A GWAS in Idiopathic/Unexplained Infertile Men Detects a Genomic Region Determining Follicle-Stimulating Hormone Levels

Abstract

Purpose Around 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic. Follicle stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single nucleotide polymorphisms (SNP) (i.e. FSHB c.-211G>T, FSHR c.2039A>G) are associated with FSH, testicular volume and spermatogenesis. It is unknown to which extent other variants are associated with FSH levels and therewith resemble causative factors for infertility. Methods We retrospectively (2010-2018) selected 1900 men with idiopathic/unexplained infertility. In the discovery study (n=760) a Genome wide association study (GWAS) was performed (Infinium PsychArrays®) with association to FSH values (Illumina®GenomeStudiov2.0). Minor allele frequencies (MAFs) were analyzed for the discovery – and an independent normozoospermic cohort. In the validation study (n=1140) TaqMan SNP-PCR was conducted for rs10031005 and rs10835638 with association to andrological parameters. Results Imputation revealed nine SNPs in high linkage disequilibrium, with genome-wide significance (p <4.28e-07) at the FSHB locus 11p.14.1 being associated with FSH. The nine SNPs accounted for up to 4.65% variance in FSH level. In the oligozoospermic subgroup this was increased up to 6.95% and the MAF was enhanced compared to an independent cohort of normozoospermic men. By validation significant association for rs110031005/rs10835638 with FSH (p=4.71e-06/5.55e-07) and FSH/LH ratio (p=2.08e-12/6.4e-12) was evident. Conclusions This GWAS delineates the polymorphic FSHB genomic region as main determinant for FSH levels in men with unexplained or idiopathic infertility. Given the essential role of FSH, molecular detection of one of the identified SNPs, that cause lowered FSH and therewith decreased spermatogenesis, could resolve the idiopathic/unexplained origin by this etiologic factor.

Follicle‐stimulating hormone effectiveness in male idiopathic infertility: What happens in daily practice?

“…This is the first demonstration of FSH clinical efficacy in azoospermia, which is generally excluded from clinical trials. A recent genome wide association study confirmed the higher incidence of genetic abnormalities in patients with non‐obstructive azoospermia 55 . In particular, a genomic region on chromosome 11p14.1, bearing the FSHβ gene, seems to be the main genetic determinant affecting FSH serum levels and thereby FSH action 55 .…”

“…A recent genome wide association study confirmed the higher incidence of genetic abnormalities in patients with non-obstructive azoospermia. 55 In particular, a genomic region on chromosome 11p14.1, bearing the FSHβ gene, seems to be the main genetic determinant affecting FSH serum levels and thereby FSH action. 55 Beyond diagnostic implications, this finding may justify FSH administration in azoospermic patients carrying genetic variants of FSHB, aimed at increasing FSH serum levels, thus potentiating its action on spermatogenesis.…”

“…55 In particular, a genomic region on chromosome 11p14.1, bearing the FSHβ gene, seems to be the main genetic determinant affecting FSH serum levels and thereby FSH action. 55 Beyond diagnostic implications, this finding may justify FSH administration in azoospermic patients carrying genetic variants of FSHB, aimed at increasing FSH serum levels, thus potentiating its action on spermatogenesis. Obviously, our result must be carefully evaluated, particularly considering the aetiopathogenic heterogeneity of non-obstructive azoospermia.…”

Translational Bioinformatics for Human Reproductive Biology Research: Examples, Opportunities and Challenges for a Future Reproductive Medicine

“…It follows that reproductive disorders associated with female infertility are often not the result of variations in a single candidate gene, but rather the interactions of multiple genes with each other and with the environment. Similarly, the same candidate loci may share the similar regulatory mechanisms in male infertility [101,102], and may also cause oocyte maturation disorder, abnormal zona pellucida and aberrant meiosis, manifesting as fertility disorders such as embryonic arrest, recurrent miscarriages or repeated embryo implantation disorders during ART [103][104][105]. There may also be a common genetic basis for clinical phenotypes [106][107][108] such as obesity, menstrual disorders, pelvic floor dysfunction, lower fetal birth weight and other systemic or psychological disorders [109][110][111][112][113] such as tumors, cardiovascular disease, diabetes and depression.…”