| Summary: | Adult height is inversely related to metabolic syndrome (MetS) risk, but its genetic impacts have not been revealed. The present study aimed to examine the hypothesis that adult height-related genetic variants interact with lifestyle to influence adult height and are associated with MetS risk in adults aged >40 in Korea during 2010–2014. Participants were divided into short stature (SS; control) and tall stature (TS; case) by the 85th percentile of adult height. The genetic variants linked to adult height were screened from a genome-wide association study in a city hospital-based cohort (n = 58,701) and confirmed in Ansan/Ansung plus rural cohorts (n = 13,783) among the Korean Genome and Epidemiology Study. Genetic variants that interacted with each other were identified using the generalized multifactor dimensionality reduction (GMDR) analysis. The interaction between the polygenic risk score (PRS) of the selected genetic variants and lifestyles was examined. Adult height was inversely associated with MetS, cardiovascular diseases, and liver function. The PRS, including zinc finger and BTB domain containing 38 (<i>ZBTB38</i>)_rs6762722, polyadenylate-binding protein-interacting protein-2B (<i>PAIP2B</i>)_rs13034890, carboxypeptidase Z (<i>CPZ</i>)_rs3756173, and latent-transforming growth factor beta-binding protein-1 (<i>LTBP1</i>)_rs4630744, was positively associated with height by 1.29 times and inversely with MetS by 0.894 times after adjusting for covariates. In expression quantitative trait loci, the gene expression of growth/differentiation factor-5 (<i>GDF5</i>)_rs224331, non-SMC condensin I complex subunit G (<i>NCAPG</i>)_rs2074974, ligand-dependent nuclear receptor corepressor like (<i>LCORL</i>)_rs7700107, and insulin-like growth factor-1 receptor (<i>IGF1R</i>)_rs2871865 was inversely linked to their risk allele in the tibial nerve and brain. The gene expression of <i>PAIP2B</i>_rs13034890 and a disintegrin and metalloproteinase with thrombospondin motifs-like-3 (<i>ADAMTSL3</i>)_rs13034890 was positively related to it. The PRS was inversely associated with MetS, hyperglycemia, HbA1c, and white blood cell counts. The wild type of <i>GDF5</i>_rs224331 (Ala276) lowered binding energy with rugosin A, D, and E (one of the hydrolyzable tannins) but not the mutated one (276Ser) in the in-silico analysis. The PRS interacted with energy intake and rice-main diet; PRS impact was higher in the high energy intake and the low rice-main diet. In conclusion, the PRS for adult height interacted with energy intake and diet patterns to modulate height and was linked to height and MetS by modulating their expression in the tibial nerve and brain.
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