Synonymous variants associated with Alzheimer disease in multiplex families.

Objective: Synonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation.
Methods: 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.
Results: Rare synonymous variants in 4 genes ( and ) 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 (β = 0.53, = 0.006) and (β = 0.50, = 0.02) was increased, and expression of (β = -0.70, = 0.02) decreased in individuals with AD at death. In line with this finding, increased expression of (β = 0.26 ± 0.08, = 4.9E-4) and decreased expression of (β = -0.60 ± 0.12, = 5.5E-7) were related to brain amyloid load ( = 0.0025). expression was associated with burden of TDP43 pathology (β = 0.58 ± 0.17, = 5.9E-4). Using eQTL data, the variant was in linkage disequilibrium with variants modulating expression levels (top single nucleotide polymorphism: rs11000035, = 4.85E-6, D' = 1.0). Using minigene splicing assays, the and variants affected splicing efficiency.
Conclusions: These findings suggest that , and possibly , 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.