Borczyk Malgorzata, Fichna Jakub P, Piechota Marcin, Gołda Sławomir, Zięba Mateusz, Hoinkis Dzesika, Cięszczyk Paweł, Korostynski Michal, Janik Piotr, Żekanowski Cezary
Laboratory of Pharmacogenomics, Department of Molecular Neuropharmacology, Polish Academy of Sciences, Maj Institute of Pharmacology, Smętna 12, 31-343, Krakow, Poland.
Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106, Warsaw, Poland.
J Appl Genet. 2025 Jan 10. doi: 10.1007/s13353-024-00930-8.
Gilles de la Tourette syndrome (GTS) and other tic disorders (TDs) have a substantial genetic component with their heritability estimated at between 60 and 80%. Here we propose an oligogenic risk score of TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients, their families, and control samples (n = 278). In this study, we first reviewed the literature to obtain a preliminary list of 84 GTS/TD candidate genes. From this list, 10 final risk score genes were selected based on single-gene burden tests (SKAT p < 0.05) between unrelated GTS cases (n = 37) and synthetic control samples based on a database of local allele frequencies. These 10 genes were CHADL, DRD2, MAOA, PCDH10, HTR2A, SLITRK5, SORCS3, KCNQ5, CDH9, and CHD8. Variants in and in the vicinity (± 20 kbp) of the ten risk genes (n = 7654) with a median minor allele frequency in the non-Finnish European population of 0.02 were integrated into an additive classifier. This risk score was then applied to healthy and GTS-affected individuals from 23 families and 100 unrelated healthy samples from the Polish population (AUC-ROC = 0.62, p = 0.02). Application of the algorithm to a group of patients with other tic disorders revealed a continuous increase of the oligogenic score with healthy individuals with the lowest mean, then patients with other tic disorders, then GTS patients, and finally with severe GTS cases with the highest oligogenic score. We have further compared our WGS results with the summary statistics of the Psychiatric Genomics Consortium genome-wide association study (PGC GWAS) of TDs and found no signal overlap except for the CHADL gene locus. Polygenic risk scores from common variants of GTS GWAS show no difference between patient and control groups, except for the comparison between patients with non-GTS TDs and patients with severe GTS. Overall, we leveraged WGS data to construct a GTS/TD risk score based on variants that may cooperatively contribute to the aetiology of these disorders. This study provides evidence that typical and severe adult GTS as well as other tic disorders may exist on a single spectrum in terms of their genetic background.
抽动秽语综合征（GTS）和其他抽动障碍（TDs）具有显著的遗传成分，其遗传度估计在60%至80%之间。在此，我们利用一组波兰GTS患者及其家族以及对照样本（n = 278）的全基因组测序（WGS）数据，提出了一种抽动障碍的多基因风险评分。在本研究中，我们首先查阅文献以获得84个GTS/TD候选基因的初步列表。从该列表中，基于非亲缘GTS病例（n = 37）与基于当地等位基因频率数据库的合成对照样本之间的单基因负担测试（SKAT p < 0.05），选择了10个最终的风险评分基因。这10个基因分别是CHADL、DRD2、MAOA、PCDH10、HTR2A、SLITRK5、SORCS3、KCNQ5、CDH9和CHD8。将这10个风险基因及其附近区域（±20 kbp）内的变异（n = 7654）整合到一个加性分类器中，这些变异在非芬兰欧洲人群中的次要等位基因频率中位数为0.02。然后将该风险评分应用于来自23个家族的健康个体和受GTS影响的个体，以及来自波兰人群的100个非亲缘健康样本（AUC-ROC = 0.62，p = 0.02）。将该算法应用于一组患有其他抽动障碍的患者，结果显示多基因评分持续增加，从平均评分最低的健康个体，到患有其他抽动障碍的患者，再到GTS患者，最后到多基因评分最高的重度GTS病例。我们进一步将我们的WGS结果与抽动障碍的精神病基因组学联盟全基因组关联研究（PGC GWAS）的汇总统计数据进行比较，发现除了CHADL基因座外没有信号重叠。GTS GWAS常见变异的多基因风险评分在患者组和对照组之间没有差异，除了非GTS TDs患者与重度GTS患者之间的比较。总体而言，我们利用WGS数据构建了一个基于可能共同导致这些疾病病因的变异的GTS/TD风险评分。这项研究提供了证据，表明典型和重度成人GTS以及其他抽动障碍在遗传背景方面可能存在于单一谱系上。
