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),