TY  - JOUR
AU  - Bentley, Amy R
AU  - Brown, Michael R
AU  - Musani, Solomon K
AU  - Schwander, Karen L
AU  - Winkler, Thomas W
AU  - Sims, Mario
AU  - Kilpeläinen, Tuomas O
AU  - Aschard, Hugues
AU  - Bartz, Traci M
AU  - Bielak, Lawrence F
AU  - Chai, Jin-Fang
AU  - Chitrala, Kumaraswamy Naidu
AU  - Franceschini, Nora
AU  - Graff, Mariaelisa
AU  - Guo, Xiuqing
AU  - Hartwig, Fernando P
AU  - Horimoto, Andrea R V R
AU  - Lim, Elise
AU  - Liu, Yongmei
AU  - Manning, Alisa K
AU  - Nolte, Ilja M
AU  - Noordam, Raymond
AU  - Richard, Melissa A
AU  - Smith, Albert V
AU  - Sung, Yun Ju
AU  - Vojinovic, Dina
AU  - Wang, Rujia
AU  - Wang, Yujie
AU  - Feitosa, Mary F
AU  - Harris, Sarah E
AU  - Lyytikäinen, Leo-Pekka
AU  - Pistis, Giorgio
AU  - Rauramaa, Rainer
AU  - van der Most, Peter J
AU  - Ware, Erin
AU  - Weiss, Stefan
AU  - Wen, Wanqing
AU  - Yanek, Lisa R
AU  - Arking, Dan E
AU  - Arnett, Donna K
AU  - Ballantyne, Christie
AU  - Boerwinkle, Eric
AU  - Chen, Yii-Der Ida
AU  - Daviglus, Martha L
AU  - de Las Fuentes, Lisa
AU  - de Vries, Paul S
AU  - Delaney, Joseph A C
AU  - Fretts, Amanda M
AU  - Ekunwe, Lynette
AU  - Faul, Jessica D
AU  - Gallo, Linda C
AU  - Heikkinen, Sami
AU  - Homuth, Georg
AU  - Ikram, M Arfan
AU  - Isasi, Carmen R
AU  - Jonas, Jost Bruno
AU  - Keltikangas-Järvinen, Liisa
AU  - Komulainen, Pirjo
AU  - Kraja, Aldi T
AU  - Krieger, Jose E
AU  - Launer, Lenore
AU  - Liu, Jianjun
AU  - Lohman, Kurt
AU  - Luik, Annemarie I
AU  - Manichaikul, Ani W
AU  - Marques-Vidal, Pedro
AU  - Milaneschi, Yuri
AU  - Mwasongwe, Stanford E
AU  - O'Connell, Jeffrey R
AU  - Rice, Kenneth
AU  - Rich, Stephen S
AU  - Schreiner, Pamela J
AU  - Schwettmann, Lars
AU  - Shikany, James M
AU  - Shu, Xiao-Ou
AU  - Smith, Jennifer A
AU  - Snieder, Harold
AU  - Sotoodehnia, Nona
AU  - Tai, E Shyong
AU  - Taylor, Kent D
AU  - Tinker, Lesley
AU  - Tsai, Michael Y
AU  - Uitterlinden, André G
AU  - van Duijn, Cornelia M
AU  - van Heemst, Diana
AU  - Waldenberger, Melanie
AU  - Wallace, Robert B
AU  - Wee, Hwee-Lin
AU  - Weir, David R
AU  - Wei, Wen-Bin
AU  - Willems van Dijk, Ko
AU  - Wilson, Gregory
AU  - Yao, Jie
AU  - Young, Kristin L
AU  - Zhang, Xiaoyu
AU  - Zhao, Wei
AU  - Zhu, Xiaofeng
AU  - Zonderman, Alan B
AU  - Deary, Ian J
AU  - Gieger, Christian
AU  - Grabe, Hans Jörgen
AU  - Lakka, Timo A
AU  - Lehtimäki, Terho
AU  - Oldehinkel, Albertine J
AU  - Preisig, Martin
AU  - Wang, Ya-Xing
AU  - Zheng, Wei
AU  - Evans, Michele K
AU  - Province, Michael
AU  - Gauderman, James
AU  - Gudnason, Vilmundur
AU  - Hartman, Catharina A
AU  - Horta, Bernardo L
AU  - Kardia, Sharon L R
AU  - Kooperberg, Charles
AU  - Liu, Ching-Ti
AU  - Mook-Kanamori, Dennis O
AU  - Penninx, Brenda Wjh
AU  - Pereira, Alexandre C
AU  - Peyser, Patricia A
AU  - Psaty, Bruce M
AU  - Rotter, Jerome I
AU  - Sim, Xueling
AU  - North, Kari E
AU  - Rao, Dabeeru C
AU  - Bierut, Laura
AU  - Miller, Clint L
AU  - Morrison, Alanna C
AU  - Rotimi, Charles N
AU  - Fornage, Myriam
AU  - Fox, Ervin R
TI  - Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.
JO  - Translational Psychiatry
VL  - 15
IS  - 1
SN  - 2158-3188
CY  - London
PB  - Nature Publishing Group
M1  - DZNE-2025-00757
SP  - 207
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Genome-Wide Association Study
KW  - Polymorphism, Single Nucleotide
KW  - Male
KW  - Lipids: blood
KW  - Lipids: genetics
KW  - Female
KW  - Gene-Environment Interaction
KW  - Adult
KW  - Genetic Loci
KW  - Middle Aged
KW  - Social Support
KW  - Lipids (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40537477
C2  - pmc:PMC12179276
DO  - DOI:10.1038/s41398-025-03418-z
UR  - https://pub.dzne.de/record/279380
ER  -