Sex- and Depression-specific Effects of Non-pathogenic CAG Repeats in <i>HTT</i> , <i>ATXN3</i> and <i>CACNA1A</i> on Sleep

Abstract The effects of non-pathogenic cytosine-adenine-guanine (CAG) repeat sizes on sleep remain unclear, although disrupted sleep has been observed in patients with pathogenic CAG expansions in polyglutamine disease-associated genes (PDAGs), particularly in HTT , ATXN3, and CACNA1A . Here, we assessed the associations between CAG repeat sizes of the three genes and self-reported sleep outcomes in the Netherlands Epidemiology of Obesity study (NEO) and the Netherlands Study of Depression and Anxiety (NESDA). Sleep outcomes included excessive daytime sleepiness (EDS) and Pittsburgh Sleep Quality Index (PSQI) in NEO, insomnia score in NESDA, and sleep duration and chronotype in both. We also stratified by sex, menopausal status in women, and questionnaire-based depression score. We observed 31 associations, of which 26 were specific to women. Larger HTT CAG repeat sizes were associated with lower EDS risk and lower PSQI score in premenopausal women, but higher PSQI score in women with depression. CAG repeats in all three PDAGs were associated with sleep duration, with ATXN3 showing U-shaped effects in all population groups except men. CAG repeat size in CACNA1A was primarily associated with chronotype in women. These findings suggest that non-pathogenic CAG repeats in PDAGs affect sleep differentially by sex and depression status.