Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia

Abstract

Androgenetic alopecia (AGA), or male-pattern baldness, is the most common form of hair loss. Its pathogenesis is androgen dependent, and genetic predisposition is the major requirement for the phenotype. We demonstrate that genetic variability in the androgen receptor gene (AR) is the cardinal prerequisite for the development of early-onset AGA, with an etiological fraction of 0.46. The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect. The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA.

Figure 1

Multipoint NPL analysis of chromosome X, calculated by the Allegro v1.2 software (Gudbjartsson et al. 2000). The X-axis is the chromosome location (top, cM; bottom, STR marker), and the Y-axis is the LOD score.

Figure 2

Gene and LD structure of the AR locus. A, Distribution of known genes (left) and typed SNPs and STRs (right) at the AR locus. The shown genomic region spans 4.4 Mb. Gene content information is based on Ensembl. B, LD in 198 individuals with AGA (upper right diagonal) and in 157 individuals without AGA (lower left diagonal) was measured with χ² and was visualized using the GOLD program (Abecasis and Cookson 2000).

Figure 3

The AR locus: LD relative to the X-chromosome and haplotype structure. A, Average pairwise LD (measured by |D′|) between SNPs retrieved from the HapMap Project database, plotted over X-chromosomal recombination rates in 1-cM–sized windows. An average LD higher than that at the AR locus was displayed by only the six windows covering the centromere and showed distinctively smaller recombination rates. B, Neighbor-joining tree of frequent haplotype sequences (>5% in the samples from the individuals with AGA, controls, and individuals without AGA) within the most strongly associated haplotype block (genetic markers rs1385695–XARx8insA). The CAG repeat, XARx7_01, and XARx8insA were omitted from tree construction, because the corresponding Pan troglodytes allele could not be retrieved from the chimpanzee genomic sequence. The AGA haplotype is shown in red, and the chimpanzee haplotype is shown in orange. The AGA haplotype shows low sequence identity to the ancestral (chimpanzee) haplotype. Haplotype frequencies of the respective samples are indicated in parentheses (affected/control/unaffected [in %]). GGN-23 is indicated as “23”; GGN-24 is indicated as “24.”