title: Dissection of chromosome 16p12 linkage peak suggests a possible role for CACNG3 variants in age-related macular degeneration susceptibility.
abstract: OBJECTIVE
  Age-related macular degeneration (AMD) is a complex disorder of the retina, characterized by drusen, geographic atrophy, and choroidal neovascularization. Cigarette smoking and the genetic variants CFH Y402H, ARMS2 A69S, CFB R32Q, and C3 R102G have been strongly and consistently associated with AMD. Multiple linkage studies have found evidence suggestive of another AMD locus on chromosome 16p12 but the gene responsible has yet to be identified.
  
  
  METHODS
  In the initial phase of the study, single-nucleotide polymorphisms (SNPs) across chromosome 16 were examined for linkage and/or association in 575 Caucasian individuals from 148 multiplex and 77 singleton families. Additional variants were tested in an independent dataset of unrelated cases and controls. According to these results, in combination with gene expression data and biological knowledge, five genes were selected for further study: CACNG3, HS3ST4, IL4R, Q7Z6F8, and ITGAM.
  
  
  RESULTS
  After genotyping additional tagging SNPs across each gene, the strongest evidence for linkage and association was found within CACNG3 (rs757200 nonparametric LOD* = 3.3, APL (association in the presence of linkage) P = 0.06, and rs2238498 MQLS (modified quasi-likelihood score) P = 0.006 in the families; rs2283550 P = 1.3 × 10(-6), and rs4787924 P = 0.002 in the case-control dataset). After adjusting for known AMD risk factors, rs2283550 remained strongly associated (P = 2.4 × 10(-4)). Furthermore, the association signal at rs4787924 was replicated in an independent dataset (P = 0.035) and in a joint analysis of all the data (P = 0.001).
  
  
  CONCLUSIONS
  These results suggest that CACNG3 is the best candidate for an AMD risk gene within the 16p12 linkage peak. More studies are needed to confirm this association and clarify the role of the gene in AMD pathogenesis.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA. kylee.spencer@vanderbilt.edu
authors.forename: Kylee L
authors.initials: KL
authors.lastname: Spencer
authors.forename: Lana M
authors.initials: LM
authors.lastname: Olson
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schnetz-Boutaud
authors.forename: Paul
authors.initials: P
authors.lastname: Gallins
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Wang
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Anita
authors.initials: A
authors.lastname: Agarwal
authors.forename: Johanna
authors.initials: J
authors.lastname: Jakobsdottir
authors.forename: Yvette
authors.initials: Y
authors.lastname: Conley
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gorin
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
mesh_terms: D000368:Aged; D015220:Calcium Channels / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C520579:CACNG3 protein, human; D015220:Calcium Channels