特发性震颤遗传率和遗传相关性的全基因组估计。
Genome-wide estimates of heritability and genetic correlations in essential tremor.
机构信息
Fundació Docència i Recerca Mútua Terrassa, University Hospital Mútua de Terrassa, Terrassa, 08221, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa, Terrassa, 08222, Barcelona, Spain.
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, 20892, MD, USA; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18016, Spain.
出版信息
Parkinsonism Relat Disord. 2019 Jul;64:262-267. doi: 10.1016/j.parkreldis.2019.05.002. Epub 2019 May 4.
INTRODUCTION
Despite considerable efforts to identify disease-causing and risk factors contributing to essential tremor (ET), no comprehensive assessment of heritable risk has been performed to date.
METHODS
We use GREML-LDMS to estimate narrow-sense heritability due to additive effects (h) and GREMLd to calculate non-additive heritability due to dominance variance (δ) using data from 1,751 ET cases and 5,311 controls. We evaluate heritability per 10 Mb segments across the genome and assess the impact of Parkinson's disease (PD) misdiagnosis on heritability estimates. We apply genetic risk score (GRS) from PD and restless legs syndrome (RLS) to explore its contribution to ET risk and further assess genetic correlations with 832 traits by Linkage disequilibrium score regression.
RESULTS
We estimated ET narrow-sense heritability to be h = 75.5% (s.e = ±0.075). In contrast, dominance variance showed insignificant effect on the overall estimates. Heritability split by 10 Mb regions revealed increased estimates at chromosomes 6 and 21. The proportion of genetic variance due to PD misdiagnosed cases was estimated to be 5.33%. PD and RLS GRS were not significantly predictive of ET case-control status.
CONCLUSIONS
We show for the first time that ET is a highly heritable condition in which additive common variability plays a prominent role. Chromosomes 6 and 21 may contain causative risk variants influencing susceptibility to ET. Despite overlapping symptomatology, ET does not seem to share genetic etiologies with PD or RLS. Our study suggests that most of ET genetic component is yet to be discovered and future GWAS will reveal additional risk factors contributing to ET.
简介
尽管人们做出了相当大的努力来识别导致原发性震颤（ET）的致病因素和风险因素，但迄今为止尚未对可遗传风险进行全面评估。
方法
我们使用 GREML-LDMS 来估计由于加性效应（h）导致的狭义遗传率，使用来自 1751 例 ET 病例和 5311 例对照的数据，使用 GREMLd 计算由于显性方差（δ）导致的非加性遗传率。我们评估了整个基因组中每 10 Mb 片段的遗传率，并评估了帕金森病（PD）误诊对遗传率估计的影响。我们应用 PD 和不宁腿综合征（RLS）的遗传风险评分（GRS）来探索其对 ET 风险的贡献，并通过连锁不平衡评分回归进一步评估与 832 个特征的遗传相关性。
结果
我们估计 ET 的狭义遗传率为 h=75.5%（标准误差为±0.075）。相比之下，显性方差对总体估计没有显著影响。按 10 Mb 区域划分的遗传率显示，6 号和 21 号染色体的估计值增加。由于 PD 误诊病例导致的遗传方差比例估计为 5.33%。PD 和 RLS GRS 对 ET 病例对照状态没有显著的预测作用。
结论
我们首次表明 ET 是一种高度遗传的疾病，其中加性常见变异性起着重要作用。6 号和 21 号染色体可能含有影响 ET 易感性的致病风险变异。尽管症状重叠，但 ET 似乎与 PD 或 RLS 没有共同的遗传病因。我们的研究表明，ET 的大部分遗传成分尚未被发现，未来的 GWAS 将揭示更多导致 ET 的风险因素。
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