LAUSR

Which single nucleotide polymorphisms (SNPs) are associated with Follicle stimulating hormone (FSH) levels in men with unexplained infertility and can affect FSH action and spermatogenesis? We identified a genomic region at chromosome 11p.14.1, including nine SNPs, that are significantly associated with FSH levels in men with unexplained infertility. FSH action is essential for the initiation and maintenance of human spermatogenesis. One well-studied SNP, FSHB c.-211G>T (rs10835638), is associated with FSHB mRNA transcription and directly affects FSH serum levels, testicular volume and spermatogenesis. Carriers of a T-allele in this promoter are diagnosed with functional secondary hypogonadism with isolated FSH deficiency. Other genetic variants, for example at the FSHR have been shown to slightly modulate FSH action, however the clinical impact in these variants seems to be low. The so far identified FSH-associated SNPs revealed an impact of up to 2.3 % on FSH serum level variance. A Genome wide association study (GWAS) was performed on a clinically well characterized cohort of 742 men with unexplained infertility (discovery study). Of the nine identified SNPs, validation was performed for rs11031005 and the already described rs10835638 in an independent cohort of 1123 men with unexplained infertility (validation study). Patients were retrospectively selected from our CeRA database Androbase® applying strict selection criteria; DNA was isolated from stored EDTA-blood samples. Informative genetic variants were identified using Illumina PsychArray v1.3. Illumina®GenomeStudio v2.0, PLINK v1.90 and R 3.6.3 were used to perform quantitative association analysis based on normalized FSH values. The validation study was performed using TaqMan PCR for SNP detection and R 3.6.3 for quantitative association to analyze the impact of each SNP on FSH level. Imputation of the GWAS data revealed 94 SNPs with suggestive significance (p < 8.56e-06) and nine SNPs (including rs10835638) with genome-wide significance (p < 4.28e-07). The nine SNPs are all located at the FSHB locus on Chromosome 11p.14.1 and are in high linkage disequilibrium (LD). The validation study of 1123 patients with unexplained infertility for the SNPs rs11003005 and rs10835638 revealed a significant association with FSH (p = 4.71e-06 and p = 5.55e-07) and FSH/LH ratio (p = 2.08e-12 and p = 6.4e-12).The nine significant SNPs accounted for 3.60 –4.65 % variance in FSH serum level each in the entire discovery cohort. In an oligozoospermic subgroup (n = 249) this effect was increased to 4.89 – 6.95 %. This the first GWAS in men with unexplained infertility. This study shows that not one single SNP, but rather a genomic region has an impact on FSH serum level in men with unexplained male infertility. This effect is even more pronounced in the more severe phenotype of oligozoospermic men. The study is restricted to men with unexplained infertility, which might cause a selection bias. Validation and functional evaluation of the eight newly identified SNPs in independent cohorts would emphasize the results more. The sample size of 742 limits detection of loci with smaller effect on FSH levels. The determination of one of the nine SNPs can improve diagnostic precision in identifying men with secondary functional hypogonadism with isolated FSH deficiency. An oligozoospermic subgroup of these men would putatively benefit from FSH treatment and has to be proven in randomized controlled trials. German Research Foundation CRU326