karol), Hwang, S.J., Bis, J.C. (Joshua), Rückert, I.M., Alonso, A. (Alvaro), Launer, L.J. (Lenore), Hottenga, J.J. (Jouke Jan), Rivadeneira Ramirez, F. (Fernando), Noseworthy, P.A. (Peter), Rice, K. (Kenneth), Perz, S. (Siegfried), Arking, D.E. (Dan), Spector, T.D. (Timothy), Kors, J.A. (Jan), Aulchenko, Y.S. (Yurii), Tarasov, K.V. (Kirill), Homuth, G. (Georg), Wild, S.H. (Sarah), Marroni, F. (Fabio), Gieger, C. (Christian), Licht, C.M. (Carmilla), Prineas, R.J. (Ronald), Hofman, A. (Albert), Rotter, J.I. (Jerome), Hicks, A.A. (Andrew), Ernst, F.D.J. (Florian), Najjar, S.S. (Samer), Wright, A.F. (Alan), Peters, A. (Annette), Fox, E.R. (Ervin), Oostra, B.A. (Ben), Kroemer, H.K. (Heyo), Couper, D.J. (David), Völzke, H. (Henry), Campbell, H. (Harry), Meitinger, T. (Thomas), Uda, M. (Manuela), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Wichmann, H.E. (Heinz Erich), Harris, T.B. (Tamara), Kääb, S. (Stefan), Siscovick, D.S. (David), Jamshidi, Y. (Yalda), Uitterlinden, A.G. (André), Folsom, A.R. (Aaron), Larson, M.G. (Martin), Wilson, J.F. (James), Penninx, B.W.J.H. (Brenda), Snieder, H. (Harold), Pramstaller, P.P. (Peter Paul), Tikka-Kleemola, P. (Päivi), Lakatta, E. (Edward), Felix, S.B. (Stephan), Gudnason, V. (Vilmundur), Pfeufer, A. (Arne), Heckbert, S.R. (Susan), Stricker, B.H.Ch. (Bruno), Boerwinkle, E.A. (Eric), O'Donnell, C.J. (Christopher), Eijgelsheim, M. (Mark), Newton-Cheh, C. (Christopher), Sotoodehnia, N. (Nona), Bakker, P.I.W. (Paul) de, Müller, M. (Martina), Morrison, A.C. (Alanna), Smith, A.V. (Albert Vernon), Isaacs, A.J. (Aaron), Sanna, S. (Serena), Dörr, M. (Marcus), Navarro, P. (Pau), Fuchsberger, C. (Christian), Nolte, I.M. (Ilja), Geus, E.J.C. (Eco) de, Estrada Gil, K. (Karol), Hwang, S.J., Bis, J.C. (Joshua), Rückert, I.M., Alonso, A. (Alvaro), Launer, L.J. (Lenore), Hottenga, J.J. (Jouke Jan), Rivadeneira Ramirez, F. (Fernando), Noseworthy, P.A. (Peter), Rice, K. (Kenneth), Perz, S. (Siegfried), Arking, D.E. (Dan), Spector, T.D. (Timothy), Kors, J.A. (Jan), Aulchenko, Y.S. (Yurii), Tarasov, K.V. (Kirill), Homuth, G. (Georg), Wild, S.H. (Sarah), Marroni, F. (Fabio), Gieger, C. (Christian), Licht, C.M. (Carmilla), Prineas, R.J. (Ronald), Hofman, A. (Albert), Rotter, J.I. (Jerome), Hicks, A.A. (Andrew), Ernst, F.D.J. (Florian), Najjar, S.S. (Samer), Wright, A.F. (Alan), Peters, A. (Annette), Fox, E.R. (Ervin), Oostra, B.A. (Ben), Kroemer, H.K. (Heyo), Couper, D.J. (David), Völzke, H. (Henry), Campbell, H. (Harry), Meitinger, T. (Thomas), Uda, M. (Manuela), Witteman, J.C.M. (Jacqueline), Psaty, B.M. (Bruce), Wichmann, H.E. (Heinz Erich), Harris, T.B. (Tamara), Kääb, S. (Stefan), Siscovick, D.S. (David), Jamshidi, Y. (Yalda), Uitterlinden, A.G. (André), Folsom, A.R. (Aaron), Larson, M.G. (Martin), Wilson, J.F. (James), Penninx, B.W.J.H. (Brenda), Snieder, H. (Harold), Pramstaller, P.P. (Peter Paul), Tikka-Kleemola, P. (Päivi), Lakatta, E. (Edward), Felix, S.B. (Stephan), Gudnason, V. (Vilmundur), Pfeufer, A. (Arne), Heckbert, S.R. (Susan), Stricker, B.H.Ch. (Bruno), Boerwinkle, E.A. (Eric), and O'Donnell, C.J. (Christopher)
Abstract: Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10-8were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regre
Published: 2010
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67. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Author: Aulchenko, Y.S. (Yurii), Ripatti, S. (Samuli), Lindqvist, I. (Ida), Boomsma, D.I. (Dorret), Heid, I.M. (Iris), Pramstaller, P.P. (Peter Paul), Penninx, B.W.J.H. (Brenda), Janssens, A.C.J.W. (Cécile), Wilson, J.F. (James), Spector, T.D. (Timothy), Martin, N.G. (Nicholas), Pedersen, N.L. (Nancy), Kyvik, K.O. (Kirsten Ohm), Kaprio, J. (Jaakko), Hofman, A. (Albert), Freimer, N.B. (Nelson), Jarvelin, M.-R. (Marjo-Riitta), Gyllensten, U. (Ulf), Campbell, H. (Harry), Rudan, I. (Igor), Johansson, A. (Åsa), Marroni, F. (Fabio), Hayward, C. (Caroline), Vitart, V. (Veronique), Jonasson, I. (Inger), Pattaro, C. (Cristian), Wright, A. (Alan), Hastie, N. (Nick), Pichler, I. (Irene), Hicks, A.A. (Andrew), Falchi, M. (Mario), Willemsen, G.A.H.M. (Gonneke), Hottenga, J.J. (Jouke Jan), Geus, E.J.C. (Eco) de, Montgomery, G.W. (Grant), Whitfield, J. (John), Magnusson, P. (Patrik), Saharinen, J. (Juha), Perola, M. (Markus), Silander, K. (Kaisa), Isaacs, A.J. (Aaron), Sijbrands, E.J.G. (Eric), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Oostra, B.A. (Ben), Elliott, P. (Paul), Ruokonen, A. (Aimo), Sabatti, C. (Chiara), Gieger, C. (Christian), Meitinger, T. (Thomas), Kronenberg, F. (Florian), Döring, A. (Angela), Wichmann, H.E. (Erich), Smit, J.H. (Johannes), McCarthy, M.I. (Mark), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Aulchenko, Y.S. (Yurii), Ripatti, S. (Samuli), Lindqvist, I. (Ida), Boomsma, D.I. (Dorret), Heid, I.M. (Iris), Pramstaller, P.P. (Peter Paul), Penninx, B.W.J.H. (Brenda), Janssens, A.C.J.W. (Cécile), Wilson, J.F. (James), Spector, T.D. (Timothy), Martin, N.G. (Nicholas), Pedersen, N.L. (Nancy), Kyvik, K.O. (Kirsten Ohm), Kaprio, J. (Jaakko), Hofman, A. (Albert), Freimer, N.B. (Nelson), Jarvelin, M.-R. (Marjo-Riitta), Gyllensten, U. (Ulf), Campbell, H. (Harry), Rudan, I. (Igor), Johansson, A. (Åsa), Marroni, F. (Fabio), Hayward, C. (Caroline), Vitart, V. (Veronique), Jonasson, I. (Inger), Pattaro, C. (Cristian), Wright, A. (Alan), Hastie, N. (Nick), Pichler, I. (Irene), Hicks, A.A. (Andrew), Falchi, M. (Mario), Willemsen, G.A.H.M. (Gonneke), Hottenga, J.J. (Jouke Jan), Geus, E.J.C. (Eco) de, Montgomery, G.W. (Grant), Whitfield, J. (John), Magnusson, P. (Patrik), Saharinen, J. (Juha), Perola, M. (Markus), Silander, K. (Kaisa), Isaacs, A.J. (Aaron), Sijbrands, E.J.G. (Eric), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Oostra, B.A. (Ben), Elliott, P. (Paul), Ruokonen, A. (Aimo), Sabatti, C. (Chiara), Gieger, C. (Christian), Meitinger, T. (Thomas), Kronenberg, F. (Florian), Döring, A. (Angela), Wichmann, H.E. (Erich), Smit, J.H. (Johannes), McCarthy, M.I. (Mark), Tikka-Kleemola, P. (Päivi), and Peltonen, L. (Leena Johanna)
Abstract: Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 × 10-8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 × 10-11; LDL, P = 2.6 × 10-10), TMEM57 (TC, P = 5.4 × 10-10), CTCF-PRMT8 region (HDL, P = 8.3 × 10-16), DNAH11 (LDL, P = 6.1 × 10-9), FADS3-FADS2 (TC, P = 1.5 × 10-10; LDL, P = 4.4 × 10-13) and MADD-FOLH1 region (HDL, P = 6 × 10-11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.
Published: 2009
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68. Genetic determinants of circulating sphingolipid concentrations in European populations

Author: Hicks, A.A. (Andrew), Pramstaller, P.P. (Peter Paul), Johansson, A. (Åsa), Vitart, V. (Veronique), Rudan, I. (Igor), Ugocsai, P. (Peter), Aulchenko, Y.S. (Yurii), Franklin, C.S. (Christopher), Liebisch, G. (Gerhard), Jonasson, I. (Inger), Zorkoltseva, I.V. (Irina), Pattaro, C. (Cristian), Hayward, C. (Caroline), Isaacs, A.J. (Aaron), Hengstenberg, C. (Christian), Campbell, S. (Susan), Gnewuch, C. (Carsten), Janssens, A.C.J.W. (Cécile), Kirichenko, A.V. (Anatoly), König, I.R. (Inke), Marroni, F. (Fabio), Polasek, O. (Ozren), Demirkan, A. (Ayşe), Kolcic, I. (Ivana), Schwienbacher, C. (Christine), Igl, W. (Wilmar), Biloglav, Z. (Zrinka), Witteman, J.C.M. (Jacqueline), Pichler, I. (Irene), Zaboli, G. (Ghazal), Axenovich, T.I. (Tatiana), Peters, A. (Annette), Schreiber, S. (Stefan), Wichmann, H.E. (Heinz Erich), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Hastie, N. (Nick), Oostra, B.A. (Ben), Wild, S.H. (Sarah), Meitinger, T. (Thomas), Gyllensten, U. (Ulf), Tikka-Kleemola, P. (Päivi), Wilson, J.F. (James), Wright, A.F. (Alan), Schmitz, G. (Gerd), Hicks, A.A. (Andrew), Pramstaller, P.P. (Peter Paul), Johansson, A. (Åsa), Vitart, V. (Veronique), Rudan, I. (Igor), Ugocsai, P. (Peter), Aulchenko, Y.S. (Yurii), Franklin, C.S. (Christopher), Liebisch, G. (Gerhard), Jonasson, I. (Inger), Zorkoltseva, I.V. (Irina), Pattaro, C. (Cristian), Hayward, C. (Caroline), Isaacs, A.J. (Aaron), Hengstenberg, C. (Christian), Campbell, S. (Susan), Gnewuch, C. (Carsten), Janssens, A.C.J.W. (Cécile), Kirichenko, A.V. (Anatoly), König, I.R. (Inke), Marroni, F. (Fabio), Polasek, O. (Ozren), Demirkan, A. (Ayşe), Kolcic, I. (Ivana), Schwienbacher, C. (Christine), Igl, W. (Wilmar), Biloglav, Z. (Zrinka), Witteman, J.C.M. (Jacqueline), Pichler, I. (Irene), Zaboli, G. (Ghazal), Axenovich, T.I. (Tatiana), Peters, A. (Annette), Schreiber, S. (Stefan), Wichmann, H.E. (Heinz Erich), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Hastie, N. (Nick), Oostra, B.A. (Ben), Wild, S.H. (Sarah), Meitinger, T. (Thomas), Gyllensten, U. (Ulf), Tikka-Kleemola, P. (Päivi), Wilson, J.F. (James), Wright, A.F. (Alan), and Schmitz, G. (Gerd)
Abstract: Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipidmetabolismare being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic b-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matchedmetabolite ratiosmeasured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08610266. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of th
Published: 2009
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69. Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide

Author: Driel, L.M.J.W. (Lydi) van, Smedts, H.P.M. (Dineke), Helbing, W.A. (Willem), Isaacs, A.J. (Aaron), Lindemans, J. (Jan), Uitterlinden, A.G. (André), Tikka-Kleemola, P. (Päivi), Vries, J.H. (Jeanne) de, Steegers-Theunissen, R.P.M. (Régine), Driel, L.M.J.W. (Lydi) van, Smedts, H.P.M. (Dineke), Helbing, W.A. (Willem), Isaacs, A.J. (Aaron), Lindemans, J. (Jan), Uitterlinden, A.G. (André), Tikka-Kleemola, P. (Päivi), Vries, J.H. (Jeanne) de, and Steegers-Theunissen, R.P.M. (Régine)
Abstract: Aims: Congenital heart defects (CHDs) have a multifactorial origin, in which subtle genetic facto
Published: 2008
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70. Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology

Author: Rijn, M.J.E. (Marie Josee) van, Bos, M.J. (Michiel), Isaacs, A.J. (Aaron), Yazdanpanah, M. (Mojgan), Arias-Vásquez, A. (Alejandro), Stricker, B.H.Ch. (Bruno), Oostra, B.A. (Ben), Klungel, O.H. (Olaf), Koudstaal, P.J. (Peter), Witteman, J.C.M. (Jacqueline), Hofman, A. (Albert), Breteler, M.M.B. (Monique), Duijn, C.M. (Cornelia) van, Rijn, M.J.E. (Marie Josee) van, Bos, M.J. (Michiel), Isaacs, A.J. (Aaron), Yazdanpanah, M. (Mojgan), Arias-Vásquez, A. (Alejandro), Stricker, B.H.Ch. (Bruno), Oostra, B.A. (Ben), Klungel, O.H. (Olaf), Koudstaal, P.J. (Peter), Witteman, J.C.M. (Jacqueline), Hofman, A. (Albert), Breteler, M.M.B. (Monique), and Duijn, C.M. (Cornelia) van
Abstract: BACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. METHODS: We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. RESULTS: We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. CONCLUSION: We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.
Published: 2007
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71. Genetic Epidemiology and Lipids: A Pattern So Grand and Complex

Author: Isaacs, A.J. (Aaron) and Isaacs, A.J. (Aaron)
Abstract: Intensive research over the course of the last several decades led to dramatic improvements in understanding, treating, and preventing cardiovascular disease. Despite this progress, cardiovascular disease remains the leading cause of mortality in both high- and low-income countries, and the leading source of morbidity in high-income countries. Lipids are well known determinants of cardiovascular disease risk; epidemiological evidence was published long ago. Total cholesterol and low-density lipoprotein cholesterol (LDL), which tend to be strongly correlated, are associated with increased disease risk. LDL can be readily oxidized, which causes inflammation and atherosclerosis to occur, and small, dense LDL particles are considered the most atherogenic lipid particles. High-density lipoprotein cholesterol (HDL), by contrast, is associated with beneficial effects, in terms of cardiovascular disease risk. Several mechanisms are likely to account for the protective consequences of increased HDL concentrations. HDL exhibits anti-inflammatory properties. Additionally, it is thought to be an anti-oxidant, helping to offset the deleterious effects of oxidized LDL. HDL is also involved in reverse cholesterol transpo
Published: 2007

72. The -514 C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.

Author: Isaacs, A.J. (Aaron), Sayed-Tabatabaei, F.A. (Fakhredin), Njajou, O.T. (Omer), Witteman, J.C.M. (Jacqueline), Duijn, C.M. (Cornelia) van, Isaacs, A.J. (Aaron), Sayed-Tabatabaei, F.A. (Fakhredin), Njajou, O.T. (Omer), Witteman, J.C.M. (Jacqueline), and Duijn, C.M. (Cornelia) van
Abstract: Investigations of the -514 C-->T single nucleotide polymorphism (SNP) in the hepatic lipase (HL) gene promoter region (LIPC) have yielded contradictory results regarding its association with changes in plasma lipids. The current study is a meta-analysis of 25 publications on this SNP, comprising over 24,000 individuals, and its relationship with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, and HL activity. Significant decreases were observed in HL activity for both the CT and TT genotypes compared with the CC genotype [weighted mean difference (WMD), -5.83 mmol/liter.h (95% confidence interval, -8.48, -3.17) and -11.05 mmol/liter.h (95% confidence interval, -14.74, -7.36), respectively]. Moreover, significant increases in HDL were found; the CT to CC comparison showed an increase in WMD of 0.04 mmol/liter (95% confidence interval, 0.02, 0.05) mmol/liter, a
Published: 2004
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72 results on '"Isaacs, A. (Aaron)"'

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

52. Nucleotide excision DNA repair is associated with age-related vascular dysfunction

53. Genome-wide association and functional follow-up reveals new loci for kidney function

54. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations

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

56. A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol

57. Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

58. Genetic architecture of circulating lipid levels

59. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14

60. Linkage and genome-wide association analysis of obesity-related phenotypes: Association of weight with the MGAT1 gene

61. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

62. A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level

63. Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease

64. Biological, clinical and population relevance of 95 loci for blood lipids

65. A genome-wide association study of optic disc parameters

66. Genome-wide association analysis identifies multiple loci related to resting heart rate

67. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

68. Genetic determinants of circulating sphingolipid concentrations in European populations

69. Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide

70. Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology

71. Genetic Epidemiology and Lipids: A Pattern So Grand and Complex

72. The -514 C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.

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