biostudies-literatureYu CCancer Council VictoriaVicHealth and Cancer Council VictoriaNHMRCAustralian NHMRC1838-1847https://www.ebi.ac.uk/biostudies/studies/S-EPMC9621069biostudies-literatureUnknown17(12)Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (<i>N</i> = 7,431) and validation (<i>N</i> = 4,307) samples. Using paired genetic-methylation data (<i>N</i> = 4,307), gene-environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing EpigeneticsDoes genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?PMC9621069and 504711251553102750510436161164455209057and 1074383105019810116181026892GTN1155163English DRDugue PAMilne RLSouthey MCJoo JESeveri GMakalic EWong EMHopper JLYu CSchmidt DFHodge AMGiles GGBuchanan DDfalseDoes genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (<i>N</i> = 7,431) and validation (<i>N</i> = 4,307) samples. Using paired genetic-methylation data (<i>N</i> = 4,307), gene-environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing 2022-01-01T00:00:00Z2022 Dec2026-04-08T11:44:13.961Z2024-11-15T11:32:07.16ZS-EPMC96210693572637210.1080/15592294.2022.2088038