Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

J. Huang, B. Howie, S. Mccarthy, Y. Memari, K. Walter, J.L. Min, P. Danecek, G. Malerba, E. Trabetti, H.-F. Zheng, G. Gambaro, J.B. Richards, R. Durbin, N.J. Timpson, J. Marchini, N. Soranzo, S. Al Turki, A. Amuzu, C.A. Anderson, R. Anney & 218 others D. Antony, M.S. Artigas, M. Ayub, S. Bala, J.C. Barrett, I. Barroso, P. Beales, M. Benn, J. Bentham, S. Bhattacharya, E. Birney, D. Blackwood, M. Bobrow, E. Bochukova, P.F. Bolton, R. Bounds, C. Boustred, G. Breen, M. Calissano, K. Carss, J.P. Casas, J.C. Chambers, R. Charlton, K. Chatterjee, L. Chen, A. Ciampi, S. Cirak, P. Clapham, G. Clement, G. Coates, M. Cocca, D.A. Collier, C. Cosgrove, T. Cox, N. Craddock, L. Crooks, S. Curran, D. Curtis, A. Daly, I.N.M. Day, A. Day-Williams, G. Dedoussis, T. Down, Y. Du, C.M. Van Duijn, I. Dunham, S. Edkins, R. Ekong, P. Ellis, D.M. Evans, I.S. Farooqi, D.R. Fitzpatrick, P. Flicek, J. Floyd, A.R. Foley, C.S. Franklin, M. Futema, L. Gallagher, P. Gasparini, T.R. Gaunt, M. Geihs, D. Geschwind, C. Greenwood, H. Griffin, D. Grozeva, X. Guo, H. Gurling, D. Hart, A.E. Hendricks, P. Holmans, L. Huang, T. Hubbard, S.E. Humphries, M.E. Hurles, P. Hysi, V. Iotchkova, A. Isaacs, D.K. Jackson, Y. Jamshidi, J. Johnson, C. Joyce, K.J. Karczewski, J. Kaye, T. Keane, J.P. Kemp, K. Kennedy, A. Kent, J. Keogh, F. Khawaja, M.E. Kleber, M. Van Kogelenberg, A. Kolb-Kokocinski, J.S. Kooner, G. Lachance, C. Langenberg, C. Langford, D. Lawson, I. Lee, E.M. Van Leeuwen, M. Lek, R. Li, Y. Li, J. Liang, H. Lin, R. Liu, J. Lönnqvist, L.R. Lopes, M. Lopes, J. Luan, D.G. Macarthur, M. Mangino, G. Marenne, W. März, J. Maslen, A. Matchan, I. Mathieson, P. Mcguffin, A.M. Mcintosh, A.G. Mckechanie, A. Mcquillin, S. Metrustry, N. Migone, H.M. Mitchison, A. Moayyeri, J. Morris, R. Morris, D. Muddyman, F. Muntoni, B.G. Nordestgaard, K. Northstone, M.C. O'Donovan, S. O'Rahilly, A. Onoufriadis, K. Oualkacha, M.J. Owen, A. Palotie, K. Panoutsopoulou, V. Parker, J.R. Parr, L. Paternoster, T. Paunio, F. Payne, S.J. Payne, J.R.B. Perry, O. Pietilainen, V. Plagnol, R.C. Pollitt, S. Povey, M.A. Quail, L. Quaye, L. Raymond, K. Rehnström, C.K. Ridout, S. Ring, G.R.S. Ritchie, N. Roberts, R.L. Robinson, D.B. Savage, P. Scambler, S. Schiffels, M. Schmidts, N. Schoenmakers, R.H. Scott, R.A. Scott, R.K. Semple, E. Serra, S.I. Sharp, A. Shaw, H.A. Shihab, S.-Y. Shin, D. Skuse, K.S. Small, C. Smee, G.D. Smith, L. Southam, O. Spasic-Boskovic, T.D. Spector, D. St. Clair, B. St. Pourcain, J. Stalker, E. Stevens, J. Sun, G. Surdulescu, J. Suvisaari, P. Syrris, I. Tachmazidou, R. Taylor, J. Tian, M.D. Tobin, D. Toniolo, M. Traglia, A. Tybjaerg-Hansen, A.M. Valdes, A.M. Vandersteen, A. Varbo, P. Vijayarangakannan, P.M. Visscher, L.V. Wain, J.T.R. Walters, G. Wang, J. Wang, Y. Wang, K. Ward, E. Wheeler, P. Whincup, T. Whyte, H.J. Williams, K.A. Williamson, C. Wilson, Scott Wilson, K. Wong, C. Xu, J. Yang, G. Zaza, E. Zeggini, F. Zhang, P. Zhang, W. Zhang

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Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.
Original languageEnglish
Pages (from-to)1-9
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

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Haplotypes
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Genotype
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Single Nucleotide Polymorphism
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Costs and Cost Analysis
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Huang, J., Howie, B., Mccarthy, S., Memari, Y., Walter, K., Min, J. L., ... Zhang, W. (2015). Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. Nature Communications, 6, 1-9. https://doi.org/10.1038/ncomms9111
Huang, J. ; Howie, B. ; Mccarthy, S. ; Memari, Y. ; Walter, K. ; Min, J.L. ; Danecek, P. ; Malerba, G. ; Trabetti, E. ; Zheng, H.-F. ; Gambaro, G. ; Richards, J.B. ; Durbin, R. ; Timpson, N.J. ; Marchini, J. ; Soranzo, N. ; Al Turki, S. ; Amuzu, A. ; Anderson, C.A. ; Anney, R. ; Antony, D. ; Artigas, M.S. ; Ayub, M. ; Bala, S. ; Barrett, J.C. ; Barroso, I. ; Beales, P. ; Benn, M. ; Bentham, J. ; Bhattacharya, S. ; Birney, E. ; Blackwood, D. ; Bobrow, M. ; Bochukova, E. ; Bolton, P.F. ; Bounds, R. ; Boustred, C. ; Breen, G. ; Calissano, M. ; Carss, K. ; Casas, J.P. ; Chambers, J.C. ; Charlton, R. ; Chatterjee, K. ; Chen, L. ; Ciampi, A. ; Cirak, S. ; Clapham, P. ; Clement, G. ; Coates, G. ; Cocca, M. ; Collier, D.A. ; Cosgrove, C. ; Cox, T. ; Craddock, N. ; Crooks, L. ; Curran, S. ; Curtis, D. ; Daly, A. ; Day, I.N.M. ; Day-Williams, A. ; Dedoussis, G. ; Down, T. ; Du, Y. ; Van Duijn, C.M. ; Dunham, I. ; Edkins, S. ; Ekong, R. ; Ellis, P. ; Evans, D.M. ; Farooqi, I.S. ; Fitzpatrick, D.R. ; Flicek, P. ; Floyd, J. ; Foley, A.R. ; Franklin, C.S. ; Futema, M. ; Gallagher, L. ; Gasparini, P. ; Gaunt, T.R. ; Geihs, M. ; Geschwind, D. ; Greenwood, C. ; Griffin, H. ; Grozeva, D. ; Guo, X. ; Gurling, H. ; Hart, D. ; Hendricks, A.E. ; Holmans, P. ; Huang, L. ; Hubbard, T. ; Humphries, S.E. ; Hurles, M.E. ; Hysi, P. ; Iotchkova, V. ; Isaacs, A. ; Jackson, D.K. ; Jamshidi, Y. ; Johnson, J. ; Joyce, C. ; Karczewski, K.J. ; Kaye, J. ; Keane, T. ; Kemp, J.P. ; Kennedy, K. ; Kent, A. ; Keogh, J. ; Khawaja, F. ; Kleber, M.E. ; Van Kogelenberg, M. ; Kolb-Kokocinski, A. ; Kooner, J.S. ; Lachance, G. ; Langenberg, C. ; Langford, C. ; Lawson, D. ; Lee, I. ; Van Leeuwen, E.M. ; Lek, M. ; Li, R. ; Li, Y. ; Liang, J. ; Lin, H. ; Liu, R. ; Lönnqvist, J. ; Lopes, L.R. ; Lopes, M. ; Luan, J. ; Macarthur, D.G. ; Mangino, M. ; Marenne, G. ; März, W. ; Maslen, J. ; Matchan, A. ; Mathieson, I. ; Mcguffin, P. ; Mcintosh, A.M. ; Mckechanie, A.G. ; Mcquillin, A. ; Metrustry, S. ; Migone, N. ; Mitchison, H.M. ; Moayyeri, A. ; Morris, J. ; Morris, R. ; Muddyman, D. ; Muntoni, F. ; Nordestgaard, B.G. ; Northstone, K. ; O'Donovan, M.C. ; O'Rahilly, S. ; Onoufriadis, A. ; Oualkacha, K. ; Owen, M.J. ; Palotie, A. ; Panoutsopoulou, K. ; Parker, V. ; Parr, J.R. ; Paternoster, L. ; Paunio, T. ; Payne, F. ; Payne, S.J. ; Perry, J.R.B. ; Pietilainen, O. ; Plagnol, V. ; Pollitt, R.C. ; Povey, S. ; Quail, M.A. ; Quaye, L. ; Raymond, L. ; Rehnström, K. ; Ridout, C.K. ; Ring, S. ; Ritchie, G.R.S. ; Roberts, N. ; Robinson, R.L. ; Savage, D.B. ; Scambler, P. ; Schiffels, S. ; Schmidts, M. ; Schoenmakers, N. ; Scott, R.H. ; Scott, R.A. ; Semple, R.K. ; Serra, E. ; Sharp, S.I. ; Shaw, A. ; Shihab, H.A. ; Shin, S.-Y. ; Skuse, D. ; Small, K.S. ; Smee, C. ; Smith, G.D. ; Southam, L. ; Spasic-Boskovic, O. ; Spector, T.D. ; St. Clair, D. ; St. Pourcain, B. ; Stalker, J. ; Stevens, E. ; Sun, J. ; Surdulescu, G. ; Suvisaari, J. ; Syrris, P. ; Tachmazidou, I. ; Taylor, R. ; Tian, J. ; Tobin, M.D. ; Toniolo, D. ; Traglia, M. ; Tybjaerg-Hansen, A. ; Valdes, A.M. ; Vandersteen, A.M. ; Varbo, A. ; Vijayarangakannan, P. ; Visscher, P.M. ; Wain, L.V. ; Walters, J.T.R. ; Wang, G. ; Wang, J. ; Wang, Y. ; Ward, K. ; Wheeler, E. ; Whincup, P. ; Whyte, T. ; Williams, H.J. ; Williamson, K.A. ; Wilson, C. ; Wilson, Scott ; Wong, K. ; Xu, C. ; Yang, J. ; Zaza, G. ; Zeggini, E. ; Zhang, F. ; Zhang, P. ; Zhang, W. / Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. In: Nature Communications. 2015 ; Vol. 6. pp. 1-9.
@article{ad358fe69ba542e4b695728aacaafc9e,
title = "Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel",
abstract = "{\circledC} 2015 Macmillan Publishers Limited. All rights reserved. Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1{\%} minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.",
author = "J. Huang and B. Howie and S. Mccarthy and Y. Memari and K. Walter and J.L. Min and P. Danecek and G. Malerba and E. Trabetti and H.-F. Zheng and G. Gambaro and J.B. Richards and R. Durbin and N.J. Timpson and J. Marchini and N. Soranzo and {Al Turki}, S. and A. Amuzu and C.A. Anderson and R. Anney and D. Antony and M.S. Artigas and M. Ayub and S. Bala and J.C. Barrett and I. Barroso and P. Beales and M. Benn and J. Bentham and S. Bhattacharya and E. Birney and D. Blackwood and M. Bobrow and E. Bochukova and P.F. Bolton and R. Bounds and C. Boustred and G. Breen and M. Calissano and K. Carss and J.P. Casas and J.C. Chambers and R. Charlton and K. Chatterjee and L. Chen and A. Ciampi and S. Cirak and P. Clapham and G. Clement and G. Coates and M. Cocca and D.A. Collier and C. Cosgrove and T. Cox and N. Craddock and L. Crooks and S. Curran and D. Curtis and A. Daly and I.N.M. Day and A. Day-Williams and G. Dedoussis and T. Down and Y. Du and {Van Duijn}, C.M. and I. Dunham and S. Edkins and R. Ekong and P. Ellis and D.M. Evans and I.S. Farooqi and D.R. Fitzpatrick and P. Flicek and J. Floyd and A.R. Foley and C.S. Franklin and M. Futema and L. Gallagher and P. Gasparini and T.R. Gaunt and M. Geihs and D. Geschwind and C. Greenwood and H. Griffin and D. Grozeva and X. Guo and H. Gurling and D. Hart and A.E. Hendricks and P. Holmans and L. Huang and T. Hubbard and S.E. Humphries and M.E. Hurles and P. Hysi and V. Iotchkova and A. Isaacs and D.K. Jackson and Y. Jamshidi and J. Johnson and C. Joyce and K.J. Karczewski and J. Kaye and T. Keane and J.P. Kemp and K. Kennedy and A. Kent and J. Keogh and F. Khawaja and M.E. Kleber and {Van Kogelenberg}, M. and A. Kolb-Kokocinski and J.S. Kooner and G. Lachance and C. Langenberg and C. Langford and D. Lawson and I. Lee and {Van Leeuwen}, E.M. and M. Lek and R. Li and Y. Li and J. Liang and H. Lin and R. Liu and J. L{\"o}nnqvist and L.R. Lopes and M. Lopes and J. Luan and D.G. Macarthur and M. Mangino and G. Marenne and W. M{\"a}rz and J. Maslen and A. Matchan and I. Mathieson and P. Mcguffin and A.M. Mcintosh and A.G. Mckechanie and A. Mcquillin and S. Metrustry and N. Migone and H.M. Mitchison and A. Moayyeri and J. Morris and R. Morris and D. Muddyman and F. Muntoni and B.G. Nordestgaard and K. Northstone and M.C. O'Donovan and S. O'Rahilly and A. Onoufriadis and K. Oualkacha and M.J. Owen and A. Palotie and K. Panoutsopoulou and V. Parker and J.R. Parr and L. Paternoster and T. Paunio and F. Payne and S.J. Payne and J.R.B. Perry and O. Pietilainen and V. Plagnol and R.C. Pollitt and S. Povey and M.A. Quail and L. Quaye and L. Raymond and K. Rehnstr{\"o}m and C.K. Ridout and S. Ring and G.R.S. Ritchie and N. Roberts and R.L. Robinson and D.B. Savage and P. Scambler and S. Schiffels and M. Schmidts and N. Schoenmakers and R.H. Scott and R.A. Scott and R.K. Semple and E. Serra and S.I. Sharp and A. Shaw and H.A. Shihab and S.-Y. Shin and D. Skuse and K.S. Small and C. Smee and G.D. Smith and L. Southam and O. Spasic-Boskovic and T.D. Spector and {St. Clair}, D. and {St. Pourcain}, B. and J. Stalker and E. Stevens and J. Sun and G. Surdulescu and J. Suvisaari and P. Syrris and I. Tachmazidou and R. Taylor and J. Tian and M.D. Tobin and D. Toniolo and M. Traglia and A. Tybjaerg-Hansen and A.M. Valdes and A.M. Vandersteen and A. Varbo and P. Vijayarangakannan and P.M. Visscher and L.V. Wain and J.T.R. Walters and G. Wang and J. Wang and Y. Wang and K. Ward and E. Wheeler and P. Whincup and T. Whyte and H.J. Williams and K.A. Williamson and C. Wilson and Scott Wilson and K. Wong and C. Xu and J. Yang and G. Zaza and E. Zeggini and F. Zhang and P. Zhang and W. Zhang",
year = "2015",
doi = "10.1038/ncomms9111",
language = "English",
volume = "6",
pages = "1--9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group - Macmillan Publishers",

}

Huang, J, Howie, B, Mccarthy, S, Memari, Y, Walter, K, Min, JL, Danecek, P, Malerba, G, Trabetti, E, Zheng, H-F, Gambaro, G, Richards, JB, Durbin, R, Timpson, NJ, Marchini, J, Soranzo, N, Al Turki, S, Amuzu, A, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Benn, M, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Casas, JP, Chambers, JC, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Day, INM, Day-Williams, A, Dedoussis, G, Down, T, Du, Y, Van Duijn, CM, Dunham, I, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gasparini, P, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, C, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Huang, L, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Iotchkova, V, Isaacs, A, Jackson, DK, Jamshidi, Y, Johnson, J, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, Kleber, ME, Van Kogelenberg, M, Kolb-Kokocinski, A, Kooner, JS, Lachance, G, Langenberg, C, Langford, C, Lawson, D, Lee, I, Van Leeuwen, EM, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lönnqvist, J, Lopes, LR, Lopes, M, Luan, J, Macarthur, DG, Mangino, M, Marenne, G, März, W, Maslen, J, Matchan, A, Mathieson, I, Mcguffin, P, Mcintosh, AM, Mckechanie, AG, Mcquillin, A, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, J, Morris, R, Muddyman, D, Muntoni, F, Nordestgaard, BG, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Povey, S, Quail, MA, Quaye, L, Raymond, L, Rehnström, K, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Scott, RA, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, S-Y, Skuse, D, Small, KS, Smee, C, Smith, GD, Southam, L, Spasic-Boskovic, O, Spector, TD, St. Clair, D, St. Pourcain, B, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Tachmazidou, I, Taylor, R, Tian, J, Tobin, MD, Toniolo, D, Traglia, M, Tybjaerg-Hansen, A, Valdes, AM, Vandersteen, AM, Varbo, A, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whincup, P, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, S, Wong, K, Xu, C, Yang, J, Zaza, G, Zeggini, E, Zhang, F, Zhang, P & Zhang, W 2015, 'Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel' Nature Communications, vol. 6, pp. 1-9. https://doi.org/10.1038/ncomms9111

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. / Huang, J.; Howie, B.; Mccarthy, S.; Memari, Y.; Walter, K.; Min, J.L.; Danecek, P.; Malerba, G.; Trabetti, E.; Zheng, H.-F.; Gambaro, G.; Richards, J.B.; Durbin, R.; Timpson, N.J.; Marchini, J.; Soranzo, N.; Al Turki, S.; Amuzu, A.; Anderson, C.A.; Anney, R.; Antony, D.; Artigas, M.S.; Ayub, M.; Bala, S.; Barrett, J.C.; Barroso, I.; Beales, P.; Benn, M.; Bentham, J.; Bhattacharya, S.; Birney, E.; Blackwood, D.; Bobrow, M.; Bochukova, E.; Bolton, P.F.; Bounds, R.; Boustred, C.; Breen, G.; Calissano, M.; Carss, K.; Casas, J.P.; Chambers, J.C.; Charlton, R.; Chatterjee, K.; Chen, L.; Ciampi, A.; Cirak, S.; Clapham, P.; Clement, G.; Coates, G.; Cocca, M.; Collier, D.A.; Cosgrove, C.; Cox, T.; Craddock, N.; Crooks, L.; Curran, S.; Curtis, D.; Daly, A.; Day, I.N.M.; Day-Williams, A.; Dedoussis, G.; Down, T.; Du, Y.; Van Duijn, C.M.; Dunham, I.; Edkins, S.; Ekong, R.; Ellis, P.; Evans, D.M.; Farooqi, I.S.; Fitzpatrick, D.R.; Flicek, P.; Floyd, J.; Foley, A.R.; Franklin, C.S.; Futema, M.; Gallagher, L.; Gasparini, P.; Gaunt, T.R.; Geihs, M.; Geschwind, D.; Greenwood, C.; Griffin, H.; Grozeva, D.; Guo, X.; Gurling, H.; Hart, D.; Hendricks, A.E.; Holmans, P.; Huang, L.; Hubbard, T.; Humphries, S.E.; Hurles, M.E.; Hysi, P.; Iotchkova, V.; Isaacs, A.; Jackson, D.K.; Jamshidi, Y.; Johnson, J.; Joyce, C.; Karczewski, K.J.; Kaye, J.; Keane, T.; Kemp, J.P.; Kennedy, K.; Kent, A.; Keogh, J.; Khawaja, F.; Kleber, M.E.; Van Kogelenberg, M.; Kolb-Kokocinski, A.; Kooner, J.S.; Lachance, G.; Langenberg, C.; Langford, C.; Lawson, D.; Lee, I.; Van Leeuwen, E.M.; Lek, M.; Li, R.; Li, Y.; Liang, J.; Lin, H.; Liu, R.; Lönnqvist, J.; Lopes, L.R.; Lopes, M.; Luan, J.; Macarthur, D.G.; Mangino, M.; Marenne, G.; März, W.; Maslen, J.; Matchan, A.; Mathieson, I.; Mcguffin, P.; Mcintosh, A.M.; Mckechanie, A.G.; Mcquillin, A.; Metrustry, S.; Migone, N.; Mitchison, H.M.; Moayyeri, A.; Morris, J.; Morris, R.; Muddyman, D.; Muntoni, F.; Nordestgaard, B.G.; Northstone, K.; O'Donovan, M.C.; O'Rahilly, S.; Onoufriadis, A.; Oualkacha, K.; Owen, M.J.; Palotie, A.; Panoutsopoulou, K.; Parker, V.; Parr, J.R.; Paternoster, L.; Paunio, T.; Payne, F.; Payne, S.J.; Perry, J.R.B.; Pietilainen, O.; Plagnol, V.; Pollitt, R.C.; Povey, S.; Quail, M.A.; Quaye, L.; Raymond, L.; Rehnström, K.; Ridout, C.K.; Ring, S.; Ritchie, G.R.S.; Roberts, N.; Robinson, R.L.; Savage, D.B.; Scambler, P.; Schiffels, S.; Schmidts, M.; Schoenmakers, N.; Scott, R.H.; Scott, R.A.; Semple, R.K.; Serra, E.; Sharp, S.I.; Shaw, A.; Shihab, H.A.; Shin, S.-Y.; Skuse, D.; Small, K.S.; Smee, C.; Smith, G.D.; Southam, L.; Spasic-Boskovic, O.; Spector, T.D.; St. Clair, D.; St. Pourcain, B.; Stalker, J.; Stevens, E.; Sun, J.; Surdulescu, G.; Suvisaari, J.; Syrris, P.; Tachmazidou, I.; Taylor, R.; Tian, J.; Tobin, M.D.; Toniolo, D.; Traglia, M.; Tybjaerg-Hansen, A.; Valdes, A.M.; Vandersteen, A.M.; Varbo, A.; Vijayarangakannan, P.; Visscher, P.M.; Wain, L.V.; Walters, J.T.R.; Wang, G.; Wang, J.; Wang, Y.; Ward, K.; Wheeler, E.; Whincup, P.; Whyte, T.; Williams, H.J.; Williamson, K.A.; Wilson, C.; Wilson, Scott; Wong, K.; Xu, C.; Yang, J.; Zaza, G.; Zeggini, E.; Zhang, F.; Zhang, P.; Zhang, W.

In: Nature Communications, Vol. 6, 2015, p. 1-9.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

AU - Huang, J.

AU - Howie, B.

AU - Mccarthy, S.

AU - Memari, Y.

AU - Walter, K.

AU - Min, J.L.

AU - Danecek, P.

AU - Malerba, G.

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PY - 2015

Y1 - 2015

N2 - © 2015 Macmillan Publishers Limited. All rights reserved. Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.

AB - © 2015 Macmillan Publishers Limited. All rights reserved. Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.

U2 - 10.1038/ncomms9111

DO - 10.1038/ncomms9111

M3 - Article

VL - 6

SP - 1

EP - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

ER -