A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy

Abstract

Importance: Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level.

Objective: To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP.

Design, setting, and participants: We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed.

Main outcomes and measures: Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP.

Results: Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD.

Conclusions and relevance: Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.

Figure 1. Comparison of the Exome Array and Related Genotyping and Sequencing Technologies

The exome array serves as a bridge between conventional single-nucleotide polymorphism (SNP) genotyping array and exome sequencing. The exome array assays primarily variants within exonic regions of the DNA, similar to exome sequencing; however, the location of the variants must be known a priori. The cost of the exome array is typically similar to that of other genotyping arrays and is much less expensive than that of exome sequencing.

Figure 2. Manhattan Plot of Associations in Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy

The association −log₁₀ P values calculated by logistic regression are presentd for for Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy. The horizontal line indicates the suggestive P value threshold of P = 1 × 10⁻⁵. X refers to chromosome X.

Figure 3. Differential Expression of DYSF and PAXIP1 in Alzheimer Disease (AD) Brain

Shown is the expression of DYSF (A) and PAXIP1 (B) in a public microarray data set of brain messenger RNA, grouped by brain region, in patients with AD (dark gray) vs healthy control subjects without dementia (light gray). The vertical axis represents the normalized expression residual, corrected for technical covariates. CB indicates cerebellum; PFC, prefrontal cortex; and VC, visual cortex.