No association between FMR1 premutation and either ADHD or anxiety in 53,707 women undergoing genetic testing for family planning purposes

Purpose: FMR1 premutation has been inconsistently associated with neuropsychiatric phenotypes, possibly because of ascertainment bias. We investigated the association between FMR1 premutation and attention deficit hyperactivity disorder (ADHD), anxiety, and other psychiatric disorders in large-scale population-based genetic carrier screening data. Methods: We defined premutation as having 58 to 200 CGG repeats. Phenotypes were identified in linked electronic medical records via formal diagnoses or relevant medication purchases. As a positive control, we assessed premature ovarian insufficiency and elevated follicle-stimulating hormone levels before the age of 40. Results: Our study included 53,707 women, among them 464 premutation heterozygotes. The premutation status was associated with premature ovarian insufficiency (hazard ratio [HR]: 4.08; 95% CI: 2.16-7.72) and high follicle-stimulating hormone (HR: 3.43; 95% CI: 2.65-4.43) but not with ADHD (HR: 1.08; 95% CI: 0.75-1.56), anxiety (HR: 0.74; 95% CI: 0.53-1.04), anxiety and depression (HR: 0.86; 95% CI: 0.69-1.07), and other psychiatric disorders (HR: 1.22; 95% CI: 0.73-2.03). Our study was sufficiently powered to detect HR approximately 1.5-2 or higher. Conclusion: No association was found between FMR1 premutation status and either ADHD or anxiety. Although our study design avoided bias toward affected families, participants may be healthier than average, and small effects cannot be excluded.