Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12.
BACKGROUND
Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD.


OBJECTIVE
To identify additional genetic risk factors for late-onset AD.


METHODS
A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set.


METHODS
Clinic populations in the continental United States.


METHODS
From a series of multiplex families affected with late-onset (> or =60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis.


METHODS
Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods.


RESULTS
Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed forchromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5, 2.6, 3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOE genotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0, 2.4, 3.7, and 3.3 and a peak multipoint MLS of 3.9.


CONCLUSIONS
A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20.
Pericak-Vance
M A
MA
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. mpv@locus.mc.duke.edu
Bass
M P
MP
Yamaoka
L H
LH
Gaskell
P C
PC
Scott
W K
WK
Terwedow
H A
HA
Menold
M M
MM
Conneally
P M
PM
Small
G W
GW
Vance
J M
JM
Saunders
A M
AM
Roses
A D
AD
Haines
J L
JL
D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002881:Chromosomes, Human, Pair 12; D002890:Chromosomes, Human, Pair 20; D002894:Chromosomes, Human, Pair 4; D002896:Chromosomes, Human, Pair 6; D004247:DNA / Q000032:analysis; D004198:Disease Susceptibility; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006579:Heterozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D012307:Risk Factors; D014481:United States
D001057:Apolipoproteins E; D005819:Genetic Markers; D004247:DNA