Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia in elderly people, following Alzheimer's disease. Only three genes, SNCA (α-synuclein), APOE (apolipoprotein E), and GBA (glucosylceramidase), have been convincingly demonstrated to be associated with DLB. Here, we applied whole-genome sequencing to blood samples from 61 DLB patients and 45 cognitively normal controls. We used accumulation of candidate mutations to detect novel DLB-associated genes. Subsequent single nucleotide polymorphism (SNP) genotyping and association studies in a large number of samples from Japanese individuals revealed novel heterozygous variants in MFSD3 (rs143475431, c.888T>A:p.C296*; n = 5,421, p = 0.00063) and MRPL43 (chr10:102746730, c.241A>C:p.N81H; n = 4,782, p = 0.0029). We further found that the MFSD3 variant increased plasma levels of butyrylcholinesterase (n = 1,206, p = 0.029). We believe that our findings will contribute to the understanding of DLB and provide insight into its pathogenic mechanism for future studies.

中文翻译：

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基于网络的荟萃分析和候选基因关联研究揭示了与路易体痴呆相关的 MFSD3 和 MRPL43 中新的种族特异性变异

路易体痴呆（DLB）是老年人中第二常见的神经退行性痴呆，仅次于阿尔茨海默病。只有三个基因：SNCA（α-突触核蛋白）、APOE（载脂蛋白 E）和GBA（葡萄糖神经酰胺酶）已被令人信服地证明与 DLB 相关。在这里，我们对 61 名 DLB 患者和 45 名认知正常对照者的血液样本进行了全基因组测序。我们利用候选突变的积累来检测新的 DLB 相关基因。随后对日本个体的大量样本进行的单核苷酸多态性 (SNP) 基因分型和关联研究揭示了MFSD3 (rs143475431, c.888T>A:p.C296*; n  = 5,421, p  = 0.00063) 和MRPL43中的新杂合变异（chr10：102746730，c.241A>C：p.N81H；n  = 4,782，p  = 0.0029）。我们进一步发现MFSD3变体增加了丁酰胆碱酯酶的血浆水平（n  = 1,206，p  = 0.029）。我们相信，我们的研究结果将有助于理解DLB，并为未来的研究提供对其致病机制的深入了解。