Hormone profiling of adults with the GNRH1 p.W16S variant and its implications in fertility

Abstract

Idiopathic Hypogonadotropic Hypogonadism (IHH) is an oligogenic disorder with many protein coding variants in relevant genes with unknown impact on the disease. This study investigated the effects of the GNRH1 p.W16S variant on hormone levels using secondary data from the MAMI Study collection. Median levels of Luteinizing Hormone, Follicle Stimulating Hormone, Dehydroepiandrosterone sulphate, Sex Hormone Binding Globulin, Oestradiol, and Testosterone were compared with genotype data for the GNRH1 p.W16S variant, to provide insights about the effect of the mutation on hormone levels and by extension on IHH. To achieve this, 991 whole genome sequencing dataset entries from the MAMI study were examined and individuals were categorized according to participant genotype for the GNRH1 p.W16S mutation. PCR techniques were used and optimised to validate the sequencing data, and the genotyping results were confirmed by Sanger sequencing. Finally, hormone levels were analysed according to genotype within relevant subgroups that were identified through demographic analysis, including sex, case-control-relative status, and age, with the latter divided into 10-year intervals. This analysis showed the variant GNRH1 p.W16S decreases testosterone levels in men over the age of 50, seen with a p-value of 0.027.