Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

LifeLines Cohort Study; Raymond Noordam; Wenyi Wang; Pavithra Nagarajan; Heming Wang; Michael R Brown; Amy R Bentley; Qin Hui; Aldi T Kraja; John L Morrison; Jeffrey R O'Connel; Songmi Lee; Karen Schwander; Traci M Bartz; Lisa de Las Fuentes; Mary F Feitosa; Xiuqing Guo; Xu Hanfei; Sarah E Harris; Zhijie Huang; Mart Kals; Christophe Lefevre; Massimo Mangino; Yuri Milaneschi; Peter J van der Most; Natasha L Pacheco; Nicholette D Palmer; Varun Rao; Qian Yang; Deborah A Lawlor; et al

doi:10.1016/j.atherosclerosis.2025.120603

Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

LifeLines Cohort Study, Raymond Noordam^*, Wenyi Wang, Pavithra Nagarajan, Heming Wang, Michael R Brown, Amy R Bentley, Qin Hui, Aldi T Kraja, John L Morrison, Jeffrey R O'Connel, Songmi Lee, Karen Schwander, Traci M Bartz, Lisa de Las Fuentes, Mary F Feitosa, Xiuqing Guo, Xu Hanfei, Sarah E Harris, Zhijie HuangMart Kals, Christophe Lefevre, Massimo Mangino, Yuri Milaneschi, Peter J van der Most, Natasha L Pacheco, Nicholette D Palmer, Varun Rao, Qian Yang, Deborah A Lawlor, et al

^*Corresponding author for this work

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

Abstract

Background and aims:

Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets.

Methods:

We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels.

Results:

The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature.

Conclusions:

Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

Original language	English
Article number	120603
Number of pages	13
Journal	Atherosclerosis
Volume	412
Early online date	26 Nov 2025
DOIs	https://doi.org/10.1016/j.atherosclerosis.2025.120603
Publication status	Published - 3 Jan 2026

Bibliographical note

Publisher Copyright:
© 2025 The Authors.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Humans
Genome-Wide Association Study
Male
Female
Sleep/genetics
Polymorphism, Single Nucleotide
Middle Aged
Dyslipidemias/genetics
Genetic Predisposition to Disease
Triglycerides/blood
Lipids/blood
Adult
Aged
Genetic Loci
Phenotype
Cholesterol, LDL/blood
Cholesterol, HDL/blood
Biomarkers/blood
Sleep Wake Disorders/genetics

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LifeLines Cohort Study, Noordam, R., Wang, W., Nagarajan, P., Wang, H., Brown, M. R., Bentley, A. R., Hui, Q., Kraja, A. T., Morrison, J. L., O'Connel, J. R., Lee, S., Schwander, K., Bartz, T. M., de Las Fuentes, L., Feitosa, M. F., Guo, X., Hanfei, X., Harris, S. E., ... al , E. (2026). Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants. Atherosclerosis, 412, Article 120603. https://doi.org/10.1016/j.atherosclerosis.2025.120603

@article{6c38de740f294b07be2e1f2eb89c0572,

title = "Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants",

abstract = "Background and aims:Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. Methods:We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 \% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 \% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. Results:The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. Conclusions:Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.",

keywords = "Humans, Genome-Wide Association Study, Male, Female, Sleep/genetics, Polymorphism, Single Nucleotide, Middle Aged, Dyslipidemias/genetics, Genetic Predisposition to Disease, Triglycerides/blood, Lipids/blood, Adult, Aged, Genetic Loci, Phenotype, Cholesterol, LDL/blood, Cholesterol, HDL/blood, Biomarkers/blood, Sleep Wake Disorders/genetics",

author = "\{LifeLines Cohort Study\} and Raymond Noordam and Wenyi Wang and Pavithra Nagarajan and Heming Wang and Brown, \{Michael R\} and Bentley, \{Amy R\} and Qin Hui and Kraja, \{Aldi T\} and Morrison, \{John L\} and O'Connel, \{Jeffrey R\} and Songmi Lee and Karen Schwander and Bartz, \{Traci M\} and \{de Las Fuentes\}, Lisa and Feitosa, \{Mary F\} and Xiuqing Guo and Xu Hanfei and Harris, \{Sarah E\} and Zhijie Huang and Mart Kals and Christophe Lefevre and Massimo Mangino and Yuri Milaneschi and \{van der Most\}, \{Peter J\} and Pacheco, \{Natasha L\} and Palmer, \{Nicholette D\} and Varun Rao and Qian Yang and Lawlor, \{Deborah A\} and et al",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

year = "2026",

month = jan,

day = "3",

doi = "10.1016/j.atherosclerosis.2025.120603",

language = "English",

volume = "412",

journal = "Atherosclerosis",

issn = "0021-9150",

publisher = "Elsevier Science Ireland",

}

LifeLines Cohort Study, Noordam, R, Wang, W, Nagarajan, P, Wang, H, Brown, MR, Bentley, AR, Hui, Q, Kraja, AT, Morrison, JL, O'Connel, JR, Lee, S, Schwander, K, Bartz, TM, de Las Fuentes, L, Feitosa, MF, Guo, X, Hanfei, X, Harris, SE, Huang, Z, Kals, M, Lefevre, C, Mangino, M, Milaneschi, Y, van der Most, PJ, Pacheco, NL, Palmer, ND, Rao, V, Yang, Q, Lawlor, DA & al , E 2026, 'Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants', Atherosclerosis, vol. 412, 120603. https://doi.org/10.1016/j.atherosclerosis.2025.120603

TY - JOUR

T1 - Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

AU - LifeLines Cohort Study

AU - Noordam, Raymond

AU - Wang, Wenyi

AU - Nagarajan, Pavithra

AU - Wang, Heming

AU - Brown, Michael R

AU - Bentley, Amy R

AU - Hui, Qin

AU - Kraja, Aldi T

AU - Morrison, John L

AU - O'Connel, Jeffrey R

AU - Lee, Songmi

AU - Schwander, Karen

AU - Bartz, Traci M

AU - de Las Fuentes, Lisa

AU - Feitosa, Mary F

AU - Guo, Xiuqing

AU - Hanfei, Xu

AU - Harris, Sarah E

AU - Huang, Zhijie

AU - Kals, Mart

AU - Lefevre, Christophe

AU - Mangino, Massimo

AU - Milaneschi, Yuri

AU - van der Most, Peter J

AU - Pacheco, Natasha L

AU - Palmer, Nicholette D

AU - Rao, Varun

AU - Yang, Qian

AU - Lawlor, Deborah A

AU - al , et

PY - 2026/1/3

Y1 - 2026/1/3

N2 - Background and aims:Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. Methods:We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. Results:The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. Conclusions:Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

AB - Background and aims:Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. Methods:We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. Results:The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. Conclusions:Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

KW - Humans

KW - Genome-Wide Association Study

KW - Male

KW - Female

KW - Sleep/genetics

KW - Polymorphism, Single Nucleotide

KW - Middle Aged

KW - Dyslipidemias/genetics

KW - Genetic Predisposition to Disease

KW - Triglycerides/blood

KW - Lipids/blood

KW - Adult

KW - Aged

KW - Genetic Loci

KW - Phenotype

KW - Cholesterol, LDL/blood

KW - Cholesterol, HDL/blood

KW - Biomarkers/blood

KW - Sleep Wake Disorders/genetics

U2 - 10.1016/j.atherosclerosis.2025.120603

DO - 10.1016/j.atherosclerosis.2025.120603

M3 - Article (Academic Journal)

C2 - 41325697

SN - 0021-9150

VL - 412

JO - Atherosclerosis

JF - Atherosclerosis

M1 - 120603

ER -

Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

Abstract

Bibliographical note

UN SDGs

Keywords

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