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@ARTICLE{Bentley:279380,
author = {Bentley, Amy R and Brown, Michael R and Musani, Solomon K
and Schwander, Karen L and Winkler, Thomas W and Sims, Mario
and Kilpeläinen, Tuomas O and Aschard, Hugues and Bartz,
Traci M and Bielak, Lawrence F and Chai, Jin-Fang and
Chitrala, Kumaraswamy Naidu and Franceschini, Nora and
Graff, Mariaelisa and Guo, Xiuqing and Hartwig, Fernando P
and Horimoto, Andrea R V R and Lim, Elise and Liu, Yongmei
and Manning, Alisa K and Nolte, Ilja M and Noordam, Raymond
and Richard, Melissa A and Smith, Albert V and Sung, Yun Ju
and Vojinovic, Dina and Wang, Rujia and Wang, Yujie and
Feitosa, Mary F and Harris, Sarah E and Lyytikäinen,
Leo-Pekka and Pistis, Giorgio and Rauramaa, Rainer and van
der Most, Peter J and Ware, Erin and Weiss, Stefan and Wen,
Wanqing and Yanek, Lisa R and Arking, Dan E and Arnett,
Donna K and Ballantyne, Christie and Boerwinkle, Eric and
Chen, Yii-Der Ida and Daviglus, Martha L and de Las Fuentes,
Lisa and de Vries, Paul S and Delaney, Joseph A C and
Fretts, Amanda M and Ekunwe, Lynette and Faul, Jessica D and
Gallo, Linda C and Heikkinen, Sami and Homuth, Georg and
Ikram, M Arfan and Isasi, Carmen R and Jonas, Jost Bruno and
Keltikangas-Järvinen, Liisa and Komulainen, Pirjo and
Kraja, Aldi T and Krieger, Jose E and Launer, Lenore and
Liu, Jianjun and Lohman, Kurt and Luik, Annemarie I and
Manichaikul, Ani W and Marques-Vidal, Pedro and Milaneschi,
Yuri and Mwasongwe, Stanford E and O'Connell, Jeffrey R and
Rice, Kenneth and Rich, Stephen S and Schreiner, Pamela J
and Schwettmann, Lars and Shikany, James M and Shu, Xiao-Ou
and Smith, Jennifer A and Snieder, Harold and Sotoodehnia,
Nona and Tai, E Shyong and Taylor, Kent D and Tinker, Lesley
and Tsai, Michael Y and Uitterlinden, André G and van
Duijn, Cornelia M and van Heemst, Diana and Waldenberger,
Melanie and Wallace, Robert B and Wee, Hwee-Lin and Weir,
David R and Wei, Wen-Bin and Willems van Dijk, Ko and
Wilson, Gregory and Yao, Jie and Young, Kristin L and Zhang,
Xiaoyu and Zhao, Wei and Zhu, Xiaofeng and Zonderman, Alan B
and Deary, Ian J and Gieger, Christian and Grabe, Hans
Jörgen and Lakka, Timo A and Lehtimäki, Terho and
Oldehinkel, Albertine J and Preisig, Martin and Wang,
Ya-Xing and Zheng, Wei and Evans, Michele K and Province,
Michael and Gauderman, James and Gudnason, Vilmundur and
Hartman, Catharina A and Horta, Bernardo L and Kardia,
Sharon L R and Kooperberg, Charles and Liu, Ching-Ti and
Mook-Kanamori, Dennis O and Penninx, Brenda Wjh and Pereira,
Alexandre C and Peyser, Patricia A and Psaty, Bruce M and
Rotter, Jerome I and Sim, Xueling and North, Kari E and Rao,
Dabeeru C and Bierut, Laura and Miller, Clint L and
Morrison, Alanna C and Rotimi, Charles N and Fornage, Myriam
and Fox, Ervin R},
collaboration = {Study, Lifelines Cohort},
othercontributors = {Aguirre-Gamboa, Raul and Deelen, Patrick and Franke, Lude
and Kuivenhoven, Jan A and Lopera Maya, Esteban A and Nolte,
Ilja M and Sanna, Serena and Snieder, Harold and Swertz,
Morris A and Visscher, Peter M and Vonk, Judith M and
Wijmenga, Cisca and Wray, Naomi},
title = {{M}ulti-ancestry genome-wide association analyses
incorporating {SNP}-by-psychosocial interactions identify
novel loci for serum lipids.},
journal = {Translational Psychiatry},
volume = {15},
number = {1},
issn = {2158-3188},
address = {London},
publisher = {Nature Publishing Group},
reportid = {DZNE-2025-00757},
pages = {207},
year = {2025},
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.},
keywords = {Humans / Genome-Wide Association Study / Polymorphism,
Single Nucleotide / Male / Lipids: blood / Lipids: genetics
/ Female / Gene-Environment Interaction / Adult / Genetic
Loci / Middle Aged / Social Support / Lipids (NLM
Chemicals)},
cin = {AG Grabe},
ddc = {610},
cid = {I:(DE-2719)5000001},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40537477},
pmc = {pmc:PMC12179276},
doi = {10.1038/s41398-025-03418-z},
url = {https://pub.dzne.de/record/279380},
}