Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions

Daniel E. Weeks, Yvette P. Conley, Hui Ju Tsai, Tammy S. Mah, Philip J. Rosenfeld, T. Otis Paul, Andrew W. Eller, Lawrence S Morse, J. P. Dailey, Robert E. Ferrell, Michael B. Gorin

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (Sall statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or Sall scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.

Original languageEnglish (US)
Pages (from-to)682-692
Number of pages11
JournalAmerican Journal of Ophthalmology
Volume132
Issue number5
DOIs
StatePublished - 2001

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Macular Degeneration
Lod Score
Genome
Retinal Dystrophies
National Heart, Lung, and Blood Institute (U.S.)
Chromosomes, Human, Pair 12
Genetic Loci
Chromosomes, Human, Pair 2
National Institutes of Health (U.S.)
Pedigree
Microsatellite Repeats
Genes
Siblings
Chromosomes
Research

ASJC Scopus subject areas

  • Ophthalmology

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Age-related maculopathy : an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. / Weeks, Daniel E.; Conley, Yvette P.; Tsai, Hui Ju; Mah, Tammy S.; 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 Ophthalmology, Vol. 132, No. 5, 2001, p. 682-692.

Research output: Contribution to journalArticle

Weeks, DE, Conley, YP, Tsai, HJ, Mah, TS, Rosenfeld, PJ, Paul, TO, Eller, AW, Morse, LS, Dailey, JP, Ferrell, RE & Gorin, MB 2001, 'Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions', American Journal of Ophthalmology, vol. 132, no. 5, pp. 682-692. https://doi.org/10.1016/S0002-9394(01)01214-4
Weeks, Daniel E. ; Conley, Yvette P. ; Tsai, Hui Ju ; Mah, Tammy S. ; Rosenfeld, Philip J. ; Paul, T. Otis ; Eller, Andrew W. ; Morse, Lawrence S ; Dailey, J. P. ; Ferrell, Robert E. ; Gorin, Michael B. / Age-related maculopathy : an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. In: American Journal of Ophthalmology. 2001 ; Vol. 132, No. 5. pp. 682-692.
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abstract = "PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (Sall statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or Sall scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.",
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T1 - Age-related maculopathy

T2 - an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions

AU - Weeks, Daniel E.

AU - Conley, Yvette P.

AU - Tsai, Hui Ju

AU - Mah, Tammy S.

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.

PY - 2001

Y1 - 2001

N2 - PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (Sall statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or Sall scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.

AB - PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (Sall statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or Sall scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.

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