Alzheimer's disease: analyzing the missing heritability

Abstract

Alzheimer's disease (AD) is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to analyze >2 million SNPs for 10,922 individuals from the Alzheimer's Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer's Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer's disease.

Figure 1. Unexplained Alzheimer’s disease variance, by chromosome.

In this figure we show phenotypic variance, by chromosome, explained by all SNPs. Error bars correspond to standard error.

Figure 2. Unexplained Alzheimer’s disease variance, by chromosome, excluding known Alzheimer’s disease markers.

This figure is the same as Figure 1 except we have removed variance explained by known Alzheimer’s disease markers. Error bars correspond to standard error.

Figure 3. Variant search space.

Real and hypothetical variants are graphed by effect size (y-axis) and population frequency (x-axis). Known Alzheimer’s disease SNPs are blue circles and hypothetical SNPs are red circles. The large box on the right outlined with dots, is the GWAS search space and the smaller box on the left, outlined with dashes, is the next-generation sequencing search space. Known Alzheimer’s disease SNPs are those found in Table 1 as well as APP and TREM2, which are both labeled on the graph.