Evaluation of DNA variants associated with androgenetic alopecia and their potential to predict male pattern baldness

Abstract

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 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.

Fig 1. Numbers of risk alleles found in phenotype categories 1 and 2.

Distribution of risk alleles in the top five SNPs selected by multivariate logistic regression for phenotype category 1 (men <50 years with significant baldness) and men in phenotype category 2 (≥ 50 years without baldness) of the discovery set samples.

Fig 2. A. Contributions to the AUC value of twenty SNPs from the extended model of MPB prediction. B. AGA prediction parameters for the 20-SNP model.

Rate of correct predictions in two groups of men, aged <50 and ≥50 years, and four distinct phenotype categories using a 65% probability threshold.

Fig 3. Entropy-based interaction graph from MDR analysis.

Entropy values in the cells of individual SNPs indicate the main independent effects. Entropy values marked on the lines connecting two SNPs represent the entropy of interaction. Blue lines indicate a high degree of redundancy, green lines a reduced degree of redundancy and gold lines represent independence or additivity.