Dissecting the shared genetic architecture between testosterone traits and attention-deficit/hyperactivity disorder

Area of Science:

• Neurogenetics
• Endocrinology
• Psychiatry

Background:

• Attention-deficit/hyperactivity disorder (ADHD) exhibits sex differences, with potential links to testosterone, though the exact relationship is unclear.
• Understanding the genetic interplay between ADHD and testosterone is crucial for elucidating underlying biological mechanisms.

Purpose of the Study:

• To investigate the genetic correlation and polygenic overlap between ADHD and testosterone traits (total testosterone, bioavailable testosterone, SHBG).
• To identify shared genomic loci and explore biological mechanisms through functional annotation.

Main Methods:

• Utilized genome-wide association study data for ADHD and testosterone traits.
• Employed MiXeR for polygenic overlap quantification and conjunctional false discovery rate (conjFDR) for shared loci identification.
• Performed functional annotation using the FUMA tool.

Main Results:

• Found negative genetic correlations between total testosterone (TT) and ADHD, and sex hormone-binding globulin (SHBG) and ADHD; a positive correlation was observed for bioavailable testosterone (BT) and ADHD.
• Over one-third of testosterone-associated variants potentially impact ADHD.
• Identified 22-51 shared genomic loci, including MCM9 and MANBA, implicated in signal transduction, synapses, cell differentiation, and neurogenesis.

Conclusions:

• Reported substantial polygenic overlap between ADHD and testosterone traits.
• Identified shared genomic loci suggesting common biological mechanisms.
• Highlighted the involvement of glutamatergic synapses and neurogenesis in the interplay between ADHD and testosterone levels.