Huntingtin CAG repeat size variations below the Huntington’s disease threshold: associations with depression, anxiety and basal ganglia structure

Huntington's disease (HD) is strongly associated with psychiatric symptoms, yet, associations between huntingtin gene (HTT) CAG repeat size variations and psychiatric phenotypes outside the HD complex are still under-investigated. In this genetic case-control study we compared the distribution of HTT CAG repeat sizes in predefined ranges between patients with major depressive disorder (MDD) (n = 2136) and anxiety disorders (ANX) (n = 493), and healthy controls (CON) (n = 1566). We used regression models to study interactions between the alleles and associations with fine-granular clinical phenotypes and basal ganglia structure. HD mutations in the range of incomplete penetrance (36-39 repeats) were not overrepresented in patients. In participants older than 48 years, 13-20 repeats on both HTT alleles were associated with a reduced ANX risk whereas a 13-20 | 21-26 combination was associated with an increased ANX risk. Post-hoc analyses confirmed a turning point around 21 repeats and trends in the same direction were detected for MDD. The joint patient | CON analysis of the full spectrum of allele combinations confirmed interaction effects and age-dependent allele | risk profiles. A short-by-long interaction effect and an age-dependent negative correlation of the short allele on the nucleus accumbens volume was detected, independently of the diagnostic group. In conclusion, we revealed that HTT CAG repeat sizes of both alleles in the non-HD range are associated with a risk modulation for common psychiatric disorders as well as basal ganglia structure differences in an age-dependent way, possibly implying that normal variation of the functionally diverse wildtype huntingtin protein may impact brain function.