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.
Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants / R. Noordam, W. Wang, P. Nagarajan, H. Wang, M.R. Brown, A.R. Bentley, Q. Hui, A.T. Kraja, J.L. Morrison, J.R. O'Connel, S. Lee, K. Schwander, T.M. Bartz, L. De Las Fuentes, M.F. Feitosa, X. Guo, X. Hanfei, S.E. Harris, Z. Huang, M. Kals, C. Lefevre, M. Mangino, Y. Milaneschi, P.J. Van Der Most, N.L. Pacheco, N.D. Palmer, V. Rao, R. Rauramaa, Q. Sun, Y. Tabara, D. Vojinovic, Y. Wang, S. Weiss, Q. Yang, W. Zhao, W. Zhu, M.A.Y. Ansari, H. Aschard, P. Anugu, T.L. Assimes, J. Attia, L.D. Baker, C. Ballantyne, L. Bazzano, E. Boerwinkle, B. Cade, H. Chen, W. Chen, Y. Ida Chen, Z. Chen, K. Cho, I. De Anda-Duran, L. Dimitrov, A. Do, T. Edwards, T. Faquih, A. Hingorani, S.P. Fisher-Hoch, J.M. Gaziano, S.A. Gharib, A. Giri, M. Ghanbari, H.J. Grabe, M. Graff, C. Charles Gu, J. He, S. Heikkinen, J. Hixson, Y. Ho, M.M. Hood, S.C. Houghton, C.A. Karvonen-Gutierrez, T. Kawaguchi, T.O. Kilpeläinen, P. Komulainen, H.J. Lin, G.V. Linchangco, A.I. Luik, J. Ma, J.B. Meigs, J.B. Mccormick, C. Menni, I.M. Nolte, J.M. Norris, L.E. Petty, H.G. Polikowsky, L.M. Raffield, S.S. Rich, R.L. Riha, T.C. Russ, E.A. Ruiz-Narvaez, C.M. Sitlani, J.A. Smith, H. Snieder, T. Sofer, B. Shen, J. Tang, K.D. Taylor, M. Teder-Laving, R. Triatin, M.Y. Tsai, H. Völzke, K.E. Westerman, R. Xia, J. Yao, K.L. Young, R. Zhang, A.B. Zonderman, X. Zhu, J.E. Below, S.R. Cox, M. Evans, M. Fornage, E.R. Fox, N. Franceschini, S.D. Harlow, E. Holliday, M.A. Ikram, T. Kelly, T.A. Lakka, D.A. Lawlor, C. Li, C. Liu, R. Mägi, A.K. Manning, F. Matsuda, A.C. Morrison, M. Nauck, K.E. North, B.W. Penninx, M.A. Province, B.M. Psaty, J.I. Rotter, T.D. Spector, L.E. Wagenknecht, K.W. Van Dijk, C.E. Jaquish, P.W. Wilson, P.A. Peyser, P.B. Munroe, P.S. De Vries, W.J. Gauderman, Y.V. Sun, H. Chen, C.L. Miller, T.W. Winkler, D.C. Rao, S. Redline, D. Van Heemst. - In: ATHEROSCLEROSIS. - ISSN 1879-1484. - 412:(2026 Jan), pp. 120603.1-120603.13. [10.1016/j.atherosclerosis.2025.120603]
Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants
W. Chen;C. Menni;
2026
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.
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