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

PURPOSE: We seek to identify genetic loci that con, tribute to age,related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age relat ed maculopathy were ascertained using eye care records and fundus photograp hs. Additional family members were used to increase the power to detect lin kage. Microsatellite genotyping was conducted by the National Heart, Lung a nd Blood Institute Mam malian Genotyping Service and the National Institute s of Health Center for Inherited Disease Research. Linkage analyses were co nducted with parametric (autosomal dominant; heterogeneity lod score) and n onparametric methods (S-all 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 pe rcent of the affected individuals had evidence of exudative disease. Four r egions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod s cores or S-all scores of 2.0 or greater (under at least one model). Under o ur most stringent diagnostic model, model A, the 1q31 heterogeneity lod sco re was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogen eity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional lo ci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report b y Klein and associates mapping an age-related maculopathy susceptibility ge ne to this region. Simulations indicate that the 1q31 and 17q25 loci are un likely to be false positives. There was no evidence that other known macula r or retinal dystrophy candidate gene regions are major contributors to the genetics of age,related maculopathy. (C) 2001 by Elsevier Science Inc. All rights reserved.