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1. Author Correction: Heritability estimates for 361 blood metabolites across 40 genome-wide association studies (Nature Communications, (2020), 11, 1, (39), 10.1038/s41467-019-13770-6)

Author

Hagenbeek, F.A. (Fiona A.), Pool, R. (Reńe), Dongen, J. (Jenny) van, Draisma, G. (Gerrit), Hottenga, J.J. (Jouke Jan), Willemsen, G. (Gonneke), Abdellaoui, A. (Abdel), Fedko, I.O. (Iryna O.), Braber, A. (Anouk) den, Visser, P. (Pim), Geus, E.J.C. (Eco) de, Willems van Dijk, K. (Ko), Verhoeven, A. (Aswin), Suchiman, H.E. (H. Eka), Beekman, M. (Marian), Slagboom, P.E. (Eline), Duijn, C.M. (Cornelia) van, Barkey Wolf, J.J.H. (J. J.H.), Cats, D. (D.), Amin, N. (N.), Beulens, J.W.J. (Joline), van der Bom, J.A. (J. A.), Bomer, N. (Nils), Demirkan, A. (Ayşe), van Hilten, J.A. (J. A.), Meessen, J.M.T.A. (J. M.T.A.), Moed, H. (Heleen), Fu, J. (J.), Onderwater, G.L.J. (G. L.J.), Rutters, F. (F.), So-Osman, C. (Cynthia), van der Flier, W.M. (W. M.), Heijden, A.A.W.A. (Amber A. W.) van der, Spek, A. (Ashley) van der, Asselbergs, F.W. (F. W.), Boersma, H. (Eric), Elders, P.M. (P. M.), Geleijnse, J.M. (J. M.), Ikram, M.A. (Arfan), Kloppenburg, M. (Margreet), Meulenbelt, I. (I.), Mooijaart, S.P. (Simon), Nelissen, R.G.H.H. (Rob), Netea, M.G. (Mihai), Penninx, B.W.J.H. (Brenda), Stehouwer, C.D.A. (C. D.A.), Teunissen, C.E. (Charlotte), Terwindt, G.M. (G. M.), ‘t Hart, L.M. (L. M.), van den Maagdenberg, A.M.J.M. (A. M.J.M.), Harst, P. (Pim) van der, van der Horst, I.C.C. (I. C.C.), Kallen, C.J. van der, van Greevenbroek, M.M.J. (M. M.J.), Spil, W.E. (Willem) van, Wijmenga, C. (Cisca), Zwinderman, A.H. (Ailko), Zhernikova, A. (A.), Jukema, J.W. (Jan Wouter), Mei, H. (H.), Slofstra, M. (M.), Swertz, M. (M.), Akker, E.B. (Erik) van den, Deelen, J. (Joris), Reinders, M.J.T. (M. J.T.), Harms, A.C. (Amy), Hankemeier, T. (Thomas), Bartels, M. (Meike), Nivard, M. (Michel), Boomsma, D.I. (Dorret), Hagenbeek, F.A. (Fiona A.), Pool, R. (Reńe), Dongen, J. (Jenny) van, Draisma, G. (Gerrit), Hottenga, J.J. (Jouke Jan), Willemsen, G. (Gonneke), Abdellaoui, A. (Abdel), Fedko, I.O. (Iryna O.), Braber, A. (Anouk) den, Visser, P. (Pim), Geus, E.J.C. (Eco) de, Willems van Dijk, K. (Ko), Verhoeven, A. (Aswin), Suchiman, H.E. (H. Eka), Beekman, M. (Marian), Slagboom, P.E. (Eline), Duijn, C.M. (Cornelia) van, Barkey Wolf, J.J.H. (J. J.H.), Cats, D. (D.), Amin, N. (N.), Beulens, J.W.J. (Joline), van der Bom, J.A. (J. A.), Bomer, N. (Nils), Demirkan, A. (Ayşe), van Hilten, J.A. (J. A.), Meessen, J.M.T.A. (J. M.T.A.), Moed, H. (Heleen), Fu, J. (J.), Onderwater, G.L.J. (G. L.J.), Rutters, F. (F.), So-Osman, C. (Cynthia), van der Flier, W.M. (W. M.), Heijden, A.A.W.A. (Amber A. W.) van der, Spek, A. (Ashley) van der, Asselbergs, F.W. (F. W.), Boersma, H. (Eric), Elders, P.M. (P. M.), Geleijnse, J.M. (J. M.), Ikram, M.A. (Arfan), Kloppenburg, M. (Margreet), Meulenbelt, I. (I.), Mooijaart, S.P. (Simon), Nelissen, R.G.H.H. (Rob), Netea, M.G. (Mihai), Penninx, B.W.J.H. (Brenda), Stehouwer, C.D.A. (C. D.A.), Teunissen, C.E. (Charlotte), Terwindt, G.M. (G. M.), ‘t Hart, L.M. (L. M.), van den Maagdenberg, A.M.J.M. (A. M.J.M.), Harst, P. (Pim) van der, van der Horst, I.C.C. (I. C.C.), Kallen, C.J. van der, van Greevenbroek, M.M.J. (M. M.J.), Spil, W.E. (Willem) van, Wijmenga, C. (Cisca), Zwinderman, A.H. (Ailko), Zhernikova, A. (A.), Jukema, J.W. (Jan Wouter), Mei, H. (H.), Slofstra, M. (M.), Swertz, M. (M.), Akker, E.B. (Erik) van den, Deelen, J. (Joris), Reinders, M.J.T. (M. J.T.), Harms, A.C. (Amy), Hankemeier, T. (Thomas), Bartels, M. (Meike), Nivard, M. (Michel), and Boomsma, D.I. (Dorret)

Abstract

The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Data 1 file, in which additional delimiters were included in the first column for a number of rows, resulting in column shifts for some of these rows. The HTML has been updated to include a corrected version of Supplementary Data 1; the original incorrect version of Supplementary Data 1 can be found as Supplementary Information associated with this Correction. In addition, the original version of this Article contained an error in the author affiliations. An affiliation of Abdel Abdellaoui with Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2020
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2. Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

Author

Hagenbeek, F.A. (Fiona A.), Pool, R. (Reńe), Dongen, J. (Jenny) van, Draisma, G. (Gerrit), Hottenga, J.J. (Jouke Jan), Willemsen, G. (Gonneke), Abdellaoui, A. (Abdel), Fedko, I.O. (Iryna O.), Braber, A. (Anouk) den, Visser, P.J. (Pieter Jelle), de Geus, E.J.C.N. (Eco J. C. N.), Willems van Dijk, K. (Ko), Verhoeven, A. (Aswin), Suchiman, H.E. (H. Eka), Beekman, M. (Marian), Slagboom, P.E. (Eline), Duijn, C.M. (Cornelia) van, Barkey Wolf, J.J.H. (J. J.H.), Cats, D. (D.), Amin, N. (N.), Beulens, J.W.J. (Joline), van der Bom, J.A. (J. A.), Bomer, N. (Nils), Demirkan, A. (Ayşe), van Hilten, J.A. (J. A.), Meessen, J.M.T.A. (J. M.T.A.), Moed, H. (Heleen), Fu, J. (J.), Onderwater, G.L.J. (G. L.J.), Rutters, F. (F.), So-Osman, C. (Cynthia), Flier, W.M. (Wiesje) van der, Heijden, A.A.W.A. (Amber A. W.) van der, Spek, A. (Ashley) van der, Asselbergs, F.W. (F. W.), Boersma, H. (Eric), Elders, P.M. (P. M.), Geleijnse, J.M. (Marianne), Ikram, M.A. (Arfan), Kloppenburg, M. (Margreet), Meulenbelt, I. (I.), Mooijaart, S.P. (Simon), Nelissen, R.G.H.H. (Rob), Netea, M.G. (Mihai), Penninx, B.W.J.H. (Brenda), Stehouwer, C.D. (Coen), Teunissen, C.E. (Charlotte), Terwindt, G.M. (Gisela), ‘t Hart, L.M. (L. M.), Maagdenberg, A.M.J.M. (Arn), Harst, P. (Pim) van der, van der Horst, I.C.C. (I. C.C.), Kallen, C.J. van der, van Greevenbroek, M.M.J. (M. M.J.), Spil, W.E. (Willem) van, Wijmenga, C. (C.), Zwinderman, A.H. (A. H.), Zhernikova, A. (A.), Jukema, J.W. (Jan Wouter), Mei, H. (H.), Slofstra, M. (M.), Swertz, M. (M.), Akker, E.B. (Erik) van den, Deelen, J. (Joris), Reinders, M.J.T. (M. J.T.), Harms, A.C. (Amy C.), Hankemeier, T. (Thomas), Bartels, M. (Meike), Nivard, M. (Michel), Boomsma, D.I. (Dorret), Hagenbeek, F.A. (Fiona A.), Pool, R. (Reńe), Dongen, J. (Jenny) van, Draisma, G. (Gerrit), Hottenga, J.J. (Jouke Jan), Willemsen, G. (Gonneke), Abdellaoui, A. (Abdel), Fedko, I.O. (Iryna O.), Braber, A. (Anouk) den, Visser, P.J. (Pieter Jelle), de Geus, E.J.C.N. (Eco J. C. N.), Willems van Dijk, K. (Ko), Verhoeven, A. (Aswin), Suchiman, H.E. (H. Eka), Beekman, M. (Marian), Slagboom, P.E. (Eline), Duijn, C.M. (Cornelia) van, Barkey Wolf, J.J.H. (J. J.H.), Cats, D. (D.), Amin, N. (N.), Beulens, J.W.J. (Joline), van der Bom, J.A. (J. A.), Bomer, N. (Nils), Demirkan, A. (Ayşe), van Hilten, J.A. (J. A.), Meessen, J.M.T.A. (J. M.T.A.), Moed, H. (Heleen), Fu, J. (J.), Onderwater, G.L.J. (G. L.J.), Rutters, F. (F.), So-Osman, C. (Cynthia), Flier, W.M. (Wiesje) van der, Heijden, A.A.W.A. (Amber A. W.) van der, Spek, A. (Ashley) van der, Asselbergs, F.W. (F. W.), Boersma, H. (Eric), Elders, P.M. (P. M.), Geleijnse, J.M. (Marianne), Ikram, M.A. (Arfan), Kloppenburg, M. (Margreet), Meulenbelt, I. (I.), Mooijaart, S.P. (Simon), Nelissen, R.G.H.H. (Rob), Netea, M.G. (Mihai), Penninx, B.W.J.H. (Brenda), Stehouwer, C.D. (Coen), Teunissen, C.E. (Charlotte), Terwindt, G.M. (Gisela), ‘t Hart, L.M. (L. M.), Maagdenberg, A.M.J.M. (Arn), Harst, P. (Pim) van der, van der Horst, I.C.C. (I. C.C.), Kallen, C.J. van der, van Greevenbroek, M.M.J. (M. M.J.), Spil, W.E. (Willem) van, Wijmenga, C. (C.), Zwinderman, A.H. (A. H.), Zhernikova, A. (A.), Jukema, J.W. (Jan Wouter), Mei, H. (H.), Slofstra, M. (M.), Swertz, M. (M.), Akker, E.B. (Erik) van den, Deelen, J. (Joris), Reinders, M.J.T. (M. J.T.), Harms, A.C. (Amy C.), Hankemeier, T. (Thomas), Bartels, M. (Meike), Nivard, M. (Michel), and Boomsma, D.I. (Dorret)

Abstract

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and 5

Published
2020
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3. WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Author

Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Elbers, C.C. (Clara), Kloosterman, W.P. (Wigard), Setten, J. (Jessica) van, Nijman, I.J. (Isaac ), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter B T), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, I. (Inge), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Peer, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Beekman, M. (Marian), Craen, A.J. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Hottenga, J.J. (Jouke Jan), Kattenberg, V.M. (Mathijs), Willemsen, G.A.H.M. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Oven, M. (Mannis) van, Kayser, M.H. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen F.), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, S. (Shan), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J.J. (Jan), Marschall, T. (Tanja), Schönhuth, A. (Alexander), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada Gil, K. (Karol), McCarroll, S.A. (Steve), Sunyaev, S.R. (Shamil), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), Ommen, G.J. (Gert) van, Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Elbers, C.C. (Clara), Kloosterman, W.P. (Wigard), Setten, J. (Jessica) van, Nijman, I.J. (Isaac ), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter B T), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, I. (Inge), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Peer, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Beekman, M. (Marian), Craen, A.J. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Hottenga, J.J. (Jouke Jan), Kattenberg, V.M. (Mathijs), Willemsen, G.A.H.M. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Oven, M. (Mannis) van, Kayser, M.H. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen F.), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, S. (Shan), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J.J. (Jan), Marschall, T. (Tanja), Schönhuth, A. (Alexander), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada Gil, K. (Karol), McCarroll, S.A. (Steve), Sunyaev, S.R. (Shamil), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), and Ommen, G.J. (Gert) van

Abstract

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Published
2019
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4. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Author

Porcu, E. (Eleonora), Rüeger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Heijmans, B.T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G.W. (Grant), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Slagboom, P.E. (Eline), Stehouwer, C.D. (Coen), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), ‘t Hoen, P.A.C. (Peter A. C.), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), van Dongen, J. (Jenny), Iterson, M. (Maarten) van, Meurs, J. (J.) van, Veldink, J.H. (Jan), Verlouw, J.A.M. (Joost), Visscher, P.M. (Peter M.), Völker, U. (Uwe), Võsa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D.I. (Dorret), Bot, J.J. (Jan), Deelen, J. (Joris), Hofman, B.A. (Bert A.), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Bonder, M.J. (Marc), Jhamai, P.M. (Mila), Kielbasa, S.M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (René), Mei, H. (Hailiang), Moed, H. (Heleen), Nooren, I. (Irene), Pool, R. (Reńe), Schalkwijk, C.G. (Casper), Stehouwer, C.D.A. (Coen D. A.), Suchiman, H.E.D. (H. Eka D.), Swertz, M.A. (Morris A.), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Berg, L.H. (Leonard) van den, Breggen, R. (Ruud) van der, Kallen, C.J. van der, Dijk, F. (Freerk) van, Dongen, J. (Jenny) van, Duijn, C.M. (Cornelia) van, Van Galen, M. (Michiel), van Greevenbroek, M.M.J. (Marleen M. J.), Heemst, D. (Diana) van, Meurs, J.B.J. (Joyce) van, van Rooij, J. (Jeroen), van’t Hof, P. (Peter), Zwet, E.W. (Erik) van, Vermaat, M. (Martijn), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Zhernakova, D.V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F.A. (Federico A.), Reymond, A. (Alexandre), Kutalik, Z. (Zoltán), Porcu, E. (Eleonora), Rüeger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Heijmans, B.T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G.W. (Grant), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Slagboom, P.E. (Eline), Stehouwer, C.D. (Coen), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), ‘t Hoen, P.A.C. (Peter A. C.), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), van Dongen, J. (Jenny), Iterson, M. (Maarten) van, Meurs, J. (J.) van, Veldink, J.H. (Jan), Verlouw, J.A.M. (Joost), Visscher, P.M. (Peter M.), Völker, U. (Uwe), Võsa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D.I. (Dorret), Bot, J.J. (Jan), Deelen, J. (Joris), Hofman, B.A. (Bert A.), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Bonder, M.J. (Marc), Jhamai, P.M. (Mila), Kielbasa, S.M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (René), Mei, H. (Hailiang), Moed, H. (Heleen), Nooren, I. (Irene), Pool, R. (Reńe), Schalkwijk, C.G. (Casper), Stehouwer, C.D.A. (Coen D. A.), Suchiman, H.E.D. (H. Eka D.), Swertz, M.A. (Morris A.), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Berg, L.H. (Leonard) van den, Breggen, R. (Ruud) van der, Kallen, C.J. van der, Dijk, F. (Freerk) van, Dongen, J. (Jenny) van, Duijn, C.M. (Cornelia) van, Van Galen, M. (Michiel), van Greevenbroek, M.M.J. (Marleen M. J.), Heemst, D. (Diana) van, Meurs, J.B.J. (Joyce) van, van Rooij, J. (Jeroen), van’t Hof, P. (Peter), Zwet, E.W. (Erik) van, Vermaat, M. (Martijn), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Zhernakova, D.V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F.A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltán)

Abstract

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majo

Published
2019
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5. Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

Author

Luijk, R. (René), Wu, H. (Haoyu), Ward-Caviness, C.K. (Cavin K.), Hannon, E. (Eilis), Carnero-Montoro, E. (Elena), Min, J. (Josine), Mandaviya, P.R. (Pooja), Müller-Nurasyid, M. (Martina), Mei, H. (Hailiang), Maarel, S.M. (Silvre) van der, Beekman, M. (Marian), der Breggen, R. (Ruud van), Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), Arindrarto, W. (Wibowo), van’t Hof, P. (Peter), Jan Bonder, M. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Relton, C.L. (Caroline), Mill, J. (Jonathan), Waldenberger, M. (Melanie), Bell, J.T. (Jordana T.), Jansen, R. (Rick), Franke, L. (Lude), ‘t Hoen, P.A.C. (Peter A. C.), Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Meurs, J.B.J. (Joyce) van, Daxinger, L. (Lucia), Slagboom, P.E. (Eline), Zwet, E.W. (Erik) van, Heijmans, B.T. (Bastiaan T.), Luijk, R. (René), Wu, H. (Haoyu), Ward-Caviness, C.K. (Cavin K.), Hannon, E. (Eilis), Carnero-Montoro, E. (Elena), Min, J. (Josine), Mandaviya, P.R. (Pooja), Müller-Nurasyid, M. (Martina), Mei, H. (Hailiang), Maarel, S.M. (Silvre) van der, Beekman, M. (Marian), der Breggen, R. (Ruud van), Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), Arindrarto, W. (Wibowo), van’t Hof, P. (Peter), Jan Bonder, M. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Relton, C.L. (Caroline), Mill, J. (Jonathan), Waldenberger, M. (Melanie), Bell, J.T. (Jordana T.), Jansen, R. (Rick), Franke, L. (Lude), ‘t Hoen, P.A.C. (Peter A. C.), Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Meurs, J.B.J. (Joyce) van, Daxinger, L. (Lucia), Slagboom, P.E. (Eline), Zwet, E.W. (Erik) van, and Heijmans, B.T. (Bastiaan T.)

Abstract

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

Published
2018
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6. Skewed X-inactivation is common in the general female population

Author

Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), Wijmenga, C. (C.), Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), and Wijmenga, C. (C.)

Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Published
2018
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7. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), Medici, M. (Marco), Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), and Medici, M. (Marco)

Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

Published
2018
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8. Genome-wide identification of directed gene networks using large-scale population genomics data

Author

Luijk, R. (René), Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Arindrarto, W. (Wibowo), Claringbould, A. (Annique), Hop, P. (Paul), Beekman, M. (Marian), Breggen, R. (Ruud) van der, Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), van ’t Hof, P. (Peter), Bonder, M.J. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Boomsma, D.I. (Dorret I.), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Franke, L. (Lude), ’t Hoen, P.A.C. (Peter A. C.), Jansen, R. (Rick), Meurs, J.B.J. (Joyce) van, Mei, H. (Hailiang), Slagboom, P.E. (Eline), Heijmans, B.T. (Bastiaan T.), Zwet, E.W. (Erik) van, Luijk, R. (René), Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Arindrarto, W. (Wibowo), Claringbould, A. (Annique), Hop, P. (Paul), Beekman, M. (Marian), Breggen, R. (Ruud) van der, Deelen, J. (Joris), Lakenberg, N. (Nico), Moed, H. (Heleen), Suchiman, H.E.D. (Eka), van ’t Hof, P. (Peter), Bonder, M.J. (Marc), Deelen, P. (Patrick), Tigchelaar, E.F. (Ettje F.), Zhernakova, A. (Alexandra), Zhernakova, D.V. (Dasha V.), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Pool, R. (Reńe), Isaacs, A. (Aaron), Hofman, B.A. (Bert A.), Jhamai, M. (Mila), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Berg, L.H. (Leonard) van den, Van Galen, M. (Michiel), Vermaat, M. (Martijn), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Kielbasa, P.S.M. (P. Szymon M.), Bot, J.J. (Jan), Nooren, I. (Irene), Dijk, F. (Freerk) van, Swertz, M.A. (Morris A.), Heemst, D. (Diana) van, Boomsma, D.I. (Dorret I.), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Franke, L. (Lude), ’t Hoen, P.A.C. (Peter A. C.), Jansen, R. (Rick), Meurs, J.B.J. (Joyce) van, Mei, H. (Hailiang), Slagboom, P.E. (Eline), Heijmans, B.T. (Bastiaan T.), and Zwet, E.W. (Erik) van

Abstract

Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene–gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal anchors, akin to Mendelian Randomization) and specific (by controlling for linkage disequilibrium and pleiotropy). Analysis of genotype and whole-blood RNA-sequencing data from 3072 individuals identified 49 genes as drivers of downstream transcriptional changes (Wald P < 7 × 10−10), among which transcription factors were overrepresented (Fisher’s P = 3.3 × 10−7). Our analysis suggests new gene functions and targets, including for SENP7 (zinc-finger genes involved in retroviral repression) and BCL2A1 (target genes possibly involved in auditory dysfunction). Our work highlights the utility of population genomics data in deriving directed gene expression networks. A resource of trans-effects for all 6600 genes with a genetic instrument can be explored individually using a web-based browser.

Published
2018
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9. 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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10. Blood lipids influence DNA methylation in circulating cells

Author

Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Slieker, R. (Roderick), Moed, H. (Heleen), Bonder, M.J. (Marc), Van Galen, M. (Michiel), Mei, S. (Shan), Zhernakova, A. (Alexandra), Berg, L.H. (Leonard) van den, Deelen, J. (Joris), Dongen, J. (Jenny) van, Heemst, D. (Diana) van, Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Franke, L. (Lude), 't Hoen, P.A.C. (Peter A.C.), Jansen, R., Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Zwet, E.W. (Erik) van, Slagboom, P.E. (Eline), Jukema, J.W. (Jan Wouter), Heijmans, B.T. (Bastiaan), Dekkers, K.F. (Koen F.), Iterson, M. (Maarten) van, Slieker, R. (Roderick), Moed, H. (Heleen), Bonder, M.J. (Marc), Van Galen, M. (Michiel), Mei, S. (Shan), Zhernakova, A. (Alexandra), Berg, L.H. (Leonard) van den, Deelen, J. (Joris), Dongen, J. (Jenny) van, Heemst, D. (Diana) van, Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Stehouwer, C.D. (Coen), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Franke, L. (Lude), 't Hoen, P.A.C. (Peter A.C.), Jansen, R., Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Greevenbroek, M.M. van, Veldink, J.H. (Jan), Wijmenga, C. (Cisca), Zwet, E.W. (Erik) van, Slagboom, P.E. (Eline), Jukema, J.W. (Jan Wouter), and Heijmans, B.T. (Bastiaan)

Abstract

Background: Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals. Results: This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and A

Published
2016
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11. Atopic dermatitis, asthma and allergic rhinitis in general practice and the open population: a systematic review

Author

Pols, D.H.J. (David), Wartna, J.B., Moed, H. (Heleen), van Alphen, E.I., Bohnen, A.M. (Arthur), Bindels, P.J.E. (Patrick), Pols, D.H.J. (David), Wartna, J.B., Moed, H. (Heleen), van Alphen, E.I., Bohnen, A.M. (Arthur), and Bindels, P.J.E. (Patrick)

Abstract

Objective: To examine whether significant differences exist between the self-reported prevalence of atopic disorders in the open population compared with physician diagnosed prevalence of atopic disorders in general practice. Methods: Medline (OvidSP), PubMed Publisher, EMBASE, Google Scholar and the Cochrane Controlled Clinical Trials Register databases were systematically reviewed for articles providing data on the prevalence of asthma, allergic rhinitis and eczema in a GP setting. Studies were only included when they had a cross-sectional or cohort design and included more than 100 children (aged 0-18 years) in a general practice setting. All ISAAC studies (i.e. the open population) that geographically matched a study selected from the first search, were also included. A quality assessment was conducted. The primary outcome measures were prevalence of eczema, asthma and allergic rhinitis in children aged 0-18 years. Results: The overall quality of the included studies was good. The annual and lifetime prevalences of the atopic disorders varied greatly in both general practice and the open population. On average, the prevalence of atopic disorders was higher in the open population. Conclusion: There are significant differences between the self-reported prevalence of atopic disorders in the open population compared with physician diagnosed prevalence of atopic disorders in general practice. Data obtained in the open population cannot simply be extrapolated to the general practice setting. This should be taken into account when considering a research topic or requirements for policy development. GPs should be aware of the possible misclassification of allergic disorders in their practice.KEY POINTSEpidemiological data on atopic disorders in children can be obtained from various sources, each having its own advantages and limitations.On average, the prevalence of atopic disorders is higher in the open population.GPs should take into account the possible misclassifica

Published
2016
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12. Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Author

Slieker, R. (Roderick), Iterson, M. (Maarten) van, Luijk, R. (René), Beekman, M. (Marian), Zhernakova, A. (Alexandra), Moed, H. (Heleen), Mei, S. (Shan), Van Galen, M. (Michiel), Deelen, P. (Patrick), Bonder, M.J. (Marc), Uitterlinden, A.G. (André), Tigchelaar, E.F. (Ettje F.), Stehouwer, C.D.A. (Coen D.A.), Schalkwijk, C.G. (Casper), Kallen, C.J. van der, Hofman, A. (Albert), Heemst, D. (Diana) van, Geus, E.J.C. (Eco) de, Dongen, J. (Jenny) van, Deelen, J. (Joris), Berg, L.H. (Leonard) van den, Meurs, J.B.J. (Joyce) van, Jansen, R., Hoen, P.A.C. (Peter) 't, Franke, L. (Lude), Wijmenga, C. (Cisca), Veldink, J.H. (Jan), Swertz, M. (Morris), Greevenbroek, M.M. van, Duijn, C.M. (Cornelia) van, Boomsma, D.I. (Dorret), Slagboom, P.E. (Eline), Heijmans, B.T. (Bastiaan), Slieker, R. (Roderick), Iterson, M. (Maarten) van, Luijk, R. (René), Beekman, M. (Marian), Zhernakova, A. (Alexandra), Moed, H. (Heleen), Mei, S. (Shan), Van Galen, M. (Michiel), Deelen, P. (Patrick), Bonder, M.J. (Marc), Uitterlinden, A.G. (André), Tigchelaar, E.F. (Ettje F.), Stehouwer, C.D.A. (Coen D.A.), Schalkwijk, C.G. (Casper), Kallen, C.J. van der, Hofman, A. (Albert), Heemst, D. (Diana) van, Geus, E.J.C. (Eco) de, Dongen, J. (Jenny) van, Deelen, J. (Joris), Berg, L.H. (Leonard) van den, Meurs, J.B.J. (Joyce) van, Jansen, R., Hoen, P.A.C. (Peter) 't, Franke, L. (Lude), Wijmenga, C. (Cisca), Veldink, J.H. (Jan), Swertz, M. (Morris), Greevenbroek, M.M. van, Duijn, C.M. (Cornelia) van, Boomsma, D.I. (Dorret), Slagboom, P.E. (Eline), and Heijmans, B.T. (Bastiaan)

Abstract

Background: Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages. Results: Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related g

Published
2016
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13. 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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14. Characteristics of de novo structural changes in the human genome

Author

Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Hormozdiari, F. (Fereydoun), Marschall, T. (Tanja), Hehir-Kwa, J. (Jayne), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Renkens, I. (Ivo), Van Roosmalen, M.J. (Markus J.), Arp, P.P. (Pascal), Coe, B.P. (Bradley P.), Handsaker, R.E. (Robert), Suchiman, E.D. (Eka D.), Cuppen, E. (Edwin), Thung, D.T. (Djie Tjwan), McVey, M. (Mitch), Wendl, M.C. (Michael C.), Uitterlinden, A.G. (André), Schönhuth, A. (Alexander), Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Ye, K. (Kai), Guryev, V. (Victor), Van Ommen, G.-J.B. (Gert-Jan B.), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Hormozdiari, F. (Fereydoun), Marschall, T. (Tanja), Hehir-Kwa, J. (Jayne), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Renkens, I. (Ivo), Van Roosmalen, M.J. (Markus J.), Arp, P.P. (Pascal), Coe, B.P. (Bradley P.), Handsaker, R.E. (Robert), Suchiman, E.D. (Eka D.), Cuppen, E. (Edwin), Thung, D.T. (Djie Tjwan), McVey, M. (Mitch), Wendl, M.C. (Michael C.), Uitterlinden, A.G. (André), Schönhuth, A. (Alexander), Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Ye, K. (Kai), Guryev, V. (Victor), and Van Ommen, G.-J.B. (Gert-Jan B.)

Abstract

Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (120 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.

Published
2015
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15. Interrelationships between atopic disorders in children

Author

Pol, D.H.J. (David H. J.), Wartna, J.B., van Alphen, E.I., Moed, H. (Heleen), Rasenberg, N., Bindels, P.J.E. (Patrick), Bohnen, A.M. (Arthur), Pol, D.H.J. (David H. J.), Wartna, J.B., van Alphen, E.I., Moed, H. (Heleen), Rasenberg, N., Bindels, P.J.E. (Patrick), and Bohnen, A.M. (Arthur)

Abstract

Purpose To study the prevalence and interrelationship between asthma, allergic rhinitis and eczema using data obtained from ISAAC questionnaires. Method The Medline, Pubmed Publisher, EMBASE, Google Scholar and the Cochrane Controlled Clinical Trials Register databases were systematically reviewed to evaluate epidemiological data of children with atopic disorders. To study these interrelationships, a new approach was used. Risk ratios were calculated, describing the risk of having two different atopic disorders when the child is known with one disorder. Results Included were 31 studies, covering a large number of surveyed children (n=1,430,329) in 102 countries. The calculated worldwide prevalence for asthma, eczema and allergic rhinitis is 12.00% (95% CI: 11.99-12.00), 7.88% (95% CI: 7.88-7.89) and 12.66% (95% CI: 12.65-12.67), respectively. The observed prevalence [1.17% (95% CI: 1.17-1.17)] of having all three diseases is 9.8 times higher than could be expected by chance. For children with asthma the calculated risk ratio of having the other two disorders is 5.41 (95% CI: 4.76-6.16), for children with eczema 4.24 (95% CI: 3.75-4.79), and for children with allergic rhinitis 6.20 (95% CI: 5.30-7.27). No studied confounders had a significant influence on these risk ratios. Conclusions Only a minority of children suffers from all three atopic disorders, however this co-occurrence is significantly higher than could be expected by chance and supports a close relationship of these disorders in children. The data of this meta-analysis supports the hypothesis that there could be a fourth distinct group of children with all three disorders. Researchers and clinicians might need to consider these children as a separate group with distinct characteristics regarding severity, causes, treatment or prognosis.

Published
2015
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16. Evaluation of clinical and immunological responses: A 2-year follow-up study in children with allergic rhinitis due to house dust mite

Author

Moed, H. (Heleen), Gerth van Wijk, R. (Roy), Hendriks, R.W. (Rudi), Wouden, J.C. (Hans) van der, Moed, H. (Heleen), Gerth van Wijk, R. (Roy), Hendriks, R.W. (Rudi), and Wouden, J.C. (Hans) van der

Abstract

Background. Allergic rhinitis is a disease with polarization towards Thand a defect of regulatory T cells. Immunological changes have been reported after immunotherapy treatment. However, there is not much known about the natural course of allergic rhinitis with respect to clinical manifestation and the relation with immunological responses. Objective. To evaluate clinical symptoms of allergic rhinitis, in relation to in vivo allergen-specific skin responses and in vitro allergen-specific effector and regulatory T cells determined at baseline and after two years. Methods. From a large trial, 59 children were randomly selected. The following variables were compared: clinical symptoms, allergen skin tests, specific IgE, T-cell proliferation, IL-5, IL-13, IFN-gamma, IL-10, TGF-beta, CD 4 + CD 25 hi cells, and Foxp3 expression. Results. Allergic symptoms had decreased after two years. Whereas skin test reactions correlated between years 0 and 2, there was no change in the size of the reaction. Also, proinflammatory reactions did not change after two years, with a positive correlation between years 0 and 2. No relevant changes were observed with respect to regulatory cells. Conclusion. Whereas, comparable to immunotherapy, allergic complaints decrease, the immunological changes of specific T-cell activity (both effector cells and regulator cells) which are observed after immunotherapy, do not change.

Published
2013
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18. Skin tests, T cell responses and self-reported symptoms in children with allergic rhinitis and asthma due to house dust mite allergy

Author

Moed, H. (Heleen), Gerth van Wijk, R. (Roy), Jongste, J.C. (Johan) de, Wouden, J.C. (Hans) van der, Moed, H. (Heleen), Gerth van Wijk, R. (Roy), Jongste, J.C. (Johan) de, and Wouden, J.C. (Hans) van der

Abstract

BACKGROUND: In allergic responses, a distinction is made between an early-phase response, several minutes after allergen exposure, and a late-phase response after several hours. During the late phase, eosinophils and T cells infiltrate the mucosa and play an important role in inflammation. OBJECTIVE: The aim of this study was to examine the relationship between allergen-induced late-phase skin responses and in vitro T cell

Published
2009

19. Determining the severity of atopic dermatitis in children presenting in general practice: an easy and fast method

Author

Willemsen, M.G. (Marjolein), Valburg, R.W.C. (Rosalinda) van, Dirven-Meijer, P.C. (Pauline), Oranje, A.P. (Arnold), Wouden, J.C. (Hans) van der, Moed, H. (Heleen), Willemsen, M.G. (Marjolein), Valburg, R.W.C. (Rosalinda) van, Dirven-Meijer, P.C. (Pauline), Oranje, A.P. (Arnold), Wouden, J.C. (Hans) van der, and Moed, H. (Heleen)

Abstract

Assessment of the severity of atopic dermatitis (AD) is necessary to evaluate the disease process. This study evaluates and validates the TIS in children with AD presenting in general practice. Independent investigators determined the severity of AD using the TIS and the objective SCORAD. The interobserver agreement for the TIS and SCORAD was calculated, as was the correlation between TIS and SCORAD. The mean time to assess the TIS was less than one minute. A moderate-to-good agreement between the observers was found for the TIS (kappa = 0.604 or 0.464), or SCORAD (kappa = 0.695 or 0.700). There was an excellent correlation between TIS and SCORAD (r(s) = 0.755-0.839). In conclusion, the TIS is an easy and fast method to score AD. Because of the moderate to good interobserver agreement and the high correlation with the SCORAD, we recommend the TIS to determine the severity of AD in general practice.

Published
2009
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20. Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: Study design and recruitment

Author

Bot, C.M.A. (Cindy) de, Moed, H. (Heleen), Berger, M.Y. (Marjolein), Röder, E. (Esther), Groot, H. (Hans) de, Jongste, J.C. (Johan) de, Gerth van Wijk, R. (Roy), Wouden, J.C. (Hans) van der, Bot, C.M.A. (Cindy) de, Moed, H. (Heleen), Berger, M.Y. (Marjolein), Röder, E. (Esther), Groot, H. (Hans) de, Jongste, J.C. (Johan) de, Gerth van Wijk, R. (Roy), and Wouden, J.C. (Hans) van der

Abstract

Background. For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the eff

Published
2008
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