Translational psychiatry · 2025

Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.

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Bentley Amy R, Brown Michael R, Musani Solomon K, Schwander Karen L, Winkler Thomas W, Sims Mario, Kilpeläinen Tuomas O, Aschard Hugues, Bartz Traci M, Bielak Lawrence F, Chai Jin-Fang, Chitrala Kumaraswamy Naidu, Franceschini Nora, Graff Mariaelisa, Guo Xiuqing, Hartwig Fernando P, Horimoto Andrea R V R, Lim Elise, Liu Yongmei, Manning Alisa K, Nolte Ilja M, Noordam Raymond, Richard Melissa A, Smith Albert V, Sung Yun Ju, Vojinovic Dina, Wang Rujia, Wang Yujie, Feitosa Mary F, Harris Sarah E, Lyytikäinen Leo-Pekka, Pistis Giorgio, Rauramaa Rainer, van der Most Peter J, Ware Erin, Weiss Stefan, Wen Wanqing, Yanek Lisa R, Arking Dan E, Arnett Donna K, Ballantyne Christie, Boerwinkle Eric, Chen Yii-Der Ida, Daviglus Martha L, de Las Fuentes Lisa, de Vries Paul S, Delaney Joseph A C, Fretts Amanda M, Ekunwe Lynette, Faul Jessica D, Gallo Linda C, Heikkinen Sami, Homuth Georg, Ikram M Arfan, Isasi Carmen R, Jonas Jost Bruno, Keltikangas-Järvinen Liisa, Komulainen Pirjo, Kraja Aldi T, Krieger Jose E, Launer Lenore, Lifelines Cohort Study, Liu Jianjun, Lohman Kurt, Luik Annemarie I, Manichaikul Ani W, Marques-Vidal Pedro, Milaneschi Yuri, Mwasongwe Stanford E, O'Connell Jeffrey R, Rice Kenneth, Rich Stephen S, Schreiner Pamela J, Schwettmann Lars, Shikany James M, Shu Xiao-Ou, Smith Jennifer A, Snieder Harold, Sotoodehnia Nona, Tai E Shyong, Taylor Kent D, Tinker Lesley, Tsai Michael Y, Uitterlinden André G, van Duijn Cornelia M, van Heemst Diana, Waldenberger Melanie, Wallace Robert B, Wee Hwee-Lin, Weir David R, Wei Wen-Bin, Willems van Dijk Ko, Wilson Gregory, Yao Jie, Young Kristin L, Zhang Xiaoyu, Zhao Wei, Zhu Xiaofeng, Zonderman Alan B, Deary Ian J, Gieger Christian, Grabe Hans Jörgen, Lakka Timo A, Lehtimäki Terho, Oldehinkel Albertine J, Preisig Martin, Wang Ya-Xing, Zheng Wei, Evans Michele K, Province Michael, Gauderman James, Gudnason Vilmundur, Hartman Catharina A, Horta Bernardo L, Kardia Sharon L R, Kooperberg Charles, Liu Ching-Ti, Mook-Kanamori Dennis O, Penninx Brenda Wjh, Pereira Alexandre C, Peyser Patricia A, Psaty Bruce M, Rotter Jerome I, Sim Xueling, North Kari E, Rao Dabeeru C, Bierut Laura, Miller Clint L, Morrison Alanna C, Rotimi Charles N, Fornage Myriam, Fox Ervin R

Аннотация

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.

Предметные рубрики MeSH

Humans Genome-Wide Association Study Polymorphism, Single Nucleotide Male Lipids Female Gene-Environment Interaction Adult Genetic Loci Middle Aged Social Support

Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.

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Аннотация

Предметные рубрики MeSH