title: The common occurrence of epistasis in the determination of human pigmentation and its impact on DNA-based pigmentation phenotype prediction.
abstract: The role of epistatic effects in the determination of complex traits is often underlined but its significance in the prediction of pigmentation phenotypes has not been evaluated so far. The prediction of pigmentation from genetic data can be useful in forensic science to describe the physical appearance of an unknown offender, victim, or missing person who cannot be identified via conventional DNA profiling. Available forensic DNA prediction systems enable the reliable prediction of several eye and hair colour categories. However, there is still space for improvement. Here we verified the association of 38 candidate DNA polymorphisms from 13 genes and explored the extent to which interactions between them may be involved in human pigmentation and their impact on forensic DNA prediction in particular. The model-building set included 718 Polish samples and the model-verification set included 307 independent Polish samples and additional 72 samples from Japan. In total, 29 significant SNP-SNP interactions were found with 5 of them showing an effect on phenotype prediction. For predicting green eye colour, interactions between HERC2 rs12913832 and OCA2 rs1800407 as well as TYRP1 rs1408799 raised the prediction accuracy expressed by AUC from 0.667 to 0.697 and increased the prediction sensitivity by >3%. Interaction between MC1R 'R' variants and VDR rs731236 increased the sensitivity for light skin by >1% and by almost 3% for dark skin colour prediction. Interactions between VDR rs1544410 and TYR rs1042602 as well as between MC1R 'R' variants and HERC2 rs12913832 provided an increase in red/non-red hair prediction accuracy from an AUC of 0.902-0.930. Our results thus underline epistasis as a common phenomenon in human pigmentation genetics and demonstrate that considering SNP-SNP interactions in forensic DNA phenotyping has little impact on eye, hair and skin colour prediction.
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland. Electronic address: ewelina.pospiech@uj.edu.pl.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Pośpiech
authors.affiliation: Department of Dermatology, Collegium Medicum of the Jagiellonian University, Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wojas-Pelc
authors.affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands; Yale Molecular Anthropology Laboratory, Department of Anthropology, Yale University, 10 Sachem Street, New Haven, CT 06511, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Walsh
authors.affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Legal Medicine, Osaka City University Medical School, Osaka, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Maeda
authors.affiliation: Department of Legal Medicine, Osaka City University Medical School, Osaka, Japan; Division of Legal Medicine, Faculty of Medicine, Tottori University, 86 Nichicho, Yonago, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Dermatology, Collegium Medicum of the Jagiellonian University, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Skowron
authors.affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Kraków, Poland; Section of Forensic Genetics, Institute of Forensic Research, Kraków, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Branicki
mesh_terms: D004247:DNA / Q000235:genetics*; D004843:Epistasis, Genetic; D005828:Genetics, Population; D006801:Humans; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics*
chemical_list: D004247:DNA
keywords: Forensic DNA phenotyping; Gene-gene interactions; Logistic regression; Multifactor dimensionality reduction; Pigmentation phenotype