Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression

Abstract

Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine-adenine-guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, to what extent the variations in CAG repeat length in the other eight polyglutamine disease-associated genes (PDAGs) are associated with depression is still unknown. We determined the CAG repeat sizes of ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1 and AR 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 individuals-aged 18-93 years. The association between PDAG CAG repeat size and the risk for depression was assessed via binary logistic regression. We found that the odds ratio (OR) for lifetime depression was significantly higher for individuals with >10, compared with subjects with ≤10, CAG repeats in both ATXN7 alleles (OR=1.90, confidence interval (CI) 1.26-2.85). For TBP we found a similar association: A CAG repeat length exceeding the median in both alleles was associated with an increased risk for lifetime depression (OR=1.33, CI 1.00-1.76). In conclusion, we observed that carriers of either ATXN7 or TBP alleles with relatively large CAG repeat sizes in both alleles had a substantially increased risk of lifetime depression. Our findings provide critical evidence for the notion that repeat polymorphisms can act as complex genetic modifiers of depression.

Figure 1

Odds ratio for lifetime depression per ATXN7 category. The odds ratio for lifetime depression increases significantly when both the relatively long ATXN7 allele and the relatively short ATXN7 allele exceed the median CAG repeat number of 10. The odds of having lifetime depression almost doubles. The group having both alleles with a CAG repeat number ⩽10 was the largest and, therefore, was set as the reference category. I, both alleles of ATXN7 contain a CAG repeat number ⩽10; II, the relatively longer ATXN7 allele contains a CAG repeat number >10 and the relatively shorter allele contains a CAG repeat number ⩽10; III, both alleles of ATXN7 contain a CAG repeat number >10. Error bars indicate±s.e. **P<0.01 by the Fisher’s exact test in comparison with the reference category; CAG, cytosine–adenine–guanine.

Figure 2

Odds ratio for lifetime depression per TBP category. The odds ratio for lifetime depression increases significantly when both the relatively shorter TBP allele and the relatively longer TBP allele exceed their median CAG repeat number (median short allele=37, median long allele=38). The group with both alleles being equal to or smaller than their medians was the largest and, therefore, is defined as the reference category. I, both TBP alleles contain a CAG repeat number ⩽ their median; II, the relatively longer TBP allele contains a CAG repeat number>the median and the relatively shorter TBP allele contains a CAG repeat number ⩽ the median; III, both TBP alleles contain a CAG repeat number > their median. Error bars indicate±one s.e. *P<0.05 by the Fisher’s exact test in comparison with the reference category. CAG, cytosine–adenine–guanine; TBP, thymine-adenine-thymine-adenine (TATA) box-binding protein.