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

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

Evaluation of the possibility of application of polymorphism in the region of the androgen receptor gene for predictive analysis of susceptibility of men to the early androgenetic alopecia.

Łysienie androgenetyczne jest dziedziczną utratą włosów ze skóry głowy występującą u 50% mężczyzn pochodzenia europejskiego do 50 roku życia. Sugeruje się, że najistotniejsze dla determinacji tej cechy są pozycje polimorficzne w regionie genu dla receptora androgenowego (AR), obejmującego również gen kodujący receptor dla ektodysplazyny A2 (EDA2R). Ostatnio zagadnienie determinacji łysienia mężczyzn stało się przedmiotem badań w genetyce sądowej, ze względu na potencjalne zastosowanie genetycznej predykcji w celu zawężenia kręgu podejrzanych w sprawach kryminalnych, a także identyfikacji szczątków ludzkich o nieustalonej tożsamości. Przeprowadzone badania miały na celu ocenę możliwości zastosowania zmienności w rejonie AR do predykcji podatności mężczyzn na wczesne łysienie androgenetyczne. W tym celu opracowano i zoptymalizowano test genetyczny zawierający 6 pozycji polimorficznych typu SNP z regionu genu dla receptora androgenowego, następnie przeprowadzono analizę asocjacyjną przyjmując dwa różne systemy definiowania próby kontrolnej i badawczej o mniejszym (176 mężczyzn) i większym kontraście fenotypowym oraz wiekowym (49 mężczyzn). Niniejsza analiza umożliwiła wyselekcjonowanie pozycji rs6625163 (OR = 6,875) (upstream AR), rs6152 (OR = 5,882) (AR) (grupa 49 mężczyzn) oraz rs1385699/rs1352015 (OR = 2,873) (EDA2R) (grupa 176 mężczyzn) jako istotnie statystycznie związanych z podatnością na wczesne łysienie mężczyzn. Wynika z tego, że pozycje polimorficzne w regionie AR należy zaklasyfikować jako obiecujące predyktory wczesnego łysienia androgenetycznego mężczyzn.Androgenetic alopecia is hereditary loss of scalp hair which affects 50% of European origin males by age 50. It has been suggested that the most significant polymorphic positions for determining this trait lie within a region of androgen receptor gene (AR) containing also ectodysplasin A2 receptor gene (EDA2R). Recently the issue of determination of male alopecia has become the subject of forensic genetics due to its potential role in reduction the pool of suspects in criminal cases and identification of untraced human remains. The aim of this study was to evaluate the possibility of application of polymorphism in AR region for predictive analysis of susceptibility of man to early androgenetic alopecia. To gain this aim genetic test containing 6 SNP-type polymorphic positions within AR region was worked out and optimised. The association study was performed with adoption of two different systems to define the control and research sample of smaller (176 men) and higher phenotypic and age contrast (49 men). Performed studies allowed selection of rs6625163 (OR = 6,875) (upstream AR), rs6152 (OR = 5,882) (AR) (group containing 49 males) and rs1385699/rs1352015 (OR = 2,873) (EDA2R) (group including 176 males) positions as significantly associated with susceptibility of man to early alopecia. Such result indicates that the polymorphic positions within AR region should be regarded as a promising predictors of early male androgenetic alopecia

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

<div><p>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 <i>AR</i>, rs1998076 in the 20p11 region, rs929626 in <i>EBF1</i>, rs12565727 in <i>TARDBP</i> and rs756853 in <i>HDAC9</i>. 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.</p></div

Genotype risk score associated with the risk of male pattern baldness.

<p>Genotype risk score associated with the risk of male pattern baldness.</p

Parameters describing the accuracy of prediction of MPB using 20-SNP logistic regression prediction model.

<p>^*Four samples from phenotype categories 3 and 4 lacked data in one of the following SNPs: rs1160312, rs6625150, rs4679955 and therefore were excluded from the analyses.</p><p>Parameters describing the accuracy of prediction of MPB using 20-SNP logistic regression prediction model.</p

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

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

Results of multivariate logistic regression analysis for AGA performed on a discovery set consisting of 305 samples.

<p>MAF: Minor allele frequency; OR: Odds ratio for the minor allele; CI: Confidence interval</p><p>Results of multivariate logistic regression analysis for AGA performed on a discovery set consisting of 305 samples.</p