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

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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.

Section snippets

Methods

This was a cohort study of families with age-related maculopathy consisting of a minimum of two individuals affected with ARM.

Probands of ARM families were initially identified by mailings from ophthalmology and vitreoretinal practices to patients with ARM from the past 3 years, as identified from medical billing records. This practice-based survey approach for families with ARM has been described elsewhere.8 Patients indicated their interest in being contacted by the study coordinators by

Results

The characteristics of the families with ARM are summarized in Table 1 (ages, gender, and percent exudative). Under model A, 72% of the genotyped affected individuals had evidence of a choroidal neovascularization in one or both eyes. In model B, the percentage decreased to 67%, because we included less advanced cases of ARM. Model C incorporated an additional group of affected individuals with a total of 65% of the cohort having exudative ARM. Under our least stringent model, we evaluated 391

Discussion

This study is not intended to be an independent replication of our first genome-wide scan but rather reflects an ongoing effort to expand our genetic studies to increase our power to detect linkage. We have nearly doubled the informativeness of the second set of families, while using the same diagnostic criteria, by the recruitment of additional siblings. The allele frequencies for the two sets of families are not identical (in part because of the fact that the genotyping was performed at

Participating centers and clinicians

Seneca Eye Surgeons, Warren, PA; Erie Retinal Surgery, Inc, Erie, PA; University Eye Care, University of Pittsburgh, Pittsburgh, PA; private offices of Drs Berk, S. Portnoy, R. Barad, G. Gerneth, D. Nadler, and T. Gordon in Pittsburgh, PA; Retinal Associates of Cleveland, Cleveland, OH; Division of Vitreoretinal Surgery, Cole Eye Institute, Cleveland Clinic, Cleveland, OH; Associated Retinal Consultants PC, Detroit, MI; Texas Retina Associates, Dallas, TX; Division of Vitreoretinal Surgery,

Acknowledgements

Our first genome-wide scan was genotyped by the NHLBI MGS (http://research.marshfieldclinic.org/genetics/), which is led by Dr James Weber. Genotyping services for our second genome-wide scan were provided by the CIDR.

We are grateful for the personal efforts of Kim Doheny and Elizabeth Pugh, PhD, who assisted us with the CIDR sample documentation and data presentation and Tammy Koepel from the NHLBI Mammalian Genotyping Center.

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    This work was supported by Smith-Kettlewell Eye Research Foundation, San Francisco, California (M.B.G., T.O.P.); Ruth and Milton Steinbach Foundation, New York, New York (M.B.G.); Research to Prevent Blindness, New York, New York (M.B.G.); The Eye and Ear Research Foundation, Pittsburgh, Pennsylvania (M.B.G.); Pennsylvania Lions Sight Conservation and Eye Research Foundation, Harrisburg, Pennsylvania (M.B.G.); Grant RO1-EY 09859 National Eye Institute, Bethesda, Maryland (M.B.G.); V. Kann Rasmussen Foundation (P.J.R.). The Mammalian Genotyping Service is funded by National Heart, Lung and Blood Institute under contract number N01-HV-48141 to the Marshfield Medical Research Foundation. Center for Inherited Disease Research is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number N01-HG-65403.

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