Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean hispanics with familial Alzheimer disease.
OBJECTIVE
To identify novel candidate regions for late-onset Alzheimer disease (LOAD) and to confirm linkage in previously identified chromosomal regions.


METHODS
Family-based linkage analysis.


METHODS
Probands with familial LOAD identified in clinics in the Dominican Republic, Puerto Rico, and the United States. Patients We conducted a genome scan in 1161 members primarily clinically diagnosed as having LOAD; these members were from 209 families of Caribbean Hispanic ancestry.


METHODS
We analyzed 376 microsatellite markers with an average intermarker distance of 9.3 centimorgan. We conducted linkage analysis using possible and probable LOAD, and we performed affecteds-only 2-point linkage analyses assuming either an autosomal dominant or a recessive model. Subsequently, we conducted a multipoint affected sibling pair linkage analysis.


RESULTS
Two-point parametric linkage analysis identified a locus at 3q28 with a genomewide empirical P value of .03 (logarithm of odds [LOD], 3.09) in a dominant model for probable and possible LOAD. Other regions suggestive of linkage included 2p25.3 (LOD, 1.77), 7p21.1 (LOD, 1.82), and 9q32 (LOD, 1.94). Under a recessive model, we also identified loci at 5p15.33 (LOD, 1.86), 12q24.21 (LOD, 2.43), 14q22.3 (LOD, 2.53), and 14q23.1 (LOD, 2.16) as suggestive for linkage. Restricted to probable LOAD, many of these loci continued to meet criteria suggestive for linkage, as did loci at 2p25.3 (LOD, 2.72), 3q28 (LOD, 2.28), 6p21.31 (LOD, 2.19), and 7p21.1 (LOD, 2.05). APOE conditional analysis indicated that the observed linkage at 3q28 was independent of the APOE epsilon4 allele. Multipoint nonparametric affected sibling pair linkage analysis provided confirmation of suggestive linkage for most, but not all, loci.


CONCLUSIONS
Seven loci with LOD scores greater than 2.0 were identified among multiple affected Caribbean Hispanic families with LOAD. The highest LOD score was found at chromosome 3q28. At least 2 other independent studies have observed support for significant linkage at chromosome 3q28, highlighting this region as a locus for further genetic exploration.
Lee
Joseph H
JH
Gertrude H. Sergievsky Center, Columbia University, 630 W 168th St, New York, NY 10032, USA.
Cheng
Rong
R
Santana
Vincent
V
Williamson
Jennifer
J
Lantigua
Rafael
R
Medrano
Martin
M
Arriaga
Alex
A
Stern
Yaakov
Y
Tycko
Benjamin
B
Rogaeva
Ekaterina
E
Wakutani
Yosuke
Y
Kawarai
Toshitaka
T
St George-Hyslop
Peter
P
Mayeux
Richard
R
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D017691:Caribbean Region / Q000453:epidemiology / Q000208:ethnology; D002874:Chromosome Mapping / Q000379:methods*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006630:Hispanic or Latino / Q000208:ethnology / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics