Genetic analyses on male-pattern hair loss

Abstract

Male pattern hair loss (MPHL) is a highly heritable condition and the most common form of hair loss in men. The phenotype is characterized by progressive hair loss in the frontotemporal and vertex areas of the scalp. Molecular genetic studies into common variants have provided substantial insights into the genetic basis of MPHL, identifying 389 risk loci and implicating numerous candidate genes and pathways. However, the underlying pathobiology of the hair loss remains incompletely understood and the identified risk loci explain only a portion of MPHL's estimated heritability, suggesting the existence of as yet unidentified genetic risk factors. On an epidemiological level, MPHL has been linked to other traits and conditions, such as cardiovascular disease and prostate cancer, and has recently emerged as a putative risk factor for severe COVID-19. In addition to epidemiologic data, the availability of large-scale genetic datasets enables a systematic investigation of pleiotropic effects between traits at individual loci and on a genome-wide level. This resulted in the identification of shared genetic factors between MPHL and e.g., Parkinson’s disease and early puberty, respectively. Leveraging data from the UK Biobank, this thesis aimed (i) to identify additional genetic risk factors through the investigation of the contribution of rare variants to MPHL, and (ii) to dissect potential associations of MPHL with COVID-19 and monogenic hair disorders on an epidemiological and/or genetic level. The investigation of rare variants involved single-variant and gene-based association analyses of exome sequencing data, marking the first systematic analysis in this context. The findings provide evidence for the involvement of rare variants in five genes in MPHL etiology, including previously implicated genes (WNT10A, EDA2R) and novel candidate genes at known risk loci (HEPH) and beyond (CEPT1, EIF3F), as well as revealing an enrichment of genes causal for genotrichoses. Regarding the potential association between MPHL and severe COVID-19, no epidemiological or genome-wide genetic correlation was identified, contrasting previous studies. The assessment of potential genetic overlap between MPHL and short anagen hair syndrome (SAH) identified c.682T>A and c.321C>A in WNT10A as shared genetic determinants for both traits. In summary, this thesis provides insights into MPHL genetics, contributing to ongoing gene identification efforts and highlighting a shared genetic basis with other hair- and skin-related conditions. These findings underscore the relevance of MPHL research in a broader dermatological context.