Recurrent missense variants identified in two of 289 candidate genes in 12 sporadic CD subtype of AMD cases by WES.

<p>Recurrent missense variants identified in two of 289 candidate genes in 12 sporadic CD subtype of AMD cases by WES.</p

Segregation analysis of rare sequence variants identified in candidate genes in cuticular drusen (CD) families by whole exome sequencing (WES).

<p>Circles, females; squares, males; empty symbols, unaffected; black symbols, affected; asterisks, exome sequenced individuals; ‘+’ symbol, wild type allele; ‘m’ symbol, mutant type allele. The age at participation is specified below the symbols.</p

Retinal images of 12 sporadic cuticular drusen (CD) cases for whom exome sequencing (WES) was performed.

<p>Panels A and B represent colour fundus photographs (1A-12A) and fluorescein angiograms (FAs) (1B-12B) of 12 cases respectively. For cases 1–5 retinal images of the right eye are shown, whereas for cases 6–12 retinal images of the left eye are shown. The CD phenotype presents with a large number of small and uniformly sized hyperfluorescent drusen on FA.</p

Pedigrees of six cuticular drusen (CD) families in which whole exome sequencing (WES) was performed.

<p>Circle and square symbols indicate female and male individuals, respectively. Symbols with slashes indicate deceased individuals. Black and empty symbols indicate affected and unaffected individuals, respectively. Asterisks indicate the family members for whom exome sequencing was performed. The numbers below the symbols indicate the age at participation of family members.</p

Rare missense variants identified in known macular degeneration genes in 12 sporadic CD subtype of AMD cases by WES.

<p>Rare missense variants identified in known macular degeneration genes in 12 sporadic CD subtype of AMD cases by WES.</p

Analysis of Rare Variants in the <i>C3</i> Gene in Patients with Age-Related Macular Degeneration

<div><p>Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15–65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (<i>C3</i>) gene have been associated with AMD and recently a rare <i>C3</i> variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the <i>C3</i> gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated <i>C3</i> mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (<i>P</i> = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2–136; <i>P</i> = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0–25; <i>P</i> = 0.05) at the <i>C3</i> locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.</p></div

Genotyping of <i>C3</i> variants in EUGENDA and Rotterdam samples.

<p>Major and minor allele indicated in capital and lower case respectively, MAF: Minor allele frequency, ND: OR could not be determined, NA: Not applicable.</p><p>EUGENDA: a multicenter database comprising participants from Germany and the Netherlands.</p

Rare variants in AMD studies.

<p>NL: The Netherlands, ISL: Iceland, GER: Germany, USA: United states of America, FRA: France.</p><p>NA: Not applicable.</p

Conditional analysis of Arg735Trp for SNPs Arg102Gly/rs2230199 and Pro314Leu/rs1047286.

<p>EUGENDA: a multicenter database comprising participants from the Cologne area, Germany and the Nijmegen area, the Netherlands.</p

<i>C3</i> variants identified by sequence analysis of 84 AMD cases.

<p>Major and minor allele indicated in capital and lower case respectively.</p><p>Reference sequence of <i>C3</i> (NM_000064) gene.</p><p>SIFT: Sorting Intolerant from Tolerant (Intolerance ≤0.05).</p><p>PolyPhen2: Polymorphism Phenotyping (score 0→1).</p