Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22.

TitleOrdered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22.
Publication TypeJournal Article
Year of Publication2003
AuthorsScott, WK, Hauser, ER, Schmechel, DE, Welsh-Bohmer, KA, Small, GW, Roses, AD, Saunders, AM, Gilbert, JR, Vance, JM, Haines, JL, Pericak-Vance, MA
JournalAm J Hum Genet
Volume73
Issue5
Pagination1041-51
Date Published2003 Nov
ISSN0002-9297
KeywordsAge of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoprotein E4, Apolipoproteins E, Chromosome Mapping, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 9, Genetic Heterogeneity, Genetic Markers, Humans, Lod Score, Middle Aged, Software
Abstract

Alzheimer disease (AD) is a complex disorder characterized by a wide range, within and between families, of ages at onset of symptoms. Consideration of age at onset as a covariate in genetic-linkage studies may reduce genetic heterogeneity and increase statistical power. Ordered-subsets analysis includes continuous covariates in linkage analysis by rank ordering families by a covariate and summing LOD scores to find a subset giving a significantly increased LOD score relative to the overall sample. We have analyzed data from 336 markers in 437 multiplex (>/=2 sampled individuals with AD) families included in a recent genomic screen for AD loci. To identify genetic heterogeneity by age at onset, families were ordered by increasing and decreasing mean and minimum ages at onset. Chromosomewide significance of increases in the LOD score in subsets relative to the overall sample was assessed by permutation. A statistically significant increase in the nonparametric multipoint LOD score was observed on chromosome 2q34, with a peak LOD score of 3.2 at D2S2944 (P=.008) in 31 families with a minimum age at onset between 50 and 60 years. The LOD score in the chromosome 9p region previously linked to AD increased to 4.6 at D9S741 (P=.01) in 334 families with minimum age at onset between 60 and 75 years. LOD scores were also significantly increased on chromosome 15q22: a peak LOD score of 2.8 (P=.0004) was detected at D15S1507 (60 cM) in 38 families with minimum age at onset >/=79 years, and a peak LOD score of 3.1 (P=.0006) was obtained at D15S153 (62 cM) in 43 families with mean age at onset >80 years. Thirty-one families were contained in both 15q22 subsets, indicating that these results are likely detecting the same locus. There is little overlap in these subsets, underscoring the utility of age at onset as a marker of genetic heterogeneity. These results indicate that linkage to chromosome 9p is strongest in late-onset AD and that regions on chromosome 2q34 and 15q22 are linked to early-onset AD and very-late-onset AD, respectively.

DOI10.1086/379083
Alternate JournalAm. J. Hum. Genet.
PubMed ID14564669
PubMed Central IDPMC1180484
Grant ListR01 AG009029 / AG / NIA NIH HHS / United States
P50 AG005128 / AG / NIA NIH HHS / United States
MH59528 / MH / NIMH NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U01 MH046373 / MH / NIMH NIH HHS / United States
MH52453 / MH / NIMH NIH HHS / United States
P30 AG010123 / AG / NIA NIH HHS / United States
AG05128 / AG / NIA NIH HHS / United States
R01 NS031153 / NS / NINDS NIH HHS / United States
R01 MH052453 / MH / NIMH NIH HHS / United States
P60 AG011268 / AG / NIA NIH HHS / United States
RR00856 / RR / NCRR NIH HHS / United States
U01 MH046290 / MH / NIMH NIH HHS / United States
NS31153 / NS / NINDS NIH HHS / United States
AG019726 / AG / NIA NIH HHS / United States
AG11268 / AG / NIA NIH HHS / United States
R01 MH059528 / MH / NIMH NIH HHS / United States
AG09029 / AG / NIA NIH HHS / United States
R01 AG019726 / AG / NIA NIH HHS / United States
U01 MH046281 / MH / NIMH NIH HHS / United States