Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans
Open accessAbstract
Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.
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Evidence supports a causal role in OSA for iron metabolism, based on increased FECH expression with lower nocturnal SaO2.
“Evidence for a causal role in OSA was supported by finding that FECH expression was increased in association with lower nocturnal SaO2. These findings suggested a novel for iron metabolism in pathway influencing OSA phenotypes.”
From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [270]
The Discussion reports that increased FECH expression was associated with lower nocturnal SaO₂ and suggests that iron/heme metabolism influences OSA traits. It does not establish a causal role; the authors say future research is needed to determine the mechanism. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLocal African ancestry has a protective effect on AHI and is associated with shorter duration events.
“Notably, local African ancestry was shown to have a protective effect on the AHI and associated with shorter duration events.”
From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [270]
The Admixture mapping section reports that local African ancestry at chromosome 2q37 was associated with lower AHI. It also reports an association between local African ancestry at chromosome 16q12-21 and event duration, but does not give its direction there; the shorter-event finding is stated for global African ancestry in Global ancestry associations. The paper describes a suggested protective association, not a demonstrated protective effect. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNovel variants were associated with AHI and oxygen desaturation measures in admixture mapping.
“Novel variants were associated with AHI as well as oxygen desaturation measures.”
From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [270]
A region on chromosome 18q21 including 20 variants on NARS/FECH was associated with both AHI and percentage time SaO2 < 90%, with 12 associations replicated in independent cohorts.
“A region on chromosome 18q21 that included 20 variants on NARS/FECH was associated with both AHI and percentage time SaO2 < 90%, with 12 associations that replicated in independent cohorts.”
From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [270]
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- Authors
- Wang, H., Cade, B. E., Sofer, T., Sands, S. A., Chen, H., Browning, S. R., Stilp, A. M., Louie, T. L., Thornton, T. A., Johnson, W. C., Below, J. E., Conomos, M. P., Evans, D. S., Gharib, S. A., Guo, X., Wood, A. C., Mei, H., Yaffe, K., Loredo, J. S., Ramos, A. R., Barrett-Connor, E., Ancoli-Israel, S., Zee, P. C., Arens, R., Shah, N. A., Taylor, K. D., Tranah, G. J., Stone, K. L., Hanis, C. L., Wilson, J. G., Gottlieb, D. J., Patel, S. R., Rice, K., Post, W. S., Rotter, J. I., Sunyaev, S. R., Cai, J., Lin, X., Purcell, S. M., Laurie, C. C., Saxena, R., Redline, S., & Zhu, X.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- The University of Texas Health Science Center at Houston (US)
- University of Washington (US)
- Vanderbilt University (US)
- California Pacific Medical Center (US)
- The Lundquist Institute (US)
- Baylor College of Medicine (US)
- University of Mississippi Medical Center (US)
- University of California, San Francisco (US)
- Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, UC San Diego School of Medicine, La Jolla, CA, USA
- University of Miami (US)
- University of California San Diego (US)
- Departments of Medicine and Psychiatry, University of California, San Diego, CA, USA
- Northwestern University (US)
- Albert Einstein College of Medicine (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Mississippi (US)
- University of Pittsburgh Medical Center (US)
- Department of Biostatistics, University of Washington, Seattle, WA, USA
- Johns Hopkins University (US)
- University of North Carolina at Chapel Hill (US)
- Harvard University (US)
- Case Western Reserve University (US)
- Corresponding author
- Redline, Susan
- Zhu, Xiaofeng
- ORCID
- Wang, Heming
- Cade, Brian E
- Sofer, Tamar
- Sands, Scott A
- Chen, Han
- Browning, Sharon R
- Stilp, Adrienne M
- Thornton, Timothy A
- Johnson, W Craig
- Below, Jennifer E
- Conomos, Matthew P
- Evans, Daniel S
- Gharib, Sina A
- Guo, Xiuqing
- Wood, Alexis C
- Mei, Hao
- Yaffe, Kristine
- Ramos, Alberto R
- Barrett-Connor, Elizabeth
- Zee, Phyllis C
- Arens, Raanan
- Shah, Neomi A
- Taylor, Kent D
- Tranah, Gregory J
- Stone, Katie L
- Hanis, Craig L
- Wilson, James G
- Gottlieb, Daniel J
- Patel, Sanjay R
- Post, Wendy S
- Rotter, Jerome I
- Sunyaev, Shamil R
- Cai, Jianwen
- Lin, Xihong
- Purcell, Shaun M
- Laurie, Cathy C
- Saxena, Richa
- Redline, Susan
- Zhu, Xiaofeng
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-11-07
- Volume
- 28
- Issue
- 4
- Pages
- 675-687
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC6360325
- OpenAlex
- W2900323873
- Semantic Scholar
- fd35bd2f0f7d680e708bdc842de6f36e5e88e4f7
- Cited by
- 56
- References
- 68
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 8 · 2023: 11 · 2022: 13 · 2021: 9 · 2020: 6 · 2019: 3
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL113338, R35HL135818, R01HL098433, R01HL46380, K01HL135405)
- National Human Genome Research Institute (HG003054)
- Sleep Research Society Foundation (018-JP-18)
- American Thoracic Society
- Topics
- Health Sciences › Medicine › Physiology › Obstructive Sleep Apnea Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- obstructive sleep apnea, admixture mapping, Hispanic/Latino Americans, genetic ancestry, African ancestry, 18q21, ferrochelatase, iron metabolism, heme metabolism, apnea-hypopnea index, oxygen saturation
- MeSH terms
- Aged, Chromosome Mapping, Female, Ferrochelatase, Genotype, Hispanic or Latino, Humans, Male, Middle Aged, Polysomnography, Sleep Apnea, Obstructive, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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