Synonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation.

To detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an independent cohort of CHs, expression quantitative trait locus (eQTL) data, brain autopsy data, and functional experiments.

Rare synonymous variants in 4 genes (CDH23, SLC9A3R1, RHBDD2, and ITIH2) segregated with AD status in multiplex families and had a significantly higher frequency in these families compared with reference populations of similar ancestry. In comparison to subjects without dementia, expression of CDH23 (β = 0.53, p = 0.006) and SLC9A3R1 (β = 0.50, p = 0.02) was increased, and expression of RHBDD2 (β = –0.70, p = 0.02) decreased in individuals with AD at death. In line with this finding, increased expression of CDH23 (β = 0.26 ± 0.08, p = 4.9E-4) and decreased expression of RHBDD2 (β = –0.60 ± 0.12, p = 5.5E-7) were related to brain amyloid load (p = 0.0025). SLC9A3R1 expression was associated with burden of TDP43 pathology (β = 0.58 ± 0.17, p = 5.9E-4). Using eQTL data, the CDH23 variant was in linkage disequilibrium with variants modulating CDH23 expression levels (top single nucleotide polymorphism: rs11000035, p = 4.85E-6, D' = 1.0). Using minigene splicing assays, the CDH23 and SLC9A3R1 variants affected splicing efficiency.

These findings suggest that CDH23, SLC9A3R1, RHBDD2, and possibly ITIH2, which are involved in synaptic function, the glutamatergic system, and innate immunity, contribute to AD etiology. In addition, this study supports the notion that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of genetic variation is warranted and critical.

同义变异可导致疾病；然而，大多数针对阿尔茨海默病（AD）的测序研究仅评估编码变异。

为了检测调节 AD 风险的同义变异，我们对 67 个受 AD 多重影响的加勒比西班牙裔 (CH) 家庭进行了全基因组测序研究。在独立的 CH 队列、表达数量性状基因座 (eQTL) 数据、脑尸检数据和功能实验中进一步评估了已识别的疾病相关变异。

4 个基因（CDH23、SLC9A3R1、RHBDD2和ITIH2）中的罕见同义变异在多重家族中与 AD 状态分离，并且与相似血统的参考群体相比，这些家族中的频率显着更高。与没有痴呆的受试者相比，个体中CDH23 (β = 0.53，p = 0.006) 和SLC9A3R1 (β = 0.50，p = 0.02) 的表达增加，而RHBDD2 (β = –0.70，p = 0.02) 的表达减少死亡时患有AD。与这一发现一致，CDH23表达增加(β = 0.26 ± 0.08，p = 4.9E-4) 和RHBDD2表达减少(β = –0.60 ± 0.12，p = 5.5E-7) 与脑淀粉样蛋白负荷相关（p = 0.0025）。SLC9A3R1表达与 TDP43 病理学负担相关（β = 0.58 ± 0.17，p = 5.9E-4）。使用 eQTL 数据，CDH23变体与调节CDH23表达水平的变体处于连锁不平衡（顶部单核苷酸多态性：rs11000035，p = 4.85E-6，D' = 1.0）。使用小基因剪接测定，CDH23和SLC9A3R1变体影响剪接效率。

这些发现表明，CDH23、SLC9A3R1、RHBDD2和可能的ITIH2参与突触功能、谷氨酸能系统和先天免疫，有助于 AD 病因学。此外，这项研究支持这样的观点，即同义变异会导致 AD 风险，并且对这种类型的遗传变异进行全面审查是必要且至关重要的。