Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia

Christopher T. Johansen; Jian Wang; Matthew B. Lanktree; Henian Cao; Adam D. McIntyre; Matthew R. Ban; Rebecca A. Martins; Brooke A. Kennedy; Reina G. Hassell; Maartje E. Visser; Stephen M. Schwartz; Benjamin F. Voight; Roberto Elosua; Veikko Salomaa; Christopher J. O'Donnell; Geesje M. Dallinga-Thie; Sonia S. Anand; Salim Yusuf; Murray W. Huff; Sekar Kathiresan; Robert A. Hegele

doi:https://doi.org/10.1038/ng.628

Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia

Christopher T. Johansen, Jian Wang, Matthew B. Lanktree, Henian Cao, Adam D. McIntyre, Matthew R. Ban, Rebecca A. Martins, Brooke A. Kennedy, Reina G. Hassell, Maartje E. Visser, Stephen M. Schwartz, Benjamin F. Voight, Roberto Elosua, Veikko Salomaa, Christopher J. O'Donnell, Geesje M. Dallinga-Thie, Sonia S. Anand, Salim Yusuf, Murray W. Huff, Sekar KathiresanRobert A. Hegele

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

379 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG

Original language	English
Pages (from-to)	684-687
Journal	Nature Genetics
Volume	42
Issue number	8
DOIs	https://doi.org/10.1038/ng.628
Publication status	Published - 2010

Access to Document

https://doi.org/10.1038/ng.628

Cite this

Johansen, C. T., Wang, J., Lanktree, M. B., Cao, H., McIntyre, A. D., Ban, M. R., Martins, R. A., Kennedy, B. A., Hassell, R. G., Visser, M. E., Schwartz, S. M., Voight, B. F., Elosua, R., Salomaa, V., O'Donnell, C. J., Dallinga-Thie, G. M., Anand, S. S., Yusuf, S., Huff, M. W., ... Hegele, R. A. (2010). Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nature Genetics, 42(8), 684-687. https://doi.org/10.1038/ng.628

@article{d5d85a4115c14e1db85fe5c81ef87b6d,

title = "Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia",

abstract = "Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG",

author = "Johansen, {Christopher T.} and Jian Wang and Lanktree, {Matthew B.} and Henian Cao and McIntyre, {Adam D.} and Ban, {Matthew R.} and Martins, {Rebecca A.} and Kennedy, {Brooke A.} and Hassell, {Reina G.} and Visser, {Maartje E.} and Schwartz, {Stephen M.} and Voight, {Benjamin F.} and Roberto Elosua and Veikko Salomaa and O'Donnell, {Christopher J.} and Dallinga-Thie, {Geesje M.} and Anand, {Sonia S.} and Salim Yusuf and Huff, {Murray W.} and Sekar Kathiresan and Hegele, {Robert A.}",

year = "2010",

doi = "https://doi.org/10.1038/ng.628",

language = "English",

volume = "42",

pages = "684--687",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

Johansen, CT, Wang, J, Lanktree, MB, Cao, H, McIntyre, AD, Ban, MR, Martins, RA, Kennedy, BA, Hassell, RG, Visser, ME, Schwartz, SM, Voight, BF, Elosua, R, Salomaa, V, O'Donnell, CJ, Dallinga-Thie, GM, Anand, SS, Yusuf, S, Huff, MW, Kathiresan, S & Hegele, RA 2010, 'Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia', Nature Genetics, vol. 42, no. 8, pp. 684-687. https://doi.org/10.1038/ng.628

TY - JOUR

T1 - Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia

AU - Johansen, Christopher T.

AU - Wang, Jian

AU - Lanktree, Matthew B.

AU - Cao, Henian

AU - McIntyre, Adam D.

AU - Ban, Matthew R.

AU - Martins, Rebecca A.

AU - Kennedy, Brooke A.

AU - Hassell, Reina G.

AU - Visser, Maartje E.

AU - Schwartz, Stephen M.

AU - Voight, Benjamin F.

AU - Elosua, Roberto

AU - Salomaa, Veikko

AU - O'Donnell, Christopher J.

AU - Dallinga-Thie, Geesje M.

AU - Anand, Sonia S.

AU - Yusuf, Salim

AU - Huff, Murray W.

AU - Kathiresan, Sekar

AU - Hegele, Robert A.

PY - 2010

Y1 - 2010

N2 - Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG

AB - Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG

U2 - https://doi.org/10.1038/ng.628

DO - https://doi.org/10.1038/ng.628

M3 - Article

C2 - 20657596

SN - 1061-4036

VL - 42

SP - 684

EP - 687

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -