Bertholim-Nasciben Luciana, Nuytemans Karen, Van Booven Derek, Rajabli Farid, Moura Sofia, Ramirez Aura M, Parker Griffin S, Dykxhoorn Derek M, Wang Liyong, Scott William K, Davis David A, Vontell Regina T, McInerney Katalina F, Cuccaro Michael L, Byrd Goldie S, Haines Jonathan L, Gearing Marla, Adams Larry D, Pericak-Vance Margaret A, Young Juan I, Griswold Anthony J, Vance Jeffery M
Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
Alzheimers Dement. 2025 Jul;21(7):e70500. doi: 10.1002/alz.70500.
We recently described that the African-specific A allele of rs10423769, which lies in an area of segmental duplications, reduces Alzheimer's disease (AD) risk by ∼ 75% in apolipoprotein E (APOE) ε4 homozygotes.
Short and long-read sequencing were used to identify the haplotype harboring rs10423769_A and examine DNA methylation and structural variation (SV).
A unique 21 kb haplotype is shared amongst all rs10423769_A carriers (r > 0.95) and is present in all African ancestry tested. We identified methylation differences between the non-protective and rs10423769_A haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2-family transcription factor binding motifs in LD with the protective haplotype. Further, rs10423769 is an eQTL for ZNF222.
The protective haplotype is unique, with haplotype changes in DNA methylation and SV that could contribute to the protective mechanism of rs10423769_A. The study generates hypothesis for future studies on this important protective mechanism for APOEε4 carriers.
We investigated an African-specific haplotype harboring a protective locus for APOEε4 carriers that significantly reduces the risk for Alzheimer Disease. The protective locus lies in an area of segmental duplications 2MB from APOE. We found that the protective haplotype is unique within the segmental duplications. The haplotype is found in all African ancestry tested but not in other ancestries. Long read whole genome sequencing identified an expanded VNTR associated with the protective haplotype containing multiple MEF2 transcription factor binding motifs. Differences in DNA methylation were found between the protective and the reference haplotype.
我们最近描述了位于节段性重复区域的rs10423769的非洲特异性A等位基因，它可使载脂蛋白E（APOE）ε4纯合子患阿尔茨海默病（AD）的风险降低约75%。
使用短读长和长读长测序来鉴定携带rs10423769_A的单倍型，并检测DNA甲基化和结构变异（SV）。
所有rs10423769_A携带者（r>0.95）共享一个独特的21kb单倍型，并且在所有测试的非洲血统中都存在。我们确定了非保护性单倍型和rs10423769_A单倍型之间的甲基化差异。一个扩展的可变数目串联重复序列（VNTR），其包含多个与保护性单倍型处于连锁不平衡状态的MEF2家族转录因子结合基序。此外，rs10423769是ZNF222的一个表达定量性状位点（eQTL）。
保护性单倍型是独特的，其DNA甲基化和SV的单倍型变化可能有助于rs10423769_A的保护机制。该研究为未来关于APOEε4携带者这一重要保护机制的研究提出了假设。
我们研究了一个非洲特异性单倍型，它含有APOEε4携带者的一个保护位点，可显著降低患阿尔茨海默病的风险。该保护位点位于距APOE 2MB的节段性重复区域。我们发现保护性单倍型在节段性重复区域内是独特的。该单倍型在所有测试的非洲血统中都存在，但在其他血统中不存在。长读长全基因组测序鉴定出一个与保护性单倍型相关的扩展VNTR，其包含多个MEF2转录因子结合基序。在保护性单倍型和参考单倍型之间发现了DNA甲基化差异。
