|
|
|
|
Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma
|
|
|
|
|
|
|
|
نویسنده
|
ulmer carnes m. ,liu y.p. ,allingham r.r. ,whigham b.t. ,havens s. ,garrett m.e. ,qiao c. ,katsanis n. ,wiggs j.l. ,pasquale l.r. ,ashley-koch a. ,oh e.c. ,hauser m.a. ,brilliant m. ,budenz d.l. ,chin h.r. ,cooke bailey j. ,fingert j. ,friedman d.s. ,gaasterland d. ,gaasterland t. ,haines j. ,hauser m.a. ,kang j.h. ,lee r.k. ,lichter p.r. ,liu y. ,loomis s. ,mccarty c.e. ,moroi s.e. ,pasquale l.r. ,pericak-vance m. ,realini a. ,richards j.e. ,schuman j.s. ,scott w.k. ,singh k. ,sit a. ,vollrath d. ,weinreb r.n. ,wiggs j.l. ,wollstein g. ,yaspan b.l. ,zack d. ,zhang k.
|
|
منبع
|
plos genetics - 2014 - دوره : 10 - شماره : 5
|
|
چکیده
|
Glaucoma is a leading cause of blindness worldwide. primary open-angle glaucoma (poag) is the most common subtype and is a complex trait with multigenic inheritance. genome-wide association studies have previously identified a significant association between poag and the six6 locus (rs10483727,odds ratio (or) = 1.32,p = 3.87×10-11). six6 plays a role in ocular development and has been associated with the morphology of the optic nerve. we sequenced the six6 coding and regulatory regions in 262 poag cases and 256 controls and identified six nonsynonymous coding variants,including five rare and one common variant,asn141his (rs33912345),which was associated significantly with poag (or = 1.27,p = 4.2×10-10) in the neighbor/glaugen datasets. these variants were tested in an in vivo danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. five variants,found primarily in poag cases,were hypomorphic or null,while the sixth variant,found only in controls,was benign. one variant in the six6 enhancer increased expression of six6 and disrupted its regulation. finally,to our knowledge for the first time,we have identified a clinical feature in poag patients that appears to be dependent upon six6 genotype: patients who are homozygous for the six6 risk allele (his141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the six6 non-risk allele (asn141). our results,in combination with previous six6 work,lead us to hypothesize that six6 risk variants disrupt the development of the neural retina,leading to a reduced number of retinal ganglion cells,thereby increasing the risk of glaucoma-associated vision loss. © 2014 ulmer carnes et al.
|
|
|
|
|
آدرس
|
the center for human genetics,duke university,durham,nc, United States, the center for human disease modeling,duke university medical center,durham,nc, United States, department of ophthalmology,duke university medical center,durham,nc,united states,department of ophthalmology,duke university school of medicine, United States, department of ophthalmology,duke university medical center,durham,nc, United States, department of ophthalmology,duke university medical center,durham,nc, United States, the center for human genetics,duke university,durham,nc, United States, department of ophthalmology,harvard medical school,boston,ma,united states,beijing tongren hospital,beijing tongren eye center,beijing ophthalmology and visual sciences key laboratory,capital medical university,beijing, China, the center for human disease modeling,duke university medical center,durham,nc, United States, department of ophthalmology,harvard medical school,boston,ma, United States, department of ophthalmology,harvard medical school,boston,ma,united states,channing division of network medicine,brigham and women's hospital,boston,ma, United States, the center for human genetics,duke university,durham,nc,united states,department of medicine,duke university medical center,durham,nc, United States, the center for human disease modeling,duke university medical center,durham,nc,united states,department of neurology,duke university medical center,durham,nc, United States, the center for human genetics,duke university,durham,nc,united states,department of ophthalmology,duke university medical center,durham,nc,united states,department of medicine,duke university medical center,durham,nc, United States, center for human genetics,marshfield clinic, United States, eye at chapel hill north,university of north carolina school of medicine, United States, national eye institute, United States, center for human genetic research,vanderbilt university school of medicine, United States, department of ophthalmology,university of iowa medical school, United States, dana center for preventive ophthalmology,johns hopkins hospital, United States, eye doctors of washington edow, United States, university of california san diego,scripps genome center, United States, center for human genetic research,vanderbilt university school of medicine, United States, center for human genetics,duke university school of medicine, United States, johns hopkins division of medical imaging physics, United States, bascom palmer eye institute,university of miami school of medicine, United States, university of michigan kellogg eye center, United States, molecular genomics core facilities,duke university school of medicine, United States, massachusetts eye and ear,harvard medical school, United States, institute of rural health,duluth,mn, United States, university of michigan kellogg eye center, United States, massachusetts eye and ear,harvard medical school, United States, hussman institute for human genomics at miller school of medicine, United States, department of ophthalmology,west virginia university eye institute, United States, university of michigan kellogg eye center, United States, mcgowan institute for regenerative medicine,university of pittsburgh, United States, hussman institute for human genomics at miller school of medicine, United States, the byers eye institute at stanford,stanford university school of medicine, United States, department of ophthalmology,mayo clinic, United States, stanford university school of medicine, United States, shiley eye center,university of california san diego, United States, massachusetts eye and ear,harvard medical school, United States, university of pittsburgh school of medicine, United States, center for human genetic research,vanderbilt university school of medicine, United States, the johns hopkins university school of medicine,department of neuroscience, United States, shiley eye center,university of california san diego, United States
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|