AUTHOR=Al-Khelaifi Fatima , Yousri Noha A. , Diboun Ilhame , Semenova Ekaterina A. , Kostryukova Elena S. , Kulemin Nikolay A. , Borisov Oleg V. , Andryushchenko Liliya B. , Larin Andrey K. , Generozov Edward V. , Miyamoto-Mikami Eri , Murakami Haruka , Zempo Hirofumi , Miyachi Motohiko , Takaragawa Mizuki , Kumagai Hiroshi , Naito Hisashi , Fuku Noriyuki , Abraham David , Hingorani Aroon , Donati Francesco , Botrè Francesco , Georgakopoulos Costas , Suhre Karsten , Ahmetov Ildus I. , Albagha Omar , Elrayess Mohamed A. TITLE=Genome-Wide Association Study Reveals a Novel Association Between MYBPC3 Gene Polymorphism, Endurance Athlete Status, Aerobic Capacity and Steroid Metabolism JOURNAL=Frontiers in Genetics VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.00595 DOI=10.3389/fgene.2020.00595 ISSN=1664-8021 ABSTRACT=Background

The genetic predisposition to elite athletic performance has been a controversial subject due to the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis.

Results

The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n = 662) and low/moderate (n = 134) aerobic component. Replication of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P = 1.43 × 10−8, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA + AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82 × 10–05) including the testosterone precursor androstenediol (3beta,17beta) disulfate.

Conclusions

This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted.