Seven new loci associated with age-related macular degeneration

Fritsche, Lars G.; Chen, Wei; Schu, Matthew; Yaspan, Brian L.; Yu, Yi; Þorleifsson, Guðmar; Zack, Donald J.; Arakawa, Satoshi; Cipriani, Valentina; Ripke, Stephan; Igo, Robert P.; Buitendijk, Gabriëlle H.S.; Sim, Xueling; Weeks, Daniel E.; Guymer, Robyn H.; Merriam, Joanna E.; Francis, Peter J.; Hannum, Gregory; Agarwal, Anita; Armbrecht, Ana Maria; Audo, Isabelle; Aung, Tin; Barile, Gaetano R.; Benchaboune, Mustapha; Bird, Alan C.; Bishop, Paul N.; Branham, Kari; Brooks, Matthew; Brucker, Alexander J.; Cade, William H.; Cain, Melinda; Campochiaro, Peter A.; Chan, Chi Chao; Cheng, Ching‐Yu; Chew, Emily Y.; Chin, Kimberly; Chowers, Itay; Clayton, David; Cojocaru, Radu; Conley, Yvette P.; Cornes, Belinda K.; Daly, Mark J.; Dhillon, Baljean; Edwards, Albert O.; Εvangelou, Εvangelos; Fagerness, Jesen; Ferreyra, Henry; Friedman, James S.; Geirsdóttir, Ásbjörg; George, Ronnie; Gieger, Christian; Gupta, Neel; Hagstrom, Stephanie A.; Harding, Simon; Haritoglou, Christos; Heckenlively, John R.; Holz, Frank G.; Hughes, Guy; Ioannidis, John P. A.; Ishibashi, Tatsuro; Joseph, Peronne; Jun, Gyungah; Kamatani, Yoichiro; Katsanis, Nicholas; Keilhauer, Claudia N.; Khan, Jane C.; Kim, Ivana K.; Kiyohara, Yutaka; Klein, Barbara E.K.; Klein, Ronald; Kovach, Jaclyn L.; Kozák, Igor; Lee, Clara J.; Lee, Kristine E.; Lichtner, Peter; Lotery, Andrew; Meitinger, Thomas; Mitchell, Paul; Mohand‐Saïd, Saddek; Moore, Anthony T.; Morgan, Denise J.; Morrison, Margaux A.; Myers, Chelsea E.; Naj, Adam C.; Nakamura, Yusuke; Okada, Yukinori; Orlin, Anton; Ortube, Maria Carolina; Othman, Mohammad; Pappas, Chris; Park, Kyu Hyung; Pauer, Gayle J.; Peachey, Neal S.; Poch, Olivier; Priya, Rinki Ratna; Reynolds, Robyn; Richardson, Andrea J.; Ripp, Raymond; Rudolph, Guenther; Ryu, Euijung; Sahel, José‐Alain; Schaumberg, Debra A.; Scholl, Hendrik P. N.; Schwartz, Stephen G.; Scott, William K.; Shahid, Humma; Sigurðsson, H.; Silvestri, G; Sivakumaran, Theru A.; Rjh, Smith; Sobrin, Lucia; Souied, Eric H.; Stambolian, Dwight; Stefánsson, Hreinn; Sturgill-Short, Gwen M.; Takahashi, Atsushi; Tosakulwong, Nirubol; Truitt, Barbara; Tsironi, Evangelia E.; Uitterlinden, André G.; Duijn, Cornelia M. van; Vijaya, Lingam; Vingerling, Johannes R.; Vithana, Eranga N.; Webster, Andrew R.; Wichmann, Heinz Erich; Winkler, Thomas W.; Wong, Tien Yin; Wright, Alan F.; Zélénika, Diana; Zhang, Ming; Zhao, Ling; Zhang, Kang; Klein, Michael L.; Hageman, Gregory S.; Lathrop, Mark; Stefánsson, Kári; Allikmets, Rando; Baird, Paul N.; Gorin, Michael B.; Wang, Jie Jin; Klaver, Caroline C.W.; Seddon, Johanna M.; Pericak‐Vance, Margaret A.; Iyengar, Sudha K.; Yates, John R.; Swaroop, Anand; Weber, Bernhard H. F.; Kubo, Michiaki; DeAngelis, Margaret M.; Léveillard, Thierry; Þorsteinsdóttir, Unnur; Haines, Jonathan L.; Farrer, Lindsay A.; Heid, Iris M.; Abecasis, Gonçalo R.

doi:10.1038/ng.2578

Cited by 682 publications

(526 citation statements)

References 62 publications

(68 reference statements)

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“…A meta‐analysis of the AMD gene consortium revealed seven new loci associated with age‐related macular degeneration reaching genomewide significance levels, including a variant in the SLC16A8 gene, which was independently associated with risk of disease 67. A large genomewide association study including over 16,000 patients with age‐related macular degeneration and almost 18,000 controls confirmed the association of the splice variant in SLC16A8 (MCT3) with strongly increased disease risk.…”

Section: Ophthalmological Diseasesmentioning

confidence: 90%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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Section: Ophthalmological Diseasesmentioning

confidence: 90%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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“…Hence, we searched for any overlap between our top association signals and those previously reported for AMD [71][72][73] . Amongst our suggestive association signals we find the TIMP metallopeptidase inhibitor 3 (TIMP3)/synapsin III (SYN3) locus at 22q12.3 (Supplementary Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…Risk factors of similar, and smaller, effect size have been discovered using GWASs for AMD 72 . Further risk factors for MacTel will likely be identified using additional cohorts.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

et al. 2017

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Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genomewide association study (GWAS) with 476 cases and 1733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10 -8 ) were identified at 3 independent loci (rs73171800 at 5q14.3, P = 7.74 × 10 -17 ; rs715 at 2q34, P = 9.97 × 10 -14 ; rs477992 at 1p12, P = 2.60 × 10 -12 ) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences of blood serum levels of glycine (P = 4.04 × 10 -6 ) and serine (P = 2.48 × 10 -4 ) between MacTel cases and controls.MacTel cases typically present at 40-60 years with abnormal right-angled juxtafoveolar capillaries and parafoveal telangiectasias. It is an uncommon disease with a 0.0045-0.1% population prevalence and no obvious sex bias [1][2][3] . Retinal lesions typically co-present with MacTel, including retinal transparency, outer retinal and choroidal neovascularization, lamellar holes or foveal cysts, photoreceptor dysfunction, minimal exudation, yellow-white parafoveal crystals, and retinal pigment epithelial (RPE) pigmentation abnormalities and atrophy. Central vision impairment and decreased visual acuity are the usual clinical outcomes. MacTel is a bilateral disease, but asymmetry of the eyes for disease severity and presence of lesions is possible. The lesions also occur in 0.06-1.18% of the general population 2 .Risk factors for MacTel are largely unknown, however associations have been observed with smoking 2,4 , diabetes 5,6 , high BMI 6 , hypertension 6 and obesity 6 .Observations of MacTel affected monozygotic twins 4,[7][8][9] , and multiplex families with vertical transmissions of MacTel 1,5,[9][10][11][12] , suggest a genetic etiology for the disease. The late-age of onset, low penetrance and variable phenotype as exemplified by asymptomatic affected relatives 9 , and positive and negative misdiagnoses, complicate the discovery of genetic variants predisposing to MacTel. We previously screened 27 candidate genes in 8 unrelated MacTel cases but found no causative mutations 13 . Linkage analysis of 17 families with MacTel individuals identified a 15.3Mb locus on chromosome 1q41-42.2 (LOD=3.45), however sequencing of the underlying genes revealed no causative mutations 14 . Results Discovery GWAS stageThe GWAS discovery stage included genotype data for 6,312,048 single nucleotide polymorphisms (SNPs) after quality control and imputation (including 1,093,805 SNPs genotyped on the Illumina Omni SNP chips) in 476 MacTel cases and 1,733 controls (see Table 1 and Online Methods). This sample size was large enough to achieve power of at least 0.90 for risk variants with allele frequencies of 0.10-...

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“…The forthcoming challenge will be how ophthalmologists deal with the ever increasing workload in medical retina disease, while being able to incorporate the exciting concepts of individualised health care that are promised by recent advances in genetics. 97 …”

Section: Resultsmentioning

confidence: 99%

25th RCOphth Congress, President's Session paper: 25 years of progress in medical retina

Gibson

2014

Eye

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Seven new loci associated with age-related macular degeneration

Cited by 682 publications

References 62 publications

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

25th RCOphth Congress, President's Session paper: 25 years of progress in medical retina

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