A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

N.J. Timpson; K.K.H. Walter; J.L. Min; I. Tachmazidou; G. Malerba; S. Shin; L. Chen; M. Futema; L. Southam; V. Iotchkova; M. Cocca; J. Huang; Y. Memari; S. Mccarthy; P. Danecek; D. Muddyman; M. Mangino; C. Menni; J.R.B. Perry; S.M. Ring; A. Gaye; G.V. Dedoussis; A.E. Farmaki; P. Burton; P.J. Talmud; G. Gambaro; T.D. Spector; G.D. Smith; R.M. Durbin; J.B. Richards; S.E. Humphries; E. Zeggini; N. Soranzo; S.A. Turki; C.A. Anderson; R.J.L. Anney; D. Antony; M.S. Artigas; M.K. Ayub; S. Balasubramaniam; J.C.J. Barrett; I. Barroso; P.L. Beales; J.R. Bentham; S. Bhattacharya; E. Birney; D.H.R. Blackwood; M.N. Bobrow; E.G. Bochukova; P.A. Bolton; R. Bounds; C.R. Boustred; G. Breen; M. Calissano; K.J. Carss; K. Chatterjee; A. Ciampi; S. Cirak; P. Clapham; G. Clement; G. Coates; D. Collier; C.L. Cosgrove; T.V. Cox; N.J. Craddock; L. Crooks; S.R. Curran; D.F. Curtis; A. Daly; A.G. Day-Williams; I.N.M. Day; T.A. Down; Y. Du; I. Dunham; S.J. Edkins; P.D. Ellis; D.M.D. Evans; S. Faroogi; G. Fatemifar; D.R. Fitzpatrick; P. Flicek; J. Flyod; A.R. Foley; C.S. Franklin; L. Gallagher; T.R. Gaunt; M. Geihs; D.H. Geschwind; C. Greenwood; H. Griffin; D. Grozeva; X. Guo; H.M.D. Gurling; D.J. Hart; A.E. Hendricks; P.A. Holmans; B.N. Howie; L. Huang; T.J.P. Hubbard; M.E. Hurles; P.G. Hysi; D.K. Jackson; Y. Jamshidi; T. Jing; C. Joyce; J. Kaye; T.M. Keane; J.M. Keogh; J.P. Kemp; K.L. Kennedy; A. Kolb-Kokocinski; G. Lachance; C.F. Langford; D.J. Lawson; I. Lee; M. Lek; J. Liang; H. Lin; R. Li; Y. Li; R. Liu; J.K. Lönnqvist; M.C. Lopes; V. Lotchkova; D.G. Macarthur; J. Marchini; J. Maslen; M. Massimo; I. Mathieson; G. Marenne; P.W. Mcguffin; A.M. Mcintosh; A.G. Mckechanie; A. Mcquillin; S.J. Metrustry; H.M. Mitchison; A. Moayyeri; J.A. Morris; F.M. Muntoni; K. Northstone; M. O'Donnovan; A. Onoufriadis; S.P. O'Rahilly; K. Oualkacha; M.J. Owen; A. Palotie; K. Panoutsopoulou; V. Parker; J.R. Parr; L. Paternoster; T. Paunio; F. Payne; O.P.H. Pietiläinen; V. Plagnol; L. Quaye; M.A. Quail; L.F. Raymond; K. Rehnström; B. Richards; G.R.S. Ritchie; N.Y. Roberts; D.B. Savage; P.J. Scambler; S. Schiffels; M. Schmidts; N.A. Schoenmakers; R.K. Semple; E. Serra; S.I. Sharp; H. Shihab; D.H. Skuse; K.S. Small; O. Spasić-Bǒsković; D.S. Clair; J.W. Stalker; E. Stevens; B.S. Pourcian; J. Sun; G.L. Surdulescu; J.M. Suvisaari; M.D. Tobin; A.A. Valdes; M. Van Kogelenberg; P. Vijayarangakannan; P.M. Visscher; L.V. Wain; J.T.R. Walters; G. Wang; J. Wang; Y. Wang; K.J. Ward; E. Wheeler; T. Whyte; H. Williams; K.A. Williamson; C. Wilson; Scott Wilson; K. Wong; C. Xu; J. Yang; F. Zhang; P. Zhang; H. Zheng

doi:10.1038/ncomms5871

A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

N.J. Timpson, K.K.H. Walter, J.L. Min, I. Tachmazidou, G. Malerba, S. Shin, L. Chen, M. Futema, L. Southam, V. Iotchkova, M. Cocca, J. Huang, Y. Memari, S. Mccarthy, P. Danecek, D. Muddyman, M. Mangino, C. Menni, J.R.B. Perry, S.M. RingA. Gaye, G.V. Dedoussis, A.E. Farmaki, P. Burton, P.J. Talmud, G. Gambaro, T.D. Spector, G.D. Smith, R.M. Durbin, J.B. Richards, S.E. Humphries, E. Zeggini, N. Soranzo, S.A. Turki, C.A. Anderson, R.J.L. Anney, D. Antony, M.S. Artigas, M.K. Ayub, S. Balasubramaniam, J.C.J. Barrett, I. Barroso, P.L. Beales, J.R. Bentham, S. Bhattacharya, E. Birney, D.H.R. Blackwood, M.N. Bobrow, E.G. Bochukova, P.A. Bolton, R. Bounds, C.R. Boustred, G. Breen, M. Calissano, K.J. Carss, K. Chatterjee, A. Ciampi, S. Cirak, P. Clapham, G. Clement, G. Coates, D. Collier, C.L. Cosgrove, T.V. Cox, N.J. Craddock, L. Crooks, S.R. Curran, D.F. Curtis, A. Daly, A.G. Day-Williams, I.N.M. Day, T.A. Down, Y. Du, I. Dunham, S.J. Edkins, P.D. Ellis, D.M.D. Evans, S. Faroogi, G. Fatemifar, D.R. Fitzpatrick, P. Flicek, J. Flyod, A.R. Foley, C.S. Franklin, L. Gallagher, T.R. Gaunt, M. Geihs, D.H. Geschwind, C. Greenwood, H. Griffin, D. Grozeva, X. Guo, H.M.D. Gurling, D.J. Hart, A.E. Hendricks, P.A. Holmans, B.N. Howie, L. Huang, T.J.P. Hubbard, M.E. Hurles, P.G. Hysi, D.K. Jackson, Y. Jamshidi, T. Jing, C. Joyce, J. Kaye, T.M. Keane, J.M. Keogh, J.P. Kemp, K.L. Kennedy, A. Kolb-Kokocinski, G. Lachance, C.F. Langford, D.J. Lawson, I. Lee, M. Lek, J. Liang, H. Lin, R. Li, Y. Li, R. Liu, J.K. Lönnqvist, M.C. Lopes, V. Lotchkova, D.G. Macarthur, J. Marchini, J. Maslen, M. Massimo, I. Mathieson, G. Marenne, P.W. Mcguffin, A.M. Mcintosh, A.G. Mckechanie, A. Mcquillin, S.J. Metrustry, H.M. Mitchison, A. Moayyeri, J.A. Morris, F.M. Muntoni, K. Northstone, M. O'Donnovan, A. Onoufriadis, S.P. O'Rahilly, K. Oualkacha, M.J. Owen, A. Palotie, K. Panoutsopoulou, V. Parker, J.R. Parr, L. Paternoster, T. Paunio, F. Payne, O.P.H. Pietiläinen, V. Plagnol, L. Quaye, M.A. Quail, L.F. Raymond, K. Rehnström, B. Richards, G.R.S. Ritchie, N.Y. Roberts, D.B. Savage, P.J. Scambler, S. Schiffels, M. Schmidts, N.A. Schoenmakers, R.K. Semple, E. Serra, S.I. Sharp, H. Shihab, D.H. Skuse, K.S. Small, O. Spasić-Bǒsković, D.S. Clair, J.W. Stalker, E. Stevens, B.S. Pourcian, J. Sun, G.L. Surdulescu, J.M. Suvisaari, M.D. Tobin, A.A. Valdes, M. Van Kogelenberg, P. Vijayarangakannan, P.M. Visscher, L.V. Wain, J.T.R. Walters, G. Wang, J. Wang, Y. Wang, K.J. Ward, E. Wheeler, T. Whyte, H. Williams, K.A. Williamson, C. Wilson, Scott Wilson, K. Wong, C. Xu, J. Yang, F. Zhang, P. Zhang, H. Zheng

Research output: Contribution to journal › Article › peer-review

59 Citations (Scopus)

Abstract

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ∼0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10 -8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10 -9). This is consistent with an effect between 0.5 and 1.5 mmol l -1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.

Original language	English
Pages (from-to)	10pp
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5871
Publication status	Published - 2014

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10.1038/ncomms5871

Cite this

Timpson, N. J., Walter, K. K. H., Min, J. L., Tachmazidou, I., Malerba, G., Shin, S., Chen, L., Futema, M., Southam, L., Iotchkova, V., Cocca, M., Huang, J., Memari, Y., Mccarthy, S., Danecek, P., Muddyman, D., Mangino, M., Menni, C., Perry, J. R. B., ... Zheng, H. (2014). A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans. Nature Communications, 5, 10pp. https://doi.org/10.1038/ncomms5871

@article{07b5544177d34f77808bbb4923a37700,

title = "A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans",

abstract = "The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ∼0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10 -8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10 -9). This is consistent with an effect between 0.5 and 1.5 mmol l -1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.",

author = "N.J. Timpson and K.K.H. Walter and J.L. Min and I. Tachmazidou and G. Malerba and S. Shin and L. Chen and M. Futema and L. Southam and V. Iotchkova and M. Cocca and J. Huang and Y. Memari and S. Mccarthy and P. Danecek and D. Muddyman and M. Mangino and C. Menni and J.R.B. Perry and S.M. Ring and A. Gaye and G.V. Dedoussis and A.E. Farmaki and P. Burton and P.J. Talmud and G. Gambaro and T.D. Spector and G.D. Smith and R.M. Durbin and J.B. Richards and S.E. Humphries and E. Zeggini and N. Soranzo and S.A. Turki and C.A. Anderson and R.J.L. Anney and D. Antony and M.S. Artigas and M.K. Ayub and S. Balasubramaniam and J.C.J. Barrett and I. Barroso and P.L. Beales and J.R. Bentham and S. Bhattacharya and E. Birney and D.H.R. Blackwood and M.N. Bobrow and E.G. Bochukova and P.A. Bolton and R. Bounds and C.R. Boustred and G. Breen and M. Calissano and K.J. Carss and K. Chatterjee and A. Ciampi and S. Cirak and P. Clapham and G. Clement and G. Coates and D. Collier and C.L. Cosgrove and T.V. Cox and N.J. Craddock and L. Crooks and S.R. Curran and D.F. Curtis and A. Daly and A.G. Day-Williams and I.N.M. Day and T.A. Down and Y. Du and I. Dunham and S.J. Edkins and P.D. Ellis and D.M.D. Evans and S. Faroogi and G. Fatemifar and D.R. Fitzpatrick and P. Flicek and J. Flyod and A.R. Foley and C.S. Franklin and L. Gallagher and T.R. Gaunt and M. Geihs and D.H. Geschwind and C. Greenwood and H. Griffin and D. Grozeva and X. Guo and H.M.D. Gurling and D.J. Hart and A.E. Hendricks and P.A. Holmans and B.N. Howie and L. Huang and T.J.P. Hubbard and M.E. Hurles and P.G. Hysi and D.K. Jackson and Y. Jamshidi and T. Jing and C. Joyce and J. Kaye and T.M. Keane and J.M. Keogh and J.P. Kemp and K.L. Kennedy and A. Kolb-Kokocinski and G. Lachance and C.F. Langford and D.J. Lawson and I. Lee and M. Lek and J. Liang and H. Lin and R. Li and Y. Li and R. Liu and J.K. L{\"o}nnqvist and M.C. Lopes and V. Lotchkova and D.G. Macarthur and J. Marchini and J. Maslen and M. Massimo and I. Mathieson and G. Marenne and P.W. Mcguffin and A.M. Mcintosh and A.G. Mckechanie and A. Mcquillin and S.J. Metrustry and H.M. Mitchison and A. Moayyeri and J.A. Morris and F.M. Muntoni and K. Northstone and M. O'Donnovan and A. Onoufriadis and S.P. O'Rahilly 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 O.P.H. Pietil{\"a}inen and V. Plagnol and L. Quaye and M.A. Quail and L.F. Raymond and K. Rehnstr{\"o}m and B. Richards and G.R.S. Ritchie and N.Y. Roberts and D.B. Savage and P.J. Scambler and S. Schiffels and M. Schmidts and N.A. Schoenmakers and R.K. Semple and E. Serra and S.I. Sharp and H. Shihab and D.H. Skuse and K.S. Small and O. Spasi{\'c}-Bǒskovi{\'c} and D.S. Clair and J.W. Stalker and E. Stevens and B.S. Pourcian and J. Sun and G.L. Surdulescu and J.M. Suvisaari and M.D. Tobin and A.A. Valdes and {Van Kogelenberg}, M. 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.J. Ward and E. Wheeler and T. Whyte and H. Williams and K.A. Williamson and C. Wilson and Scott Wilson and K. Wong and C. Xu and J. Yang and F. Zhang and P. Zhang and H. Zheng",

year = "2014",

doi = "10.1038/ncomms5871",

language = "English",

volume = "5",

pages = "10pp",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group - Macmillan Publishers",

}

Timpson, NJ, Walter, KKH, Min, JL, Tachmazidou, I, Malerba, G, Shin, S, Chen, L, Futema, M, Southam, L, Iotchkova, V, Cocca, M, Huang, J, Memari, Y, Mccarthy, S, Danecek, P, Muddyman, D, Mangino, M, Menni, C, Perry, JRB, Ring, SM, Gaye, A, Dedoussis, GV, Farmaki, AE, Burton, P, Talmud, PJ, Gambaro, G, Spector, TD, Smith, GD, Durbin, RM, Richards, JB, Humphries, SE, Zeggini, E, Soranzo, N, Turki, SA, Anderson, CA, Anney, RJL, Antony, D, Artigas, MS, Ayub, MK, Balasubramaniam, S, Barrett, JCJ, Barroso, I, Beales, PL, Bentham, JR, Bhattacharya, S, Birney, E, Blackwood, DHR, Bobrow, MN, Bochukova, EG, Bolton, PA, Bounds, R, Boustred, CR, Breen, G, Calissano, M, Carss, KJ, Chatterjee, K, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Collier, D, Cosgrove, CL, Cox, TV, Craddock, NJ, Crooks, L, Curran, SR, Curtis, DF, Daly, A, Day-Williams, AG, Day, INM, Down, TA, Du, Y, Dunham, I, Edkins, SJ, Ellis, PD, Evans, DMD, Faroogi, S, Fatemifar, G, Fitzpatrick, DR, Flicek, P, Flyod, J, Foley, AR, Franklin, CS, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, DH, Greenwood, C, Griffin, H, Grozeva, D, Guo, X, Gurling, HMD, Hart, DJ, Hendricks, AE, Holmans, PA, Howie, BN, Huang, L, Hubbard, TJP, Hurles, ME, Hysi, PG, Jackson, DK, Jamshidi, Y, Jing, T, Joyce, C, Kaye, J, Keane, TM, Keogh, JM, Kemp, JP, Kennedy, KL, Kolb-Kokocinski, A, Lachance, G, Langford, CF, Lawson, DJ, Lee, I, Lek, M, Liang, J, Lin, H, Li, R, Li, Y, Liu, R, Lönnqvist, JK, Lopes, MC, Lotchkova, V, Macarthur, DG, Marchini, J, Maslen, J, Massimo, M, Mathieson, I, Marenne, G, Mcguffin, PW, Mcintosh, AM, Mckechanie, AG, Mcquillin, A, Metrustry, SJ, Mitchison, HM, Moayyeri, A, Morris, JA, Muntoni, FM, Northstone, K, O'Donnovan, M, Onoufriadis, A, O'Rahilly, SP, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Pietiläinen, OPH, Plagnol, V, Quaye, L, Quail, MA, Raymond, LF, Rehnström, K, Richards, B, Ritchie, GRS, Roberts, NY, Savage, DB, Scambler, PJ, Schiffels, S, Schmidts, M, Schoenmakers, NA, Semple, RK, Serra, E, Sharp, SI, Shihab, H, Skuse, DH, Small, KS, Spasić-Bǒsković, O, Clair, DS, Stalker, JW, Stevens, E, Pourcian, BS, Sun, J, Surdulescu, GL, Suvisaari, JM, Tobin, MD, Valdes, AA, Van Kogelenberg, M, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, KJ, Wheeler, E, Whyte, T, Williams, H, Williamson, KA, Wilson, C, Wilson, S, Wong, K, Xu, C, Yang, J, Zhang, F, Zhang, P & Zheng, H 2014, 'A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans', Nature Communications, vol. 5, pp. 10pp. https://doi.org/10.1038/ncomms5871

TY - JOUR

T1 - A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

AU - Timpson, N.J.

AU - Walter, K.K.H.

AU - Min, J.L.

AU - Tachmazidou, I.

AU - Malerba, G.

AU - Shin, S.

AU - Chen, L.

AU - Futema, M.

AU - Southam, L.

AU - Iotchkova, V.

AU - Cocca, M.

AU - Huang, J.

AU - Memari, Y.

AU - Mccarthy, S.

AU - Danecek, P.

AU - Muddyman, D.

AU - Mangino, M.

AU - Menni, C.

AU - Perry, J.R.B.

AU - Ring, S.M.

AU - Gaye, A.

AU - Dedoussis, G.V.

AU - Farmaki, A.E.

AU - Burton, P.

AU - Talmud, P.J.

AU - Gambaro, G.

AU - Spector, T.D.

AU - Smith, G.D.

AU - Durbin, R.M.

AU - Richards, J.B.

AU - Humphries, S.E.

AU - Zeggini, E.

AU - Soranzo, N.

AU - Turki, S.A.

AU - Anderson, C.A.

AU - Anney, R.J.L.

AU - Antony, D.

AU - Artigas, M.S.

AU - Ayub, M.K.

AU - Balasubramaniam, S.

AU - Barrett, J.C.J.

AU - Barroso, I.

AU - Beales, P.L.

AU - Bentham, J.R.

AU - Bhattacharya, S.

AU - Birney, E.

AU - Blackwood, D.H.R.

AU - Bobrow, M.N.

AU - Bochukova, E.G.

AU - Bolton, P.A.

AU - Bounds, R.

AU - Boustred, C.R.

AU - Breen, G.

AU - Calissano, M.

AU - Carss, K.J.

AU - Chatterjee, K.

AU - Ciampi, A.

AU - Cirak, S.

AU - Clapham, P.

AU - Clement, G.

AU - Coates, G.

AU - Collier, D.

AU - Cosgrove, C.L.

AU - Cox, T.V.

AU - Craddock, N.J.

AU - Crooks, L.

AU - Curran, S.R.

AU - Curtis, D.F.

AU - Daly, A.

AU - Day-Williams, A.G.

AU - Day, I.N.M.

AU - Down, T.A.

AU - Du, Y.

AU - Dunham, I.

AU - Edkins, S.J.

AU - Ellis, P.D.

AU - Evans, D.M.D.

AU - Faroogi, S.

AU - Fatemifar, G.

AU - Fitzpatrick, D.R.

AU - Flicek, P.

AU - Flyod, J.

AU - Foley, A.R.

AU - Franklin, C.S.

AU - Gallagher, L.

AU - Gaunt, T.R.

AU - Geihs, M.

AU - Geschwind, D.H.

AU - Greenwood, C.

AU - Griffin, H.

AU - Grozeva, D.

AU - Guo, X.

AU - Gurling, H.M.D.

AU - Hart, D.J.

AU - Hendricks, A.E.

AU - Holmans, P.A.

AU - Howie, B.N.

AU - Huang, L.

AU - Hubbard, T.J.P.

AU - Hurles, M.E.

AU - Hysi, P.G.

AU - Jackson, D.K.

AU - Jamshidi, Y.

AU - Jing, T.

AU - Joyce, C.

AU - Kaye, J.

AU - Keane, T.M.

AU - Keogh, J.M.

AU - Kemp, J.P.

AU - Kennedy, K.L.

AU - Kolb-Kokocinski, A.

AU - Lachance, G.

AU - Langford, C.F.

AU - Lawson, D.J.

AU - Lee, I.

AU - Lek, M.

AU - Liang, J.

AU - Lin, H.

AU - Li, R.

AU - Li, Y.

AU - Liu, R.

AU - Lönnqvist, J.K.

AU - Lopes, M.C.

AU - Lotchkova, V.

AU - Macarthur, D.G.

AU - Marchini, J.

AU - Maslen, J.

AU - Massimo, M.

AU - Mathieson, I.

AU - Marenne, G.

AU - Mcguffin, P.W.

AU - Mcintosh, A.M.

AU - Mckechanie, A.G.

AU - Mcquillin, A.

AU - Metrustry, S.J.

AU - Mitchison, H.M.

AU - Moayyeri, A.

AU - Morris, J.A.

AU - Muntoni, F.M.

AU - Northstone, K.

AU - O'Donnovan, M.

AU - Onoufriadis, A.

AU - O'Rahilly, S.P.

AU - Oualkacha, K.

AU - Owen, M.J.

AU - Palotie, A.

AU - Panoutsopoulou, K.

AU - Parker, V.

AU - Parr, J.R.

AU - Paternoster, L.

AU - Paunio, T.

AU - Payne, F.

AU - Pietiläinen, O.P.H.

AU - Plagnol, V.

AU - Quaye, L.

AU - Quail, M.A.

AU - Raymond, L.F.

AU - Rehnström, K.

AU - Richards, B.

AU - Ritchie, G.R.S.

AU - Roberts, N.Y.

AU - Savage, D.B.

AU - Scambler, P.J.

AU - Schiffels, S.

AU - Schmidts, M.

AU - Schoenmakers, N.A.

AU - Semple, R.K.

AU - Serra, E.

AU - Sharp, S.I.

AU - Shihab, H.

AU - Skuse, D.H.

AU - Small, K.S.

AU - Spasić-Bǒsković, O.

AU - Clair, D.S.

AU - Stalker, J.W.

AU - Stevens, E.

AU - Pourcian, B.S.

AU - Sun, J.

AU - Surdulescu, G.L.

AU - Suvisaari, J.M.

AU - Tobin, M.D.

AU - Valdes, A.A.

AU - Van Kogelenberg, M.

AU - Vijayarangakannan, P.

AU - Visscher, P.M.

AU - Wain, L.V.

AU - Walters, J.T.R.

AU - Wang, G.

AU - Wang, J.

AU - Wang, Y.

AU - Ward, K.J.

AU - Wheeler, E.

AU - Whyte, T.

AU - Williams, H.

AU - Williamson, K.A.

AU - Wilson, C.

AU - Wilson, Scott

AU - Wong, K.

AU - Xu, C.

AU - Yang, J.

AU - Zhang, F.

AU - Zhang, P.

AU - Zheng, H.

PY - 2014

Y1 - 2014

N2 - The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ∼0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10 -8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10 -9). This is consistent with an effect between 0.5 and 1.5 mmol l -1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.

AB - The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ∼0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10 -8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10 -9). This is consistent with an effect between 0.5 and 1.5 mmol l -1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.

U2 - 10.1038/ncomms5871

DO - 10.1038/ncomms5871

M3 - Article

SN - 2041-1723

VL - 5

SP - 10pp

JO - Nature Communications

JF - Nature Communications

ER -

A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

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