Huntingtin gene repeat size variations affect risk of lifetime depression

Abstract

Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = -0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression.

Fig. 1. Distribution of HTT CAG repeat sizes

The figure displays the frequency distribution of the number of CAG repeats in the HTT gene in 2165 subjects with and 1058 subjects without a lifetime depression diagnosis, respectively

Fig. 2. HTT CAG repeat size is non-linearly associated with lifetime depression risk

The red line indicates the model predicted mean odds ratio for lifetime depression for each HTT CAG repeat size (adjusted for age, sex, and education level): Both subjects with a relatively low and a relatively high repeat size have a higher odds of developing depression compared to the odds of depression in the total group. Error bars indicate ± standard error. Please note that there was only one subject (with depression) who had a HTT CAG repeat size of 14 in the longer allele, therefore, no standard error could be calculated for this CAG repeat category. Please also note that the logistic model estimates of odds ratios for lifetime depression are slightly different from those presented in Table 1 as these estimates are obtained using data from all participants simultaneously, whereas the estimates in Table 1 are calculated for each subgroup of HTT CAG repeat size separately

Fig. 3. HTT CAG repeat size influences depression risk

The odds of a diagnosis of lifetime depression is non-linearly associated with CAG repeat size in the longer HTT allele: Both subjects with a relatively low and a relatively high repeat size have a higher risk of developing depression compared to the odds of depression in the total group. Error bars indicate ± standard error. *P < 0.05 by the Fisher’s exact test in comparison to the odds of lifetime depression in the total cohort