Weight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD.

Using data from different recent genome-wide association studies, we performed a 2-sample mendelian randomization (MR) analysis to assess whether genetic markers of body mass index (BMI) are causally related to residual age at onset in HD, i.e., the difference between observed and expected age at onset based on mutation size. Our study had a statistical power of 90% to detect a causal effect of ≥3.8 months per BMI unit change at a type I error rate of 0.05.

Inverse-variance weighted MR estimates showed that a higher genetically determined BMI was not causally related to residual age at onset in HD (β = –0.44 years per unit increase in BMI, confidence interval: –1.33 to 0.46, p = 0.34). All other complementary (nonparametric) MR regression methods yielded similar results.

Although maintaining a healthy and stable body weight remains important in patients with HD, promoting weight gain with the aim of delaying disease onset or slowing down disease progression should be discouraged. Our findings point toward the existence of underlying pathologic processes that dictate both the rate of clinical progression and weight loss in HD, which need further elucidation as targeting these pathways, rather than body weight per se, could be of therapeutic value.

体重减轻与亨廷顿病 (HD) 的临床进展有关，但体重是否会影响疾病的发作或进展尚不清楚。因此，我们旨在评估遗传决定的体重变化是否与 HD 发病年龄有因果关系。

使用最近不同的全基因组关联研究的数据，我们进行了 2 样本孟德尔随机化 (MR) 分析，以评估体重指数 (BMI) 的遗传标记是否与 HD 发病时的剩余年龄有因果关系，即差异根据突变大小在观察到的和预期的发病年龄之间。我们的研究在 I 型错误率为 0.05 时检测到每 BMI 单位变化≥3.8 个月的因果效应的统计功效为 90%。

逆方差加权 MR 估计表明，较高的遗传决定的 BMI 与 HD 发病时的剩余年龄没有因果关系（β = –0.44 年每增加 BMI，置信区间：–1.33 至 0.46，p = 0.34）。所有其他互补（非参数）MR 回归方法产生了类似的结果。

尽管维持健康和稳定的体重对于 HD 患者仍然很重要，但不应鼓励通过促进体重增加来延缓疾病发作或减缓疾病进展。我们的研究结果表明存在潜在的病理过程，这些过程决定了 HD 的临床进展速度和体重减轻，这需要进一步阐明，因为靶向这些途径而不是体重本身可能具有治疗价值。