A broad exome study of the genetic architecture of asthma reveals novel patient subgroups

Cameron-Christie, S.; Mackay, A.; Wang, Q.; Olsson, H.; Angermann, B.; Lassi, G.; Lindgren, J.; Hühn, M.; Cameron-Christie, Y. O.; Gavala, M.; Wang, J.; Povysil, G.; Deevi, S. V. V.; Belfield, G.; Dillmann, I.; Muthas, D.; Cohen, S.; Young, S.; Platt, A.; Petrovski, S.

doi:10.1101/2020.12.10.419663

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bioRxiv · 10.1101/2020.12.10.419663

A broad exome study of the genetic architecture of asthma reveals novel patient subgroups

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Abstract

IntroductionAsthma risk is a complex interplay between genetic susceptibility and environment. Despite many significantly-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. MethodsWe performed case-control analyses on three genetic units: variant-, gene- 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. ResultsVariant-level analyses identified statistically significant variants at moderate-to-common allele frequency, including protein-truncating variants in FLG and IL33. Asthma risk was significantly increased not only by individual, common FLG protein-truncating variants, but also among the collection of rare-to-private FLG protein-truncating variants (p=6.8x10-7). 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 significantly protective (p=8.0x10-10), 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 significantly enriched among individuals with asthma. ConclusionsAccess 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 significant drivers, we detected a significant enrichment of protein-truncating variants in loss-of-function intolerant genes.

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Cameron-Christie, S., Mackay, A., Wang, Q., Olsson, H., Angermann, B., Lassi, G., Lindgren, J., Hühn, M., Cameron-Christie, Y. O., Gavala, M., Wang, J., Povysil, G., Deevi, S. V. V., Belfield, G., Dillmann, I., Muthas, D., Cohen, S., Young, S., Platt, A., Petrovski, S.. 2020-12-11. A broad exome study of the genetic architecture of asthma reveals novel patient subgroups. https://doi.org/10.1101/2020.12.10.419663

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