Faculty Bibliography

Hair traits are nonpathogenic features that vary among individuals. Unlike hair follicle (HF) diseases, which are rare in the population, hair traits can be measured in everyone. This facilitates the construction of large cohorts that are well-powered for gene discovery. GWASs identify genetic variants that are widely shared among people globally, providing knowledge with broad population relevance. We compile findings from hair trait GWASs to deepen our understanding of HF biology. In reviewing genetic factors that influence hair traits, we demonstrate overlap with disease genes, underscoring that genetic studies of traits improve our knowledge about health and disease.

Over 85% of the population experience acne at some point in their lives, with its severity spanning a quantitative spectrum, from mild, transient outbreaks to more persistent, severe forms of the condition. Moderate to severe disease poses a substantial global burden arising from both the physical and psychological impacts of this highly visible condition. The analytical approach taken in this study aimed to address the impact of variation in the dichotomisation of acne case control status, driven by ascertainment and study design, on effect size estimates across independent genetic association studies of acne. Through a fixed intercept meta-regression framework, we combined evidence genome-wide for association with acne across studies in which case-control status had been ascertained in different settings, allowing for different severity threshold definitions. Across a combined sample of 73,997 cases and 1,103,940 controls of European, South Asian and African American ancestry we identify genetic variation at 165 genomic loci that influence acne risk. There is evidence for both shared and ancestry specific components to the genetic susceptibility to acne and for sex differences in the magnitude of effect of risk alleles at three loci. We observe that common genetic variation explains 13.4% of acne heritability on the liability scale. Consistent with the hypothesis that genetic risk primarily operates at the level of individual pilosebaceous units, a polygenic score derived from this case-control study of acne susceptibility is associated with both self-reported and clinically assessed acne severity in adolescence, further strengthening the link between genetic risk and disease severity. Prioritisation of causal genes at the identified acne risk loci, provides genetic validation of the targets of established and emerging acne therapies, including retinoid treatments. The identified acne risk loci are enriched for genes encoding downstream effectors of RXRA signalling, including SOX9 and components of the WNT and p53 pathways. Illustrating that the control of stem cell lineage plasticity and cellular fate are important mechanisms through which genetic variation influences acne susceptibility within the pilosebaceous unit.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by nodules, abscesses, and sinus tunnels, primarily in intertriginous areas. Symptoms of HS are associated with reduced psychosocial health and physical function. HS shares some pathogenic, cellular, and molecular features with other inflammatory skin diseases, highlighting its heterogeneity and complexity. This heterogeneity in disease presentation may contribute to the diagnosis delay observed with HS. The primary objective of this review is to highlight the initiating events, inflammatory signature, molecular features, and clinical features that differentiate HS from other inflammatory skin diseases to improve outcomes for patients with HS.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with many unmet needs. It is characterized by significant clinical heterogeneity, which suggests that a diagnosis of HS captures multiple distinct disease entities and that research aimed at identifying medically relevant HS subtypes will improve its management. Precision medicine is an approach to disease management that uses information encoded in a patient's genome, and operationalized in clinical presentations and drug responses, to identify disease subtypes. Prior research aimed at identifying HS subtypes has largely focused on phenotypic classifications derived from clinical features of cutaneous lesions. Limitations of existing HS taxonomies emphasize a need for a more nuanced understanding of disease subtypes. Evidence that has emerged from initial genetic studies of HS suggests the presence of at least three HS subtypes, each of which has different clinical implications in terms of disease risks and drug responses. These preliminary findings are instructive in terms of expanding our definitions of HS phenotypes to not only include characteristics of skin lesions, but also disease comorbidities and molecular and cellular phenotypes. Here we provide a comprehensive review of HS phenotype and genotype knowledge, and propose a strategic framework for implementing precision medicine in HS management. Future research should focus on expanding phenotype assessments to include data on multiple scales. Iterative research designs performed with phenotype and genotype data from large diverse cohorts are needed to rigorously define clinically relevant HS subtypes.

Digital biobanks that integrate genetic data with health data captured by digital sources are used routinely to discover genes, biomarkers, gene–environment interactions and pharmacogenetic relationships across many clinical areas. There remain many opportunities in dermatology to further use biobank data to increase our knowledge about the genetic architecture of skin disease, to resolve disease mechanisms that can be modulated by medical interventions and to discover genetically derived disease relationships that inform on drug repurposing and adverse events. Such knowledge promises to reduce the global burden of skin disease and facilitates the development of tailored medical care.

Opportunities to improve the clinical management of skin disease are being created by advances in genomic medicine. Large-scale sequencing increasingly challenges notions about single-gene disorders. It is now apparent that monogenic etiologies make appreciable contributions to the population burden of disease and that they are underrecognized in clinical practice. A genetic diagnosis informs on molecular pathology and may direct targeted treatments and tailored prevention strategies for patients and family members. It also generates knowledge about disease pathogenesis and management that is relevant to patients without rare pathogenic variants. Inborn errors of immunity are a large class of monogenic etiologies that have been well-studied and contribute to the population burden of inflammatory diseases. To further delineate the contributions of inborn errors of immunity to the pathogenesis of skin disease, we performed a set of analyses that identified 316 inborn errors of immunity associated with skin pathologies, including common skin diseases. These data suggest that clinical sequencing is underutilized in dermatology. We next use these data to derive a network that illuminates the molecular relationships of these disorders and suggests an underlying etiological organization to immune-mediated skin disease. Our results motivate the further development of a molecularly derived and data-driven reorganization of clinical diagnoses of skin disease.