“A Broad Exome Study of the Genetic Architecture of Asthma Reveals Novel Patient Subgroups”, Sophia Cameron-Christie, Alex Mackay, Quanli Wang, Henric Olsson, Bastian Angermann, Glenda Lassi, Julia Lindgren, Michael Hühn, Yoichiro Ohne, Monica Gavala, Jingya Wang, Gundula Povysil, Sri V. V. Deevi, Graham Belfield, Inken Dillmann, Daniel Muthas, Suzanne Cohen, Simon Young, Adam Platt, Slavé Petrovski2020-12-11 (; similar)⁠:

Introduction

Asthma risk is a complex interplay between genetic susceptibility and environment. Despite many-associated common variants, the contribution of rarer variants with potentially greater effect sizes has not been as extensively studied. We present an exome-based study adopting 24,576 cases and 120,530 controls to assess the contribution of rare protein-coding variants to the risk of early-onset or all-comer asthma.

Method: We performed case-control analyses on 3 genetic units: variant-level, gene-level and pathway-level, using sequence data from the Scandinavian Asthma Genetic Study and UK Biobank participants with asthma. Cases were defined as all-comer asthma (n = 24,576) and early-onset asthma (n = 5,962). Controls were 120,530 UK Biobank participants without reported history of respiratory illness.

Results: Variant-level analyses identified statistically-significant variants at moderate-to-common allele frequency, including protein-truncating variants in FLG and IL33. Asthma risk was increased not only by individual, common FLG protein-truncating variants, but also among the collection of rare-to-private FLG protein-truncating variants (p = 6.8×10−7). This signal was driven by early-onset asthma and did not correlate with circulating eosinophil levels. In contrast, a single splice variant in IL33 was protective (p = 8.0×10−10), while the collection of remaining IL33 protein-truncating variants showed no class effect (p = 0.54). A pathway-based analysis identified that protein-truncating variants in loss-of-function intolerant genes were statistically-significantly enriched among individuals with asthma.

Conclusion: Access to the full allele frequency spectrum of protein-coding variants provides additional clarity about the potential mechanisms of action for FLG and IL33. Beyond these two drivers, we detected an enrichment of protein-truncating variants in loss-of-function intolerant genes.