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1. The effect of three-monthly albendazole treatment on Th2 responses

Author

Ruiter, K. (Karin) de, Tahapary, D.L. (Dick), Wammes, L.J., Wiria, A.E., Hamid, F., Lieshout, L.M.C. (Leo M.) van, Smit, J.W.A., Houwing-Duistermaat, J.J. (Jeanine), Sartono, B. (Bagus), Supali, T. (T.), Yazdanbakhsh, M. (Maria), Ruiter, K. (Karin) de, Tahapary, D.L. (Dick), Wammes, L.J., Wiria, A.E., Hamid, F., Lieshout, L.M.C. (Leo M.) van, Smit, J.W.A., Houwing-Duistermaat, J.J. (Jeanine), Sartono, B. (Bagus), Supali, T. (T.), and Yazdanbakhsh, M. (Maria)

Abstract

Helminth parasites induce a strong Th2 response, characterized by high levels of IgE and elevated signature cytokines such as IL-5. As many global deworming programmes are underway, there is concern that this might lead to emergence of Th1-mediated pathologies when the counterbalancing helminth-induced Th2 response is absent. Therefore, we assessed the effect of deworming on Th2-mediated responses in a household-clustered randomized controlled trial in Indonesia. Total plasma IgE and whole-blood IL-5 responses to mitogen phytohaemagglutinin (PHA) were measured in 1494 and 682 subjects, respectively, at baseline, 9 and 21 months after three-monthly single-dose treatment with albendazole or placebo. Anthelmintic treatment did not result in complete removal of helminth infections in the community. However, treatment significantly decreased IgE levels in albendazole- compared to placebo-treated subjects. IL-5 responses to PHA were not significantly affected by anthelmintic treatment and tended to increase in albendazole-treated subjects, indicating that intensive treatment of helminth parasites has different outcomes on B-cell (IgE levels) and T-cell (IL-5) responses. The data shows that 2 years of deworming can have differential effects on responses typified as Th2-mediated, which needs to be taken into account when examining the impact of helminths on noncommunicable diseases.

Published
2017
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2. Correction: The complex genetics of gait speed: Genome-wide metaanalysis approach [Aging, (Albany NY), 9, 1, (2017), (209-246)]doi 10.18632/aging.101151

Author

Ben-Avraham, D. (Dan), Karasik, D. (David), Verghese, J. (Joe), Lunetta, K.L. (Kathryn), Smith, J.A. (Jennifer A), Eicher, J.D. (John D.), Vered, R. (Rotem), Deelen, J. (Joris), Arnold, A.M. (Alice), Buchman, A.S. (Aron), Tanaka, T. (Toshiko), Faul, J.D. (Jessica D.), Nethander, M. (Maria), Fornage, M. (Myriam), Adams, H.H.H. (Hieab), Matteini, A.M. (Amy M.), Callisaya, M. (Michele), Smith, A.V. (Albert Vernon), Yu, L. (Lei), Jager, P.L. (Philip) de, Evans, D.A. (Denis), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Pattie, A. (Alison), Corley, J. (Janie), Launer, L.J. (Lenore), Knopman, D.S. (Davis S.), Parimi, N. (Neeta), Turner, S.T. (Stephen T.), Bandinelli, S. (Stefania), Beekman, M. (Marian), Gutman, D. (Danielle), Sharvit, L. (Lital), Mooijaart, S.P. (Simon), Liewald, D.C.M. (David), Houwing-Duistermaat, J.J. (Jeanine), Ohlsson, C. (Claes), Moed, H. (Heleen), Verlinden, V.J.A. (Vincent), Mellström, D. (Dan), Geest, J.N. (Jos) van der, Karlsson, M. (Magnus), Hernandez, D.G. (Dena), McWhirter, R. (Rebekah), Liu, Y. (YongMei), Thomson, R. (Russell), Tranah, G.J. (Gregory), Uitterlinden, A.G. (André), Weir, D.R. (David R.), Zhao, W. (Wei), Starr, J.M. (John), Johnson, A.D. (Andrew), Ikram, M.A. (Arfan), Bennett, D.A. (David), Cummings, S., Deary, I.J. (Ian), Harris, T.B. (Tamara), Kardia, S.L.R. (Sharon L.R.), Mosley, T.H. (Thomas H.), Srikanth, V. (Velandai), Windham, B.G. (Gwen), Newman, A.B. (Anne B.), Walston, J. (Jeremy), Davies, G. (Gail), Evans, D.S. (Daniel), Slagboom, P.E. (Eline), Ferrucci, L. (Luigi), Kiel, D.P. (Douglas P.), Murabito, J. (Joanne), Atzmon, G. (Gil), Ben-Avraham, D. (Dan), Karasik, D. (David), Verghese, J. (Joe), Lunetta, K.L. (Kathryn), Smith, J.A. (Jennifer A), Eicher, J.D. (John D.), Vered, R. (Rotem), Deelen, J. (Joris), Arnold, A.M. (Alice), Buchman, A.S. (Aron), Tanaka, T. (Toshiko), Faul, J.D. (Jessica D.), Nethander, M. (Maria), Fornage, M. (Myriam), Adams, H.H.H. (Hieab), Matteini, A.M. (Amy M.), Callisaya, M. (Michele), Smith, A.V. (Albert Vernon), Yu, L. (Lei), Jager, P.L. (Philip) de, Evans, D.A. (Denis), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Pattie, A. (Alison), Corley, J. (Janie), Launer, L.J. (Lenore), Knopman, D.S. (Davis S.), Parimi, N. (Neeta), Turner, S.T. (Stephen T.), Bandinelli, S. (Stefania), Beekman, M. (Marian), Gutman, D. (Danielle), Sharvit, L. (Lital), Mooijaart, S.P. (Simon), Liewald, D.C.M. (David), Houwing-Duistermaat, J.J. (Jeanine), Ohlsson, C. (Claes), Moed, H. (Heleen), Verlinden, V.J.A. (Vincent), Mellström, D. (Dan), Geest, J.N. (Jos) van der, Karlsson, M. (Magnus), Hernandez, D.G. (Dena), McWhirter, R. (Rebekah), Liu, Y. (YongMei), Thomson, R. (Russell), Tranah, G.J. (Gregory), Uitterlinden, A.G. (André), Weir, D.R. (David R.), Zhao, W. (Wei), Starr, J.M. (John), Johnson, A.D. (Andrew), Ikram, M.A. (Arfan), Bennett, D.A. (David), Cummings, S., Deary, I.J. (Ian), Harris, T.B. (Tamara), Kardia, S.L.R. (Sharon L.R.), Mosley, T.H. (Thomas H.), Srikanth, V. (Velandai), Windham, B.G. (Gwen), Newman, A.B. (Anne B.), Walston, J. (Jeremy), Davies, G. (Gail), Evans, D.S. (Daniel), Slagboom, P.E. (Eline), Ferrucci, L. (Luigi), Kiel, D.P. (Douglas P.), Murabito, J. (Joanne), and Atzmon, G. (Gil)

Abstract

Applying HaploReg v4.1 analysis to the 536 variants resulted in 9 categories (Supplementary Table 8): miscRNA (1 variant); snoRNA (2 variants); microRNA (4 variants); snRNA (9 variants); pseudogenes (14 variants); sequencing in progress (43 variants); LINC RNA (86 variants); and 372 variants within protein coding genes. In addition, some variants annotate to the same gene resulting in a total of 139 genes (protein-coding or non-coding). Of those genes, 6 are exceptionally long, containing over a million base-pairs, the longest of which is PTPRT coded by 1117219bp. The shortest genes are the ones coding for micro (MIR3143) or small nuclear (U7) RNAs at 63bp each. There is only partial information regarding the chromatin state of each variant. However, from the information gathered in the analysis we observed 14 transcription start sites and 245 enhancers (Supplementary Table 8).

Published
2017
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3. Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers

Author

Ghorbanoghli, Z., Nieuwenhuis, M.H. (Mary), Houwing-Duistermaat, J.J. (Jeanine), Jagmohan-Changur, S.C. (Shantie), Hes, F.J. (Frederik), Tops, C. (Carli), Wagner, A. (Anja), Aalfs, C.M. (Cora), Verhoef, S., Gómez García, E.B. (Encarna), Sijmons, R.H. (Rolf), Menko, F. (Fred), Letteboer, T.G.W. (Tom), Hoogerbrugge, N. (Nicoline), Wezel, T. (Tom) van, Vasen, H. (Hans), Wijnen, J.T. (Juul), Ghorbanoghli, Z., Nieuwenhuis, M.H. (Mary), Houwing-Duistermaat, J.J. (Jeanine), Jagmohan-Changur, S.C. (Shantie), Hes, F.J. (Frederik), Tops, C. (Carli), Wagner, A. (Anja), Aalfs, C.M. (Cora), Verhoef, S., Gómez García, E.B. (Encarna), Sijmons, R.H. (Rolf), Menko, F. (Fred), Letteboer, T.G.W. (Tom), Hoogerbrugge, N. (Nicoline), Wezel, T. (Tom) van, Vasen, H. (Hans), and Wijnen, J.T. (Juul)

Published
2016
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4. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

Author

Teumer, A. (Alexander), Qi, Q., Nethander, M. (Maria), Aschard, H. (Hugues), Bandinelli, S. (Stefania), Beekman, M. (Marian), Berndt, S.I. (Sonja), Bidlingmaier, M. (Martin), Broer, L. (Linda), Cappola, A.R. (Anne), Ceda, G.P. (Gian Paolo), Chanock, S.J. (Stephen), Chen, M.-H. (Ming-Huei), Chen, T.C. (Tai C.), Chen, Y.D. (Y.), Chung, J. (Jonathan), Del Greco Miglianico, F. (Fabiola), Eriksson, J. (Joel), Ferrucci, L. (Luigi), Friedrich, N. (Nele), Gnewuch, C. (Carsten), Goodarzi, M. (Mark), Grarup, N. (Niels), Guo, T. (Tingwei), Hammer, E. (Elke), Hayes, R.B. (Richard), Hicks, A.A. (Andrew), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Hu, F. (Frank), Hunter, D. (David), Husemoen, L.L.N. (Lise Lotte), Isaacs, A.J. (Aaron), Jacobs, K.B. (Kevin), Janssen, J.A.M.J.L. (Joop), Jansson, J.-O. (John-Olov), Jehmlich, N. (Nico), Johnson, S. (Simon), Juul, A. (Anders), Karlsson, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Kovacs, P. (Peter), Kraft, P. (Peter), Li, C. (Chao), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lorentzon, M. (Mattias), Lu, Y. (Yingchang), Maggio, M. (Marcello), Mägi, R. (Reedik), Meigs, J.B. (James), Mellström, D. (Dan), Nauck, M. (Matthias), Newman, A.B. (Anne B.), Pollak, M.N. (Michael), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Psaty, B.M. (Bruce), Reincke, M. (Martin), Rimm, E.B. (Eric B.), Rotter, J.I. (Jerome I.), Saint Pierre, A. (Aude), Schurmann, C. (Claudia), Seshadri, S. (Sudha), Sjögren, K. (Klara), Slagboom, P.E. (Eline), Strickler, H.D. (Howard D.), Stumvoll, M. (Michael), Suh, Y. (Yousin), Sun, Q. (Qi), Zhang, C. (Cuilin), Svensson, J. (Johan), Tanaka, T. (Toshiko), Tare, A. (Archana), Tönjes, A. (Anke), Uh, H.-W. (Hae-Won), Duijn, C.M. (Cornelia) van, Heemst, D. (Diana) van, Vandenput, L. (Liesbeth), Vasan, R.S. (Ramachandran Srini), Völker, U. (Uwe), Willems, S.M. (Sara), Ohlsson, C. (Claes), Wallaschofski, H. (Henri), Kaplan, R.C. (Robert), Teumer, A. (Alexander), Qi, Q., Nethander, M. (Maria), Aschard, H. (Hugues), Bandinelli, S. (Stefania), Beekman, M. (Marian), Berndt, S.I. (Sonja), Bidlingmaier, M. (Martin), Broer, L. (Linda), Cappola, A.R. (Anne), Ceda, G.P. (Gian Paolo), Chanock, S.J. (Stephen), Chen, M.-H. (Ming-Huei), Chen, T.C. (Tai C.), Chen, Y.D. (Y.), Chung, J. (Jonathan), Del Greco Miglianico, F. (Fabiola), Eriksson, J. (Joel), Ferrucci, L. (Luigi), Friedrich, N. (Nele), Gnewuch, C. (Carsten), Goodarzi, M. (Mark), Grarup, N. (Niels), Guo, T. (Tingwei), Hammer, E. (Elke), Hayes, R.B. (Richard), Hicks, A.A. (Andrew), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Hu, F. (Frank), Hunter, D. (David), Husemoen, L.L.N. (Lise Lotte), Isaacs, A.J. (Aaron), Jacobs, K.B. (Kevin), Janssen, J.A.M.J.L. (Joop), Jansson, J.-O. (John-Olov), Jehmlich, N. (Nico), Johnson, S. (Simon), Juul, A. (Anders), Karlsson, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Kovacs, P. (Peter), Kraft, P. (Peter), Li, C. (Chao), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lorentzon, M. (Mattias), Lu, Y. (Yingchang), Maggio, M. (Marcello), Mägi, R. (Reedik), Meigs, J.B. (James), Mellström, D. (Dan), Nauck, M. (Matthias), Newman, A.B. (Anne B.), Pollak, M.N. (Michael), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Psaty, B.M. (Bruce), Reincke, M. (Martin), Rimm, E.B. (Eric B.), Rotter, J.I. (Jerome I.), Saint Pierre, A. (Aude), Schurmann, C. (Claudia), Seshadri, S. (Sudha), Sjögren, K. (Klara), Slagboom, P.E. (Eline), Strickler, H.D. (Howard D.), Stumvoll, M. (Michael), Suh, Y. (Yousin), Sun, Q. (Qi), Zhang, C. (Cuilin), Svensson, J. (Johan), Tanaka, T. (Toshiko), Tare, A. (Archana), Tönjes, A. (Anke), Uh, H.-W. (Hae-Won), Duijn, C.M. (Cornelia) van, Heemst, D. (Diana) van, Vandenput, L. (Liesbeth), Vasan, R.S. (Ramachandran Srini), Völker, U. (Uwe), Willems, S.M. (Sara), Ohlsson, C. (Claes), Wallaschofski, H. (Henri), and Kaplan, R.C. (Robert)

Abstract

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through

Published
2016
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5. Community deworming alleviates geohelminth-induced immune hyporesponsiveness

Author

Wammes, L.J. (Linda J.), Hamid, F. (Firdaus), Wiria, A.E. (Aprilianto Eddy), May, L. (Linda), Kaisar, M.M.M. (Maria M.M.), Prasetyani-Gieseler, M.A. (Margaretta A.), Djuardi, Y. (Yenny), Wibowo, H. (Heri), Kruize, Y.C.M. (Yvonne C.M.), Verweij, J.J. (Jaco J.), De Jon, S.E. (Sanne E.), Tsonaka, R. (Roula), Houwing-Duistermaat, J.J. (Jeanine), Sartono, B. (Bagus), Luty, A.J.F. (Adrian), Supali, T. (T.), Yazdanbakhsh, M. (Maria), Wammes, L.J. (Linda J.), Hamid, F. (Firdaus), Wiria, A.E. (Aprilianto Eddy), May, L. (Linda), Kaisar, M.M.M. (Maria M.M.), Prasetyani-Gieseler, M.A. (Margaretta A.), Djuardi, Y. (Yenny), Wibowo, H. (Heri), Kruize, Y.C.M. (Yvonne C.M.), Verweij, J.J. (Jaco J.), De Jon, S.E. (Sanne E.), Tsonaka, R. (Roula), Houwing-Duistermaat, J.J. (Jeanine), Sartono, B. (Bagus), Luty, A.J.F. (Adrian), Supali, T. (T.), and Yazdanbakhsh, M. (Maria)

Abstract

In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminthspecific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 mo - estimate [95% confidence interval], 0.37 [0.21-0.53], P value over time (Ptime) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) on CD4+ T cells of albendazoletreated individuals, -0.060 [-0.107 to -0.013] and -0.057 [-0.105 to -0.008] at 9 and 21 mo, respectively; Ptime = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low- compared with high-income countries.

Published
2016
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6. To the editor: Uncompromised 10-year survival of oldest old carrying somatic mutations in DNMT3A and TET2

Author

Akker, E.B. (Erik) van den, Pitts, S.J. (Steven J.), Deelen, J. (Joris), Moed, H. (Heleen), Potluri, S. (Shobha), Rooij, J.G.J. (Jeroen) van, Suchiman, H.E.D. (Eka), Lakenberg, N. (Nico), De Dijcker, W.J. (Wesley J.), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Hofman, A. (Albert), De Craen, A.J.M. (Anton J. M.), Houwing-Duistermaat, J.J. (Jeanine), Van Ommen, G.-J.B. (Gert-Jan B.), Cox, D.R. (David), Meurs, J.B.J. (Joyce) van, Beekman, M. (Marian), Reinders, M.J. (Marcel), Slagboom, P.E. (Eline), Akker, E.B. (Erik) van den, Pitts, S.J. (Steven J.), Deelen, J. (Joris), Moed, H. (Heleen), Potluri, S. (Shobha), Rooij, J.G.J. (Jeroen) van, Suchiman, H.E.D. (Eka), Lakenberg, N. (Nico), De Dijcker, W.J. (Wesley J.), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Hofman, A. (Albert), De Craen, A.J.M. (Anton J. M.), Houwing-Duistermaat, J.J. (Jeanine), Van Ommen, G.-J.B. (Gert-Jan B.), Cox, D.R. (David), Meurs, J.B.J. (Joyce) van, Beekman, M. (Marian), Reinders, M.J. (Marcel), and Slagboom, P.E. (Eline)

Published
2016
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7. The impact of low-frequency and rare variants on lipid levels

Author

Surakka, I. (Ida), Horikoshi, M. (Momoko), Mägi, R. (Reedik), Sarin, A.-P., Mahajan, A. (Anubha), Lagou, V. (Vasiliki), Marullo, L. (Letizia), Ferreira, T. (Teresa), Miraglio, B. (Benjamin), Timonen, S. (Sanna), Kettunen, J. (Johannes), Pirinen, M. (Matti), Karjalainen, J. (Juha), Thorleifsson, G. (Gudmar), Hägg, S. (Sara), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Ladenvall, C. (Claes), Beekman, M. (Marian), Esko, T. (Tõnu), Ried, J.S. (Janina), Nelson, C.P. (Christopher P.), Willenborg, C. (Christina), Gustafsson, S. (Stefan), Westra, H.J. (Harm-Jan), Blades, M. (Matthew), De Craen, A.J.M. (Anton J. M.), Geus, E.J.C. (Eco) de, Deelen, J. (Joris), Grallert, H. (Harald), Hamsten, A. (Anders), Havulinna, A.S. (Aki), Hengstenberg, C. (Christian), Houwing-Duistermaat, J.J. (Jeanine), Hypponen, E. (Elina), Karssen, L.C. (Lennart), Lehtimäki, T. (Terho), Lyssenko, V. (Valeriya), Magnusson, P.K. (Patrik), Mihailov, E. (Evelin), Müller-Nurasyid, M. (Martina), Mpindi, J.-P. (John-Patrick), Pedersen, N.L. (Nancy L.), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pers, T.H. (Tune), Peters, A. (Annette), Rung, J. (Johan), Smit, J.H. (Johannes), Steinthorsdottir, V. (Valgerdur), Tobin, M.D. (Martin), Tsernikova, N. (Natalia), Leeuwen, E.M. (Elisa) van, Viikari, J. (Jorma), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Schunkert, H. (Heribert), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), Kaprio, J. (Jaakko), Lind, L. (Lars), Gieger, C. (Christian), Metspalu, A. (Andres), Slagboom, P.E. (Eline), Groop, L. (Leif), Duijn, C.M. (Cornelia) van, Eriksson, J.G. (Johan G.), Jula, A. (Antti), Salomaa, V. (Veikko), Boomsma, D.I. (Dorret), Power, C. (Christopher), Raitakari, O.T. (Olli T.), Ingelsson, E. (Erik), Jarvelin, M.-R. (Marjo-Riitta), Thorsteinsdottir, U. (Unnur), Franke, L. (Lude), Ikonen, E. (Elina), Kallioniemi, O. (Olli), Pietiäinen, V. (Vilja), Lindgren, C.M. (Cecilia M.), Zwart, J-A. (John-Anker), Palotie, A. (Aarno), McCarthy, M.I. (Mark), Morris, A.P. (Andrew), Prokopenko, I. (Inga), Ripatti, S. (Samuli), Surakka, I. (Ida), Horikoshi, M. (Momoko), Mägi, R. (Reedik), Sarin, A.-P., Mahajan, A. (Anubha), Lagou, V. (Vasiliki), Marullo, L. (Letizia), Ferreira, T. (Teresa), Miraglio, B. (Benjamin), Timonen, S. (Sanna), Kettunen, J. (Johannes), Pirinen, M. (Matti), Karjalainen, J. (Juha), Thorleifsson, G. (Gudmar), Hägg, S. (Sara), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Ladenvall, C. (Claes), Beekman, M. (Marian), Esko, T. (Tõnu), Ried, J.S. (Janina), Nelson, C.P. (Christopher P.), Willenborg, C. (Christina), Gustafsson, S. (Stefan), Westra, H.J. (Harm-Jan), Blades, M. (Matthew), De Craen, A.J.M. (Anton J. M.), Geus, E.J.C. (Eco) de, Deelen, J. (Joris), Grallert, H. (Harald), Hamsten, A. (Anders), Havulinna, A.S. (Aki), Hengstenberg, C. (Christian), Houwing-Duistermaat, J.J. (Jeanine), Hypponen, E. (Elina), Karssen, L.C. (Lennart), Lehtimäki, T. (Terho), Lyssenko, V. (Valeriya), Magnusson, P.K. (Patrik), Mihailov, E. (Evelin), Müller-Nurasyid, M. (Martina), Mpindi, J.-P. (John-Patrick), Pedersen, N.L. (Nancy L.), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pers, T.H. (Tune), Peters, A. (Annette), Rung, J. (Johan), Smit, J.H. (Johannes), Steinthorsdottir, V. (Valgerdur), Tobin, M.D. (Martin), Tsernikova, N. (Natalia), Leeuwen, E.M. (Elisa) van, Viikari, J. (Jorma), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Schunkert, H. (Heribert), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), Kaprio, J. (Jaakko), Lind, L. (Lars), Gieger, C. (Christian), Metspalu, A. (Andres), Slagboom, P.E. (Eline), Groop, L. (Leif), Duijn, C.M. (Cornelia) van, Eriksson, J.G. (Johan G.), Jula, A. (Antti), Salomaa, V. (Veikko), Boomsma, D.I. (Dorret), Power, C. (Christopher), Raitakari, O.T. (Olli T.), Ingelsson, E. (Erik), Jarvelin, M.-R. (Marjo-Riitta), Thorsteinsdottir, U. (Unnur), Franke, L. (Lude), Ikonen, E. (Elina), Kallioniemi, O. (Olli), Pietiäinen, V. (Vilja), Lindgren, C.M. (Cecilia M.), Zwart, J-A. (John-Anker), Palotie, A. (Aarno), McCarthy, M.I. (Mark), Morris, A.P. (Andrew), Prokopenko, I. (Inga), and Ripatti, S. (Samuli)

Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

Published
2015
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8. The transcriptional landscape of age in human peripheral blood

Author

Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), Singleton, A., Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), and Singleton, A.

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015
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9. CHEK2*1100delC homozygosity in the Netherlands-prevalence and risk of breast and lung cancer

Author

Huijts, P. (Petra), Hollestelle, A. (Antoinette), Balliu, B. (Brunilda), Houwing-Duistermaat, J.J. (Jeanine), Meijers, J.C.M., Blom, J. (Jannet), Ozturk, B. (Bahar), Krol-Warmerdam, E.M.M. (Elly), Wijnen, J. (Jasper), Berns, P.M.J.J. (Els), Martens, J.W.M. (John), Seynaeve, C.M. (Caroline), Kiemeney, L.A.L.M. (Bart), Heijden, H.F. (Henricus) van der, Tollenaar, R.A.E.M. (Rob), Devilee, P. (Peter), Asperen, C.J. (Christi) van, Huijts, P. (Petra), Hollestelle, A. (Antoinette), Balliu, B. (Brunilda), Houwing-Duistermaat, J.J. (Jeanine), Meijers, J.C.M., Blom, J. (Jannet), Ozturk, B. (Bahar), Krol-Warmerdam, E.M.M. (Elly), Wijnen, J. (Jasper), Berns, P.M.J.J. (Els), Martens, J.W.M. (John), Seynaeve, C.M. (Caroline), Kiemeney, L.A.L.M. (Bart), Heijden, H.F. (Henricus) van der, Tollenaar, R.A.E.M. (Rob), Devilee, P. (Peter), and Asperen, C.J. (Christi) van

Abstract

The 1100delC mutation in the CHEK2 gene has a carrier frequency of up to 1.5% in individuals from North-West Europe. Women heterozygous for 1100delC have an increased breast cancer risk (odds ratio 2.7). To explore the prevalence and clinical consequences of 1100delC homozygosity in the Nether

Published
2014
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10. The Genome of the Netherlands: Design, and project goals

Author

Boomsma, D.I. (Dorret), Wijmenga, C. (Cisca), Slagboom, P.E. (Eline), Swertz, M. (Morris), Karssen, L.C. (Lennart), Abdellaoui, A. (Abdel), Ye, K. (Kai), Guryev, V. (Victor), Vermaat, J.S. (Joost), Dijk, F. (Freerk) van, Francioli, L.C. (Laurent), Hottenga, J.J. (Jouke Jan), Laros, J.F.J. (Jeroen F.), Li, Q. (Qibin), Li, Y. (Yingrui), Cao, H. (Hongzhi), Chen, R. (Ruoyan), Du, Y. (Yangchun), Li, N. (Ning), Cao, S. (Sherry), Setten, J. (Jessica) van, Menelaou, A. (Androniki), Pulit, S.L. (Sara), Hehir-Kwa, J. (Jayne), Beekman, M. (Marian), Elbers, C.C. (Clara), Byelas, H. (Heorhiy), Craen, A.J. (Anton) de, Deelen, P. (Patrick), Dijkstra, M. (Martijn), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Houwing-Duistermaat, J.J. (Jeanine), Koval, V. (Vyacheslav), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kanterakis, A. (Alexandros), Enckevort, D. (David) van, Mai, H. (Hailiang), Kattenberg, V.M. (Mathijs), Leeuwen, E.M. (Elisa) van, Neerincx, P.B.T. (Pieter B T), Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Suchiman, H.E.D. (Eka), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Wolffenbuttel, B.H.R. (Bruce), Wang, J. (Jinxia), Bakker, P.I.W. (Paul) de, Ommen, G.J. (Gert) van, Duijn, C.M. (Cornelia) van, Boomsma, D.I. (Dorret), Wijmenga, C. (Cisca), Slagboom, P.E. (Eline), Swertz, M. (Morris), Karssen, L.C. (Lennart), Abdellaoui, A. (Abdel), Ye, K. (Kai), Guryev, V. (Victor), Vermaat, J.S. (Joost), Dijk, F. (Freerk) van, Francioli, L.C. (Laurent), Hottenga, J.J. (Jouke Jan), Laros, J.F.J. (Jeroen F.), Li, Q. (Qibin), Li, Y. (Yingrui), Cao, H. (Hongzhi), Chen, R. (Ruoyan), Du, Y. (Yangchun), Li, N. (Ning), Cao, S. (Sherry), Setten, J. (Jessica) van, Menelaou, A. (Androniki), Pulit, S.L. (Sara), Hehir-Kwa, J. (Jayne), Beekman, M. (Marian), Elbers, C.C. (Clara), Byelas, H. (Heorhiy), Craen, A.J. (Anton) de, Deelen, P. (Patrick), Dijkstra, M. (Martijn), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Houwing-Duistermaat, J.J. (Jeanine), Koval, V. (Vyacheslav), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kanterakis, A. (Alexandros), Enckevort, D. (David) van, Mai, H. (Hailiang), Kattenberg, V.M. (Mathijs), Leeuwen, E.M. (Elisa) van, Neerincx, P.B.T. (Pieter B T), Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Suchiman, H.E.D. (Eka), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Wolffenbuttel, B.H.R. (Bruce), Wang, J. (Jinxia), Bakker, P.I.W. (Paul) de, Ommen, G.J. (Gert) van, and Duijn, C.M. (Cornelia) van

Abstract

Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project.

Published
2014
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11. Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways

Author

Deelen, J. (Joris), Uh, H.-W., Monajemi, R. (Ramin), Heemst, D. (Diana) van, Thijssen, P.E. (Peter), Böhringer, S. (Stefan), Akker, E.B. (Erik) van den, de Craen, A.J.M. (Anton J.M.), Rivadeneira Ramirez, F. (Fernando), Westendorp, R.G.J. (Rudi), Uitterlinden, A.G. (André), Goeman, J.J. (Jelle), Slagboom, P.E. (Eline), Houwing-Duistermaat, J.J. (Jeanine), Beekman, M. (Marian), Deelen, J. (Joris), Uh, H.-W., Monajemi, R. (Ramin), Heemst, D. (Diana) van, Thijssen, P.E. (Peter), Böhringer, S. (Stefan), Akker, E.B. (Erik) van den, de Craen, A.J.M. (Anton J.M.), Rivadeneira Ramirez, F. (Fernando), Westendorp, R.G.J. (Rudi), Uitterlinden, A.G. (André), Goeman, J.J. (Jelle), Slagboom, P.E. (Eline), Houwing-Duistermaat, J.J. (Jeanine), and Beekman, M. (Marian)

Abstract

In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from l

Published
2013
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12. A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

Author

Porcu, E. (Eleonora), Medici, M. (Marco), Pistis, G. (Giorgio), Volpato, C.B., Wilson, S.G. (Scott), Cappola, A.R. (Anne), Bos, S.D. (Steffan), Deelen, J. (Joris), Heijer, M. (Martin) den, Freathy, R.M. (Rachel), Lahti, J. (Jari), Liu, C. (Chunyu), Lopez, L.M. (Lorna), Nolte, I.M. (Ilja), O´Connell, J.R., Tanaka, T. (Toshiko), Trompet, S. (Stella), Arnold, A.M. (Alice), Bandinelli, S. (Stefania), Beekman, M. (Marian), Böhringer, S. (Stefan), Brown, S.J. (Stephen), Buckley, B.M. (Brendan M.), Camaschella, C. (Clara), Craen, A.J. (Anton) de, Davies, G. (Gail), Visser, M.C.H. (Marieke) de, Ford, I. (Ian), Forsen, T. (Tom), Frayling, T.M. (Timothy), Fugazzola, L. (Laura), Gögele, M. (Martin), Hattersley, A.T. (Andrew), Hermus, A.R.M.M. (Ad), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Jensen, R.A. (Richard), Kajantie, E. (Eero), Kloppenburg, M. (Margreet), Lim, E.M. (Ee Mun), Masciullo, C. (Corrado), Mariotti, S. (Stefano), Minelli, C. (Cosetta), Mitchell, B.D. (Braxton), Nagaraja, R. (Ramaiah), Netea-Maier, R.T. (Romana), Palotie, A. (Aarno), Persani, L. (Luca), Piras, M.G. (Maria Grazia), Psaty, B.M. (Bruce), Räikkönen, K. (Katri), Richards, J.B. (Brent), Rivadeneira Ramirez, F. (Fernando), Sala, C. (Cinzia), Sabra, M.M. (Mona), Sattar, N. (Naveed), Shields, B.M. (Beverley), Soranzo, N. (Nicole), Starr, J.M. (John), Stott, D.J. (David. J.), Sweep, F.C. (Fred), Usala, G., Klauw, M.M. (Melanie) van der, Heemst, D. (Diana) van, Mol-van Mullem, A.A.A. (Alies) van, Vermeulen, S.H. (Sita), Walsh, J.P. (John), Westendorp, R.G.J. (Rudi), Widen, E. (Elisabeth), Zhai, G. (Guangju), Cucca, F. (Francesco), Deary, I.J. (Ian), Visser, W.E. (Edward), Eriksson, J.G. (Johan), Ferrucci, L. (Luigi), Fox, C. (Craig), Jukema, J.W. (Jan Wouter), Kiemeney, L.A.L.M. (Bart), Pramstaller, P.P. (Peter Paul), Schlessinger, D., Shuldiner, A.R. (Alan), Slagboom, P.E. (Eline), Uitterlinden, A.G. (André), Vaidya, B. (Bijay), Visser, T.J. (Theo), Wolffenbuttel, B.H.R. (Bruce), Meulenbelt, I. (Ingrid), Rotter, J.I. (Jerome), Spector, T.D. (Timothy), Hicks, A.A. (Andrew), Toniolo, D. (Daniela), Sanna, S. (Serena), Peeters, R.P. (Robin), Naitza, S. (Silvia), Porcu, E. (Eleonora), Medici, M. (Marco), Pistis, G. (Giorgio), Volpato, C.B., Wilson, S.G. (Scott), Cappola, A.R. (Anne), Bos, S.D. (Steffan), Deelen, J. (Joris), Heijer, M. (Martin) den, Freathy, R.M. (Rachel), Lahti, J. (Jari), Liu, C. (Chunyu), Lopez, L.M. (Lorna), Nolte, I.M. (Ilja), O´Connell, J.R., Tanaka, T. (Toshiko), Trompet, S. (Stella), Arnold, A.M. (Alice), Bandinelli, S. (Stefania), Beekman, M. (Marian), Böhringer, S. (Stefan), Brown, S.J. (Stephen), Buckley, B.M. (Brendan M.), Camaschella, C. (Clara), Craen, A.J. (Anton) de, Davies, G. (Gail), Visser, M.C.H. (Marieke) de, Ford, I. (Ian), Forsen, T. (Tom), Frayling, T.M. (Timothy), Fugazzola, L. (Laura), Gögele, M. (Martin), Hattersley, A.T. (Andrew), Hermus, A.R.M.M. (Ad), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Jensen, R.A. (Richard), Kajantie, E. (Eero), Kloppenburg, M. (Margreet), Lim, E.M. (Ee Mun), Masciullo, C. (Corrado), Mariotti, S. (Stefano), Minelli, C. (Cosetta), Mitchell, B.D. (Braxton), Nagaraja, R. (Ramaiah), Netea-Maier, R.T. (Romana), Palotie, A. (Aarno), Persani, L. (Luca), Piras, M.G. (Maria Grazia), Psaty, B.M. (Bruce), Räikkönen, K. (Katri), Richards, J.B. (Brent), Rivadeneira Ramirez, F. (Fernando), Sala, C. (Cinzia), Sabra, M.M. (Mona), Sattar, N. (Naveed), Shields, B.M. (Beverley), Soranzo, N. (Nicole), Starr, J.M. (John), Stott, D.J. (David. J.), Sweep, F.C. (Fred), Usala, G., Klauw, M.M. (Melanie) van der, Heemst, D. (Diana) van, Mol-van Mullem, A.A.A. (Alies) van, Vermeulen, S.H. (Sita), Walsh, J.P. (John), Westendorp, R.G.J. (Rudi), Widen, E. (Elisabeth), Zhai, G. (Guangju), Cucca, F. (Francesco), Deary, I.J. (Ian), Visser, W.E. (Edward), Eriksson, J.G. (Johan), Ferrucci, L. (Luigi), Fox, C. (Craig), Jukema, J.W. (Jan Wouter), Kiemeney, L.A.L.M. (Bart), Pramstaller, P.P. (Peter Paul), Schlessinger, D., Shuldiner, A.R. (Alan), Slagboom, P.E. (Eline), Uitterlinden, A.G. (André), Vaidya, B. (Bijay), Visser, T.J. (Theo), Wolffenbuttel, B.H.R. (Bruce), Meulenbelt, I. (Ingrid), Rotter, J.I. (Jerome), Spector, T.D. (Timothy), Hicks, A.A. (Andrew), Toniolo, D. (Daniela), Sanna, S. (Serena), Peeters, R.P. (Robin), and Naitza, S. (Silvia)

Published
2013
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13. Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis

Author

Meulenbelt, I. (Ingrid), Min, J. (Josine), Bos, S.D. (Steffan), Riyazi, N. (Naghmeh), Houwing-Duistermaat, J.J. (Jeanine), Wijk, H.J. van der, Kroon, H.M. (Herman), Nakajima, M., Ikegawa, S. (Shiro), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Deure, W.M. (Wendy) van der, Visser, T.J. (Theo), Seymour, A.B. (Albert), Lakenberg, N. (Nico), Breggen, R. (Ruud) van der, Kremer, D. (Dennis), Tikka-Kleemola, P. (Päivi), Kloppenburg, M. (Margreet), Loughlin, J. (John), Slagboom, P.E. (Eline), Meulenbelt, I. (Ingrid), Min, J. (Josine), Bos, S.D. (Steffan), Riyazi, N. (Naghmeh), Houwing-Duistermaat, J.J. (Jeanine), Wijk, H.J. van der, Kroon, H.M. (Herman), Nakajima, M., Ikegawa, S. (Shiro), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Deure, W.M. (Wendy) van der, Visser, T.J. (Theo), Seymour, A.B. (Albert), Lakenberg, N. (Nico), Breggen, R. (Ruud) van der, Kremer, D. (Dennis), Tikka-Kleemola, P. (Päivi), Kloppenburg, M. (Margreet), Loughlin, J. (John), and Slagboom, P.E. (Eline)

Abstract

Osteoarthritis [MIM 165720] is a common late-onset articular joint disease for which no pharmaceutical intervention is available to attenuate the cartilage degeneration. To identify a new osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis were applied to 179 affected siblings and four trios with generalized osteoarthritis (The GARP study). We tested, for confirmation by association, 1478 subjects who required joint replacement and 734 controls in a UK population. Additional replication was tested in 1582 population-based females from the Rotterdam study that contained 94 cases with defined hip osteoarthritis and in 267 Japanese females with symptomatic hip osteoarthritis and 465 controls. Suggested evidence for linkage in the GARP study was observed on chromosome 14q32.11 (log of odds = 3.03, P = 1.9 × 10-4). Genotyping tagging single-nucleotide polymorphisms covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 [MIM 601413]) which significantly explained the linkage signal (P = 0.006). Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval (CI) 1.37-2.34 with P = 2.02 × 10-5in female cases with advanced/symptomatic hip osteoarthritis. The gene product of this DIO2 converts intracellular pro-hormone-3,3′,5,5′-tetraiodothyronine (T4) into the active thyroid hormone 3,3′,5-triiodothyronine (T3) thereby regulating intracellular levels of active T3 in target tissues such as the growth plate. Our results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis.

Published
2008
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14. Octapeptide repeat insertions in the prion protein gene and early onset dementia

Author

Croes, E.A. (Esther), Theuns, J. (Jessie), Houwing-Duistermaat, J.J. (Jeanine), Dermaut, B. (Bart), Sleegers, K. (Kristel), Roks, C.M.A.A. (Gerwin), Broeckhoven, C. (Christine) van, Harten, B. van, Swieten, J.C. (John) van, Cruts, M. (Marc), Duijn, C.M. (Cornelia) van, Croes, E.A. (Esther), Theuns, J. (Jessie), Houwing-Duistermaat, J.J. (Jeanine), Dermaut, B. (Bart), Sleegers, K. (Kristel), Roks, C.M.A.A. (Gerwin), Broeckhoven, C. (Christine) van, Harten, B. van, Swieten, J.C. (John) van, Cruts, M. (Marc), and Duijn, C.M. (Cornelia) van

Abstract

Objectives: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. Methods: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. Results: We found an increasing number of repeats associated with younger age at onset (p<0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p<0,001) when adjusting for age at onset. Conclusions: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.

Published
2004
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15. Octapeptide repeat insertions in the prion protein gene and early onset dementia

Author

Croes, E.A. (Esther), Houwing-Duistermaat, J.J. (Jeanine), Sleegers, K. (Kristel), Forey, F., Harten, B. van, Cruts, M. (Marc), Duijn, C.M. (Cornelia) van, Theuns, J. (Jessie), Swieten, J.C. (John) van, Broeckhoven, C. (Christine) van, Croes, E.A. (Esther), Houwing-Duistermaat, J.J. (Jeanine), Sleegers, K. (Kristel), Forey, F., Harten, B. van, Cruts, M. (Marc), Duijn, C.M. (Cornelia) van, Theuns, J. (Jessie), Swieten, J.C. (John) van, and Broeckhoven, C. (Christine) van

Abstract

OBJECTIVES: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. METHODS: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. RESULTS: We found an increasing number of repeats associated with younger age at onset (p < 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p < 0.001) when adjusting for age at onset. CONCLUSIONS: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies

Published
2004

16. Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease

Author

Croes, E.A. (Esther), Alizadeh, B.Z. (Behrooz), Bertoli Avella, A.M. (Aida), Rademaker, T.A.M. (Tessa), Vergeer-Drop, J. (Jeannette), Dermaut, B. (Bart), Houwing-Duistermaat, J.J. (Jeanine), Wientjens, D.P.W.M. (Dorothee), Hofman, A. (Albert), Broeckhoven, C. (Christine) van, Duijn, C.M. (Cornelia) van, Croes, E.A. (Esther), Alizadeh, B.Z. (Behrooz), Bertoli Avella, A.M. (Aida), Rademaker, T.A.M. (Tessa), Vergeer-Drop, J. (Jeannette), Dermaut, B. (Bart), Houwing-Duistermaat, J.J. (Jeanine), Wientjens, D.P.W.M. (Dorothee), Hofman, A. (Albert), Broeckhoven, C. (Christine) van, and Duijn, C.M. (Cornelia) van

Abstract

The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.

Published
2004
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17. Insulin-like growth factor I gene promoter polymorphism, collagen type II alpha1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study

Author

Zhai, G. (Guangju), Duijn, C.M. (Cornelia) van, Rivadeneira Ramirez, F. (Fernando), Houwing-Duistermaat, J.J. (Jeanine), Meulenbelt, I. (Ingrid), Bijkerk, C. (Casper), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Pols, H.A.P. (Huib), Slagboom, P.E. (Eline), Hofman, A. (Albert), Zhai, G. (Guangju), Duijn, C.M. (Cornelia) van, Rivadeneira Ramirez, F. (Fernando), Houwing-Duistermaat, J.J. (Jeanine), Meulenbelt, I. (Ingrid), Bijkerk, C. (Casper), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Pols, H.A.P. (Huib), Slagboom, P.E. (Eline), and Hofman, A. (Albert)

Abstract

OBJECTIVE: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene. METHODS: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested. RESULTS: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years. CONCLUSIONS: SUBJECTS: with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested.

Published
2004

18. Association between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: the Rotterdam Study

Author

Rivadeneira Ramirez, F. (Fernando), Houwing-Duistermaat, J.J. (Jeanine), Vaessen, N. (Norbert), Vergeer-Drop, J.M., Pols, H.A.P. (Huib), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Houwing-Duistermaat, J.J. (Jeanine), Vaessen, N. (Norbert), Vergeer-Drop, J.M., Pols, H.A.P. (Huib), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), and Hofman, A. (Albert)

Abstract

Studies of the roles of variants of the IGF-I gene in the regulation of bone mineral density (BMD) have yielded conflicting results. We examined the role of a microsatellite repeat polymorphism in one of the promoter regions of the IGF-I gene in relation to femoral BMD in elderly women and men from the Rotterdam Study. We studied 5648 and 4134 individuals at baseline and follow-up ( approximately 2 yr later), respectively. Femoral BMD measurements were performed using dual energy x-ray absorptiometry. In women, baseline BMD levels were, on the average, 0.02 g/cm(2) [95% confidence interval (CI) for difference, -0.03, -0.00 g/cm(2)] lower in individuals without the 192-bp allele as compared with the homozygotes for the allele (P = 0.03). The mean rate of BMD change from baseline to follow-up was -6.9 mg/cm(2) (95% CI, -10.8, -3.0), -4.5 mg/cm(2) (95% CI, -6.4, -2.5), and -2.3 mg/cm(2) (95% CI, -4.2, 0.3) in noncarriers, heterozygotes, and homozygotes for the 192-bp allele, respectively (P trend = 0.03). Adjustment for age and body mass index did not essentially change this relation. No such effects were observed in men. Our findings suggest that this promoter polymorphism or another functional polymorphism in linkage disequilibrium may be a genetic determinant of BMD levels and rate of bone loss in postmenopausal women.

Published
2003

19. A genome-wide search for genes involved in type 2 diabetes in a recently genetically isolated population from the Netherlands

Author

Aulchenko, Y.S. (Yurii), Vaessen, N. (Norbert), Heutink, P. (Peter), Pullen, J. (Jan), Snijders, P.J.L.M. (Pieter), Hofman, A. (Albert), Sandkuijl, L.A. (Lodewijk), Houwing-Duistermaat, J.J. (Jeanine), Bennett, S. (Simon), Oostra, B.A. (Ben), Duijn, C.M. (Cornelia) van, Edwards, M. (Mark), Aulchenko, Y.S. (Yurii), Vaessen, N. (Norbert), Heutink, P. (Peter), Pullen, J. (Jan), Snijders, P.J.L.M. (Pieter), Hofman, A. (Albert), Sandkuijl, L.A. (Lodewijk), Houwing-Duistermaat, J.J. (Jeanine), Bennett, S. (Simon), Oostra, B.A. (Ben), Duijn, C.M. (Cornelia) van, and Edwards, M. (Mark)

Abstract

Multiple genes, interacting with the environment, contribute to the susceptibility to type 2 diabetes. We performed a genome-wide search to localize type 2 diabetes susceptibility genes in a recently genetically isolated population in the Netherlands. We identified 79 nuclear families with type 2 diabetes who were related within 13 generations and performed a 770-marker genome-wide scan search for shared founder alleles. Twenty-six markers yielded a logarithm of odds (LOD) score >0.59 (nominal P < 0.05), of which 7 reached LOD scores >1.17 (nominal P < 0.01). The strongest evidence for a type 2 diabetes locus was at marker D18S63 on chromosome 18p (LOD 2.3, P = 0.0006). This region was investigated further using additional markers. For one of these markers (D18S1105), we found a significant association with type 2 diabetes (odds ratio 6.7 [95% CI 1.5-30.7], P = 0.005 for the 97-bp allele, assuming a dominant model), which increased when limiting the analysis to patients with high BMI (12.25 [2.1-71], P = 0.003). A locus on chromosome 18p in patients with high BMI was suggested earlier by Parker et al. Our study is the first to confirm this locus.

Published
2003
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20. Early cognitive decline is associated with prion protein codon 129 polymorphism

Author

Croes, E.A. (Esther), Dermaut, B. (Bart), Houwing-Duistermaat, J.J. (Jeanine), Broeck, M. (Marleen) van den, Cruts, M. (Marc), Breteler, M.M.B. (Monique), Hofman, A. (Albert), Broeckhoven, C. (Christine) van, Duijn, C.M. (Cornelia) van, Croes, E.A. (Esther), Dermaut, B. (Bart), Houwing-Duistermaat, J.J. (Jeanine), Broeck, M. (Marleen) van den, Cruts, M. (Marc), Breteler, M.M.B. (Monique), Hofman, A. (Albert), Broeckhoven, C. (Christine) van, and Duijn, C.M. (Cornelia) van

Published
2003
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21. A genome-wide search for linkage-disequilibrium with type 1 diabetes in a recent genetically isolated population from the Netherlands

Author

Vaessen, N. (Norbert), Houwing-Duistermaat, J.J. (Jeanine), Rademaker, T.A.M. (Tessa), Testers, L., Batstra, M.R. (Manou), Sandkuijl, L.A. (Lodewijk), Duijn, C.M. (Cornelia) van, Oostra, B.A. (Ben), Snijders, P.J.L.M. (Pieter), Heutink, P. (Peter), Vaessen, N. (Norbert), Houwing-Duistermaat, J.J. (Jeanine), Rademaker, T.A.M. (Tessa), Testers, L., Batstra, M.R. (Manou), Sandkuijl, L.A. (Lodewijk), Duijn, C.M. (Cornelia) van, Oostra, B.A. (Ben), Snijders, P.J.L.M. (Pieter), and Heutink, P. (Peter)

Abstract

Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome scans have identified >18 other genomic regions that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in mapping susceptibility loci than in complex outbred populations. We describe a genome-wide search in a recently Dutch isolated population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a genome-wide scan using a combined linkage- and association-based approach. In addition to the HLA locus, evidence for type 1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and 17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved ancestral haplotype was found for chromosome 8q24.

Published
2002

22. The role of hemochromatosis C282Y and H63D gene mutations in type 2diabetes: findings from the Rotterdam Study and meta-analysis

Author

Njajou, O.T. (Omer), Alizadeh, B.Z. (Behrooz), Vaessen, N. (Norbert), Vergeer, J.M. (Jeanette), Houwing-Duistermaat, J.J. (Jeanine), Hofman, A. (Albert), Pols, H.A.P. (Huib), Duijn, C.M. (Cornelia) van, Njajou, O.T. (Omer), Alizadeh, B.Z. (Behrooz), Vaessen, N. (Norbert), Vergeer, J.M. (Jeanette), Houwing-Duistermaat, J.J. (Jeanine), Hofman, A. (Albert), Pols, H.A.P. (Huib), and Duijn, C.M. (Cornelia) van

Abstract

Letter

Published
2002

23. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36

Author

Duijn, C.M. (Cornelia) van, Breedveld, G.J. (Guido), Horstink, M. (Marten), Sandkuijl, L.A. (Lodewijk), Oostra, B.A. (Ben), Swieten, J.C. (John) van, Bonifati, V. (Vincenzo), Galjaard, R-J.H. (Robert-Jan), Houwing-Duistermaat, J.J. (Jeanine), Testers, L., Dekker, M.C.J. (Marieke), Snijders, P.J.L.M. (Pieter), Heutink, P. (Peter), Duijn, C.M. (Cornelia) van, Breedveld, G.J. (Guido), Horstink, M. (Marten), Sandkuijl, L.A. (Lodewijk), Oostra, B.A. (Ben), Swieten, J.C. (John) van, Bonifati, V. (Vincenzo), Galjaard, R-J.H. (Robert-Jan), Houwing-Duistermaat, J.J. (Jeanine), Testers, L., Dekker, M.C.J. (Marieke), Snijders, P.J.L.M. (Pieter), and Heutink, P. (Peter)

Abstract

Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.

Published
2001

24. Heritabilities of radiologic OA in peripheral joins and of disc degeneration of the spine

Author

Bijkerk, C. (Casper), Houwing-Duistermaat, J.J. (Jeanine), Valkenburg, H.A. (Hans), Meulenbelt, I. (Ingrid), Hofman, A. (Albert), Breedveld, F.C. (Ferdinand), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), Pols, H.A.P. (Huib), Bijkerk, C. (Casper), Houwing-Duistermaat, J.J. (Jeanine), Valkenburg, H.A. (Hans), Meulenbelt, I. (Ingrid), Hofman, A. (Albert), Breedveld, F.C. (Ferdinand), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), and Pols, H.A.P. (Huib)

Abstract

OBJECTIVE: To estimate the genetic influence on the occurrence of radiologic osteoarthritis (ROA) in the knees, hips, and hands and disc degeneration of the spine in the general population. METHODS: A random sample of 1,583 individuals was drawn to estimate the prevalence of ROA and disc degeneration in the general population. Of 118 probands with multiple affected joint sites who were derived from this sample, we were able to recruit 257 siblings. The variance of ROA and disc degeneration within sibling pairs was compared with the variance between sibling pairs. Heritability estimates for ROA in the knees, hips, and hands and for disc degeneration of the spine were calculated. OA was defined according to radiologic criteria, using the Kellgren/Lawrence grading system. RESULTS: We observed that hand ROA and disc degeneration of the spine were statistically significantly more frequent in siblings than in the random sample, whereas the prevalence of knee and of hip ROA was similar and lower, respectively. Heritability estimates for hand ROA and disc degeneration were statistically significant, P = 0.56 (95% confidence interval [95% CI] 0.34-0.76) and P = 0.75 (95% CI 0.30-1.00), respectively. For knee and hip ROA, no evidence of a genetic effect in the general population was found. Finally, the heritability estimate for a score that summed the number of joints affected in the knees, hips, hands, and spine was 0.78 (95% CI 0.52-0.98). All heritability estimates were adjusted for age, sex, body mass index, and bone mineral density. CONCLUSION: The present study shows that in the general population, there is a strong genetic effect for hand ROA and disc degeneration of the spine. The findings on the total number of joints affected at multiple sites suggest genetic susceptibility to generalized OA.

Published
1999
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