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

Perry G. Ridge, Kaitlyn B. Hoyt, Kevin L. Boehme, Shubhabrata Mukherjee, Paul K. Crane, Jonathan L. Haines, Richard Mayeux, Lindsay A. Farrer, Margaret A. Pericak‐Vance, Gerard D. Schellenberg,

Neurobiology of Aging · 2016 · 255 citations · 26 references

DOI Full text

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TL;DR

Alzheimer’s disease is a complex genetic disorder with many common and rare variants identified, yet its full genetic architecture remains unresolved. The study seeks to quantify the genetic contribution to late‑onset AD, determine how much known SNPs explain, and locate loci responsible for the remaining heritability. The authors used Genome‑wide Complex Trait Analysis to partition phenotypic variance and map genomic regions. They estimated that genetics explain 53.24% of phenotypic variance, known SNPs account for only 30.62% of that genetic variance, and about 41% of the remaining variance is attributable to unknown SNPs near known loci, with the rest elsewhere.

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 Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (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 single nucleotide polymorphisms (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.