@article {781, title = {Automated discovery and quantification of image-based complex phenotypes: a twin study of drusen phenotypes in age-related macular degeneration.}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Nov 25}, pages = {9195-206}, abstract = {

PURPOSE: Determining the relationships between phenotype and genotype of many disorders can improve clinical diagnoses, identify disease mechanisms, and enhance therapy. Most genetic disorders result from interaction of many genes that obscure the discovery of such relationships. The hypothesis for this study was that image analysis has the potential to enable formalized discovery of new visible phenotypes. It was tested in twins affected with age-related macular degeneration (AMD).

METHODS: Fundus images from 43 monozygotic (MZ) and 32 dizygotic (DZ) twin pairs with AMD were examined. First, soft and hard drusen were segmented. Then newly defined phenotypes were identified by using drusen distribution statistics that significantly separate MZ from DZ twins. The ACE model was used to identify the contributions of additive genetic (A), common environmental (C), and nonshared environmental (E) effects on drusen distribution phenotypes.

RESULTS: Four drusen distribution characteristics significantly separated MZ from DZ twin pairs. One encoded the quantity, and the remaining three encoded the spatial distribution of drusen, achieving a zygosity prediction accuracy of 76\%, 74\%, 68\%, and 68\%. Three of the four phenotypes had a 55\% to 77\% genetic effect in an AE model, and the fourth phenotype showed a nonshared environmental effect (E model).

CONCLUSIONS: Computational discovery of genetically determined features can reveal quantifiable AMD phenotypes that are genetically determined without explicitly linking them to specific genes. In addition, it can identify phenotypes that appear to result predominantly from environmental exposure. The approach is rapid and unbiased, suitable for large datasets, and can be used to reveal unknown phenotype-genotype relationships.

}, keywords = {Aged, 80 and over, Diseases in Twins, Female, Genetic Predisposition to Disease, Genotype, Humans, Macular Degeneration, Male, Phenotype, Registries, Retinal Drusen, Twins, Dizygotic, Twins, Monozygotic}, issn = {1552-5783}, doi = {10.1167/iovs.10-6793}, author = {Quellec, Gw{\'e}nol{\'e} and Russell, Stephen R and Seddon, Johanna M and Reynolds, Robyn and Scheetz, Todd and Mahajan, Vinit B and Stone, Edwin M and Abr{\`a}moff, Michael D} } @article {175, title = {Estrogen receptor alpha and matrix metalloproteinase 2 polymorphisms and age-related maculopathy in older women.}, journal = {American journal of epidemiology}, volume = {167}, year = {2008}, month = {2008 May 15}, pages = {1217-25}, abstract = {

In this study, the authors sought to determine whether single nucleotide polymorphisms in the estrogen receptor alpha (ESR1) and matrix metalloproteinase 2 (MMP2) genes are associated with age-related maculopathy (ARM) in older women. Subjects comprised a random sample of Caucasian women aged \> or =74 years participating in the Study of Osteoporotic Fractures year 10 follow-up (n = 906) in 1997-1998. Fundus photographs were graded for ARM using a modification of the Wisconsin Age-Related Maculopathy Grading System. The prevalences of early ARM and late ARM were 46\% and 4\%, respectively. The MMP2 rs2287074 single nucleotide polymorphism (G--\>A) was associated with ARM. The A allele was present in 47\%, 43\%, and 30\% of subjects with no, early, and late ARM, respectively (p = 0.01), and was associated with lower odds of any ARM (for AG vs. GG, odds ratio = 0.80, 95\% confidence interval: 0.65, 0.99; for AA vs. GG, odds ratio = 0.64, 95\% confidence interval: 0.42, 0.98). An interaction with use of postmenopausal hormone therapy was significant (p = 0.02). The MMP2 rs2287074 A allele may be associated with a lower likelihood of ARM in older Caucasian women, particularly those who have never used hormone therapy. The role of MMP2 rs2287074 in ARM should be further elucidated.

}, keywords = {Aged, Aged, 80 and over, Confounding Factors (Epidemiology), Estrogen Receptor alpha, Estrogen Replacement Therapy, Female, Gene Frequency, Genetic Linkage, Genotype, Humans, Logistic Models, Macular Degeneration, Matrix Metalloproteinase 2, Osteoporosis, Postmenopausal, Pigment Epithelium of Eye, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Severity of Illness Index}, author = {Seitzman, Robin L and Mahajan, Vinit B and Mangione, Carol and Cauley, Jane A and Ensrud, Kristine E and Stone, Katie L and Cummings, Steven R and Hochberg, Marc C and Hillier, Teresa A and Sinsheimer, Janet S and Yu, Fei and Coleman, Anne L} }