TY - JOUR
T1 - Odered-Subsets Linkage Analysis Detects Novel Alzheimer Disease Loci on Chromosomes 2q34 and 15q22
AU - Scott, William K.
AU - Hauser, Elizabeth R.
AU - Schmechel, Donald E.
AU - Welsh-Bohmer, Kathleen A.
AU - Small, Gary W.
AU - Roses, Allen D.
AU - Saunders, Ann M.
AU - Gilbert, John R.
AU - Vance, Jeffery M.
AU - Haines, Jonathan L.
AU - Pericak-Vance, Margaret A.
N1 - Funding Information:
We thank the families for their participation and support of AD research. We thank the research staffs of the Duke Center for Human Genetics and Vanderbilt Program in Human Genetics for their efforts on this study. This study was supported by research grants NS31153, MH59528, AG05128, AG11268, AG09029, MH52453, AG10123, RR00856, and AG019726 from the National Institutes of Health; grants II-RG94101, RG2-96044, II-RG00-05, and TLL-97-012 from the Alzheimer's Association; an Alzheimer's Association Zenith award; and a grant from the Neurosciences Education and Research Foundation. Data and biomaterials were collected in three projects that participated in the NIMH Alzheimer Disease Genetics Initiative. From 1991 to 1998, the principal investigators and coinvestigators were: Marilyn S. Albert, Ph.D., and Deborah Blacker, M.D., Sc.D., Massachusetts General Hospital, Boston (NIMH grant U01 MH46281); Susan S. Bassett, Ph.D., Gary A. Chase, Ph.D., and Marshal F. Folstein, M.D., Johns Hopkins University, Baltimore (NIMH grant U01 MH46290); and Rodney C. P. Go, Ph.D., and Lindy E. Harrell, M.D., University of Alabama, Birmingham (NIMH grant U01 MH46373).
PY - 2003/11
Y1 - 2003/11
N2 - 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.
AB - 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.
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U2 - 10.1086/379083
DO - 10.1086/379083
M3 - Article
C2 - 14564669
AN - SCOPUS:0242691247
VL - 73
SP - 1041
EP - 1051
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -