Abstract
Abstract: :
Purpose: A genome–wide linkage scan for age–related macular degeneration (AMD) was conducted with 110 affected sib–pair (ASP) families in an attempt to replicate findings from our prior genome scans of 158 ASP families (Seddon et al. AJHG 2003) and 42 extremely discordant sib–pair families (Santangelo et al. IOVS, ARVO abstract 2004). In addition, ordered subset analysis (OSA) was used to try to identify a more homogeneous subset of families that might increase the evidence for linkage. Methods: The extent of IBD gene–sharing among ASPs was assessed via the multipoint non–parametric LOD (NPL) score based on the Spairs statistic in the Genehunter Plus package. The multipoint heterogeneity LOD score was also computed. The OSA analysis used pack–years of cigarette smoking among the affecteds as a way to potentially decrease genetic heterogeneity. AMD classification was based on fundus photography, with grades assigned ranging from 1 to 5 according to the Clinical Age–Related Maculopathy Grading System. Results: The strongest evidence for linkage was found on chromosome 1q in the 1q25–31 region, where several other studies have also seen evidence for linkage (Klein et al. 1998; Weeks et al. 2001; Majewski et al. 2003; Schultz et al. 2003; Iyengar et al. 2004). We observed an NPL score of 2.04, p = 0.006, at 202.21 cM and a heterogeneity LOD score of 2.66 at 200.19 cM under a dominant model. These peaks were in the same region reported by Majewski et al. (2003) and Iyengar et al. (2004), and approximately 8 to 10cM distal to the signals observed in our prior genome scans. Modest evidence for linkage was also seen across much of chromosome 6, with several small peaks in regions spanning 34.0 – 89.0 cM and 173.0 – 187.0 cM. The strongest signal was an NPL score of 1.54, p = 0.03, on 6p at 73.0 cM, approximately 8 cM away from a significant signal in our prior ASP scan. OSA analysis showed evidence of an interaction between smoking and a gene on chromosome 6p. Ranking pack–years of smoking from high to low produced a maximum OSA LOD score of 2.75 at 42.0 cM, whereas the unconditional LOD score computed for all families at this location was 0.51 (p–value for change in LOD score = 0.04). Sixty six families with mean pack–years of smoking > 25 contributed to the increased LOD score. Conclusions: These results show continued support for an AMD susceptibility locus in the 1q25–31 region. There is also evidence for another susceptibility locus on chromosome 6, which may interact with smoking to increase risk for AMD.
Keywords: age-related macular degeneration • gene mapping • linkage analysis