Adaptive PRKAA1 variant in Andeans is associated with improved ventilation and sleep phenotypes
Highland groups have adapted to the extreme selective pressures of hypoxia at high altitude via alterations in the oxygen-transport cascade. <i>PRKAA1</i>, which encodes the catalytic subunit of the AMP-activated protein kinase (AMPK), is a notable target of natural selection in Andeans and has been associated with protective fetal phenotypes in this population. AMPK is a universal cellular energy sensor involved in a multitude of physiological processes, including ventilation and the hypoxic ventilatory response (HVR) in animal models. We localized a signal of positive selection and identified a regulatory promoter variant (rs10035235, C>T) of adaptive significance that is associated with ventilatory and sleep phenotypes in male Andean highlanders as well as sleep phenotypes in publicly available lowland cohorts. This work identifies a functional, adaptive, and likely pleiotropic regulatory variant in <i>PRKAA1</i> in Andeans that may accentuate hypoxia-induced ventilation and provide protection from sleep-disordered breathing in both high- and lowland populations.
Authors
- Ana Sánchez-Azofra (ORCID: https://orcid.org/0000-0002-9838-9047)
- Wanjun Gu (ORCID: https://orcid.org/0000-0002-7342-7000)
- Elijah S. Lawrence (ORCID: https://orcid.org/0000-0001-7656-0600)
- Jeremy E. Orr (ORCID: https://orcid.org/0000-0002-4498-5337)
- James J. Yu (ORCID: https://orcid.org/0000-0002-9967-8449)
- Rómulo Figueroa‐Mujíca (ORCID: https://orcid.org/0000-0003-1364-350X)
- Gustavo Vizcardo‐Galindo (ORCID: https://orcid.org/0000-0002-8131-8808)
- Daniela Bermúdez (ORCID: https://orcid.org/0000-0001-7879-0485)
- Tatum S. Simonson (ORCID: https://orcid.org/0000-0003-4062-2587)
- Noemí Corante (ORCID: https://orcid.org/0000-0003-0083-7380)
- A. Mark Evans (ORCID: https://orcid.org/0000-0002-4650-7208)
- Amy M. Cole (ORCID: https://orcid.org/0000-0003-4429-1105)
- Gianpiero L. Cavalleri (ORCID: https://orcid.org/0000-0002-9802-0506)
- Eduardo Gaio (ORCID: https://orcid.org/0000-0001-9621-2443)
- José Luis Macarlupú (ORCID: https://orcid.org/0000-0001-9764-1020)
- Atul Malhotra (ORCID: https://orcid.org/0000-0002-9509-1827)
- Cecilia Anza‐Ramirez (ORCID: https://orcid.org/0000-0001-7364-8252)
- Frank L. Powell (ORCID: https://orcid.org/0000-0002-5166-4347)
- Mitchell C. Kong (ORCID: https://orcid.org/0000-0002-1657-7934)
- Erica C. Heinrich (ORCID: https://orcid.org/0000-0002-6861-6165)
- James E. Hall (ORCID: https://orcid.org/0000-0002-9843-7520)
- Rany M. Salem (ORCID: https://orcid.org/0000-0001-8816-6862)
- Francisco C. Villafuerte (ORCID: https://orcid.org/0000-0003-0731-8911)
- Steven Cao
- Esteban A. Moya (ORCID: https://orcid.org/0000-0002-9243-5057)
- Santiago Fassardi
- Andrew Lin (ORCID: https://orcid.org/0000-0002-8752-7408)
- Pamela DeYoung
Institutions
- University of California, Riverside (US)
- Royal College of Surgeons in Ireland (IE)
- Universidade de Brasília (BR)
- Universidad Peruana Cayetano Heredia (PE)
- University of California System (US)
- University of California San Diego (US)
- Human Longevity (United States) (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- iScience
- Published
- 2025-06-16
- DOI
- https://doi.org/10.1016/j.isci.2025.112911
- Citations
- 2
- Primary Topic
- Neuroscience of respiration and sleep
- Type
- article
- Field-Weighted Citation Impact
- 1.83