Abstract
Purpose: :
While cortical cataract is the second most common type of age–related cataract, its molecular genetics and pathogenesis is largely unknown.
Methods: :
We conducted a genome–wide scan (GWS) with 2252 individuals (N=1009 sibpairs) from 487 pedigrees in the Beaver Dam Eye Study (BDES). We performed a model–free linkage analysis using a quantitative trait for cortical cataract adjusted for covariates, both untransformed and transformed.
Results: :
For the most significant regions in the GWS, we tested linkage heterogeneity by removing chromosome linked sib pairs. We assessed gene–gene and gene–environment interactions for the markers with the nominal P 0.01. We obtained evidence for linkage on 1p36 (D1S3669; p=8.3x10–4), 1p21 (D1S1631; p=6.7x10–5), 1q31 (D1S1660; p=1.3x10–4), 3q13 (D3S2460; p=1.8x10–4), 5q22 (D5S2501; p=2.4x10–5), 12q24 (D12S1045; p=7.1x10–5), and 21q22 (D21S1446; p=1.2x10–6) in the GWS, either with untransformed or transformed phenotype. Removal of 117 linked pairs on 1p36 revealed heterogeneity on 1q31 (D1S1677; before removal (BR): 0.15, after removal (AR): 9x10–4) and on 1q41 (D1S2141; BR: 0.0088, AR: 5x10–7). Linkage signals best explained by smoking were on 1p36 (main effect (ME): 0.17, interaction (I): 1x10–4) and 1p21 (ME: 0.33, I: 0.008). Significant gene–gene interactions with the marker D1S3669 were observed on 2q11 (ME: 0.003, I: 6x10–4), 3q13 (ME: 0.99, I: 7x10–7), 6q16 (ME: 0.19, I: 6x10–5), 8q13 (ME: 0.065, I: 4x10–4), 14q22 (ME: 0.023, I: 3x10–6), 14q14 (ME: 0.003, I: 5x10–5), and 21q22 (ME: 0.65; I: 3x10–4). We recognize that multiple testing is an issue and permutation tests are being conducted.
Conclusions: :
The 1p36 region for cortical cataract is involved in linkage heterogeneity, as well as in gene–gene and gene–environment interaction.
Keywords: cataract • gene screening • linkage analysis