Identification of a putatively adaptive promoter variant in PRKAA1 in Andean highlanders and associations with hypoxia adaptation
Authors: Kong Mitchell , Lawrence Elijah , Gu Wanjun , Fassardi Santiago , Lin Andrew , Moya Esteban , Hall James , O'Brien Katie , Simonson Tatum 
Published: May 2023

Andeans have resided at high altitude for thousands of years and exhibit distinct physiological phenotypes to maintain homeostasis under the selective pressure of hypoxia. Based on previous whole-genome sequence data generated in 40 Andeans from Cerro De Pasco, Peru, at an altitude of 4340m, we utilized the composite of multiple signals (CMS) test of selection and identified an adaptive signal at PRKAA1, the gene which encodes the alpha-1 subunit of the AMP-activated protein kinase (AMPK). We hypothesize that genetic variants in PRKAA1 are associated with control of breathing in highland populations exposed to chronic hypoxia.While no protein-coding variants were identified as potential functional targets of selection, we identified several putatively adaptive variants within epigenetic regulatory regions of PRKAA1. The variants identified were in high linkage-disequilibrium (LD) with our selection scan markers as well as previously reported PRKAA1 variants associated with uterine artery diameter and other fetal phenotypes in Andeans. Our in-silico analyses reveal that the epigenetic landscape within the gene promoter region containing rs10035235 strongly implicates the role of rs10035235 in transcriptional regulation of PRKAA1.We demonstrated genotype-phenotype associations between a PRKAA1 promoter variant rs10035235 (chr5:40798644, C>T) and control of breathing phenotypes in Andeans. Males with copies of the putatively adaptive T allele were shown to have increased hypoxic ventilatory response (p < 0.03). The variant was also associated with end-tidal CO2 (p < 0.01), ventilation (p < 0.05), and heart rate (p < 0.05). We further examined the effect of rs10035235 on PRKAA1 gene expression using a luciferase assay in HEK293 cells and found the T allele resulted in a 203% increase in expression relative to cells with the non-adaptive C allele (p < 0.05).To assess whether rs10035235 was associated with other phenotypes, we tested for associations with a subset of phenotypes from the Hispanic Community Health Study, Study of Latinos (HCHS-SOL) (n = 11,893). We identified associations with apneic events (FDR < 3.30E-3), total time spent in apnea (FDR < 7.90E-4) as well as the apnea/hypopnea index (FDR < 3.09E-3). These findings suggest that adaptation at the PRKAA1 locus is associated with increased breathing responses to hypoxia in Andean highlanders and may underlie variation in sleep-apnea related phenotypes in the Hispanic/Latino population.In conclusion, we indentify rs10035235 as a positively selected, functional regulatory variant in the promoter of PRKAA1 using in-silico prediction and cellular models. We also utilized our prior genotype-phenotype associations and the HCHS-SOL cohort data to demonstrate novel association of rs10035235 with pulmonary, cardiac, and sleep phenotypes. 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.