Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease

Abstract

One of every 5 persons aged 65 years is predicted to develop Alzheimer disease (AD) in their lifetime, and genetic variants may play an important part in the development of the disease.¹ The apparent substantial heritability of late-onset AD² is inadequately explained by genetic variation within the well-replicated genes (apolipoprotein E [APOE; RefSeq NG_007084], presenilin-1 [PSEN1; RefSeq NG_007386], presenilin-2 [PSEN2; RefSeq NG_007381], and amyloid beta precursor protein [APP; RefSeq NM_000484]).³ Initial genome-wide association studies (GWAS) identified putative new candidate genes (GRB2-associated binding protein [GAB2; RefSeq NG_016171], protocadherin 11 x-linked [PCDH11X; RefSeq NG_016251], lecithin retinol acyltransferase [LRAT; RefSeq NG_009110], and transient receptor potential cation channel, subfamily C, member 4– associated protein [TRPC4AP; RefSeq NM_015638 ])^4-6 and regions of interest (eg, on chromosomes 14q, 10q, and 12q),^7-10 but no locus outside of the APOE region consistently reached genome-wide significance.^4,11,12 These disappointing results are most likely explained by the modest sample size and, hence, limited statistical power of early studies to detect genes with small effects. Recently, 2 large GWAS, the United Kingdom–led Genetic and Environmental Risk in Alzheimer Disease 1 consortium (GERAD1)¹³ and the European Alzheimer Disease Initiative stage 1 (EADI1),¹⁴ reported 3 new genome-wide significant loci for AD: within the CLU gene (GenBank AY341244) encoding clusterin (also called apolipoprotein J), near the PICALM gene (GenBank BC073961) encoding phosphatidylinositol–binding clathrin assembly protein, and within the CR1 (RefSeq NG_007481) gene encoding complement component (3b/4b) receptor 1.^13,14