The Potential Effect of Aberrant Testosterone Levels on Common Diseases: A Mendelian Randomization Study

Testosterone has historically been linked to sexual dysfunction; however, it has recently been shown to affect other physical and mental attributes. We attempted to determine whether changes in serum testosterone could play a role in chronic or degenerative diseases. We used two separate genetic instruments comprising of variants from JMJD1C and SHBG regions and conducted a two-sample Mendelian randomization for type II diabetes (T2D), gout, rheumatoid arthritis (RA), schizophrenia, bipolar disorder, Alzheimer's disease and depression. For the JMJD1C locus, one unit increase in log transformed testosterone was significantly associated with RA (OR = 1.69, p = 0.02), gout (OR = 0.469, p = 0.001) and T2D (OR = 0.769, p = 0.048). Similarly, one unit increase in log transformed testosterone using variants from the SHBG locus was associated with depression (OR = 1.02, p < 0.0001), RA (OR = 1.254, p < 0.0001) and T2D (OR = 0.88, p < 0.0001). Our results show that low levels of serum testosterone levels may cause gout and T2D, while higher than normal levels of testosterone may result in RA and depression. Our findings suggest that fluctuations in testosterone levels may have severe consequences that warrant further investigation.