Complex effects of sequence variants on lipid levels and coronary artery disease

Audunn S. Snaebjarnarson; Anna Helgadottir; Gudny A. Arnadottir; Erna V. Ivarsdottir; Gudmar Thorleifsson; Egil Ferkingstad; Gudmundur Einarsson; Gardar Sveinbjornsson; Thorgeir E. Thorgeirsson; Magnus O. Ulfarsson; Bjarni V. Halldorsson; Isleifur Olafsson; Christian Erikstrup; Ole B. Pedersen; Mette Nyegaard; Mie T. Bruun; Henrik Ullum; Søren Brunak; Kasper Karmark Iversen; Alex Hoerby Christensen; Morten S. Olesen; Jonas Ghouse; Karina Banasik; Kirk U. Knowlton; David O. Arnar; Gudmundur Thorgeirsson; Lincoln Nadauld; Sisse Rye Ostrowski; Henning Bundgaard; Hilma Holm; Patrick Sulem; Kari Stefansson; Daniel F. Gudbjartsson; DBDS Genomic Consortium

doi:10.1016/j.cell.2023.08.012

Complex effects of sequence variants on lipid levels and coronary artery disease

Audunn S. Snaebjarnarson, Anna Helgadottir, Gudny A. Arnadottir, Erna V. Ivarsdottir, Gudmar Thorleifsson, Egil Ferkingstad, Gudmundur Einarsson, Gardar Sveinbjornsson, Thorgeir E. Thorgeirsson, Magnus O. Ulfarsson, Bjarni V. Halldorsson, Isleifur Olafsson, Christian Erikstrup, Ole B. Pedersen, Mette Nyegaard, Mie T. Bruun, Henrik Ullum, Søren Brunak, Kasper Karmark Iversen, Alex Hoerby ChristensenMorten S. Olesen, Jonas Ghouse, Karina Banasik, Kirk U. Knowlton, David O. Arnar, Gudmundur Thorgeirsson, Lincoln Nadauld, Sisse Rye Ostrowski, Henning Bundgaard, Hilma Holm, Patrick Sulem, Kari Stefansson^*, Daniel F. Gudbjartsson, DBDS Genomic Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

7 Citations (Scopus)

Abstract

Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.

Original language	English
Journal	Cell
Volume	186
Issue number	19
Pages (from-to)	4085-4099.e15
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2023.08.012
Publication status	Published - 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

blood lipids
cholesterol
coronary artery disease
correlation effects
dominance effects
epistasis
gene-environment interaction effects
gene-gene interaction effects
genome-wide association study
variance effects

Access to Document

10.1016/j.cell.2023.08.012

Cite this

Snaebjarnarson, A. S., Helgadottir, A., Arnadottir, G. A., Ivarsdottir, E. V., Thorleifsson, G., Ferkingstad, E., Einarsson, G., Sveinbjornsson, G., Thorgeirsson, T. E., Ulfarsson, M. O., Halldorsson, B. V., Olafsson, I., Erikstrup, C., Pedersen, O. B., Nyegaard, M., Bruun, M. T., Ullum, H., Brunak, S., Iversen, K. K., ... DBDS Genomic Consortium (2023). Complex effects of sequence variants on lipid levels and coronary artery disease. Cell, 186(19), 4085-4099.e15. https://doi.org/10.1016/j.cell.2023.08.012

Complex effects of sequence variants on lipid levels and coronary artery disease. / Snaebjarnarson, Audunn S.; Helgadottir, Anna; Arnadottir, Gudny A.; Ivarsdottir, Erna V.; Thorleifsson, Gudmar; Ferkingstad, Egil; Einarsson, Gudmundur; Sveinbjornsson, Gardar; Thorgeirsson, Thorgeir E.; Ulfarsson, Magnus O.; Halldorsson, Bjarni V.; Olafsson, Isleifur; Erikstrup, Christian; Pedersen, Ole B.; Nyegaard, Mette; Bruun, Mie T.; Ullum, Henrik; Brunak, Søren ; Iversen, Kasper Karmark ; Christensen, Alex Hoerby ; Olesen, Morten S.; Ghouse, Jonas; Banasik, Karina; Knowlton, Kirk U.; Arnar, David O.; Thorgeirsson, Gudmundur; Nadauld, Lincoln; Ostrowski, Sisse Rye ; Bundgaard, Henning; Holm, Hilma; Sulem, Patrick; Stefansson, Kari; Gudbjartsson, Daniel F.; DBDS Genomic Consortium.

In: Cell, Vol. 186, No. 19, 2023, p. 4085-4099.e15.

Research output: Contribution to journal › Journal article › Research › peer-review

Snaebjarnarson, AS, Helgadottir, A, Arnadottir, GA, Ivarsdottir, EV, Thorleifsson, G, Ferkingstad, E, Einarsson, G, Sveinbjornsson, G, Thorgeirsson, TE, Ulfarsson, MO, Halldorsson, BV, Olafsson, I, Erikstrup, C, Pedersen, OB, Nyegaard, M, Bruun, MT, Ullum, H, Brunak, S , Iversen, KK , Christensen, AH , Olesen, MS, Ghouse, J, Banasik, K, Knowlton, KU, Arnar, DO, Thorgeirsson, G, Nadauld, L, Ostrowski, SR , Bundgaard, H, Holm, H, Sulem, P, Stefansson, K, Gudbjartsson, DF & DBDS Genomic Consortium 2023, 'Complex effects of sequence variants on lipid levels and coronary artery disease', Cell, vol. 186, no. 19, pp. 4085-4099.e15. https://doi.org/10.1016/j.cell.2023.08.012

Snaebjarnarson, Audunn S. ; Helgadottir, Anna ; Arnadottir, Gudny A. ; Ivarsdottir, Erna V. ; Thorleifsson, Gudmar ; Ferkingstad, Egil ; Einarsson, Gudmundur ; Sveinbjornsson, Gardar ; Thorgeirsson, Thorgeir E. ; Ulfarsson, Magnus O. ; Halldorsson, Bjarni V. ; Olafsson, Isleifur ; Erikstrup, Christian ; Pedersen, Ole B. ; Nyegaard, Mette ; Bruun, Mie T. ; Ullum, Henrik ; Brunak, Søren ; Iversen, Kasper Karmark ; Christensen, Alex Hoerby ; Olesen, Morten S. ; Ghouse, Jonas ; Banasik, Karina ; Knowlton, Kirk U. ; Arnar, David O. ; Thorgeirsson, Gudmundur ; Nadauld, Lincoln ; Ostrowski, Sisse Rye ; Bundgaard, Henning ; Holm, Hilma ; Sulem, Patrick ; Stefansson, Kari ; Gudbjartsson, Daniel F. ; DBDS Genomic Consortium. / Complex effects of sequence variants on lipid levels and coronary artery disease. In: Cell. 2023 ; Vol. 186, No. 19. pp. 4085-4099.e15.

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abstract = "Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.",

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AU - Snaebjarnarson, Audunn S.

AU - Helgadottir, Anna

AU - Arnadottir, Gudny A.

AU - Ivarsdottir, Erna V.

AU - Thorleifsson, Gudmar

AU - Ferkingstad, Egil

AU - Einarsson, Gudmundur

AU - Sveinbjornsson, Gardar

AU - Thorgeirsson, Thorgeir E.

AU - Ulfarsson, Magnus O.

AU - Halldorsson, Bjarni V.

AU - Olafsson, Isleifur

AU - Erikstrup, Christian

AU - Pedersen, Ole B.

AU - Nyegaard, Mette

AU - Bruun, Mie T.

AU - Ullum, Henrik

AU - Brunak, Søren

AU - Iversen, Kasper Karmark

AU - Christensen, Alex Hoerby

AU - Olesen, Morten S.

AU - Ghouse, Jonas

AU - Banasik, Karina

AU - Knowlton, Kirk U.

AU - Arnar, David O.

AU - Thorgeirsson, Gudmundur

AU - Nadauld, Lincoln

AU - Ostrowski, Sisse Rye

AU - Bundgaard, Henning

AU - Holm, Hilma

AU - Sulem, Patrick

AU - Stefansson, Kari

AU - Gudbjartsson, Daniel F.

AU - DBDS Genomic Consortium

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N2 - Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.

AB - Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.

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KW - cholesterol

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KW - correlation effects

KW - dominance effects

KW - epistasis

KW - gene-environment interaction effects

KW - gene-gene interaction effects

KW - genome-wide association study

KW - variance effects

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DO - 10.1016/j.cell.2023.08.012

M3 - Journal article

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VL - 186

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JO - Cell

JF - Cell

SN - 0092-8674

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ER -