Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

TitleAssociation of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.
Publication TypeJournal Article
Year of Publication2019
AuthorsPatel D, Mez J, Vardarajan BN, Staley L, Chung J, Zhang X, Farrell JJ, Rynkiewicz MJ, Cannon-Albright LA, Teerlink CC, Stevens J, Corcoran C, Murcia JDGonzalez, Lopez OL, Mayeux R, Haines JL, Pericak-Vance MA, Schellenberg G, Kauwe JSK, Lunetta KL, Farrer LA
Corporate AuthorsAlzheimer’s Disease Sequencing Project
JournalJAMA Netw Open
Volume2
Issue3
Paginatione191350
Date Published03/2019
ISSN2574-3805
KeywordsAged, Aged, 80 and over, Alzheimer Disease, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Male, Membrane Glycoproteins, Mutation, Polymorphism, Single Nucleotide, Receptor, Notch3, Receptors, Immunologic
Abstract

Importance: Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations.Objective: To identify genetic variants associated with AD risk using a nonstatistical approach.Design, Setting, and Participants: Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018.Main Outcomes and Measures: Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative.Results: Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006).Conclusions and Relevance: Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.

DOI10.1001/jamanetworkopen.2019.1350
Alternate JournalJAMA Netw Open
PubMed ID30924900
PubMed Central IDPMC6450321
Grant ListU01 AG052410 / AG / NIA NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States
U01 AG049507 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
R01 AG048927 / AG / NIA NIH HHS / United States
UF1 AG047133 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
U01 AG049506 / AG / NIA NIH HHS / United States
U54 AG052427 / AG / NIA NIH HHS / United States
RF1 AG057519 / AG / NIA NIH HHS / United States
U01 AG049508 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
K23 AG046377 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States