Genome-Wide Association Study Reveals a Novel Association Between MYBPC3 Gene Polymorphism, Endurance Athlete Status, Aerobic Capacity and Steroid Metabolism

Fatima Al-Khelaifi; Noha A Yousri; Ilhame Diboun; Ekaterina A Semenova; Elena S Kostryukova; Nikolay A Kulemin; Oleg V Borisov; Liliya B Andryushchenko; Andrey K Larin; Edward V Generozov; Eri Miyamoto-Mikami; Haruka Murakami; Hirofumi Zempo; Motohiko Miyachi; Mizuki Takaragawa; Hiroshi Kumagai; Hisashi Naito; Noriyuki Fuku; David Abraham; Aroon Hingorani; Francesco Donati; Francesco Botrè; Costas Georgakopoulos; Karsten Suhre; Ildus I Ahmetov; Omar Albagha; Mohamed A Elrayess

doi:10.3389/fgene.2020.00595

Genome-Wide Association Study Reveals a Novel Association Between MYBPC3 Gene Polymorphism, Endurance Athlete Status, Aerobic Capacity and Steroid Metabolism

Front Genet. 2020 Jun 16:11:595. doi: 10.3389/fgene.2020.00595. eCollection 2020.

Authors

Fatima Al-Khelaifi^{1

2}, Noha A Yousri^{3

4}, Ilhame Diboun⁵, Ekaterina A Semenova^{6

7}, Elena S Kostryukova⁶, Nikolay A Kulemin⁶, Oleg V Borisov^{6

8}, Liliya B Andryushchenko⁹, Andrey K Larin⁶, Edward V Generozov⁶, Eri Miyamoto-Mikami¹⁰, Haruka Murakami¹¹, Hirofumi Zempo^{10

12}, Motohiko Miyachi¹¹, Mizuki Takaragawa¹⁰, Hiroshi Kumagai^{10

13}, Hisashi Naito¹⁰, Noriyuki Fuku¹⁰, David Abraham², Aroon Hingorani², Francesco Donati¹⁴, Francesco Botrè¹⁴, Costas Georgakopoulos¹, Karsten Suhre¹⁵, Ildus I Ahmetov^{6

9

16

17}, Omar Albagha^{5

18}, Mohamed A Elrayess¹⁹

Affiliations

¹ Anti-Doping Laboratory Qatar, Doha, Qatar.
² UCL-Medical School, London, United Kingdom.
³ Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Qatar-Foundation, Doha, Qatar.
⁴ Department of Computer and Systems Engineering, Alexandria University, Alexandria, Egypt.
⁵ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁶ Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.
⁷ Department of Biochemistry, Kazan Federal University, Kazan, Russia.
⁸ Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany.
⁹ Department of Physical Education, Plekhanov Russian University of Economics, Moscow, Russia.
¹⁰ Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.
¹¹ Department of Physical Activity Research, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan.
¹² Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan.
¹³ Japanese Society for the Promotion of Science, Tokyo, Japan.
¹⁴ Laboratorio Antidoping, Federazione Medico Sportiva Italiana, Rome, Italy.
¹⁵ Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Qatar-Foundation, Doha, Qatar.
¹⁶ Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom.
¹⁷ Laboratory of Molecular Genetics, Kazan State Medical University, Kazan, Russia.
¹⁸ Center for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
¹⁹ Biomedical Research Institute (BRC), Qatar University, Doha, Qatar.

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 VO₂ _max 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.

Keywords: GWAS; SNP; elite athletes; endurance; metabolites; metabolomics.

Copyright © 2020 Al-Khelaifi, Yousri, Diboun, Semenova, Kostryukova, Kulemin, Borisov, Andryushchenko, Larin, Generozov, Miyamoto-Mikami, Murakami, Zempo, Miyachi, Takaragawa, Kumagai, Naito, Fuku, Abraham, Hingorani, Donati, Botrè, Georgakopoulos, Suhre, Ahmetov, Albagha and Elrayess.