Department of Neurology, Mount Sinai Beth Israel, and Icahn School of Medicine, New York, New York, USA.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Mov Disord. 2022 Nov;37(11):2217-2225. doi: 10.1002/mds.29197. Epub 2022 Aug 27.
Although men and women with the LRRK2 G2019S variant appear to be equally likely to have Parkinson's disease (PD), the sex-distribution among glucocerebrosidase (GBA) variant carriers with PD, including limited to specific variant severities of GBA, is not well understood. Further, the sex-specific genetic contribution to PD without a known genetic variant is controversial.
To better understand sex differences in genetic contribution to PD, especially sex-specific frequencies among GBA variant carriers with PD (GBA PD) and LRRK2-G2019S variant carriers with PD (LRRK2 PD).
We assess differences in the sex-specific frequency in GBA PD, including in subsets of GBA variant severity, LRRK2 PD, and idiopathic PD in an Ashkenazi Jewish cohort with PD. Further, we expand prior work evaluating differences in family history of parkinsonism.
Both idiopathic PD (267/420 men, 63.6%) (P < 0.001) and GBA PD overall (64/107, 59.8%) (P = 0.042) were more likely to be men, whereas no difference was seen in LRRK2 PD (50/99, 50.5%) and LRRK2/GBA PD (5/10, 50%). However, among GBA PD probands, severe variant carriers were more likely to be women (15/19 women, 79.0%) (P = 0.005), whereas mild variant carriers (44/70 men, 62.9%) (P = 0.039) and risk-variant carriers (15/17 men, 88.2%) (P = 0.001) were more likely to be men.
Our study demonstrates that the male-sex predominance present in GBA PD overall was not consistent across GBA variant severities, and a female-sex predominance was present among severe GBA variant carriers. Therefore, research and trial designs for PD should consider sex-specific differences, including across GBA variant severities. © 2022 International Parkinson and Movement Disorder Society.
尽管 LRRK2 G2019S 变异携带者出现帕金森病（PD）的可能性似乎与男性和女性相等，但携带糖脑苷脂酶（GBA）变异的 PD 患者中性别分布情况，包括仅限于特定 GBA 变异严重程度的性别分布情况，目前尚不清楚。此外，在没有已知遗传变异的情况下，PD 与性别特异性遗传贡献之间的关系存在争议。
为了更好地了解 PD 中遗传贡献的性别差异，特别是 GBA 变异携带者 PD（GBA PD）和 LRRK2-G2019S 变异携带者 PD（LRRK2 PD）中性别特异性频率。
我们评估了在一个具有 PD 的阿什肯纳兹犹太人群体中，GBA PD 中的性别特异性频率差异，包括 GBA 变异严重程度的亚组、LRRK2 PD 和特发性 PD。此外，我们扩展了之前评估帕金森病家族史差异的工作。
特发性 PD（267/420 名男性，63.6%）（P<0.001）和 GBA PD 总体（64/107，59.8%）（P=0.042）更可能是男性，而 LRRK2 PD（50/99，50.5%）和 LRRK2/GBA PD（5/10，50%）则没有差异。然而，在 GBA PD 先证者中，严重变异携带者更可能是女性（15/19 名女性，79.0%）（P=0.005），而轻度变异携带者（44/70 名男性，62.9%）（P=0.039）和风险变异携带者（15/17 名男性，88.2%）（P=0.001）更可能是男性。
我们的研究表明，GBA PD 总体上的男性优势在 GBA 变异严重程度上并不一致，而严重 GBA 变异携带者中存在女性优势。因此，PD 的研究和试验设计应考虑性别特异性差异，包括 GBA 变异严重程度。
