@article {303976, title = {Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration.}, journal = {Hum Mol Genet}, volume = {23}, number = {21}, year = {2014}, month = {2014 Nov 1}, pages = {5827-37}, abstract = {Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch{\textquoteright}s membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 {\texttimes} 10(-5)). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch{\textquoteright}s membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.}, issn = {1460-2083}, doi = {10.1093/hmg/ddu276}, author = {Ratnapriya, Rinki and Zhan, Xiaowei and Fariss, Robert N and Branham, Kari E and Zipprer, David and Chakarova, Christina F and Sergeev, Yuri V and Campos, Maria M and Othman, Mohammad and Friedman, James S and Maminishkis, Arvydas and Waseem, Naushin H and Brooks, Matthew and Rajasimha, Harsha K and Edwards, Albert O and Lotery, Andrew and Klein, Barbara E and Truitt, Barbara J and Li, Bingshan and Schaumberg, Debra A and Morgan, Denise J and Morrison, Margaux A and Souied, Eric and Tsironi, Evangelia E and Grassmann, Felix and Fishman, Gerald A and Silvestri, Giuliana and Scholl, Hendrik P N and Kim, Ivana K and Ramke, Jacqueline and Tuo, Jingsheng and Merriam, Joanna E and Merriam, John C and Park, Kyu Hyung and Olson, Lana M and Farrer, Lindsay A and Johnson, Matthew P and Peachey, Neal S and Lathrop, Mark and Baron, Robert V and Igo, Robert P and Klein, Ronald and Hagstrom, Stephanie A and Kamatani, Yoichiro and Martin, Tammy M and Jiang, Yingda and Conley, Yvette and Sahel, Jose-Alan and Zack, Donald J and Chan, Chi-Chao and Pericak-Vance, Margaret A and Jacobson, Samuel G and Gorin, Michael B and Klein, Michael L and Allikmets, Rando and Iyengar, Sudha K and Weber, Bernhard H and Haines, Jonathan L and L{\'e}veillard, Thierry and Deangelis, Margaret M and Stambolian, Dwight and Weeks, Daniel E and Bhattacharya, Shomi S and Chew, Emily Y and Heckenlively, John R and Abecasis, Gon{\c c}alo R and Swaroop, Anand} }