Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82

Stephanie O Erjavec,Sahar Gelfman,Isha Monga,Iuliana Ionita-Laza,Angela M Christiano,Alexa R Abdelaziz,Lynn Petukhova,Anna Alkelai,Eunice Y Lee

doi:10.1038/s41467-022-28343-3

Stephanie O Erjavec, Sahar Gelfman + Show 7 more

Open Access

https://doi.org/10.1038/s41467-022-28343-3

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Abstract

Alopecia areata is a complex genetic disease that results in hair loss due to the autoimmune-mediated attack of the hair follicle. We previously defined a role for both rare and common variants in our earlier GWAS and linkage studies. Here, we identify rare variants contributing to Alopecia Areata using a whole exome sequencing and gene-level burden analyses approach on 849 Alopecia Areata patients compared to 15,640 controls. KRT82 is identified as an Alopecia Areata risk gene with rare damaging variants in 51 heterozygous Alopecia Areata individuals (6.01%), achieving genome-wide significance (p = 2.18E−07). KRT82 encodes a hair-specific type II keratin that is exclusively expressed in the hair shaft cuticle during anagen phase, and its expression is decreased in Alopecia Areata patient skin and hair follicles. Finally, we find that cases with an identified damaging KRT82 variant and reduced KRT82 expression have elevated perifollicular CD8 infiltrates. In this work, we utilize whole exome sequencing to successfully identify a significant Alopecia Areata disease-relevant gene, KRT82, and reveal a proposed mechanism for rare variant predisposition leading to disrupted hair shaft integrity.

Highlights

Alopecia areata is a complex genetic disease that results in hair loss due to the autoimmunemediated attack of the hair follicle
Due to the predicted tolerant nature of Keratin 82 (KRT82), we investigated whether the stringent frequency threshold for rare variants in the loss of function (LOF) model excluded common variants that would have altered the KRT82 burden in cases and controls
We performed an additional analysis on common LOF variants (MAF > 1%) to ensure that the finding of an increased frequency of LOF KRT82 variants in cases was not an artifact of excluding common variants found in either cases or controls

Summary

Introduction

Alopecia areata is a complex genetic disease that results in hair loss due to the autoimmunemediated attack of the hair follicle. We identify rare variants contributing to Alopecia Areata using a whole exome sequencing and gene-level burden analyses approach on 849 Alopecia Areata patients compared to 15,640 controls. Whole exome sequencing (WES) and exome-wide association studies in large cohorts of patients with complex disorders such as congenital kidney malformations[7], amyotrophic lateral sclerosis[8], pulmonary fibrosis[9], epilepsy[10], coronary disease[11], myocardial infarction[12], and autism[13] have successfully identified rare disease variants using WES followed by gene-level collapsing approaches. Gene-level collapsing methods have emerged as the accepted framework for identifying genetic burden, the enrichment of variants in a given gene, in disease cases compared to controls[7]. Model parameters, such as variant function and population frequency, are used to select qualifying variants for testing. We performed WES and gene-based collapsing in 849 AA cases and 15,640 controls to assess the genetic burden of rare damaging variants in unknown genes associated with AA

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