Genetic susceptibility to heat identifies rare neurological diseases at particular risk from climate change impacts

Background Climate change is one of the greatest contemporary challenges to human health, undermining human health through multiple mechanisms. Among relatively understudied mechanisms are those related to individual genomic variation. We aimed to examine this possibility.

Methods Through a defined, agnostic literature review-based approach, we curated human genetic variants with functionally characterised temperature-dependent effects: we call these ‘calortypic variants’, some of which are linked to temperature-sensitive disease phenotypes. Next, we examined their occurrence in whole-genome sequenced rare disease cohort and analysed their associated phenotypes. Finally, we performed transcriptomic analysis in astrocyte models to examine the impact of short-term exposure to elevated ambient temperature.

Results A set of 159 calortypic variants across 65 calortypic genes was identified; most (66.7%) calortypic variants caused temperature-sensitive disease phenotypes, and 44.7% were found in neurological and neurodevelopmental diseases. Calortypic variants were also found in 300/39 834 participants recruited to the Genomics England (GEL) 100 000 Genomes rare disease programme. Temperature-related phenotypes were documented in eight GEL participants; in 6/8 participants (two probands and four of their relatives), calortypic variants had already been identified as the disease-causing variant. Gene expression changes across human astrocyte transcriptomes studied under different temperature exposures prominently featured genes related to extracellular matrix maintenance, inflammation, immune response and energy metabolism, all processes that feature in various neurological diseases.

Conclusions Genetic variation may generate latent phenotypes that manifest only at elevated ambient temperatures, with some neurological disease groups being highlighted. This is an exploratory study. Identifying more calortypic variants will help uncover the full spectrum of human genetic vulnerability to climate change impacts.