Mundy Jessica, Hall Alisha S M, Agerbo Esben, Albiñana Clara, Steinbach Jette, Vilhjálmsson Bjarni J, Østergaard Søren D, Musliner Katherine L
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Department of Affective Disorders, Aarhus University Hospital-Psychiatry, Aarhus, Denmark.
Acta Psychiatr Scand. 2025 Apr;151(4):529-536. doi: 10.1111/acps.13774. Epub 2025 Jan 2.
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; PGS-MDD: 1.21 [1.16-1.27], p = 1.22 x 10). 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; PGS-SCZ: 1.09 [1.04-1.14], p = 8.61 × 10).
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.
先前的研究表明，使用激素避孕的女性患抑郁症的风险增加，且该风险在青少年中最高。虽然这一发现可能反映了外源性激素对心理健康的年龄特异性影响，但精神障碍的遗传易感性可能会混淆这种关联。我们的目标是通过确定重度抑郁症（MDD）、双相情感障碍（BD）、精神分裂症（SCZ）和注意力缺陷多动障碍（ADHD）的多基因易感性是否与开始使用激素避孕的年龄较小有关，来检验这一假设的合理性。
我们使用丹麦iPSYCH2015子队列的数据进行了一项队列研究，该子队列是1981年5月至2008年12月在丹麦出生人群的代表性样本。使用精神基因组学联盟最新的全基因组关联研究荟萃分析创建了MDD、BD、SCZ和ADHD的多基因分数（PGS）。通过Cox回归检查PGS与以下年龄组开始使用激素避孕之间的关联：10 - 14岁、15 - 19岁、20 - 24岁和25岁及以上。我们研究了任何激素避孕、口服避孕和非口服避孕情况。
PGS - MDD和PGS - ADHD与10 - 14岁开始使用激素避孕的关联最强（PGS - ADHD：风险比[HR] = 1.21 [95%置信区间（CI）= 1.16 - 1.27]，p = 6.16×10；PGS - MDD：1.21 [1.16 - 1.27]，p = 1.22×10）。随着开始使用激素避孕年龄的增加，这种关联随后稳步下降。PGS - MDD和PGS - ADHD与15 - 19岁开始使用激素避孕也有关联，但与20 - 24岁或25岁及以上无关。PGS - BD和PGS - SCZ也仅与10 - 14岁开始使用激素避孕有关联，尽管关联强度较弱（PGS - BD：1.07 [1.02 - 1.13]，p = 6.87×10；PGS - SCZ：1.09 [1.04 - 1.14]，p = 8.61×10）。
这些结果表明，遗传混杂因素可能解释了早期使用激素避孕与抑郁症之间的部分关联。在研究这一重要课题时，研究人员应尽可能考虑精神障碍遗传易感性可能造成的混杂影响。
