eCite Digital Repository

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)


Grassmann, F and Cantsilieris, S and Schulz-Kuhnt, AS and White, SJ and Richardson, AJ and Hewitt, AW and Vote, BJ and Schmied, D and Guymer, RH and Weber, BH and Baird, PN, Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD), Journal of Neuroinflammation, 13 Article 81. ISSN 1742-2094 (2016) [Refereed Article]


Copyright Statement

2016 Grassmann et al. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

DOI: doi:10.1186/s12974-016-0548-0


BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of vision loss in Western societies with a strong genetic component. Candidate gene studies as well as genome-wide association studies strongly implicated genetic variations in complement genes to be involved in disease risk. So far, no association of AMD with complement component 4 (C4) was reported probably due to the complex nature of the C4 locus on chromosome 6.

METHODS: We used multiplex ligation-dependent probe amplification (MLPA) to determine the copy number of the C4 gene as well as of both relevant isoforms, C4A and C4B, and assessed their association with AMD using logistic regression models.

RESULTS: Here, we report on the analysis of 2645 individuals (1536 probands and 1109 unaffected controls), across three different centers, for multiallelic copy number variation (CNV) at the C4 locus. We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4  10(-5), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)). Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years.

CONCLUSIONS: Our data strengthen the notion that complement dysregulation plays a crucial role in AMD etiology, an important finding for early intervention strategies and future therapeutics. In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology.

Item Details

Item Type:Refereed Article
Keywords:AMD, Age-related macular degeneration, C4, Complement, Copy number variation (CNV), Genetic association, Multiallelic
Research Division:Medical and Health Sciences
Research Group:Ophthalmology and Optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Hearing, Vision, Speech and Their Disorders
Author:Hewitt, AW (Professor Alex Hewitt)
Author:Vote, BJ (Dr Brendan Vote)
ID Code:108762
Year Published:2016
Web of Science® Times Cited:7
Deposited By:Menzies Institute for Medical Research
Deposited On:2016-05-05
Last Modified:2017-11-06
Downloads:45 View Download Statistics

Repository Staff Only: item control page