Polygenic Scores Clarify the Relationship Between Mental Health and Gender Diversity

Gender-diverse individuals are at increased risk for mental health problems, but it is unclear whether this is due to shared environmental or genetic factors.

In two SPARK samples, we tested for associations of 16 polygenic scores (PGSs) with quantitative measures of gender diversity and mental health. In study 1, 639 independent adults (59% autistic) reported their mental health with the Adult Self-Report and their gender diversity with the Gender Self-Report (GSR). The GSR has 2 dimensions: binary (degree of identification with the gender opposite that implied by sex designated at birth) and nonbinary (degree of identification with a gender that is neither male nor female). In study 2 (N = 5165), we used a categorical measure of gender identity.

In study 1, neuropsychiatric PGSs were positively associated with Adult Self-Report scores: externalizing was positively associated with the attention-deficit/hyperactivity disorder PGS (β = 0.10 [0.03-0.17]), and internalizing was positively associated with the PGSs for depression (β = 0.07 [0-0.14]) and neuroticism (β = 0.10 [0.03-0.17]). Interestingly, GSR scores were not significantly associated with any neuropsychiatric PGS. However, GSR nonbinary was positively associated with the cognitive performance PGS (β = 0.11 [0.05-0.18]), with the effect size comparable in magnitude to the associations of the neuropsychiatric PGSs with the Adult Self-Report. Additionally, GSR binary was positively associated with the nonheterosexual sexual behavior PGS (β = 0.07 [0-0.14]). In study 2, the cognitive performance PGS effect replicated; transgender and nonbinary individuals had higher PGSs (t₃₁₆ = 4.16).

We showed that while gender diversity is phenotypically positively associated with mental health problems, the strongest PGS associations with gender diversity were with the cognitive performance PGS, not the neuropsychiatric PGSs.