Putatively adaptive missense variant at Adrenergic Receptor Alpha-1A associated with decreased risk of Chronic Mountain Sickness in Andean highlanders

Andean highlanders living at high altitude (>4200 m) for hundreds of generations exhibit distinct cardiovascular and ventilatory traits in response to environmental stress. Adrenergic Receptor Alpha-1A ( ADRA1A), a gene coding for the Alpha 1-A adrenergic receptor, has been previously shown to be under positive natural selection in the Andeans. ADRA1A has also been demonstrated to have a protective effect against cardiovascular complications in other lowland populations. We hypothesized that putatively adaptive single nucleotide variants (SNVs) of strong functional impact can be found in ADRA1A and associated with cardiovascular traits in the Andean highlanders.We examined data from the Composite of Multiple Signals test in 40 high-coverage whole genomes of Andean highlanders living in Cerro de Pasco, Peru (~4340 m), specifically focusing on SNVs with strong predicted functional impact. Genetic variants of interests were then genotyped and tested for phenotypic associations in an extended Andean cohort (132 males, 46 females). The presence of Chronic Mountain Sickness (CMS), a maladaptive syndrome observed in Andean highlanders characterized by excessive erythrocytosis, and resting heart rate during hypoxia were prioritized for the regression analysis. The genotype-phenotype association analysis adapted a multivariate linear model with sex as a stratum and age as a covariate.A missense variant (rs1048101, A>G) in the second exon of ADRA1A with strong predicted functional impact was tagged by the Composite of Multiple Signals analysis. In Andean males, the rs1048101 A allele was associated with 1.52-fold decreased risk for CMS (p<0.018) and attenuated resting heart rate at room air (~10% inspired O 2 ) and at 21% inspired O 2 (room air: p<0.019, 21% O 2 : p<0.012). In women, the association between ADRA1A rs1048101 and CMS was not significant (p>0.917). In addition, women with more copies of the putatively adaptive A allele demonstrated increased heart rate both at room air and 21% inspired O 2 (room air: p<0.033, 21% O 2 : p<0.044) in contrast to observations in men.In conclusion, the putatively adaptive missense variant rs1048101 at ADRA1A demonstrated a protective effect against Chronic Mountain Sickness and was further associated with decreased resting heart rate in Andean males. The lack of replicability of these associations in females suggests potential sex-dependent effect of ADRA1A. Further experiments functionalizing the variant and validating the associations in large genome cohorts may shed light on the mechanisms of the gene. This project is funded by R01HL145470. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.