Journal Article

DZNE-2025-01371

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants.

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. ; Huang, Z. ; Kals, M. ; Lefevre, C. ; Mangino, M. ; Milaneschi, Y. ; van der Most, P. J. ; Pacheco, N. L. ; Palmer, N. D. ; Rao, V. ; Rauramaa, R. ; Sun, Q. ; Tabara, Y. ; Vojinovic, D. ; Wang, Y. ; Weiss, S. ; Yang, Q. ; Zhao, W. ; Zhu, W. ; Ansari, M. A. Y. ; Aschard, H. ; Anugu, P. ; Assimes, T. L. ; Attia, J. ; Baker, L. D. ; Ballantyne, C. ; Bazzano, L. ; Boerwinkle, E. ; Cade, B. ; Chen, H.-H. ; Chen, W. ; Ida Chen, Y.-D. ; Chen, Z. ; Cho, K. ; De Anda-Duran, I. ; Dimitrov, L. ; Do, A. ; Edwards, T. ; Faquih, T. ; Hingorani, A. ; Fisher-Hoch, S. P. ; Gaziano, J. M. ; Gharib, S. A. ; Giri, A. ; Ghanbari, M. ; Grabe, H. J.DZNE* ; Graff, M. ; Charles Gu, C. ; He, J. ; Heikkinen, S. ; Hixson, J. ; Ho, Y.-L. ; Hood, M. M. ; Houghton, S. C. ; Karvonen-Gutierrez, C. A. ; Kawaguchi, T. ; Kilpeläinen, T. O. ; Komulainen, P. ; Lin, H. J. ; Linchangco, G. V. ; Luik, A. I. ; Ma, J. ; Meigs, J. B. ; McCormick, J. B. ; Menni, C. ; Nolte, I. M. ; Norris, J. M. ; Petty, L. E. ; Polikowsky, H. G. ; Raffield, L. M. ; Rich, S. S. ; Riha, R. L. ; Russ, T. C. ; Ruiz-Narvaez, E. A. ; Sitlani, C. M. ; Smith, J. A. ; Snieder, H. ; Sofer, T. ; Shen, B. ; Tang, J. ; Taylor, K. D. ; Teder-Laving, M. ; Triatin, R. ; Tsai, M. Y. ; Völzke, H. ; Westerman, K. E. ; Xia, R. ; Yao, J. ; Young, K. L. ; Zhang, R. ; Zonderman, A. B. ; Zhu, X. ; Below, J. E. ; Cox, S. R. ; Evans, M. ; Fornage, M. ; Fox, E. R. ; Franceschini, N. ; Harlow, S. D. ; Holliday, E. ; Ikram, M. A. ; Kelly, T. ; Lakka, T. A. ; Lawlor, D. A. ; Li, C. ; Liu, C.-T. ; Mägi, R. ; Manning, A. K. ; Matsuda, F. ; Morrison, A. C. ; Nauck, M. ; North, K. E. ; Penninx, B. W. ; Province, M. A. ; Psaty, B. M. ; Rotter, J. I. ; Spector, T. D. ; Wagenknecht, L. E. ; van Dijk, K. W. ; Study, L. C. (Collaboration Author) ; Program, M. V. (Collaboration Author) ; Jaquish, C. E. ; Wilson, P. W. ; Peyser, P. A. ; Munroe, P. B. ; de Vries, P. S. ; Gauderman, W. J. ; Sun, Y. V. ; Chen, H. ; Miller, C. L. ; Winkler, T. W. ; Rao, D. C. ; Redline, S. ; van Heemst, D.

2026
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.atherosclerosis.2025.120603

Abstract: 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.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.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.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.

Keyword(s): Humans (MeSH) ; Genome-Wide Association Study (MeSH) ; Male (MeSH) ; Female (MeSH) ; Sleep: genetics (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Middle Aged (MeSH) ; Dyslipidemias: genetics (MeSH) ; Dyslipidemias: blood (MeSH) ; Dyslipidemias: diagnosis (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Triglycerides: blood (MeSH) ; Lipids: blood (MeSH) ; Adult (MeSH) ; Aged (MeSH) ; Genetic Loci (MeSH) ; Phenotype (MeSH) ; Cholesterol, LDL: blood (MeSH) ; Cholesterol, HDL: blood (MeSH) ; Biomarkers: blood (MeSH) ; Sleep Wake Disorders: genetics (MeSH) ; Sleep Wake Disorders: blood (MeSH) ; Sleep Wake Disorders: physiopathology (MeSH) ; Triglycerides ; Lipids ; Cholesterol, LDL ; Cholesterol, HDL ; Biomarkers

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Contributing Institute(s):

1. Biomarkers of Dementia in the General Population (AG Grabe)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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