Baldness and the androgen receptor: the AR polyglycine repeat polymorphism does not confer susceptibility to androgenetic alopecia

Abstract

Androgenetic alopecia, or male pattern baldness, is a complex condition with a strong heritable component. In 2001, we published the first significant evidence of a genetic association between baldness and a synonymous coding SNP (rs6152) in the androgen receptor gene, AR. Recently, this finding was replicated in three independent studies, confirming an important role for AR in the baldness phenotype. In one such replication study, it was claimed that the causative variant underlying the association was likely to be the polyglycine (GGN) repeat polymorphism, one of two apparently functional triplet repeat polymorphisms located in the exon 1 transactivating domain of the gene. Here, we extend our original association finding and present comprehensive evidence from approximately 1,200 fathers and sons drawn from 703 families of the Victorian Family Heart Study, a general population Caucasian cohort, that neither exon 1 triplet repeat polymorphism is causative in this condition. Seventy-eight percent of fathers (531/683) and 30% of sons (157/520) were affected to some degree with AGA. We utilised statistical methods appropriate for the categorical nature of the phenotype and familial structure of the cohort, and determined that whilst SNP rs6152 was strongly associated with baldness (P < 0.0001), the GGN triplet repeat was not (P = 0.13). In the absence of any other known common functional coding variants, we argue that the causative variant is likely to be in the non-coding region, and yet to be identified. The identification of functional non-coding variants surrounding AR may have significance not only for baldness, but also for the many other complex conditions that have thus far been linked to AR.

Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

“…a negative association with circulating E 2 (total, free, bioavailable). Intriguingly, the major allele of rs6152 (G), associated with higher E 2 levels, is strongly associated with male-pattern baldness (40) and higher-grade prostate cancer (41). Although the connection of the latter associations with altered circulating estrogen levels is hypothetical, altered estrogen/androgen ratio may be involved.…”

Androgenic Alopecia: Cross-Talk Between Cell Signal Transduction Pathways

“…Finasteride (type 2 5a-reductase inhibitor) reduces dihydrotestosterone (DHT) level in scalp skin and increases hair growth in more than 60% of men with AGA [25]. Androgen receptor (AR) gene is the only risk gene for AGA phenotype confirmed in gene association studies [26]. Androgen receptors level was higher in cultured dermal papilla cells derived from balding scalp hair follicles, compared to dermal cell from nonbalding follicles [5,8].…”

“…Follicles from frontal and parietal areas of the human scalp are considered to be androgen-sensitive. There are also two more types of hair follicles: androgen-independent hair follicles, such as eyelashes, and androgen-dependent pigmented terminal hair follicles, such as beard [26,29,30]. Why do hair follicles have different sensitivity to androgens is still open question.…”

Specification of Generalized Linear Mixed Models for Family Data using Markov Chain Monte Carlo Methods

“…Details on the specification of logistic regression models that incorporate random effects that can reproduce within-family correlation structures for ordinal outcomes due to shared environmental and genetic risk factors are described in Zaloumis [16]. In addition, Ellis et al [17] analyzed data from the VFHS to investigate risk factors for male pattern baldness (a fourcategory ordinal outcome variable) using generalized linear mixed models similar to those proposed here.…”