Browsing by Author "Liu, Fan"
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Item Erratum to: Global skin colour prediction from DNA(Springer Nature, 2017-07) Walsh, Susan; Chaitanya, Lakshmi; Breslin, Krystal; Muralidharan, Charanya; Bronikowska, Agnieszka; Pospiech, Ewelina; Koller, Julia; Kovatsi, Leda; Wollstein, Andreas; Branicki, Wojciech; Liu, Fan; Kayser, Manfred; Biology, School of ScienceErratum for Global skin colour prediction from DNA. [Hum Genet. 2017]Item Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up(Springer, 2015-08) Liu, Fan; Duffy, David L.; Hysi, Pirro G.; Jacobs, Leonie C.; Lao, Oscar; Zhong, Kaiyin; Walsh, Susan; Chaitanya, Lakshmi; Wollstein, Andreas; Zhu, Gu; Montgomery, Grant W.; Henders, Anjali K.; Mangino, Massimo; Glass, Daniel; Bataille, Veronique; Sturm, Richard A.; Rivadeneira, Fernando; Hofman, Albert; van IJcken, Wilfred F. J.; Uitterlinden, André G.; Palstra, Robert‑Jan T. S.; Spector, Timothy D.; Department of Biology, School of ScienceIn the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.Item Genome-wide association studies identify multiple genetic loci influencing eyebrow color variation in Europeans(Elsevier, 2019) Peng, Fuduan; Zhu, Gu; Hysi, Pirro G.; Eller, Ryan J.; Chen, Yan; Li, Yi; Hamer, Merel A.; Zeng, Changqing; Hopkins, Racquel L.; Jacobus, Case L.; Wallace, Paige L.; Uitterlinden, André G.; Ikram, M. Arfan; Duffy, David L.; Nijsten, Tamar; Medland, Sarah E.; Spector, Timothy D.; Walsh, Susan; Martin, Nicholas G.; Liu, Fan; Kayser, Manfred; Biology, School of ScienceItem Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure(Nature Publishing Group, 2018-05-08) Visconti, Alessia; Duffy, David L.; Liu, Fan; Zhu, Gu; Wu, Wenting; Chen, Yan; Hysi, Pirro G.; Zeng, Changqing; Sanna, Marianna; Iles, Mark M.; Kanetsky, Peter A.; Demenais, Florence; Hamer, Merel A.; Uitterlinden, Andre G.; Ikram, M. Arfan; Nijsten, Tamar; Martin, Nicholas G.; Kayser, Manfred; Spector, Tim D.; Han, Jiali; Bataille, Veronique; Falchi, Mario; Epidemiology, School of Public HealthThe skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.Item Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color(American Association for the Advancement of Science, 2021-03-10) Simcoe, Mark; Valdes, Ana; Liu, Fan; Furlotte, Nicholas A.; Evans, David M.; Hemani, Gibran; Ring, Susan M.; Smith, George Davey; Duffy, David L.; Zhu, Gu; Gordon, Scott D.; Medland, Sarah E.; Vuckovic, Dragana; Girotto, Giorgia; Sala, Cinzia; Catamo, Eulalia; Concas, Maria Pina; Brumat, Marco; Gasparini, Paolo; Toniolo, Daniela; Cocca, Massimiliano; Robino, Antonietta; Yazar, Seyhan; Hewitt, Alex; Wu, Wenting; Kraft, Peter; Hammond, Christopher J.; Shi, Yuan; Chen, Yan; Zeng, Changqing; Klaver, Caroline C. W.; Uitterlinden, Andre G.; Ikram, M. Arfan; Hamer, Merel A.; van Duijn, Cornelia M.; Nijsten, Tamar; Han, Jiali; Mackey, David A.; Martin, Nicholas G.; Cheng, Ching-Yu; 23andMe Research Team; International Visible Trait Genetics Consortium; Hinds, David A.; Spector, Timothy D.; Kayser, Manfred; Hysi, Pirro G.; Epidemiology, School of Public HealthHuman eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.Item Global skin colour prediction from DNA(Springer Berlin Heidelberg, 2017) Walsh, Susan; Chaitanya, Lakshmi; Breslin, Krystal; Muralidharan, Charanya; Bronikowska, Agnieszka; Pospiech, Ewelina; Koller, Julia; Kovatsi, Leda; Wollstein, Andreas; Branicki, Wojciech; Liu, Fan; Kayser, Manfred; Biology, School of ScienceHuman skin colour is highly heritable and externally visible with relevance in medical, forensic, and anthropological genetics. Although eye and hair colour can already be predicted with high accuracies from small sets of carefully selected DNA markers, knowledge about the genetic predictability of skin colour is limited. Here, we investigate the skin colour predictive value of 77 single-nucleotide polymorphisms (SNPs) from 37 genetic loci previously associated with human pigmentation using 2025 individuals from 31 global populations. We identified a minimal set of 36 highly informative skin colour predictive SNPs and developed a statistical prediction model capable of skin colour prediction on a global scale. Average cross-validated prediction accuracies expressed as area under the receiver-operating characteristic curve (AUC) ± standard deviation were 0.97 ± 0.02 for Light, 0.83 ± 0.11 for Dark, and 0.96 ± 0.03 for Dark-Black. When using a 5-category, this resulted in 0.74 ± 0.05 for Very Pale, 0.72 ± 0.03 for Pale, 0.73 ± 0.03 for Intermediate, 0.87±0.1 for Dark, and 0.97 ± 0.03 for Dark-Black. A comparative analysis in 194 independent samples from 17 populations demonstrated that our model outperformed a previously proposed 10-SNP-classifier approach with AUCs rising from 0.79 to 0.82 for White, comparable at the intermediate level of 0.63 and 0.62, respectively, and a large increase from 0.64 to 0.92 for Black. Overall, this study demonstrates that the chosen DNA markers and prediction model, particularly the 5-category level; allow skin colour predictions within and between continental regions for the first time, which will serve as a valuable resource for future applications in forensic and anthropologic genetics.Item The HIrisPlex-S system for eye, hair and skin colour prediction from DNA: Introduction and forensic developmental validation(Elsevier, 2018) Chaitanya, Lakshmi; Breslin, Krystal; Zuñiga, Sofia; Wirken, Laura; Pośpiech, Ewelina; Kukla-Bartoszek, Magdalena; Sijen, Titia; de Knijff, Peter; Liu, Fan; Branicki, Wojciech; Kayser, Manfred; Walsh, Susan; Biology, School of ScienceForensic DNA Phenotyping (FDP), i.e. the prediction of human externally visible traits from DNA, has become a fast growing subfield within forensic genetics due to the intelligence information it can provide from DNA traces. FDP outcomes can help focus police investigations in search of unknown perpetrators, who are generally unidentifiable with standard DNA profiling. Therefore, we previously developed and forensically validated the IrisPlex DNA test system for eye colour prediction and the HIrisPlex system for combined eye and hair colour prediction from DNA traces. Here we introduce and forensically validate the HIrisPlex-S DNA test system (S for skin) for the simultaneous prediction of eye, hair, and skin colour from trace DNA. This FDP system consists of two SNaPshot-based multiplex assays targeting a total of 41 SNPs via a novel multiplex assay for 17 skin colour predictive SNPs and the previous HIrisPlex assay for 24 eye and hair colour predictive SNPs, 19 of which also contribute to skin colour prediction. The HIrisPlex-S system further comprises three statistical prediction models, the previously developed IrisPlex model for eye colour prediction based on 6 SNPs, the previous HIrisPlex model for hair colour prediction based on 22 SNPs, and the recently introduced HIrisPlex-S model for skin colour prediction based on 36 SNPs. In the forensic developmental validation testing, the novel 17-plex assay performed in full agreement with the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines, as previously shown for the 24-plex assay. Sensitivity testing of the 17-plex assay revealed complete SNP profiles from as little as 63 pg of input DNA, equalling the previously demonstrated sensitivity threshold of the 24-plex HIrisPlex assay. Testing of simulated forensic casework samples such as blood, semen, saliva stains, of inhibited DNA samples, of low quantity touch (trace) DNA samples, and of artificially degraded DNA samples as well as concordance testing, demonstrated the robustness, efficiency, and forensic suitability of the new 17-plex assay, as previously shown for the 24-plex assay. Finally, we provide an update of the publically available HIrisPlex website https://hirisplex.erasmusmc.nl/, now allowing the estimation of individual probabilities for 3 eye, 4 hair, and 5 skin colour categories from HIrisPlex-S input genotypes. The HIrisPlex-S DNA test represents the first forensically validated tool for skin colour prediction, and reflects the first forensically validated tool for simultaneous eye, hair and skin colour prediction from DNA.Item The impact of correlations between pigmentation phenotypes and underlying genotypes on genetic prediction of pigmentation traits(Elsevier, 2021-01) Chen, Yan; Branicki, Wojciech; Walsh, Susan; Nothnagel, Michael; Kayser, Manfred; Liu, Fan; Biology, School of SciencePredicting appearance phenotypes from genotypes is relevant for various areas of human genetic research and applications such as genetic epidemiology, human history, anthropology, and particularly in forensics. Many appearance phenotypes, and thus their underlying genotypes, are highly correlated, with pigmentation traits serving as primary examples. However, all available genetic prediction models, including those for pigmentation traits currently used in forensic DNA phenotyping, ignore phenotype correlations. Here, we investigated the impact of appearance phenotype correlations on genetic appearance prediction in the exemplary case of three pigmentation traits. We used data for categorical eye, hair and skin colour as well as 41 DNA markers utilized in the recently established HIrisPlex-S system from 762 individuals with complete phenotype and genotype information. Based on these data, we performed genetic prediction modelling of eye, hair and skin colour via three different strategies, namely the established approach of predicting phenotypes solely based on genotypes while not considering phenotype correlations, and two novel approaches that considered phenotype correlations, either incorporating truly observed correlated phenotypes or DNA-predicted correlated phenotypes in addition to the DNA predictors. We found that using truly observed correlated pigmentation phenotypes as additional predictors increased the DNA-based prediction accuracies for almost all eye, hair and skin colour categories, with the largest increase for intermediate eye colour, brown hair colour, dark to black skin colour, and particularly for dark skin colour. Outcomes of dedicated computer simulations suggest that this prediction accuracy increase is due to the additional genetic information that is implicitly provided by the truly observed correlated pigmentation phenotypes used, yet not covered by the DNA predictors applied. In contrast, considering DNA-predicted correlated pigmentation phenotypes as additional predictors did not improve the performance of the genetic prediction of eye, hair and skin colour, which was in line with the results from our computer simulations. Hence, in practical applications of DNA-based appearance prediction where no phenotype knowledge is available, such as in forensic DNA phenotyping, it is not advised to use DNA-predicted correlated phenotypes as predictors in addition to the DNA predictors. In the very least, this is not recommended for the pigmentation traits and the established pigmentation DNA predictors tested here.Item Likelihood ratio and posterior odds in forensic genetics: Two sides of the same coin(Elsevier, 2017-05) Caliebe, Amke; Walsh, Susan; Liu, Fan; Kayser, Manfred; Krawczak, Michael; Department of Biology, School of ScienceIt has become widely accepted in forensics that, owing to a lack of sensible priors, the evidential value of matching DNA profiles in trace donor identification or kinship analysis is most sensibly communicated in the form of a likelihood ratio (LR). This restraint does not abate the fact that the posterior odds (PO) would be the preferred basis for returning a verdict. A completely different situation holds for Forensic DNA Phenotyping (FDP), which is aimed at predicting externally visible characteristics (EVCs) of a trace donor from DNA left behind at the crime scene. FDP is intended to provide leads to the police investigation helping them to find unknown trace donors that are unidentifiable by DNA profiling. The statistical models underlying FDP typically yield posterior odds (PO) for an individual possessing a certain EVC. This apparent discrepancy has led to confusion as to when LR or PO is the appropriate outcome of forensic DNA analysis to be communicated to the investigating authorities. We thus set out to clarify the distinction between LR and PO in the context of forensic DNA profiling and FDP from a statistical point of view. In so doing, we also addressed the influence of population affiliation on LR and PO. In contrast to the well-known population dependency of the LR in DNA profiling, the PO as obtained in FDP may be widely population-independent. The actual degree of independence, however, is a matter of (i) how much of the causality of the respective EVC is captured by the genetic markers used for FDP and (ii) by the extent to which non-genetic such as environmental causal factors of the same EVC are distributed equally throughout populations. The fact that an LR should be communicated in cases of DNA profiling whereas the PO are suitable for FDP does not conflict with theory, but rather reflects the immanent differences between these two forensic applications of DNA information.Item Meta-analysis of genome-wide association studies identifies 8 novel loci involved in shape variation of human head hair(Oxford University Press, 2018-02-01) Liu, Fan; Chen, Yan; Zhu, Gu; Hysi, Pirro G.; Wu, Sijie; Adhikari, Kaustubh; Breslin, Krystal; Pośpiech, Ewelina; Hamer, Merel A.; Peng, Fuduan; Muralidharan, Charanya; Acuna-Alonzo, Victor; Canizales-Quinteros, Samuel; Bedoya, Gabriel; Gallo, Carla; Poletti, Giovanni; Rothhammer, Francisco; Bortolini, Maria Catira; Gonzalez-Jose, Rolando; Zeng, Changqing; Xu, Shuhua; Jin, Li; Uitterlinden, André G.; Ikram, M. Arfan; van Duijn, Cornelia M.; Nijsten, Tamar; Walsh, Susan; Branicki, Wojciech; Wang, Sijia; Ruiz-Linares, Andrés; Spector, Timothy D.; Martin, Nicholas G.; Medland, Sarah E.; Kayser, Manfred; Biology, School of ScienceShape variation of human head hair shows striking variation within and between human populations, while its genetic basis is far from being understood. We performed a series of genome-wide association studies (GWASs) and replication studies in a total of 28 964 subjects from 9 cohorts from multiple geographic origins. A meta-analysis of three European GWASs identified 8 novel loci (1p36.23 ERRFI1/SLC45A1, 1p36.22 PEX14, 1p36.13 PADI3, 2p13.3 TGFA, 11p14.1 LGR4, 12q13.13 HOXC13, 17q21.2 KRTAP, and 20q13.33 PTK6), and confirmed 4 previously known ones (1q21.3 TCHH/TCHHL1/LCE3E, 2q35 WNT10A, 4q21.21 FRAS1, and 10p14 LINC00708/GATA3), all showing genome-wide significant association with hair shape (P < 5e-8). All except one (1p36.22 PEX14) were replicated with nominal significance in at least one of the 6 additional cohorts of European, Native American and East Asian origins. Three additional previously known genes (EDAR, OFCC1, and PRSS53) were confirmed at the nominal significance level. A multivariable regression model revealed that 14 SNPs from different genes significantly and independently contribute to hair shape variation, reaching a cross-validated AUC value of 0.66 (95% CI: 0.62-0.70) and an AUC value of 0.64 in an independent validation cohort, providing an improved accuracy compared with a previous model. Prediction outcomes of 2504 individuals from a multiethnic sample were largely consistent with general knowledge on the global distribution of hair shape variation. Our study thus delivers target genes and DNA variants for future functional studies to further evaluate the molecular basis of hair shape in humans.