Evaluation of DNA Variants Associated with Androgenetic Alopecia and Their Potential to Predict Male Pattern Baldness

May Evaluation of DNA Variants Associated with Androgenetic Alopecia and Their Potential to Predict Male Pattern Baldness Magdalena Marciska 0 1 2 Ewelina Popiech 0 1 2 Sarah Abidi 0 1 2 Jeppe Dyrberg Andersen 0 1 2 Margreet van den Berge 0 1 2 ngel Carracedo 0 1 2 Mayra Eduardoff 0 1 2 Anna Marczakiewicz- Lustig 0 1 2 Niels Morling 0 1 2 Titia Sijen 0 1 2 Magorzata Skowron 0 1 2 Jens Schtig 0 1 2 Denise Syndercombe-Court 0 1 2 Natalie Weiler 0 1 2 The EUROFORGEN-NoE Consortium 0 1 2 Peter M. Schneider 0 1 2 David Ballard 0 1 2 Claus Brsting 0 1 2 Walther Parson 0 1 2 Chris Phillips 0 1 2 Wojciech Branicki 0 1 2 0 1 Institute of Forensic Research, Section of Forensic Genetics , Krakow , Poland , 2 Department of Genetics and Evolution, Jagiellonian University , Krakow , Poland , 3 Faculty of Life Sciences, King's College , London , United Kingdom , 4 Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, 5 Department of Human Biological Traces, Netherlands Forensic Institute , The Hague , The Netherlands , 6 Forensic Genetics Unit, Institute of Forensic Medicine, Faculty of Medicine, University of Santiago de Compostela , Santiago de Compostela , Spain , 7 Genomic Medicine Group, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III , Madrid , Spain , 8 Institute of Legal Medicine, Medical University of Innsbruck , Innsbruck , Austria , 9 Department of Analytical Biochemistry, Jagiellonian University Medical College , Krakow , Poland , 10 Department of Dermatology, Medical College of Jagiellonian University , Krakow , Poland , 11 Institute of Legal Medicine, Medical Faculty, University of Cologne , Cologne, Germany , 12 Forensic Science Program, The Pennsylvania State University , University Park, Pennsylvania , United States of America 1 Funding: The work leading to these results was financially supported from a grant from the European Union Seventh Framework Programme (FP7/2007- 2013) under grant agreement no. 285487 (EUROFORGEN-NoE) , www.euroforgen.eu 2 Academic Editor: Ludmila Prokunina-Olsson, National Cancer Institute, National Institutes of Health , UNITED STATES Androgenetic alopecia, known in men as male pattern baldness (MPB), is a very conspicuous condition that is particularly frequent among European men and thus contributes markedly to variation in physical appearance traits amongst Europeans. Recent studies have revealed multiple genes and polymorphisms to be associated with susceptibility to MPB. In this study, 50 candidate SNPs for androgenetic alopecia were analyzed in order to verify their potential to predict MPB. Significant associations were confirmed for 29 SNPs from chromosomes X, 1, 5, 7, 18 and 20. A simple 5-SNP prediction model and an extended 20-SNP model were developed based on a discovery panel of 305 males from various European populations fitting one of two distinct phenotype categories. The first category consisted of men below 50 years of age with significant baldness and the second; men aged 50 years or older lacking baldness. The simple model comprised the five best predictors: rs5919324 near AR, rs1998076 in the 20p11 region, rs929626 in EBF1, rs12565727 in - Competing Interests: The authors have declared that no competing interests exist. TARDBP and rs756853 in HDAC9. The extended prediction model added 15 SNPs from five genomic regions that improved overall prevalence-adjusted predictive accuracy measured by area under the receiver characteristic operating curve (AUC). Both models were evaluated for predictive accuracy using a test set of 300 males reflecting the general European population. Applying a 65% probability threshold, high prediction sensitivity of 87.1% but low specificity of 42.4% was obtained in men aged <50 years. In men aged 50, prediction sensitivity was slightly lower at 67.7% while specificity reached 90%. Overall, the AUC=0.761 calculated for men at or above 50 years of age indicates these SNPs offer considerable potential for the application of genetic tests to predict MPB patterns, adding a highly informative predictive system to the emerging field of forensic analysis of externally visible characteristics. Androgenetic alopecia (AGA), often termed male pattern baldness (MPB), is a widespread type of gradual hair loss from the scalp that is particularly frequent among European males. The etiology of male pattern baldness has been widely researched and although it is still not fully understood, major factors behind this condition have been identified to comprise genetic predisposition and hormone dependency [1]. It has been estimated that approximately 80% of the variance of AGA-related hair loss can be explained by genetic factors [2,3]. Multiple studies including several recent genome-wide association analyses have disclosed a large number of single nucleotide polymorphisms (SNPs) associated with AGA susceptibility and provided strong evidence that the region on chromosome X, which includes the two neighboring genes of androgen receptor (AR) and ectodysplasin A2 receptor (EDA2R), is involved in MPB [4 12]. Although involvement of the Xq12 region in AGA appears to be undisputed, various reports are discordant in terms of the number of loci and effect size associated with particular variants located near the AR/EDA2R genes. Fine mapping of this region by Brockschmidt et al. in 2010 indicated locus rs12558842, located upstream of AR and EDA2R, has the strongest association with AGA and suggested there are likely to be 12 causative variants in this region regulating expression of AR and/or EDA2R genes [10]. The complexity of genetic determination of MPB was further highlighted by a study that reported three SNPs from the AR/EDA2R region to be monomorphic among Asians, concluding that this locus is unlikely to play any role in AGA in Asia [13]. A region located at 20p11 represents the second MPB susceptibility locus, discovered independently by two genome wide association studies (GWAS) and further confirmed in both Europeans and Asians. Effect size attributed to this locus was found to be lower than AR/EDA2R indicating approximately two-fold increased risk of AGA in Europeans and Asians [9,13,14]. GWAS followed by fine-mapping analysis has confirmed the significance of both chromosome X and chromosome 20 regions [10], whereas a further study by the same group in 2011 identified HDAC9 in 7p21.1 to be a novel susceptibility locus for AGA [15]. The large meta-analysis confirmed the association of Xq12, 20p11, and HDAC9 while discovering five additional loci associated with early onset baldness in Europeans. These novel AGA risk loci comprised: region 17q21.31; TARDBP (chr1); HDAC4 (chr2); AUTS2 (chr7); and SETBP1 (chr18) [12]. In the follow-up study, Heilmann et al. (2013) investigated 12 genomic regions for which Li et al. (2012) found suggestive associations, however these ad (...truncated)