Age-related maculopathy: A genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions

Daniel E. Weeks, Yvette P. Conley, Hui Ju Tsai, Tammy S. Mah, Silke Schmidt, Eric A. Postel, Anita Agarwal, Jonathan L. Haines, Margaret A. Pericak-Vance, Philip J. Rosenfeld, T. Otis Paul, Andrew W. Eller, Lawrence S Morse, J. P. Dailey, Robert E. Ferrell, Michael B. Gorin

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)174-189
Number of pages16
JournalAmerican Journal of Human Genetics
Volume75
Issue number2
DOIs
StatePublished - Aug 2004

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Macular Degeneration
Smoking
Vision Disorders
Apolipoproteins E
Nonparametric Statistics
Age of Onset
Developed Countries
History
Alleles
Population
Genes

ASJC Scopus subject areas

  • Genetics

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Age-related maculopathy : A genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. / Weeks, Daniel E.; Conley, Yvette P.; Tsai, Hui Ju; Mah, Tammy S.; Schmidt, Silke; Postel, Eric A.; Agarwal, Anita; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Rosenfeld, Philip J.; Paul, T. Otis; Eller, Andrew W.; Morse, Lawrence S; Dailey, J. P.; Ferrell, Robert E.; Gorin, Michael B.

In: American Journal of Human Genetics, Vol. 75, No. 2, 08.2004, p. 174-189.

Research output: Contribution to journalArticle

Weeks, DE, Conley, YP, Tsai, HJ, Mah, TS, Schmidt, S, Postel, EA, Agarwal, A, Haines, JL, Pericak-Vance, MA, Rosenfeld, PJ, Paul, TO, Eller, AW, Morse, LS, Dailey, JP, Ferrell, RE & Gorin, MB 2004, 'Age-related maculopathy: A genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions', American Journal of Human Genetics, vol. 75, no. 2, pp. 174-189. https://doi.org/10.1086/422476
Weeks, Daniel E. ; Conley, Yvette P. ; Tsai, Hui Ju ; Mah, Tammy S. ; Schmidt, Silke ; Postel, Eric A. ; Agarwal, Anita ; Haines, Jonathan L. ; Pericak-Vance, Margaret A. ; Rosenfeld, Philip J. ; Paul, T. Otis ; Eller, Andrew W. ; Morse, Lawrence S ; Dailey, J. P. ; Ferrell, Robert E. ; Gorin, Michael B. / Age-related maculopathy : A genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. In: American Journal of Human Genetics. 2004 ; Vol. 75, No. 2. pp. 174-189.
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abstract = "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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