TY - JOUR
T1 - Age-related maculopathy
T2 - A genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions
AU - Weeks, Daniel E.
AU - Conley, Yvette P.
AU - Tsai, Hui Ju
AU - Mah, Tammy S.
AU - Schmidt, Silke
AU - Postel, Eric A.
AU - Agarwal, Anita
AU - Haines, Jonathan L.
AU - Pericak-Vance, Margaret A.
AU - Rosenfeld, Philip J.
AU - Paul, T. Otis
AU - Eller, Andrew W.
AU - Morse, Lawrence S.
AU - Dailey, J. P.
AU - Ferrell, Robert E.
AU - Gorin, Michael B.
N1 - Funding Information:
Foremost, we would like to thank the participating families and their clinicians, for their generous support that made this project possible. We would also like to thank Robert Elston and colleagues for providing us with a prepublication copy of Schick et al. ( 2003 ); Jacek Majewski and Michael Klein for an advanced copy of Majewski et al. ( 2003 ); Anand Swaroop and colleagues for an advanced summary of Abecasis et al. ( 2004 ); and Susan Santangelo and Chen-Hsing Yen for extensive discussions regarding the results of Seddon et al. ( 2003 ). Because we used methodology nearly identical to what we had used previously, some of the text of this article is taken verbatim from our article published elsewhere (Weeks et al. 2001 ), with the permission of Elsevier Science Incorporated. This study was funded initially by the Smith Kettlewell Eye Research Foundation, San Francisco (M.B.G. and T.O.P.), and the Pennsylvanian Lions Sight Conservation and Eye Research Foundation (M.B.G.). Additional support was provided by The Eye and Ear Foundation of Pittsburgh (NEI R01-EY09859 to M.B.G.); by Research to Prevent Blindness, New York; and by The Steinbach Foundation, New York (M.B.G.). Our first genomewide scan was genotyped by the NHLBI MGS, which is led by Dr. James Weber. The MGS is funded by NHLBI under contract N01-HV-48141 to the Marshfield Medical Research Foundation. Genotyping services for our second and third genomewide scans were provided by CIDR. CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract N01-HG-65403.
PY - 2004/8
Y1 - 2004/8
N2 - Age-related maculopathy (ARM), or age-related macular degeneration, is one of the most common causes of visual impairment in the elderly population of developed nations. In a combined analysis of two previous genomewide scans that included 391 families, containing up to 452 affected sib pairs, we found linkage evidence in four regions: 1q31, 9p13, 10q26, and 17q25. We now have added a third set of families and have performed an integrated analysis incorporating 530 families and up to 736 affected sib pairs. Under three diagnostic models, we have conducted linkage analyses using parametric (heterogeneity LOD [HLOD] scores under an autosomal dominant model) and nonparametric (S α∥ statistic) methods. There is ongoing evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. If we treat the third set of families as a replication set, then two regions (10q26 and 17q25) are replicated, with LOD scores >1.0. If we pool all our data together, then four regions (1q31, 2q14.3, 10q26, and 17q25) show HLOD or S α∥ scores ≥2.0. Within the 1q31 region, we observed an HLOD of 2.72 (genomewide P = .061) under our least stringent diagnostic model, whereas the 17q25 region contained a maximal HLOD of 3.53 (genomewide P = .007) under our intermediate diagnostic model. We have evaluated our results with respect to the findings from several new independent genomewide linkage studies and also have completed ordered subset analyses (OSAs) with apolipoprotein E alleles, smoking history, and age at onset as stratifying covariates. The OSAs generate the interesting hypothesis that the effect of smoking on the risk of ARM is accentuated by a gene in the 10q26 region-a region implicated by four other studies.
AB - Age-related maculopathy (ARM), or age-related macular degeneration, is one of the most common causes of visual impairment in the elderly population of developed nations. In a combined analysis of two previous genomewide scans that included 391 families, containing up to 452 affected sib pairs, we found linkage evidence in four regions: 1q31, 9p13, 10q26, and 17q25. We now have added a third set of families and have performed an integrated analysis incorporating 530 families and up to 736 affected sib pairs. Under three diagnostic models, we have conducted linkage analyses using parametric (heterogeneity LOD [HLOD] scores under an autosomal dominant model) and nonparametric (S α∥ statistic) methods. There is ongoing evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. If we treat the third set of families as a replication set, then two regions (10q26 and 17q25) are replicated, with LOD scores >1.0. If we pool all our data together, then four regions (1q31, 2q14.3, 10q26, and 17q25) show HLOD or S α∥ scores ≥2.0. Within the 1q31 region, we observed an HLOD of 2.72 (genomewide P = .061) under our least stringent diagnostic model, whereas the 17q25 region contained a maximal HLOD of 3.53 (genomewide P = .007) under our intermediate diagnostic model. We have evaluated our results with respect to the findings from several new independent genomewide linkage studies and also have completed ordered subset analyses (OSAs) with apolipoprotein E alleles, smoking history, and age at onset as stratifying covariates. The OSAs generate the interesting hypothesis that the effect of smoking on the risk of ARM is accentuated by a gene in the 10q26 region-a region implicated by four other studies.
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U2 - 10.1086/422476
DO - 10.1086/422476
M3 - Article
C2 - 15168325
AN - SCOPUS:3242703945
VL - 75
SP - 174
EP - 189
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -