Hormonal regulation in male androgenetic alopecia-Sex hormones and beyond: Evidence from recent genetic studies.

Male-pattern hair loss, also termed androgenetic alopecia (AGA), is a highly prevalent age-related condition that is characterized by a distinct pattern of hair loss from the frontotemporal and vertex regions of the scalp. The phenotype is highly heritable and hormone dependent, with androgens being the recognized critical hormonal factor. Numerous molecular genetic studies have focused on genetic variation in and around the gene that encodes the androgen receptor. More recently, however, the availability of high-throughput molecular genetic methods, novel methods of data analysis and sufficiently large sample sizes have rendered possible the systematic investigation of the contribution of other components of the androgen receptor pathway or hormonal pathways beyond the androgen receptor signalling pathways. Over the past decade, genome-wide association studies of increasingly large cohorts have enabled the genome-wide identification of genetic risk factors for AGA, and yielded unprecedented insights into the underlying pathobiology. The present review discusses some of the most intriguing genetic findings on the relevance of (sex)hormonal signalling in AGA.

Mapping of cis-acting expression quantitative trait loci in human scalp hair follicles.

BACKGROUND: The association of molecular phenotypes, such as gene transcript levels, with human common genetic variation can help to improve our understanding of interindividual variability of tissue-specific gene regulation and its implications for disease. METHODS: With the aim to capture the spectrum of biological processes affected by regulatory common genetic variants (minor allele frequency ≥ 1%) in healthy hair follicles (HFs) from scalp tissue, we performed a genome-wide mapping of cis-acting expression quantitative trait loci (eQTLs) in plucked HFs, and applied these eQTLs to help further explain genomic findings for hair-related traits. RESULTS: We report 374 high-confidence eQTLs found in occipital scalp tissue, whose associated genes (eGenes) showed enrichments for metabolic, mitotic and immune processes, as well as responses to steroid hormones. We were able to replicate 68 of these associations in a smaller, independent dataset, in either frontal and/or occipital scalp tissue. Furthermore, we found three genomic regions overlapping reported genetic loci for hair shape and hair color. We found evidence to confirm the contributions of PADI3 to human variation in hair traits and suggest a novel potential candidate gene within known loci for androgenetic alopecia. CONCLUSIONS: Our study shows that an array of basic cellular functions relevant for hair growth are genetically regulated within the HF, and can be applied to aid the interpretation of interindividual variability on hair traits, as well as genetic findings for common hair disorders.

Expression profiling and bioinformatic analyses suggest new target genes and pathways for human hair follicle related microRNAs.

BACKGROUND: Human hair follicle (HF) cycling is characterised by the tight orchestration and regulation of signalling cascades. Research shows that micro(mi)RNAs are potent regulators of these pathways. However, knowledge of the expression of miRNAs and their target genes and pathways in the human HF is limited. The objective of this study was to improve understanding of the role of miRNAs and their regulatory interactions in the human HF. METHODS: Expression levels of ten candidate miRNAs with reported functions in hair biology were assessed in HFs from 25 healthy male donors. MiRNA expression levels were correlated with mRNA-expression levels from the same samples. Identified target genes were tested for enrichment in biological pathways and accumulation in protein-protein interaction (PPI) networks. RESULTS: Expression in the human HF was confirmed for seven of the ten candidate miRNAs, and numerous target genes for miR-24, miR-31, and miR-106a were identified. While the latter include several genes with known functions in hair biology (e.g., ITGB1, SOX9), the majority have not been previously implicated (e.g., PHF1). Target genes were enriched in pathways of interest to hair biology, such as integrin and GnRH signalling, and the respective gene products showed accumulation in PPIs. CONCLUSIONS: Further investigation of miRNA expression in the human HF, and the identification of novel miRNA target genes and pathways via the systematic integration of miRNA and mRNA expression data, may facilitate the delineation of tissue-specific regulatory interactions, and improve our understanding of both normal hair growth and the pathobiology of hair loss disorders.

Hunting the genes in male-pattern alopecia: how important are they, how close are we and what will they tell us?

Androgenetic alopecia (AGA) is a highly heritable condition, and the most common form of hair loss in men. The phenotype is characterized by an androgen-dependent, progressive loss of hair from the scalp, which may commence during puberty. Up to 80% of European men experience some degree of androgen-dependent hair loss during their lifetime. Current treatment options for AGA have limited efficacy, and improved understanding of the underlying biological causes is required to facilitate novel therapeutic approaches. To date, molecular genetic studies have implicated 12 genomic regions in AGA and identified a number of candidate genes. The latter include those encoding the androgen receptor (AR), the histone deacetylases (HDAC) 4 and 9, and the WNT molecule WNT10A. However, the majority of contributing genetic risk factors still await identification. This review describes the current status of AGA genetic research. We discuss the strength of the genetic approach and anticipated developments in the field, and how these will facilitate the systematic unravelling of AGA pathobiology, a process which may lead to the identification of new therapeutic targets.

Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.

More than 300 genetic risk loci have been identified for male pattern baldness (MPB) but little is known about the exact molecular mechanisms through which the associated variants exert their effects on MPB pathophysiology. Here, we aimed at further elucidating the regulatory architecture of the MPB risk locus on chromosome (chr.) 2q35, where we have previously reported a regulatory effect of the MPB lead variant on the expression of WNT10A. A HaploReg database research for regulatory annotations revealed that the association signal at 2q35 maps to a binding site for the transcription factor EBF1, whose gene is located at a second MPB risk locus on chr. 5q33.3. To investigate a potential interaction between EBF1 and WNT10A during MPB development, we performed in vitro luciferase reporter assays as well as expression analyses and immunofluorescence co-stainings in microdissected human hair follicles. Our experiments confirm that EBF1 activates the WNT10A promoter and that the WNT10A/EBF1 interaction is impacted by the allelic expression of the MPB risk allele at 2q35. Expression analyses across different hair cycle phases and immunhistochemical (co)stainings against WNT10A and EBF1 suggest a predominant relevance of EBF1/WNT10A interaction for hair shaft formation during anagen. Based on these findings we suggest a functional mechanism at the 2q35 risk locus for MPB, where an MPB-risk allele associated reduction in WNT10A promoter activation via EBF1 results in a decrease in WNT10A expression that eventually results in anagen shortening, that is frequently observed in MPB affected hair follicles. To our knowledge, this study is the first follow-up study on MPB that proves functional interaction between two MPB risk loci and sheds light on the underlying pathophysiological mechanism at these loci.

LAMP-Seq enables sensitive, multiplexed COVID-19 diagnostics using molecular barcoding.

Frequent testing of large population groups combined with contact tracing and isolation measures will be crucial for containing Coronavirus Disease 2019 outbreaks. Here we present LAMP-Seq, a modified, highly scalable reverse transcription loop-mediated isothermal amplification (RT-LAMP) method. Unpurified biosamples are barcoded and amplified in a single heat step, and pooled products are analyzed en masse by sequencing. Using commercial reagents, LAMP-Seq has a limit of detection of ~2.2 molecules per µl at 95% confidence and near-perfect specificity for severe acute respiratory syndrome coronavirus 2 given its sequence readout. Clinical validation of an open-source protocol with 676 swab samples, 98 of which were deemed positive by standard RT-qPCR, demonstrated 100% sensitivity in individuals with cycle threshold values of up to 33 and a specificity of 99.7%, at a very low material cost. With a time-to-result of fewer than 24 h, low cost and little new infrastructure requirement, LAMP-Seq can be readily deployed for frequent testing as part of an integrated public health surveillance program.

Male-pattern baldness and incident coronary heart disease and risk factors in the Heinz Nixdorf Recall Study.

Male-pattern baldness (MPB) is characterized by a progressive hair loss from the frontal and vertex scalp that affects about 80% of men at the age of 80 years. Epidemiological studies show positive associations between MPB and coronary heart disease (CHD) and CHD related risk factors such as blood pressure (BP), diabetes mellitus (DM) or elevated blood lipid levels. The results however vary with regard to the pattern of hair loss (i.e. moderate, severe, frontal or vertex). Further, no study has investigated for a shared genetic determinant between MPB and CHD as well as CHD related risk factors. Using the longitudinal data from the population-based Heinz Nixdorf Recall study we aimed to systematically investigate the association between MPB and incident CHD and CHD risk factors on (i) an epidemiological (N = 1,673 males) and (ii) a genetic (N = 1,357 males) level. The prevalence of any baldness in our study population was 88% (mean age ± SD: 64±7.5 years). Compared to men with 'no baldness', in men with any kind of baldness a slightly increased risk for CHD (Hazard ratio [95% confidence interval (95%CI)] = 1.2 [0.8; 1.9]), a slightly higher extend of coronary artery calcification (CAC) (Beta [95%CI] = 0.2 [-0.1; 0.6]), a moderately increased risk for DM (prevalence ratio [95%CI] = 1.4 [0.9; 2.0]) and higher body mass index (BMI) (Beta [95%CI] = 0.6 [0.00003; 1.2]) seem to be indicated in the adjusted model. In contrast, the MPB genetic risk score did not show any association with CHD or CHD risk factors. Taken together, the results of our study suggest a weak association between MPB and a few CHD risk factors (CAC, DM and BMI) but do not point to MPB as a strong surrogate measure for CHD and CHD risk factors in general.

Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness.

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10-8, METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options. The data provide molecular evidence that rather than being an isolated trait, MPB shares a substantial biological basis with numerous other human phenotypes and may deserve evaluation as an early prognostic marker, for example, for prostate cancer, sudden cardiac arrest and neurodegenerative disorders.