Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder.
Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder.
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DOI：
10.1212/wnl.0000000000011464
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发表时间：
2021-03-09
期刊：
影响因子：
9.9
通讯作者：
Gan-Or Z
中科院分区：
文献类型：
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作者：
Mufti K;Yu E;Rudakou U;Krohn L;Ruskey JA;Asayesh F;Laurent SB;Spiegelman D;Arnulf I;Hu MTM;Montplaisir JY;Gagnon JF;Desautels A;Dauvilliers Y;Gigli GL;Valente M;Janes F;Bernardini A;Högl B;Stefani A;Holzknecht E;Sonka K;Kemlink D;Oertel W;Janzen A;Plazzi G;Antelmi E;Figorilli M;Puligheddu M;Mollenhauer B;Trenkwalder C;Sixel-Döring F;Cochen De Cock V;Monaca CC;Heidbreder A;Ferini-Strambi L;Dijkstra F;Viaene M;Abril B;Boeve BF;Trempe JF;Rouleau GA;Postuma RB;Gan-Or Z
目的：探讨通过帕金森病（PD）全基因组关联研究（GWASs）鉴定的基因在孤立性快速眼动睡眠行为障碍（iRBD）风险中的作用。我们对1039名iRBD患者和1852名对照患者的PD GWASs中先前鉴定的25个基因进行了完全测序。用负荷试验检验了这些基因中罕见杂合变异体的作用。进一步测试了双等位基因变异的贡献。为了研究罕见的非同义BST1变异对蛋白质结构的潜在影响，我们进行了硅结构分析。最后，我们使用调整年龄和性别的逻辑回归检查了常见变异的关联。我们发现BST1和iRBD中罕见的杂合非同义变异体之间存在关联（在覆盖率为>50倍时p = 0.0003，在覆盖率为>30倍时p = 0.0004），主要由3个非同义变异体（p.V85M, p.I101V和p.V272M）驱动，分别在22例（1.2%）对照和2例（0.2%）患者中发现。所有3种变异似乎都是功能丧失变异，对蛋白质结构和稳定性有潜在影响。LAMP3中罕见的非编码杂合变异也与iRBD相关（p = 0.0006，在bbb30倍时）。我们发现其余基因的罕见杂合变异体与iRBD之间没有关联。几个双等位基因变异的携带者被鉴定出来，但在iRBD中没有过度代表。我们的研究结果表明，BST1中罕见的编码变异和LAMP3中罕见的非编码变异与iRBD相关。需要进一步的研究来重复这些结果，并检查BST1功能丧失是否可以作为治疗靶点。
To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD). We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex. We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in LAMP3 were also associated with iRBD (p = 0.0006 at >30×). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD. Our results suggest that rare coding variants in BST1 and rare noncoding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of BST1 could be a therapeutic target.