Cross-sectional and longitudinal observational studies have shown that higher levels of testosterone are associated with better lung function in men and a small attenuation of lung function decline in women. We used multivariable Mendelian randomization (MVMR), which is not affected by classical confounding, to assess the independent causal effect of total testosterone (TT) and sex hormone-binding globulin (SHBG) on lung function (FVC and FEV₁/FVC) in men and women.

To select SNPs associated with TT and SHBG for MR, we performed genome-wide association studies and replicated results in independent UK Biobank samples (N=323,144/161,572). SNPs were considered replicated with same direction of effect and p-value < Bonferroni corrected p-value. For each replicated SNP, we estimated the effect on pre-bronchodilator lung function in UK Biobank (N=341,826) separately by sex adjusting for age, age², height, genotyping batch, and centre and accounting for population stratification/relatedness (BOLT-LMM). We used several MVMR methods to investigate and adjust for pleiotropy. We performed subgroup analyses by level of moderate physical activity and by menopausal status in women. To assess a possible source of pleiotropy, we removed 25 SNPs associated with weight/obesity related outcomes.

For TT, we replicated 63 SNP in females and 92 SNPs in males, and 308 SNPs were associated with SHBG in both sexes. In women, the MVMR analyses suggest that a natural log increase in TT is associated with a 33.9 mL increase in FVC independently of SHBG (figure 1A). Stratified analyses showed a beneficial effect of SHBG on FVC in physically active and post-menopausal women. In males, the MVMR analyses suggest that a log increase in SHBG is associated with 0.62% lower FEV₁/FVC and 54.6 mL higher FVC independently of TT (figure 1A/B). However, no associations were found with TT in males in the main analysis nor subgroup analyses. For all analyses there was an indication of high heterogeneity (Q statistic p-value <0.0001), however results remained similar after removing SNPs associated with weight/obesity.

Our MR analyses show that higher hormone levels are associated with better lung function, with higher TT levels being beneficial for FVC in women and higher SHBG levels being beneficial for FVC in males.

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Abstract T2 Figure 1

The association of total testosterone (TT) and sex hormone-binding (SHBG) with FVC (A) and FEV:/FVC (B) in MVMR analyses separately per sex. Effect estimates show the difference in lung function (mL or%) per log increase in hormone level for 4 MR methods: Two-Stage Least Squares regression (2SLS), fixed-effect (F-IVW) and random-effect (R-IVW) inverse variance-weighted (IVW) meta-analysis; and MR-Egger.