Causal effects of serum sex hormone binding protein levels on the risk of amyotrophic lateral sclerosis: a mendelian randomization study

BACKGROUND: Extensive observational studies have suggested an association between serum sex-hormone binding globulin (SHBG) and Alzheimer’s disease (AD); however, causality remains unclear. Furthermore, the effects on other neurodegenerative diseases have been poorly investigated. We aimed to explore the causal effects of genetically predicted SHBG serum levels on common neurodegenerative diseases. METHODS: A two-sample Mendelian randomization (MR) approach was used. Genetic variants of SHBG levels in the serum, detected using the chemiluminescent two-step sandwich immunoassay method, were identified from a genome-wide association meta-analysis from the UK Biobank (N=363,228). Summary-level data for AD, and other common neurodegenerative diseases including Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) were adopted from the corresponding large genome-wide association studies of individuals of European ancestry, which were either clinically or autopsy-diagnosed. Causal estimates were calculated using the inverse-variance weighted (IVW) method and several sensitivity methods (MR-Egger, weighted median, and weighted mode). Egger intercept, MR-PRESSO, and leave-one-out analyses were used to identify potential violations. RESULTS: Genetically determined serum SHBG levels [odds ratio (OR(IVW)) =1.113, 95% CI: 1.019–1.215, P=0.017] were associated with an increased risk of ALS. This causal effect was confirmed using sensitivity analyses, including the MR-Egger (OR =1.229, 95% CI: 1.049–1.441, P=0.012), weighted median (OR =1.231, 95% CI: 1.077–1.406, P=0.002), and weighted mode (OR =1.235, 95% CI: 1.067–1.431, P=0.005) methods. No notable heterogeneity or directional pleiotropy was observed. However, leave-one-out analysis showed that rs9892297 drove the observed effects. There was no evidence that genetically predicted serum SHBG levels affect other neurodegenerative diseases, including AD, PD, MS, DLB, and FTD (all P>0.05). CONCLUSIONS: This MR analysis found that genetically determined serum SHBG was associated with an increased risk of ALS rather than AD, which is inconsistent with previous observational studies. This novel finding highlights the potential of SHBG in peripheral serum for ALS prevention. Further research into the effects of SHBG on other neurodegenerative diseases is required, especially because of the increased utilization of hormone therapy.