Assessment of the genetic variance of late-onset Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in APP, TREM2, and UNC5C that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to 1) estimate phenotypic variance explained by genetics, 2) calculate genetic variance explained by known AD SNPs, and 3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Rho‐associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

“…The majority of AD cases (> 99%) are non‐familial and late‐onset, lacking a defining etiological mechanism that underlies disease development (Ridge et al . ). Post‐mortem analysis of human AD brains identified extracellular plaques consisting of aggregated deposits of amyloid‐beta peptides (Aβ) and neurofibrillary tangles composed of misfolded hyperphosphorylated tau (Citron ).…”

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

“…By contrast, TREM2 mutations associated with AD contribute to disease risk as heterozygous variants. In addition to R47H, the coding mutation R62H is associated with increased risk of AD in independent studies (Jin et al, 2014; Ridge et al, 2016). These two variants have the strongest risk link to AD.…”

Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers

“…Several genome-wide association studies (GWAS) have identified at least 24 loci containing common variants associated with AD risk [37, 39, 48, 56]. AD is a complex disease that is highly heritable, with an estimated heritability as high as 79% in twin studies [31] and genetic variance analyses estimate >53% of the variance in AD status can be explained by common variants (minor allele frequency, MAF > 1%) [64]. Polygenic studies have illustrated the genetic complexity underlying AD; recent studies using polygenic risk scores (PRS) calculated by combining the small effects of independent SNPs associated with AD risk ( P < 0.5) provided AD risk prediction accuracy, as measured by area under the receiver operating curve (AUC) > 0.74, which is near the maximum AUC (0.82) [22, 23].…”