Huntingtin CAG repeat is a continuous modifier of brain structure and health vulnerability

Huntingtons disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT) above a pathogenic threshold; however, the biological consequences of repeat-length variation below this threshold remain poorly understood. Using whole-genome sequencing and linked phenotypic data from UK Biobank participants, we show that repeat-length variation within the normal and intermediate range is associated with measurable differences in brain volume, neuropsychiatric risk, and cognitive processing, and that only one third of pathogenic allele carriers have a recorded clinical diagnosis. Analyses were performed in 474,446 UK Biobank participants, including 30,052 with intermediate repeats (27-35), 873 with reduced-penetrance repeats (36-39), and 155 with pathogenic repeats ([≥]40); 48,378 individuals had structural MRI. For quantitative phenotypes (brain volumes and cognition), associations with continuous repeat length were modelled using linear regression within the normal and intermediate range ([≤]35 repeats); deviation at [≥]36 repeats was defined as departure from the extrapolated linear trend. For clinical outcomes (depression, anxiety, dementia, and delirium), repeat length was analysed categorically using Kaplan-Meier and Cox proportional hazards models with age as the timescale. Within the normal and intermediate range, longer HTT CAG repeat length was associated with smaller subcortical and global brain volumes, including the accumbens, putamen, thalamus, hippocampus, and total grey and white matter, with effects amplified in older individuals. Intermediate alleles were associated with an increase in age-dependent depression risk (HR = 1.05, 95% CI 1.02-1.10) and longer repeat length within the normal and intermediate range predicted faster reaction time, a pattern that reversed sharply at pathogenic lengths. Among carriers of 40-41 CAG repeats, only 42% (95% CI 19-59%) had received a recorded Huntingtons disease diagnosis by age 84; however, the majority of pathogenic allele carriers who underwent neuroimaging met biomarker criteria for Stage 1 disease, indicating that early neurodegeneration is present in these individuals. This work challenges the current understanding of the HTT CAG repeat length as a purely categorical determinant of monogenic disease and shows that repeat length acts as a quantitative modifier of brain structure and neuropsychiatric vulnerability across the population. These findings have implications for risk prediction, penetrance estimation, and the interpretation of repeat variation in population genomics.