TY - JOUR
T1 - Age-related macular degeneration - A genome scan in extended families
AU - Majewski, Jacek
AU - Schultz, Dennis W.
AU - Weleber, Richard G.
AU - Schain, Mitchell B.
AU - Edwards, Albert O.
AU - Matise, Tara C.
AU - Acott, Ted S.
AU - Ott, Jurg
AU - Klein, Michael L.
N1 - Funding Information:
This work was supported by grant HG00008 (to J.O., T.C.M., and J.M.) National Human Genome Research Institute, Bethesda, MD; grant EY 12203 (to M.L.K.) and grants EY 03279, EY 08247, and EY 10572 (all to T.S.A.) from the National Institutes of Health, Bethesda, MD; the Collins Medical Trust, Portland, OR (support to D.W.S.); The Foundation Fighting Blindness, Owings Mills, MD (support to D.W.S. and R.G.W.); the George and Carolyn Goodall Macular Degeneration Fund; and an unrestricted grant from Research to Prevent Blindness, New York. We thank Blair Berselli, Susan Nolte, Heather Cooper, and Genet Friess, for help with family ascertainment, and Rebecca Barra, for sample DNA amplification.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - We performed a genomewide scan and genetic linkage analysis, to identify loci associated with age-related macular degeneration (AMD). We collected 70 families, ranging from small nuclear families to extended multigenerational pedigrees and consisting of a total of 344 affected and 217 unaffected members available for genotyping. We performed linkage analyses using parametric and allele-sharing models. We performed the analyses on the complete pedigrees but also subdivided the families into nuclear pedigrees. Finally, to dissect potential genetic factors responsible for differences in disease manifestation, we stratified the sample by two major AMD phenotypes (neovascular AMD and geographic atrophy) and by age of affected family members at the time of our evaluation. We have previously demonstrated linkage between AMD and 1q25-31 in a single large family. In the combined sample, we have detected the following loci with scores exceeding a LOD = 2 cutoff under at least one of the models considered: 1q31 (HLOD = 2.07 at D1S518), 3p13 (HLOD = 2.19 at D3S1304/D3S4545), 4q32 (HLOD = 2.66 at D4S2368, for the subset of families with predominantly dry AMD), 9q33 (LODZlr = 2.01 at D9S930/D9S934), and 10q26 (HLOD = 3.06 at D10S1230). Using correlation analysis, we have found a statistically significant correlation between LOD scores at 3p13 and 10q26, providing evidence for epistatic interactions between the loci and, hence, a complex basis of AMD. Our study has identified new loci that should be considered in future mapping and mutational analyses of AMD and has strengthened the evidence in support of loci suggested by other studies.
AB - We performed a genomewide scan and genetic linkage analysis, to identify loci associated with age-related macular degeneration (AMD). We collected 70 families, ranging from small nuclear families to extended multigenerational pedigrees and consisting of a total of 344 affected and 217 unaffected members available for genotyping. We performed linkage analyses using parametric and allele-sharing models. We performed the analyses on the complete pedigrees but also subdivided the families into nuclear pedigrees. Finally, to dissect potential genetic factors responsible for differences in disease manifestation, we stratified the sample by two major AMD phenotypes (neovascular AMD and geographic atrophy) and by age of affected family members at the time of our evaluation. We have previously demonstrated linkage between AMD and 1q25-31 in a single large family. In the combined sample, we have detected the following loci with scores exceeding a LOD = 2 cutoff under at least one of the models considered: 1q31 (HLOD = 2.07 at D1S518), 3p13 (HLOD = 2.19 at D3S1304/D3S4545), 4q32 (HLOD = 2.66 at D4S2368, for the subset of families with predominantly dry AMD), 9q33 (LODZlr = 2.01 at D9S930/D9S934), and 10q26 (HLOD = 3.06 at D10S1230). Using correlation analysis, we have found a statistically significant correlation between LOD scores at 3p13 and 10q26, providing evidence for epistatic interactions between the loci and, hence, a complex basis of AMD. Our study has identified new loci that should be considered in future mapping and mutational analyses of AMD and has strengthened the evidence in support of loci suggested by other studies.
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U2 - 10.1086/377701
DO - 10.1086/377701
M3 - Article
C2 - 12900797
AN - SCOPUS:0041886495
SN - 0002-9297
VL - 73
SP - 540
EP - 550
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -