Can rare or uncommon coding variants confer risk of late-onset Alzheimer disease across different ethnic groups?
Via this transethnic meta-analysis combining whole-exome and whole-genome sequencing data from 15 030 participants in 3 case-control studies, novel variants in a new locus PINX1 and in a late-onset Alzheimer disease–associated gene TREM2 were identified.
Genetic investigations across different ethnic groups in large study cohorts can improve understanding of late-onset Alzheimer disease genetic mechanisms and provide new, biologically testable hypotheses.
Genetic causes of late-onset Alzheimer disease (LOAD) are not completely explained by known genetic loci. Whole-exome and whole-genome sequencing can improve the understanding of the causes of LOAD and provide initial steps required to identify potential therapeutic targets.
To identify the genetic loci for LOAD across different ethnic groups.
Design, Setting, and Participants
This multicenter cohort study was designed to analyze whole-exome sequencing data from a multiethnic cohort using a transethnic gene-kernel association test meta-analysis, adjusted for sex, age, and principal components, to identify genetic variants associated with LOAD. A meta-analysis was conducted on the results of 2 independent studies of whole-exome and whole-genome sequence data from individuals of European ancestry. This group of European American, African American, and Caribbean Hispanic individuals participating in an urban population-based study were the discovery cohort; the additional cohorts included affected individuals and control participants from 2 publicly available data sets. Replication was achieved using independent data sets from Caribbean Hispanic families with multiple family members affected by LOAD and the International Genetics of Alzheimer Project.
Main Outcomes and Measures
Late-onset Alzheimer disease.
The discovery cohort included 3595 affected individuals, while the additional cohorts included 5931 individuals with LOAD and 5504 control participants. Of 3916 individuals in the discovery cohort, we included 3595 individuals (1397 with LOAD and 2198 cognitively healthy controls; 2451 [68.2%] women; mean [SD] age, 80.3 [6.83] years). Another 321 individuals (8.2%) were excluded because of non-LOAD diagnosis, age younger than 60 years, missing covariates, duplicate data, or genetic outlier status. Gene-based tests that compared affected individuals (n = 7328) and control participants (n = 7702) and included only rare and uncommon variants annotated as having moderate-high functional effect supported PINX1 (8p23.1) as a locus with gene-wide significance (P = 2.81 × 10−6) after meta-analysis across the 3 studies. The PINX1 finding was replicated using data from the family-based study and the International Genetics of Alzheimer Project. Full meta-analysis of discovery and replication cohorts reached a P value of 6.16 × 10−7 for PINX1 (in 7620 affected individuals vs 7768 control participants). We also identified TREM2 in an annotation model that prioritized highly deleterious variants with a combined annotation dependent depletion greater than 20 (P= 1.0 × 10−7).
Conclusions and Relevance
This gene-based, transethnic approach identified PINX1, a gene involved in telomere integrity, and TREM2, a gene with a product of an immune receptor found in microglia, as associated with LOAD. Both genes have well-established roles in aging and neurodegeneration.
Tosto G, Vardarajan B, Sariya S, et al. Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease. JAMA Neurol. Published online May 06, 201976(8):942–948. doi:10.1001/jamaneurol.2019.1066
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