Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans

Heming Wang^{1

2

3

4}, Brian E Cade^{2

3

4}, Tamar Sofer^{2

3

5}, Scott A Sands^{2

3}, Han Chen^{6

7}, Sharon R Browning⁵, Adrienne M Stilp⁵, Tin L Louie⁵, Timothy A Thornton⁵, W Craig Johnson⁵, Jennifer E Below⁸, Matthew P Conomos⁵, Daniel S Evans⁹, Sina A Gharib¹⁰, Xiuqing Guo¹¹, Alexis C Wood¹², Hao Mei¹³, Kristine Yaffe^{14

15}, Jose S Loredo¹⁶, Alberto R Ramos¹⁷, Elizabeth Barrett-Connor¹⁸, Sonia Ancoli-Israel^{19

20}, Phyllis C Zee²¹, Raanan Arens²², Neomi A Shah²³, Kent D Taylor¹¹, Gregory J Tranah⁹, Katie L Stone⁹, Craig L Hanis⁶, James G Wilson²⁴, Daniel J Gottlieb^{2

3

25}, Sanjay R Patel²⁶, Ken Rice⁵, Wendy S Post²⁷, Jerome I Rotter¹¹, Shamil R Sunyaev^{4

28

29}, Jianwen Cai³⁰, Xihong Lin³¹, Shaun M Purcell^{2

4

32}, Cathy C Laurie⁵, Richa Saxena^{2

3

4

33}, Susan Redline^{2

3

34}, Xiaofeng Zhu¹

Affiliations

¹ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
² Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
³ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute, Cambridge, MA 02142, USA.
⁵ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁶ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷ Center for Precision Health, School of Public Health & School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁸ Vanderbilt Genetics Institute, Department of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ California Pacific Medical Center Research Institute, San Francisco, CA, USA.
¹⁰ Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA.
¹¹ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹² USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
¹³ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁴ Departments of Psychiatry and Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
¹⁶ Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, UC San Diego School of Medicine, La Jolla, CA, USA.
¹⁷ Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
¹⁸ Department of Family and Preventive Medicine, University of California, San Diego, CA, USA.
¹⁹ Departments of Medicine and Psychiatry, University of California, San Diego, CA, USA.
²⁰ Department of Veterans Affairs, San Diego Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
²¹ Department of Neurology and Sleep Medicine Center, Northwestern University, Chicago, IL, USA.
²² The Children's Hospital at Montefiore, Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
²³ Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Physiology and Biophysics, University of Mississippi, Jackson, MS, USA.
²⁵ VA Boston Healthcare System, Boston, MA, USA.
²⁶ Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
²⁷ Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
²⁸ Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
²⁹ Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
³⁰ Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
³¹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³² Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³³ Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁴ Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

PMID: 30403821
PMCID: PMC6360325
DOI: 10.1093/hmg/ddy387

Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans

Heming Wang et al. Hum Mol Genet. 2019.

. 2019 Feb 15;28(4):675-687.

doi: 10.1093/hmg/ddy387.

Authors

Affiliations

¹ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
² Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
³ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute, Cambridge, MA 02142, USA.
⁵ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁶ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷ Center for Precision Health, School of Public Health & School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁸ Vanderbilt Genetics Institute, Department of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ California Pacific Medical Center Research Institute, San Francisco, CA, USA.
¹⁰ Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA.
¹¹ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹² USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
¹³ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁴ Departments of Psychiatry and Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
¹⁶ Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, UC San Diego School of Medicine, La Jolla, CA, USA.
¹⁷ Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
¹⁸ Department of Family and Preventive Medicine, University of California, San Diego, CA, USA.
¹⁹ Departments of Medicine and Psychiatry, University of California, San Diego, CA, USA.
²⁰ Department of Veterans Affairs, San Diego Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
²¹ Department of Neurology and Sleep Medicine Center, Northwestern University, Chicago, IL, USA.
²² The Children's Hospital at Montefiore, Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
²³ Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Physiology and Biophysics, University of Mississippi, Jackson, MS, USA.
²⁵ VA Boston Healthcare System, Boston, MA, USA.
²⁶ Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
²⁷ Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
²⁸ Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
²⁹ Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
³⁰ Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
³¹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³² Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³³ Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁴ Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

PMID: 30403821
PMCID: PMC6360325
DOI: 10.1093/hmg/ddy387

Abstract

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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Figures

**Figure 1**
Associations between identified independent variants and OSA traits among background groups.

**Figure 2**
Admixture mapping results of significant ancestry and OSA traits with and without adjusting for target SNPs.

See this image and copyright information in PMC

References

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Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans

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Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans

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