Genetic Confounding of the Association Between Age at First Hormonal Contraception and Depression

Previous research has shown that females who use hormonal contraception are at increased risk of developing depression, and that the risk is highest among adolescents. While this finding could reflect age-specific effects of exogenous hormones on mental health, genetic liability for mental disorders could be confounding the association. Our goal was to test the plausibility of this hypothesis by determining whether polygenic liabilities for major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ), and attention deficit hyperactivity disorder (ADHD) are associated with younger age at hormonal contraception initiation.

We conducted a cohort study using data from the Danish iPSYCH2015 sub-cohort, a representative sample of people born in Denmark between May 1981 and December 2008. Polygenic scores (PGSs) for MDD, BD, SCZ, and ADHD were created using the most recent genome-wide association study meta-analyses from the Psychiatric Genomics Consortium. Associations between PGSs and hormonal contraception initiation in the following age categories: 10-14, 15-19, 20-24, and 25+ were examined via Cox regression. We examined any hormonal contraception, oral contraception, and non-oral contraception.

PGS-MDD and PGS-ADHD showed the strongest associations with hormonal contraception initiation at age 10-14 (PGS-ADHD: HR = 1.21 [95% CI = 1.16-1.27], p = 6.16 x 10^-18; PGS-MDD: 1.21 [1.16-1.27], p = 1.22 x 10^-17). The associations then steadily decreased as age at hormonal contraception initiation increased. Both PGS-MDD and PGS-ADHD were also associated with initiation at ages 15-19, but not at 20-24 or 25+. PGS-BD and PGS-SCZ were also associated, albeit not as strongly, with initiation at age 10-14 only (PGS-BD: 1.07 [1.02-1.13], p = 6.87 × 10^-3; PGS-SCZ: 1.09 [1.04-1.14], p = 8.61 × 10^-4).

These results suggest that genetic confounding could explain some of the association between early hormonal contraception use and depression. Where possible, researchers studying this important topic should account for possible confounding by genetic liability for mental disorders.