Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Epistasis, Genetic*; Eye Color/*genetics ; Eye Proteins/*genetics ; Melanins/*genetics ; Pigmentation/*genetics; Aged ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Antiporters/genetics ; Antiporters/metabolism ; Diagnostic Imaging ; Down Syndrome/genetics ; Down Syndrome/metabolism ; Europe ; Eye Proteins/metabolism ; Female ; Genome-Wide Association Study ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Image Processing, Computer-Assisted ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Iris/anatomy & histology ; Iris/diagnostic imaging ; Iris/metabolism ; Male ; Melanins/metabolism ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/metabolism ; Phenotype ; Polymorphism, Single Nucleotide ; Quantitative Trait, Heritable ; Ubiquitin-Protein Ligases ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism ; White People

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.

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United Kingdom Medical Research Council

0 (Antigens, Neoplasm)
0 (Antiporters)
0 (Eye Proteins)
0 (Guanine Nucleotide Exchange Factors)
0 (Interferon Regulatory Factors)
0 (LYST protein, human)
0 (Melanins)
0 (Membrane Transport Proteins)
0 (SLC24A4 protein, human)
0 (SLC45A2 protein, human)
0 (Vesicular Transport Proteins)
0 (interferon regulatory factor-4)
0 (pheomelanin)
12627-86-0 (eumelanin)
EC 2.3.2.27 (HERC2 protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)

Down Syndrome Critical Region

Date Created: 20170228 Date Completed: 20181102 Latest Revision: 20221207

20231215

PMC5327401

10.1038/srep43359

28240252