Androgenetic Alopecia: Identification of Four Genetic Risk Loci and Evidence for the Contribution of WNT Signaling to Its Etiology

Abstract

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.

Prediction of male-pattern baldness from genotypes

“…All the cases and controls were of German descent. 13 Note that the 581 cases and the 146 controls from the BONN Study used here were part of the initial MAAN study, 16 and all BONN subjects were also part of the previous study of Heilmann et al, 17 based on which the SNPs used here for MPB prediction were initially discovered. There is thus a potential risk in overestimating the prediction accuracy in BONN but at most by only a small degree as BONN was only a small component of the MAAN study 16 (ie, 14.9% of cases and 1.6% of controls in MAAN and 21.1% of cases and 15.6% of controls in the Heilmann study).…”

“…We initially selected 20 SNPs from 12 genomic loci for prediction analysis from the Table 2 and the Supplementary Table S2 of Li et al 16 as well as Table 1 of Heilmann et al 17 A candidate SNP analysis was conducted using logistic regression in all three cohorts for the 20 SNPs assuming additive allele effect adjusted for age at examination when appropriate. As the AR locus has a relatively large effect, we additionally selected four SNPs from the AR locus showing some residual effect based on a conditional logistic regression analysis of all SNPs within 66.5-67.9 Mbp of the AR locus in a stepwise manner, that is, until the newly included SNP is not significant anymore at Po0.05 level in a multivariate analysis of all SNPs accumulated in previous steps.…”

“…We focused on 20 candidate SNPs from 11 autosomal loci and the AR/EDA2R locus on X chromosome previously reported by Li et al 16 and Heilmann et al 17 (Table 1). Part of the BONN subjects was used in Li et al and Heilmann et al, so as expected, the allelic effects in BONN for all tested SNPs was consistent with previous reports and most of the tested SNPs showed significant association with MPB (Po0.05).…”

“…Individuals in the highest-risk quartile of a genotype score had an approximately sixfold increased risk of earlyonset MPB. In addition, the most recent study by Heilmann et al 17 comprising 2759 cases and 2661 controls successfully identified four additional autosomal loci showing genome-wide significant association with MPB; these included 2q35, 3q25.1, 5q33.3, and 12p12.1 (identifying a total of 12 genetic loci so far). These findings on one hand highlight a relatively strong X-linked major gene locus effect (odds ratio per risk allele~2.5 at the AR locus) and on the other hand suggest a highly polygenetic autosomal component (odds ratios at individual loci o1.5).…”

Forensic DNA Phenotyping: Predicting human appearance from crime scene material for investigative purposes

“…Currently, there are 12 genes and genomic regions known with genome-wide significant association with early-onset androgenetic alopecia (male pattern baldness, AGA), the most common form of hair loss in humans: AR/EDA2R, TARDBP, HDAC9, AUTS2, SETBP1, PAX1/FOXA2, WNT10A, 17q21.31, 3q25, 5q33.3, and 12p12.1 [63][64][65]. The by far strongest association is seen for SNPs located in the AR/EDA2R region on the X-chromosome.…”