Vater Magdalena, Rost Nicolas, Eckstein Gertrud, Sauer Susann, Tontsch Alina, Erhardt Angelika, Lucae Susanne, Brückl Tanja, Klopstock Thomas, Sämann Philipp G, Binder Elisabeth B
Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany.
International Max Planck Research School for Translational Psychiatry, Munich, Germany.
Eur J Hum Genet. 2025 May;33(5):624-632. doi: 10.1038/s41431-024-01737-1. Epub 2024 Nov 21.
Huntington's disease (HD) is strongly associated with psychiatric symptoms, yet, associations between huntingtin gene (HTT) CAG repeat size variations and psychiatric phenotypes outside the HD complex are still under-investigated. In this genetic case-control study we compared the distribution of HTT CAG repeat sizes in predefined ranges between patients with major depressive disorder (MDD) (n = 2136) and anxiety disorders (ANX) (n = 493), and healthy controls (CON) (n = 1566). We used regression models to study interactions between the alleles and associations with fine-granular clinical phenotypes and basal ganglia structure. HD mutations in the range of incomplete penetrance (36-39 repeats) were not overrepresented in patients. In participants older than 48 years, 13-20 repeats on both HTT alleles were associated with a reduced ANX risk whereas a 13-20 | 21-26 combination was associated with an increased ANX risk. Post-hoc analyses confirmed a turning point around 21 repeats and trends in the same direction were detected for MDD. The joint patient | CON analysis of the full spectrum of allele combinations confirmed interaction effects and age-dependent allele | risk profiles. A short-by-long interaction effect and an age-dependent negative correlation of the short allele on the nucleus accumbens volume was detected, independently of the diagnostic group. In conclusion, we revealed that HTT CAG repeat sizes of both alleles in the non-HD range are associated with a risk modulation for common psychiatric disorders as well as basal ganglia structure differences in an age-dependent way, possibly implying that normal variation of the functionally diverse wildtype huntingtin protein may impact brain function.
亨廷顿舞蹈症（HD）与精神症状密切相关，然而，亨廷顿基因（HTT）CAG重复序列长度变异与HD复合体以外的精神疾病表型之间的关联仍未得到充分研究。在这项基因病例对照研究中，我们比较了重度抑郁症（MDD）患者（n = 2136）、焦虑症（ANX）患者（n = 493）和健康对照者（CON）（n = 1566）中HTT CAG重复序列长度在预定义范围内的分布情况。我们使用回归模型来研究等位基因之间的相互作用以及与细粒度临床表型和基底神经节结构的关联。不完全显性范围内（36 - 39个重复序列）的HD突变在患者中并未过度出现。在48岁以上的参与者中，两个HTT等位基因上有13 - 20个重复序列与ANX风险降低相关，而13 - 20 | 21 - 26的组合与ANX风险增加相关。事后分析证实了21个重复序列左右存在一个转折点，并且在MDD中也检测到了相同方向的趋势。对所有等位基因组合进行的联合患者|对照分析证实了相互作用效应以及年龄依赖性等位基因|风险特征。检测到短 - 长相互作用效应以及短等位基因对伏隔核体积的年龄依赖性负相关，且与诊断组无关。总之，我们发现非HD范围内两个等位基因的HTT CAG重复序列长度与常见精神疾病的风险调节以及基底神经节结构差异存在年龄依赖性关联，这可能意味着功能多样的野生型亨廷顿蛋白的正常变异可能会影响脑功能。
