As the prevalence of metabolic syndrome (MetS) in children and young adults is increasing, a better understanding of genetics that underlie MetS will provide critical insights into the origin of the disease. We examined associations of common genetic variants and repeated MetS score from early childhood to adolescence in a pan-european, prospective iDeficS/i.family cohort study with baseline survey and follow-up examinations after two and six years. We tested associations in 3067 children using a linear mixed model and confirmed the results with meta-analysis of identified SNPs. With a stringent Bonferroni adjustment for multiple comparisons we obtained significant associations(p < 1.4 × 10 −4 ) for 5 SNPs, which were in high LD (r 2 > 0.85) in the 16q12.2 non-coding intronic chromosomal region of FTO gene with strongest association observed for rs8050136 (effect size(β) = 0.31, p Wald = 1.52 × 10 −5 ). We also observed a strong association of rs708272 in CETP with increased HDL (p = 5.63 × 10 −40 ) and decreased tRG (p = 9.60 × 10 −5 ) levels. These findings along with meta-analysis advance etiologic understanding of childhood MetS, highlighting that genetic predisposition to MetS is largely driven by genes of obesity and lipid metabolism. inclusion of the associated genetic variants in polygenic scores for MetS may prove to be fundamental for identifying children and subsequently adults of the high-risk group to allow earlier targeted interventions.A collection of risk factors, including central obesity, insulin resistance, dyslipidemia, and hypertension, describes metabolic syndrome (MetS). Additionally, MetS is a known precursor in cardiovascular disease development 1 . MetS has become a major public health concern globally due to its increasing prevalence and association with various chronic diseases 2 . MetS etiology is quite complex, involving a strong interplay between multiple genetic, environmental and lifestyle-related factors. In European ancestry, the heritability of the MetS was estimated to be between 13-30% 3,4 . The early prognosis of MetS is therefore extremely valuable for early detection of individuals at high genetic risk of developing the disease later in life and for encouraging change in lifestyle to reduce risk. While numerous single nucleotide polymorphisms (SNPs) associated with individual metabolic components and diseases have been reported in genome-wide association studies (GWAS) 5-8 , the effect of these polymorphisms on the MetS network and related diseases is not well studied.Further, of all MetS components, lipid levels seem under higher genetic determination 9 . This has also been observed in the genetic association studies suggesting that genetic effects on lipid levels are more pronounced than for other traits 10 . Most of the genetic association studies for MetS have been conducted in adult population 5,10,11 and are limited by the usage of one-point measurements 7,[12][13][14] . As the prevalence of MetS in children and young adults is increasing 15 , a better understanding ...
