Sex-specific genetic scores for depression show distinct brain links in early adolescence

Depression does not leave the same molecular fingerprint in female and male brains, and a new study suggests those differences may begin shaping risk long before adolescence ends. Researchers have built separate genetic scores that estimate how closely an individual’s genome matches depression-related patterns of brain gene activity in each sex, then tracked what those scores predicted in thousands of children. The results show that the female and male scores point to different brain structures and different behavioral outcomes, with no crossover between the sexes.

The work, published in Biology of Sex Differences, centers on a tool called a transcriptome-based polygenic risk score, or tPRS. The tPRS approach takes a different route: it starts with genes whose activity is measurably altered in the brains of people with major depressive disorder, then asks how strongly a person’s genetic profile aligns with those transcriptional patterns. In earlier work, the team used genes altered in depression in both sexes combined and found sex-specific associations with brain structure and depressive symptoms in adolescents and adults.

For the new study, the researchers leveraged sex-specific MDD gene expression data to construct two distinct scores: a female-specific tPRS, called tPRS-F, and a male-specific tPRS, called tPRS-M. They then evaluated the associations of these scores with regional cortical thickness, cortical surface area, subcortical volume, and depressive symptoms at baseline and 2-year follow-up in 5002 adolescents from the ABCD study. If genetically driven shifts toward a depression-like brain transcriptome leave measurable traces during this period, those traces could reveal the developmental pathways through which early risk takes hold.

The sample was 46.6 percent female, and the children were between 8.9 and 11.0 years old at the start.

The male-specific score told a consistent story. In boys, higher tPRS-M was associated with more depressive symptoms at both the baseline assessment and the two-year follow-up.

The female-specific score painted a different picture entirely. In girls, higher tPRS-F was associated with smaller volumes of the right accumbens area, the right caudate, and the hippocampi on both sides of the brain at follow-up.

Crucially, some of these brain differences did more than correlate with the genetic score. In females, the volumes of the right caudate and right hippocampus partially mediated an indirect association between tPRS-F and depressive symptoms.

Perhaps the most striking result is what did not happen. For each sex-specific score, no effects emerged in the opposite sex. The male score predicted nothing in girls, and the female score predicted nothing in boys.

The findings carry implications for how depression risk is studied and potentially prevented.

The study is observational, and the associations reported here do not establish that the genetic scores cause the brain differences or the symptoms. The two-year follow-up captures only a slice of early adolescence, and the tPRS scores summarize genome-wide alignment with adult depression transcriptomes rather than measuring gene activity in the children’s own brains. Still, the convergence of sex-specific genetic scores, sex-specific brain structure associations, and a partial mediation pathway in girls provides a concrete developmental framework for a disorder whose sex differences have long been recognized but poorly explained.

Subject of Research: Sex-specific transcriptome-based polygenic risk scores for depression and their associations with brain development in early adolescence

Article Title: Distinct neurodevelopmental signatures of sex-specific transcriptome-based polygenic risk scores for depression

Article References: Rashid, S. S., Clifford, K. P., Miles, A. E., Dos Santos, F. C., Felsky, D., Sibille, E., & Nikolova, Y. S. (2026). Distinct neurodevelopmental signatures of sex-specific transcriptome-based polygenic risk scores for depression. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-01006-4

Image Credits: AI Generated

DOI: 10.1186/s13293-026-01006-4

Keywords: major depressive disorder, transcriptome-based polygenic risk score, ABCD study, adolescent brain development, posterior cingulate cortex, hippocampus volume, caudate, accumbens, depressive symptoms, sex differences, gene expression, neurodevelopment