Genome-wide association meta-analysis identifies 29 new acne susceptibility loci

Brittany Mitchell ,Nicholas G Martin ,Kristian Hveem ,Miguel E Rentería ,Jouke Jan Hottenga ,Catherine Smith ,Michelle K Lupton ,Xianjun Dong ,Mari Løset ,Xin Li ,Meike Bartels ,Dorret I Boomsma ,Josine L Min ,Nick Dand ,Jake Saklatvala ,Jiali Han ,Jonathan Barker ,Laurent F Thomas ,Fiona A Hagenbeek ,Michael A Simpson

doi:10.1038/s41467-022-28252-5

Abstract

Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin. Severely inflamed lesions may leave permanent scars that have been associated with long-term psychosocial consequences. Here, we perform a GWAS meta-analysis comprising 20,165 individuals with acne from nine independent European ancestry cohorts. We identify 29 novel genome-wide significant loci and replicate 14 of the 17 previously identified risk loci, bringing the total number of reported acne risk loci to 46. Using fine-mapping and eQTL colocalisation approaches, we identify putative causal genes at several acne susceptibility loci that have previously been implicated in Mendelian hair and skin disorders, including pustular psoriasis. We identify shared genetic aetiology between acne, hormone levels, hormone-sensitive cancers and psychiatric traits. Finally, we show that a polygenic risk score calculated from our results explains up to 5.6% of the variance in acne liability in an independent cohort.

Highlights

Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin
To further characterise the genetic architecture of acne vulgaris and identify additional genomic loci contributing to the disease susceptibility, we have performed a meta-analysis of genome-wide association studies (GWAS) of acne undertaken in nine independent cohorts that in total comprise 615,396 study participants (20,165 cases and 595,231 controls)
The resulting metaanalysis of the fourteen GWAS datasets demonstrated moderate inflation of test statistics, though the Linkage disequilibrium (LD)-score regression (LDSC) intercept (1.02) indicated that the inflation is driven by trait polygenicity rather than confounding bias

Summary

Introduction

Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin. According to the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD)[3] acne was estimated to be responsible for nearly 5 million disability-adjusted life years (DALYs) globally in 2019, of which the majority occurred in those aged 15–49 years This is greater than other chronic inflammatory conditions such as psoriasis or rheumatoid arthritis. Recent molecular genetic studies identified 17 genomic loci harbouring alleles associated with the disease—15 loci with a reported effect in European populations[16,17] and two in a Han Chinese population[18] Functional characterisation of these genetic association signals has implicated a series of causal genes whose genetic perturbation impacts the development and maintenance of the hair follicle and wound healing. To further characterise the genetic architecture of acne vulgaris and identify additional genomic loci contributing to the disease susceptibility, we have performed a meta-analysis of genome-wide association studies (GWAS) of acne undertaken in nine independent cohorts that in total comprise 615,396 study participants (20,165 cases and 595,231 controls). We combine finemapping and genome-wide analytical approaches to gain insights into the underlying genes and pathways through which the associated loci contribute to disease susceptibility, and the relationship between the genetic architecture of acne and other traits

Methods

Results

Conclusion