Genetics of Alzheimer disease in the pre- and post-GWAS era

Nilüfer Ertekin-Taner

doi:10.1186/alzrt26

Abstract

Since the 1990s, the genetics of Alzheimer disease (AD) has been an active area of research. The identification of deterministic mutations in the APP, PSEN1, and PSEN2 genes responsible for early-onset autosomal dominant familial forms of AD led to a better understanding of the pathophysiology of this disease. In the past decade, the plethora of candidate genes and regions emerging from genetic linkage and smaller-scale association studies yielded intriguing 'hits' that have often proven difficult to replicate consistently. In the last two years, 11 published genome-wide association studies (GWASs) in AD confirmed the universally accepted role of APOE as a genetic risk factor for late-onset AD as well as generating additional candidate genes that require confirmation. It is unclear whether GWASs, though a promising novel approach in the genetics of complex diseases, can help explain most of the underlying genetic risk for AD. This review provides a brief summary of the genetic studies in AD preceding the GWAS era, with the main focus on the findings from recent GWASs. Potential approaches that could provide further insight into the genetics of AD in the post-GWAS era are also discussed.

Highlights

Since the 1990s, the genetics of Alzheimer disease (AD) has been an active area of research
Late-onset Alzheimer disease The identification of a chromosome 19 risk locus in late-onset Alzheimer disease (LOAD) families [27] was followed by the discovery of a higher frequency of the APOE ε4 allele in LOAD patients compared with controls [28,29]
Another way to consider Population attributable risk (PAR) is the amount of decrease that would be observed in the incidence of AD if the genetic factor could be eliminated

Summary

Study design

Li et al [53], January Canada/UK Case control 1 discovery and Abraham et al [54], UK September 2008. Abbreviations Aβ, amyloid β; AD, Alzheimer disease; APP, amyloid precursor protein (gene); CALHM1, calcium homeostasis modulator 1 (gene); CLU, clusterin (gene); CR1, complement component receptor 1 (gene); EOFAD, early-onset familial Alzheimer disease; FDR-BUM, false discovery rate-beta uniform mixture; GAB2, GRB-associated binding protein 2 (gene); GALP, galanin-like peptide precursor (gene); GWAS, genome-wide association study; LD, linkage disequilibrium; LOAD, late-onset Alzheimer disease; OR, odds ratio; PAR, population attributable risk; PCDH11X, protocadherin 11X (gene); PCK1, phosphoenolpyruvate carboxykinase 1 (gene); PICALM, phosphatidylinositolbinding clathrin assembly protein (gene); PSEN, presenilin (gene); SNP, singlenucleotide polymorphism; SORL1, sortilin-related receptor (gene); TRPC4AP, transient receptor potential cation channel, subfamily C, member 4 associated protein (gene). Competing interests The author declares that she has no competing interests

35. Ertekin-Taner N

Findings

65. Goodman AB