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Identifying novel causal genes and proteins in Alzheimer’s disease
Author(s) -
Robins Chloe,
Wingo Aliza P.,
Meigs Jacob,
Duong Duc,
Cutler David J.,
De Jager Philip L.,
Lah James J.,
Bennett David A.,
Seyfried Nicholas T.,
Wingo Thomas S.,
Levey Allan I.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043523
Subject(s) - genome wide association study , phenotype , alzheimer's disease , dementia , biology , disease , genetics , gene , genetic association , medicine , single nucleotide polymorphism , pathology , genotype
Background Recent large‐scale proteomic analyses have shown Alzheimer’s disease (AD) phenotypes (i.e., clinical manifestations of AD or AD pathology) to correlate with expression levels of hundreds of proteins in brain. However, it is currently unknown whether variation in these protein levels are causes or consequences of AD. Here, we use mediation analysis to identify brain proteins that are under genetic control and play a causal role in AD. Method Genetic variants were selected as instruments for causality testing if they were both associated with variation in cis brain protein levels in 144 cognitively unimpaired participants of the Religious Order Study (ROS) and Memory and Aging Project (MAP) (FDR<0.05) (Robins et al. 2019) and suggestive risk loci in a published large‐scale GWAS of AD (p < 0.00001) (Jansen et al. 2019; Kunkle et al. 2019). These variants, and their associated proteins, were tested via mediation analysis using matched protein expression data (MS), whole genome sequencing, and clinical and pathologic data from 345 cognitively impaired and unimpaired participants of ROS/MAP. For each genetic variant and protein pair, a regression framework was used assess if some of the causal effect of the genetic variant on AD can be explained by the associated protein. Separate analyses were performed for the following AD phenotypes: 1) amyloid beta protein levels; 2) neurofibrillary tangle density; 3) clinical diagnosis of dementia; 4) cognitive trajectory. Result We found the proteins coded by the following four genes to be consistent with causality in AD: 1) MADD ; 2) RTFDC1 ; 3) SF3B3 ; 4) DOC2A . The protein coded by MADD was found to have a significant causal effect (p < 0.05) on neurofibrillary tangle density and clinical diagnosis of dementia. The protein coded by RTFDC1 was found to have a significant causal effect on neurofibrillary tangle density. The proteins coded by SF3B3 and DOC2A were found to have a significant causal effect on cognitive trajectory. Conclusion Our results suggest that proteins play causal roles in AD. Furthermore, our results suggest that different proteins may have a causal effect on different aspects of the disease. Future work clarifying the causal mechanisms of each protein will aid the development of drug interventions.