Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases

Abstract

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

Prediction of male-pattern baldness from genotypes

“…Except 6p25.1, all loci have been previously associated with MPB. [14][15][16] The associated SNP at 6p25.1 is a single genome-wide significant finding not supported by additional SNPs in the region and thus warrants further validation.…”

“…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). The RS and ERF subjects are completely independent from previous studies.…”

“…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).…”

“…In the present meta-analysis of the three cohorts, the only locus that did not show significant association was 3q25.1, but the allelic effect was in the same direction as Li et al Overall, the observed allele effect sizes were similar between RS and ERF, and similar to previous estimates in other populations. [14][15][16] Noticeable exceptions were: (1) the chromosome 20p11 SNPs showed much smaller effects in RS and ERF (eg, rs6047844 OR = 1.09 in RS and 1.18 in ERF, Table 1) than previous estimations (OR = 1.60 in Li et al and 1.82 in BONN); and (2) the SNPs at the EDA2R/AR locus showed much larger effect (rs1511061 OR = 9.07) in BONN than in RS and ERF (OR 2.68-2.75). These differences are likely explained by the extreme design in BONN, as BONN included only early-onset MPB cases (o40 years of age) and a set of super controls (⩾ 60 years, no signs of MPB) while no MPB pre-selection was made in RS and ERF, in which the majority of the subjects were elderly people.…”

“…11,12 In addition, two genetic loci on chromosome 20p11 (PAX1/FOXA2) and 7p21.1 (HDAC9) were identified to be involved in MPB. [13][14][15] A meta-analysis of seven GWASs for early-onset MPB involving~13 000 individuals of European origin conducted by the International MAAN Consortium 16 replicated these loci and highlighted five additional loci showing genome-wide significant association with MPB; these included 1p36.22, 2q37.3, 7q11.22, 17q21.31, and 18q12.3. Individuals in the highest-risk quartile of a genotype score had an approximately sixfold increased risk of earlyonset MPB.…”