Development of a Genetic Risk Score to predict the risk of overweight and obesity in European adolescents from the HELENA study

Miguel Seral-Cortes,Éva Erhardt,Kurt Widhalm,Anthony Kafatos,Luis Esteban ,Luís A Moreno ,Aline Meirhaeghe,Eva Gesteiro,Sergio Sabroso-Lasa,Jonatan R Ruiz ,Frédéric Gottrand ,Yannis Μanios ,Stefaan De Henauw,Diego Salazar‐Tortosa ,Marcela González‐Gross ,Cristina Molina‐Hidalgo ,Christina Mavrogianni,María Plada ,Pilar De Miguel-Etayo,Idoia Labayen

doi:10.1038/s41598-021-82712-4

Abstract

Obesity is the result of interactions between genes and environmental factors. Since monogenic etiology is only known in some obesity-related genes, a genetic risk score (GRS) could be useful to determine the genetic predisposition to obesity. Therefore, the aim of our study was to build a GRS able to predict genetic predisposition to overweight and obesity in European adolescents. A total of 1069 adolescents (51.3% female), aged 11–19 years participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study were genotyped. The sample was divided in non-overweight (non-OW) and overweight/obesity (OW/OB). From 611 single nucleotide polymorphisms (SNP) available, a first screening of 104 SNPs univariately associated with obesity (p < 0.20) was established selecting 21 significant SNPs (p < 0.05) in the multivariate model. Unweighted GRS (uGRS) was calculated by summing the number of risk alleles and weighted GRS (wGRS) by multiplying the risk alleles to each estimated coefficient. The area under curve (AUC) was calculated in uGRS (0.723) and wGRS (0.734) using tenfold internal cross-validation. Both uGRS and wGRS were significantly associated with body mass index (BMI) (p < .001). Both GRSs could potentially be considered as useful genetic tools to evaluate individual’s predisposition to overweight/obesity in European adolescents.

Highlights

Within European populations, Seyednasrollah et al.[21] computed two weighted genetic risk score (GRS) of 97 and 19 single nucleotide polymorphisms (SNP) previously related to the risk of obesity in two cohorts including 2262 Finnish children and adolescents (3–18 years)
Two GRSs, unweighted GRS (uGRS) and weighted GRS (wGRS), including 21 SNPs associated with body mass index (BMI), were successfully developed to assess the risk of overweight and obesity in European adolescents
There are few previous studies focusing on BMI-specific GRSs with overweight and obesity in European pediatric populations and none exclusively in European adolescents, which reinforces the potential of our GRS analysis

Summary

Introduction

The FTO gene still remains the locus explaining the largest association with obesity in adults, children and a dolescents[7,8] In this regard, previous studies have shown that each copy of the FTO rs9939609 polymorphism A allele is associated with 2.8% higher body fat in European adolescents[9,10]. Within European populations, Seyednasrollah et al.[21] computed two weighted GRS (wGRS) of 97 and 19 SNPs previously related to the risk of obesity in two cohorts including 2262 Finnish children and adolescents (3–18 years). Viljakainen et al.[22] developed a wGRS to predict the risk of overweight and obesity in a cohort of 1142 Finnish preadolescents (11.3 ± 0.2 years) considering body mass index (BMI) and 30 BMI-related SNPs from previous genome-wide association studies (GWAS). As only few studies testing obesity risk in European adolescents with GRSs have been conducted, the aim of the present study was to develop a GRS for overweight and obesity in adolescents participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study

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Results

Conclusion