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.
We carried out a genome-wide association study in 296 individuals with male-pattern baldness (androgenetic alopecia) and 347 controls. We then investigated the 30 best SNPs in an independent replication sample and found highly significant association for five SNPs on chromosome 20p11 (rs2180439 combined P = 2.7 x 10(-15)). No interaction was detected with the X-chromosomal androgen receptor locus, suggesting that the 20p11 locus has a role in a yet-to-be-identified androgen-independent pathway.
Two intervals of sequence identity at the tips of X and Y chromosomes, the human pseudoautosomal regions PAR1 and PAR2, have drawn interest from researchers in human genetics, cytogenetics, and evolutionary biology. However, they have been widely ignored in linkage and association studies. The pseudoautosomal regions (PARs) pair and recombine during meiosis like autosomes, but the recombination activity in PAR1 is extremely different between sexes. In men, it exhibits the highest recombination frequencies of the genome. Conflicting genetic maps of this region have been estimated by using three-generation pedigrees, sperm typing, and by using haplotypes from single nucleotide polymorphisms. Male genetic map lengths in the literature vary, and linkage disequilibrium has not been analyzed in detail. We review existing tools like genetic and physical maps, linkage disequilibrium methods, linkage and association analysis, implemented statistical methods, and their suitability for PARs. For multipoint linkage analysis, sex specificity must be indicated twice, first using sex-specific maps, and second by considering the sex-specific pseudoautosomal inheritance pattern. Currently, microsatellite panels and single nucleotide polymorphism chips do not contain sufficient numbers of markers in PAR1 and PAR2. The number of markers in PAR1, needed in indirect association studies, should be much larger than for autosomal regions alike in size, since linkage disequilibrium is very low. For genome-wide studies, it is essential to include pseudoautosomal markers since such expensive studies cannot afford to oversee pseudoautosomal linkage or association. This drawback could be solved with a sufficient number of markers, statistical methods that are adopted for the PARs, and their integration into softwares.
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