Abstract：
BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson\'s disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2.
OBJECTIVE: Our goal was to investigate the effects of genetic variants on risk and time to LID.
METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID.
RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147).
CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
OBJECTIVE: Our goal was to investigate the effects of genetic variants on risk and time to LID.
METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID.
RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147).
CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
摘要：
背景：左旋多巴诱发的运动障碍（LID）是左旋多巴的常见不良反应，用于治疗帕金森病（PD）运动症状的主要疗法之一。先前的证据表明LID与多巴胺能系统的破坏以及与PD有关的基因之间存在联系，包括GBA1和LRRK2。
目的：我们的目标是研究遗传变异对LID风险和时间的影响。
方法：我们进行了全基因组关联研究（GWAS），并对GBA1和LRRK2变体进行了分析。我们还计算了多基因风险评分（PRS），包括PD的风险变异和涉及多巴胺能传递途径的基因变异。为了测试遗传学对LID风险的影响，我们使用了逻辑回归，为了检查其对LID时间的影响，我们进行了Cox回归，包括1612例PD患者和3175例无LID患者。
结果：我们发现GBA1变异与LID风险相关(比值比[OR]=1.65;95%置信区间[CI],1.21-2.26；P=0.0017）和LRRK2变体的LID发作时间缩短（风险比[HR]=1.42；95％CI，1.09-1.84；P=0.0098）。PDPRS的第四个四分位数与LID风险增加相关(ORfetrfour_quartile=1.27;95%CI,1.03-1.56;P=0.0210)。第三和第四多巴胺途径PRS四分位数与LID发生时间缩短相关(HRthird_quartile=1.38;95%CI,1.07-1.79;P=0.0128;HRfour_quartile=1.38;95%CI=1.06-1.78;P=0.0147)。
结论：这项研究表明，与PD和多巴胺能传递途径有关的变异在发生LID的风险/时间中起作用。需要进一步的研究来检查这些发现如何为临床护理提供信息。©2024作者（S）。由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。
目的：我们的目标是研究遗传变异对LID风险和时间的影响。
方法：我们进行了全基因组关联研究（GWAS），并对GBA1和LRRK2变体进行了分析。我们还计算了多基因风险评分（PRS），包括PD的风险变异和涉及多巴胺能传递途径的基因变异。为了测试遗传学对LID风险的影响，我们使用了逻辑回归，为了检查其对LID时间的影响，我们进行了Cox回归，包括1612例PD患者和3175例无LID患者。
结果：我们发现GBA1变异与LID风险相关(比值比[OR]=1.65;95%置信区间[CI],1.21-2.26；P=0.0017）和LRRK2变体的LID发作时间缩短（风险比[HR]=1.42；95％CI，1.09-1.84；P=0.0098）。PDPRS的第四个四分位数与LID风险增加相关(ORfetrfour_quartile=1.27;95%CI,1.03-1.56;P=0.0210)。第三和第四多巴胺途径PRS四分位数与LID发生时间缩短相关(HRthird_quartile=1.38;95%CI,1.07-1.79;P=0.0128;HRfour_quartile=1.38;95%CI=1.06-1.78;P=0.0147)。
结论：这项研究表明，与PD和多巴胺能传递途径有关的变异在发生LID的风险/时间中起作用。需要进一步的研究来检查这些发现如何为临床护理提供信息。©2024作者（S）。由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。
