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1. 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
Full Text
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2. Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data

Author

Fokkema, I., Velde, K. (KJoeri) van der, Slofstra, M.K., Ruivenkamp, C.A. (Claudia), Vogel, M.J. (Maartje), Pfundt, R. (Rolph), Blok, M.J.C., Deprez, R.H.L., Waisfisz, Q. (Quinten), Abbott, K.M. (Kristin), Sinke, R.J. (Richard), Rahman, R. (Rosanna), Nijman, I.J. (Isaac ), Koning, B.A.E. (Barbara) de, Thijs, G., Wieskamp, N., Moritz, R.J.G., Charbon, B., Saris, J.J. (Jasper), Dunnen, J.T. (Johan) den, Laros, J.F.J. (Jeroen F.), Bakker, P.I.W. (Paul) de, Gijn, M. (Marielle) van, Fokkema, I., Velde, K. (KJoeri) van der, Slofstra, M.K., Ruivenkamp, C.A. (Claudia), Vogel, M.J. (Maartje), Pfundt, R. (Rolph), Blok, M.J.C., Deprez, R.H.L., Waisfisz, Q. (Quinten), Abbott, K.M. (Kristin), Sinke, R.J. (Richard), Rahman, R. (Rosanna), Nijman, I.J. (Isaac ), Koning, B.A.E. (Barbara) de, Thijs, G., Wieskamp, N., Moritz, R.J.G., Charbon, B., Saris, J.J. (Jasper), Dunnen, J.T. (Johan) den, Laros, J.F.J. (Jeroen F.), Bakker, P.I.W. (Paul) de, and Gijn, M. (Marielle) van

Abstract

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next‐generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5‐tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as “consensus” w

Published
2019
Full Text
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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 L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), 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.B. (Gert-Jan) van, The Genome of the Netherlands Consortium, Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), 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.B. (Gert-Jan) van, and The Genome of the Netherlands Consortium

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
Full Text
View/download PDF

4. 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 L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), 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.B. (Gert-Jan) van, The Genome of the Netherlands Consortium, Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), 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.B. (Gert-Jan) van, and The Genome of the Netherlands Consortium

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
Full Text
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5. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Author

Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), Nijman, I.J. (Isaac), Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), and Nijman, I.J. (Isaac)

Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.

Published
2016
Full Text
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6. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Author

Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), Nijman, I.J. (Isaac), Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), and Nijman, I.J. (Isaac)

Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.

Published
2016
Full Text
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7. Next-generation sequencing-based genome diagnostics across clinical genetics centers: Implementation choices and their effects

Author

Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), Cuppen, E. (Edwin), Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), and Cuppen, E. (Edwin)

Abstract

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

Published
2015
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