Journal Article

DZNE-2025-00757

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.

Bentley, A. R. ; Brown, M. R. ; Musani, S. K. ; Schwander, K. L. ; Winkler, T. W. ; Sims, M. ; Kilpeläinen, T. O. ; Aschard, H. ; Bartz, T. M. ; Bielak, L. F. ; Chai, J.-F. ; Chitrala, K. N. ; Franceschini, N. ; Graff, M. ; Guo, X. ; Hartwig, F. P. ; Horimoto, A. R. V. R. ; Lim, E. ; Liu, Y. ; Manning, A. K. ; Nolte, I. M. ; Noordam, R. ; Richard, M. A. ; Smith, A. V. ; Sung, Y. J. ; Vojinovic, D. ; Wang, R. ; Wang, Y. ; Feitosa, M. F. ; Harris, S. E. ; Lyytikäinen, L.-P. ; Pistis, G. ; Rauramaa, R. ; van der Most, P. J. ; Ware, E. ; Weiss, S. ; Wen, W. ; Yanek, L. R. ; Arking, D. E. ; Arnett, D. K. ; Ballantyne, C. ; Boerwinkle, E. ; Chen, Y. I. ; Daviglus, M. L. ; de Las Fuentes, L. ; de Vries, P. S. ; Delaney, J. A. C. ; Fretts, A. M. ; Ekunwe, L. ; Faul, J. D. ; Gallo, L. C. ; Heikkinen, S. ; Homuth, G. ; Ikram, M. A. ; Isasi, C. R. ; Jonas, J. B. ; Keltikangas-Järvinen, L. ; Komulainen, P. ; Kraja, A. T. ; Krieger, J. E. ; Launer, L. ; Study, L. C. (Collaboration Author) ; Liu, J. ; Lohman, K. ; Luik, A. I. ; Manichaikul, A. W. ; Marques-Vidal, P. ; Milaneschi, Y. ; Mwasongwe, S. E. ; O'Connell, J. R. ; Rice, K. ; Rich, S. S. ; Schreiner, P. J. ; Schwettmann, L. ; Shikany, J. M. ; Shu, X.-O. ; Smith, J. A. ; Snieder, H. ; Sotoodehnia, N. ; Tai, E. S. ; Taylor, K. D. ; Tinker, L. ; Tsai, M. Y. ; Uitterlinden, A. G. ; van Duijn, C. M. ; van Heemst, D. ; Waldenberger, M. ; Wallace, R. B. ; Wee, H.-L. ; Weir, D. R. ; Wei, W.-B. ; Willems van Dijk, K. ; Wilson, G. ; Yao, J. ; Young, K. L. ; Zhang, X. ; Zhao, W. ; Zhu, X. ; Zonderman, A. B. ; Deary, I. J. ; Gieger, C. ; Grabe, H. J.DZNE* ; Lakka, T. A. ; Lehtimäki, T. ; Oldehinkel, A. J. ; Preisig, M. ; Wang, Y.-X. ; Zheng, W. ; Evans, M. K. ; Province, M. ; Gauderman, J. ; Gudnason, V. ; Hartman, C. A. ; Horta, B. L. ; Kardia, S. L. R. ; Kooperberg, C. ; Liu, C.-T. ; Mook-Kanamori, D. O. ; Penninx, B. W. ; Pereira, A. C. ; Peyser, P. A. ; Psaty, B. M. ; Rotter, J. I. ; Sim, X. ; North, K. E. ; Rao, D. C. ; Bierut, L. ; Miller, C. L. ; Morrison, A. C. ; Rotimi, C. N. ; Fornage, M. ; Fox, E. R. ; Aguirre-Gamboa, R. (Contributor) ; Deelen, P. (Contributor) ; Franke, L. (Contributor) ; Kuivenhoven, J. A. (Contributor) ; Lopera Maya, E. A. (Contributor) ; Nolte, I. M. (Contributor) ; Sanna, S. (Contributor) ; Snieder, H. (Contributor) ; Swertz, M. A. (Contributor) ; Visscher, P. M. (Contributor) ; Vonk, J. M. (Contributor) ; Wijmenga, C. (Contributor) ; Wray, N. (Contributor)

2025
Nature Publishing Group London

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Please use a persistent id in citations: doi:10.1038/s41398-025-03418-z

Abstract: Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P < 10-5) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P < 5 × 10-8) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.

Keyword(s): Humans (MeSH) ; Genome-Wide Association Study (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Male (MeSH) ; Lipids: blood (MeSH) ; Lipids: genetics (MeSH) ; Female (MeSH) ; Gene-Environment Interaction (MeSH) ; Adult (MeSH) ; Genetic Loci (MeSH) ; Middle Aged (MeSH) ; Social Support (MeSH) ; Lipids

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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)

Appears in the scientific report 2025

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; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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