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Synonymous variants associated with Alzheimer disease in multiplex families.

TitleSynonymous variants associated with Alzheimer disease in multiplex families.
Publication TypeJournal Article
Year of Publication2020
AuthorsTang M, Alaniz MEugenia, Felsky D, Vardarajan B, Reyes-Dumeyer D, Lantigua R, Medrano M, Bennett DA, De Jager PL, Mayeux R, Santa-Maria I, Reitz C
JournalNeurol Genet
Date Published2020 Aug

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.

Pubmed Link
Alternate JournalNeurol Genet
PubMed ID32637632
PubMed Central IDPMC7323483
Grant ListR01 AG067501 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
RF1 AG015473 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
R01 NS095922 / NS / NINDS NIH HHS / United States
R56 AG063908 / AG / NIA NIH HHS / United States
P30 AG066462 / AG / NIA NIH HHS / United States

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