Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.
Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.
Bertram
Lars
L
Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Lange
Christoph
C
Mullin
Kristina
K
Parkinson
Michele
M
Hsiao
Monica
M
Hogan
Meghan F
MF
Schjeide
Brit M M
BM
Hooli
Basavaraj
B
Divito
Jason
J
Ionita
Iuliana
I
Jiang
Hongyu
H
Laird
Nan
N
Moscarillo
Thomas
T
Ohlsen
Kari L
KL
Elliott
Kathryn
K
Wang
Xin
X
Hu-Lince
Diane
D
Ryder
Marie
M
Murphy
Amy
A
Wagner
Steven L
SL
Blacker
Deborah
D
Becker
K David
KD
Tanzi
Rudolph E
RE
D017668:Age of Onset; D000465:Algorithms; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D001499:Bayes Theorem; D016022:Case-Control Studies; D002883:Chromosomes, Human, Pair 14; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics; D044465:White People
D001057:Apolipoproteins E; C571163:CD33 protein, human; D005819:Genetic Markers; D063268:Sialic Acid Binding Ig-like Lectin 3