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

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.

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Overview publication

Title	Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants.
Date	November 26th, 2025
Issue name	Atherosclerosis
Issue number	v412:120603
DOI	10.1016/j.atherosclerosis.2025.120603
PubMed	41325697
Authors	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, Rauramaa R, Sun Q, Tabara Y, Vojinovic D, Wang Y, Weiss S, Yang Q, Zhao W, Zhu W, Ansari MAY, Aschard H, Anugu P, Assimes TL, Attia J, Baker LD, Ballantyne C, Bazzano L, Boerwinkle E, Cade B, Chen HH, Chen W, Ida Chen YD, Chen Z, Cho K, De Anda-Duran I, Dimitrov L, Do A, Edwards T, Faquih T, Hingorani A, Fisher-Hoch SP, Gaziano JM, Gharib SA, Giri A, Ghanbari M, Grabe HJ, Graff M, Charles Gu C, He J, Heikkinen S, Hixson J, Ho YL, Hood MM, Houghton SC, Karvonen-Gutierrez CA, Kawaguchi T, Kilpeläinen TO, Komulainen P, Lin HJ, Linchangco GV, Luik AI, Ma J, Meigs JB, McCormick JB, Menni C, Nolte IM, Norris JM, Petty LE, Polikowsky HG, Raffield LM, Rich SS, Riha RL, Russ TC, Ruiz-Narvaez EA, Sitlani CM, Smith JA, Snieder H, Sofer T, Shen B, Tang J, Taylor KD, Teder-Laving M, Triatin R, Tsai MY, Völzke H, Westerman KE, Xia R, Yao J, Young KL, Zhang R, Zonderman AB, Zhu X, Below JE, Cox SR, Evans M, Fornage M, Fox ER, Franceschini N, Harlow SD, Holliday E, Ikram MA, Kelly T, Lakka TA, Lawlor DA, Li C, Liu CT, Mägi R, Manning AK, Matsuda F, Morrison AC, Nauck M, North KE, Penninx BW, Province MA, Psaty BM, Rotter JI, Spector TD, Wagenknecht LE, van Dijk KW, Jaquish CE, Wilson PW, Peyser PA, Munroe PB, de Vries PS, Gauderman WJ, Sun YV, Chen H, Miller CL, Winkler TW, Rao DC, Redline S & van Heemst D
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