Polymorphisms in JMJD1C are associated with pubertal onset in boys and reproductive function in men

Nina Mørup,Loa Nordkap,Kristian Almstrup,John E Nielsen,Alexander Siegfried Busch,Anne Kirstine Bang,Anders Juul,Ewa Rajpert-De Meyts,Niels Jørgensen

doi:10.1038/s41598-017-17575-9

Abstract

JMJD1C, a member of the Jumonji-domain containing histone demethylases protein family, has been associated with levels of sex-hormone binding globulin (SHBG) and testosterone in men, and knock-out rodent models show age-dependent infertility. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) nearby JMJD1C are associated with pubertal onset in boys and with male reproduction. 671 peri-pubertal boys, 1,027 young men, 315 fertile men, and 252 infertile men were genotyped for two JMJD1C SNPs (rs7910927 and rs10822184). rs7910927 and rs10822184 showed high linkage. Boys with the rs7910927 TT genotype entered puberty 3.6 months earlier than their peers (p = 2.5 × 10−2). In young men, the number of T alleles was associated with decreased levels of SHBG, follicle-stimulating hormone (FSH), testosterone, and testosterone x luteinizing hormone, as well as increased levels of Inhibin B, Inhibin B/FSH ratio, and testis size. No significant associations with semen parameters were observed and the genotype distribution was comparable among fertile and infertile men. In conclusion, genetic variation in the vicinity of JMJD1C had a surprisingly large impact on the age at pubertal onset in boys as well as levels of reproductive hormones and testis size in men, emphasizing the relationship between JMJD1C and reproductive functions.

Highlights

Male reproduction is a strictly regulated process
We show that the two JMJD1C single nucleotide polymorphisms (SNPs) are significantly associated with circulating levels of sex-hormone binding globulin (SHBG) and testosterone in accordance with previous studies, and with age at pubertal onset in boys as well as testicular volume and levels of follicle-stimulating hormone (FSH) and Inhibin B in young men
We did not calculate the linkage in the smaller cohorts of fertile and infertile men, since they were only genotyped for the rs7910927 SNP

Summary

Introduction

Male reproduction is a strictly regulated process. The process relies on proper testicular development and hormonal feedback loops that have to be well-balanced for optimal reproductive function. Recent genome-wide association studies (GWAS) with focus on reproductive hormones, such as Sex Hormone-Binding Globulin (SHBG)[2] and testosterone (T)[3] in men, have revealed associations with two single nucleotide polymorphisms (SNPs) (rs7910927 and rs10822184, respectively) within or in close proximity to the jumonji domain-containing 1 C (JMJD1C) gene. Large GWAS have identified several SNPs in JmjC-domain containing loci associated with age at menarche in girls[10] and type 2 diabetes in adult men and women[11]. We show that the two JMJD1C SNPs are significantly associated with circulating levels of SHBG and testosterone in accordance with previous studies, and with age at pubertal onset in boys as well as testicular volume and levels of FSH and Inhibin B in young men

Objectives

Results

Conclusion