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Genome-wide association study of semen volume, sperm concentration, testis size, and plasma inhibin B levels

Journal of Human Genetics volume 65, pages 683–691 (2020)Cite this article

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Abstract

Semen quality is affected by environmental factors, endocrine function abnormalities, and genetic factors. A GWAS recently identified ERBB4 at 2q34 as a genetic locus associated with sperm motility. However, GWASs for human semen volume and sperm concentration have not been conducted. In addition, testis size also reportedly correlates with semen quality, and it is important to identify genes that affect testis size. Reproductive hormones also play an important role in spermatogenesis. To date, genetic loci associated with plasma testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels have been identified using GWASs. However, GWASs have not identified any relevant loci for plasma inhibin B levels. We conducted a two-stage GWAS using 811 Japanese men in a discovery stage followed by a replication stage using an additional 721 Japanese men. The results of the discovery and replication stages were combined into a meta-analysis. After setting a suggestive significance threshold for P values < 5 × 10−6　in the discovery stage, we identified ten regions with SNPs (semen volume: one, sperm concentration: three, testes size: two, and inhibin B: four). We selected only the most significant SNP in each region for replication genotyping. Combined discovery and replication results in the meta-analysis showed that the locus 12q21.31 associated with plasma inhibin B levels (rs11116724) had the most significant association (P = 5.7 × 10−8). The LRRIQ1 and TSPAN19 genes are located in the 12q21.31 region. This study provides new susceptibility variants that contribute to plasma inhibin B levels.

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References

  1. World Health Organization Department of Reproductive Health and Research. WHO laboratory manual for the examination and processing of human semen, 5th edn. World Health Organization, 2010.

  2. Zhang J, Ding X, Li Y, Xia Y, Nie J, Yi C, et al. Association of CLOCK gene variants with semen quality in idiopathic infertile Han-Chinese males. Reprod Biomed Online. 2012;25:536–42.

    Article  CAS  Google Scholar 

  3. Zhao D, Wu W, Xu B, Niu X, Cui H, Zhang Y, et al. Variants in the SRD5A2 gene are associated with quality of semen. Mol Med Rep. 2012;6:639–44.

    Article  CAS  Google Scholar 

  4. Tüttelmann F, Krenková P, Römer S, Nestorovic AR, Ljujic M, Stambergová A, et al. A common haplotype of protamine 1 and 2 genes is associated with higher sperm counts. Int J Androl. 2010;33:e240–8.

    Article  Google Scholar 

  5. Teng YN, Chang YP, Tseng JT, Kuo PH, Lee IW, Lee MS, et al. A single-nucleotide polymorphism of the DAZL gene promoter confers susceptibility to spermatogenic failure in the Taiwanese Han. Hum Reprod. 2012;27:2857–65.

    Article  CAS  Google Scholar 

  6. Sato Y, Tajima A, Katsurayama M, Nozawa S, Yoshiike M, Koh E, et al. A replication study of a candidate locus for follicle-stimulating hormone levels and association analysis for semen quality traits in Japanese men. J Hum Genet. 2016;61:911–5.

    Article  CAS  Google Scholar 

  7. Lindgren KE, Nordqvist S, Kårehed K, Sundström-Poromaa I, Åkerud H. The effect of a specific histidine-rich glycoprotein polymorphism on male infertility and semen parameters. Reprod Biomed Online. 2016;33:180–8.

    Article  CAS  Google Scholar 

  8. Pan L, Liu Q, Li J, Wu W, Wang X, Zhao D, et al. Association of the VDAC3 gene polymorphism with sperm count in Han-Chinese population with idiopathic male infertility. Oncotarget. 2017;8:45242–8.

    Article  Google Scholar 

  9. Sato Y, Tajima A, Sato T, Nozawa S, Yoshiike M, Imoto I, et al. Genome-wide association study identifies ERBB4 on 2q34 as a novel locus associated with sperm motility in Japanese men. J Med Genet. 2018;55:415–21.

    Article  CAS  Google Scholar 

  10. Sakamoto H, Yajima T, Nagata M, Okumura T, Suzuki K, Ogawa Y. Relationship between testicular size by ultrasonography and testicular function: measurement of testicular length, width, and depth in patients with infertility. Int J Urol. 2008;15:529–33.

    Article  Google Scholar 

  11. Belchetz PE, Plant TM, Nakai EJ, Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978;202:631–3.

    Article  CAS  Google Scholar 

  12. Smith MA, Vale WW. Desensitization to gonadotropin-releasing hormone observed in superfused pituitary cells on Cytodex beads. Endocrinology. 1981;108:752–9.

    Article  CAS  Google Scholar 

  13. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26:833–76.

    Article  CAS  Google Scholar 

  14. McLachlan RI, O’Donnell L, Meachem. SJ, Stanton PG, De Kretser DM, Pratis K, et al. Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys and man. Recent Prog Horm Res. 2002;57:149–79.

    Article  CAS  Google Scholar 

  15. Schlatt S, Ehmcke J. Regulation of spermatogenesis: an evolutionary biologist’s perspective. Semin Cell Dev Biol. 2014;29C:2–16.

    Article  Google Scholar 

  16. Kuijper EA, Lambalk CB, Boomsma DI, van der Sluis S, Blankenstein MA, de Geus EJ, et al. Heritability of reproductive hormones in adult male twins. Hum Reprod. 2007;22:2153–9.

    Article  CAS  Google Scholar 

  17. Ohlsson C, Wallaschofski H, Lunetta KL, Stolk L, Perry JR, Koster A, et al. Genetic determinants of serum testosterone concentrations in men. PLoS Genet. 2011;7:e1002313.

    Article  CAS  Google Scholar 

  18. Jin G, Sun J, Kim ST, Feng J, Wang Z, Tao S, et al. Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men. Hum Mol Genet. 2012;21:5222–8.

    Article  CAS  Google Scholar 

  19. Chen Z, Tao S, Gao Y, Zhang J, Hu Y, Mo L, et al. Genome-wide association study of sex hormones, gonadotropins and sex hormone-binding protein in Chinese men. J Med Genet. 2013;50:794–801.

    Article  CAS  Google Scholar 

  20. Coviello AD, Haring R, Wellons M, Vaidya D, Lehtimäki T, Keildson S, et al. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. PLoS Genet. 2012;8:e1002805.

    Article  CAS  Google Scholar 

  21. Ruth KS, Campbell PJ, Chew S, Lim EM, Hadlow N, Stuckey BG, et al. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. Eur J Hum Genet. 2016;24:284–90.

    Article  CAS  Google Scholar 

  22. Iwamoto T, Nozawa S, Mieno MN, Yamakawa K, Baba K, Yoshiike M, et al. Semen quality of 1559 young men from four cities in Japan: a cross-sectional population-based study. BMJ Open. 2013;3:e002222.

    Article  Google Scholar 

  23. Iwamoto T, Nozawa S, Yoshiike M, Namiki M, Koh E, Kanaya J, et al. Semen quality of fertile Japanese men: a cross-sectional population-based study of 792 men. BMJ Open. 2013;3:e002223.

    Article  Google Scholar 

  24. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    Article  CAS  Google Scholar 

  25. Browning SR, Browning BL. Rapid and accurate haplotype phasing and missing data inference for whole genome association studies by use of localized haplotype clustering. Am J Hum Genet. 2007;81:1084–97.

    Article  CAS  Google Scholar 

  26. Browning BL, Browning SR. Genotype imputation with millions of reference samples. Am J Hum Genet. 2016;98:116–26.

    Article  CAS  Google Scholar 

  27. The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526:68–74.

    Article  Google Scholar 

  28. The 1000 Genomes Project Consortium. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526:75–81.

    Article  Google Scholar 

  29. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    Article  Google Scholar 

  30. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7.

    Article  CAS  Google Scholar 

  31. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–4.

    Article  CAS  Google Scholar 

  32. GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5.

    Article  Google Scholar 

  33. Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.

    Article  CAS  Google Scholar 

  34. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen‐2. Curr Protoc Hum Genet. 2013;chapter7:unit7.20. https://doi.org/10.1002/0471142905.hg0720s76.

  35. Huttlin EL, Bruckner RJ, Paulo JA, Cannon JR, Ting L, Baltier K, et al. Architecture of the human interactome defines protein communities and disease networks. Nature. 2017;545:505–9.

    Article  CAS  Google Scholar 

  36. Mathews LS, Vale WW. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991;65:973–2.

    Article  CAS  Google Scholar 

  37. Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM, et al. Betaglycan binds inhibin and can mediate functional antagonism of activin signaling. Nature. 2000;404:411–4.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to the late Prof. Yutaka Nakahori and Profs. Eitetsue Koh, Jiro Kanaya, Mikio Namiki, Kiyomi Matsumiya, Akira Tsujimura, Kiyoshi Komatsu, Naoki Itoh, and Jiro Eguchi for collecting blood samples from participants. We also thank Prof. Toyomasa Katagiri for his assistance with the AB GeneAmp PCR system 9700. This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to TI), Grant-in-Aids for Scientific Research (C) (26462461) (to YS), (23510242) (to AT), and Grant-in-Aids for Scientific Research (B) (17H04331) (to YS), (15H04320) (to AT) from the Japan Society for the Promotion of Science, and the European Union (BMH4-CT96-0314) (to TI). We would like to thank Editage (www.editage.com) for English language editing.

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Authors and Affiliations

  1. Department of Pharmaceutical Information Science, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8505, Japan

    Youichi Sato, Misaki Kiguchi, Suzu Kogusuri & Aki Fujii

  2. Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Ishikawa, 920-8640, Japan

    Atsushi Tajima & Takehiro Sato

  3. Department of Urology, St. Marianna University School of Medicine, Kanagawa, 216-8511, Japan

    Shiari Nozawa, Miki Yoshiike & Teruaki Iwamoto

  4. Department of Medical Informatics, Center for Information, Jichi Medical University, Tochigi, 329-0498, Japan

    Makiko Mieno

  5. Center for Infertility and IVF, International University of Health and Welfare Hospital, Tochigi, 329-2763, Japan

    Kosuke Kojo, Masahiro Uchida, Haruki Tsuchiya, Kazumitu Yamasaki & Teruaki Iwamoto

  6. Department of Urology, University of Tsukuba Hospital, Ibaraki, 305-8576, Japan

    Kosuke Kojo

  7. Urology department, Tsukuba Gakuen Hospital, Ibaraki, 305-0854, Japan

    Masahiro Uchida & Kazumitu Yamasaki

  8. Division of Molecular Genetics, Aichi Cancer Center Research Institute, Aichi, 464-8681, Japan

    Issei Imoto

  9. Department of Male Infertility, Reproduction Center, Sanno Hospital, Tokyo, 107-0052, Japan

    Teruaki Iwamoto

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  1. Youichi Sato
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Correspondence to Youichi Sato or Atsushi Tajima.

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Sato, Y., Tajima, A., Kiguchi, M. et al. Genome-wide association study of semen volume, sperm concentration, testis size, and plasma inhibin B levels. J Hum Genet 65, 683–691 (2020). https://doi.org/10.1038/s10038-020-0757-3

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