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; DBDS Genomic Consortium; Kirk U Knowlton; David O Arnar; Gudmundur Thorgeirsson; Lincoln Nadauld; Sisse Rye Ostrowski; Henning Bundgaard; Hilma Holm; Patrick Sulem; Kari Stefansson; Daniel F Gudbjartsson

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, DBDS Genomic Consortium, Kirk U Knowlton, David O Arnar, Gudmundur Thorgeirsson, Lincoln Nadauld, Sisse Rye Ostrowski, Henning Bundgaard, Hilma Holm, Patrick Sulem, Kari Stefansson^*, Daniel F Gudbjartsson^*

^*Corresponding author for this work

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

2 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
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2023.08.012
Publication status	Published - 14 Sept 2023

Bibliographical note

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

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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., ... Gudbjartsson, D. F. (2023). Complex effects of sequence variants on lipid levels and coronary artery disease. Cell, 186(19), 4085-4099. https://doi.org/10.1016/j.cell.2023.08.012

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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.",

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",

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

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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, DBDS Genomic Consortium, Knowlton, KU, Arnar, DO, Thorgeirsson, G, Nadauld, L, Ostrowski, SR, Bundgaard, H, Holm, H, Sulem, P, Stefansson, K & Gudbjartsson, DF 2023, 'Complex effects of sequence variants on lipid levels and coronary artery disease', Cell, vol. 186, no. 19, pp. 4085-4099. https://doi.org/10.1016/j.cell.2023.08.012

TY - JOUR

T1 - Complex effects of sequence variants on lipid levels and coronary artery disease

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 - DBDS Genomic Consortium

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

PY - 2023/9/14

Y1 - 2023/9/14

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.

KW - blood lipids

KW - cholesterol

KW - coronary artery disease

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

UR - http://www.scopus.com/inward/record.url?scp=85170703455&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.08.012

DO - 10.1016/j.cell.2023.08.012

M3 - Journal article

C2 - 37714134

SN - 0092-8674

VL - 186

SP - 4085

EP - 4099

JO - Cell

JF - Cell

IS - 19

ER -

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

Abstract

Bibliographical note

Keywords

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