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

Authors: WANG, HEMING - Case Western Reserve University (CWRU); CADE, BRIAN - Brigham & Women'S Hospital; SOFER, TAMAR - Brigham & Women'S Hospital; SANDS, SCOTT - Brigham & Women'S Hospital; CHEN, HAN - University Of Texas Health Science Center; BROWNING, SHARON - University Of Washington; STILP, ADRIENNE - University Of Washington; LOUIE, TIN - University Of Washington; THORNTON, TIMOTHY - University Of Washington; JOHNSON, W - University Of Washington; BELOW, JENNIFER - Vanderbilt University Medical Center; CONOMOS, MATTHEW - University Of Washington; EVANS, DANIEL - California Pacific Medical Center; GHARIB, SINA - University Of Washington; GUO, XIUQING - Harbor-Ucla Medical Center; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); MEI, HAO - University Of Mississippi Medical Center; YAFFE, KRISTINE - University Of California; LOREDO, JOSE - University Of California; RAMOS, ALBERTO - University Of Miami; BARRETT-CONNOR, ELIZABETH - University Of California; ANCOLI-ISRAEL, SONIA - University Of California; ZEE, PHYLLIS - Northwestern University; ARENS, RAANAN - Albert Einstein College Of Medicine; SHAH, NEOMI - The Icahn School Of Medicine At Mount Sinai; TAYLOR, KENT - Harbor-Ucla Medical Center; TRANAH, GREGORY - California Pacific Medical Center; STONE, KATIE - California Pacific Medical Center; HANIS, CRAIG - University Of Texas Health Science Center; WILSON, JAMES - University Of Mississippi; GOTTLIEB, DANIEL - Brigham & Women'S Hospital; PATEL, SANJAY - Brigham & Women'S Hospital; RICE, KEN - University Of Washington; POST, WENDY - Johns Hopkins University; ROTTER, JEROME - Harbor-Ucla Medical Center; SUNYAEV, SHAMIL - Broad Institute Of Mit/harvard; CAI, JIANWEN - University Of North Carolina; LIN, XIHONG - Harvard School Of Public Health; PURCELL, SHAUN - Brigham & Women'S Hospital; LAURIE, CATHY - University Of Washington; SAXENA, RICHA - Brigham & Women'S Hospital; REDLINE, SUSAN - Brigham & Women'S Hospital; ZHU, XIAOFENG - Case Western Reserve University (CWRU)

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/2018
Publication Date: 11/7/2018
Citation: 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. 2018. Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddy387.
DOI: https://doi.org/10.1093/hmg/ddy387

Interpretive Summary: Obstructive Sleep Apnea (OSA) is a common disorder whereby upper airway obstruction during sleep results in abnormally low concentration of oxygen in the blood. OSA affects more than 10% of adults and increases risk of adverse health outcomes, including hypertension and cardiovascular disease as well as increased mortality. Additionally, OSA is more common in those with obesity, and in Hispanic/Latino Americans, who are a rapidly growing group in the United States. Often self-reports of sleep quality are used in studies designed to understand what causes OSA, but these are prone to error and so a lack of accuracy. There is a lack of studies examining the causes of objectively measured OSA. OSA is heritable, but we know very little about which genes underlie OSA. Previous studies into the genetics of OSA have been limited by the modest number of available datasets, which prohibited independent replication and validation of any significant associations between genetic variation and OSA measures. Our study showed that African ancestry was associated with a lower apnea hypopnea index and shorter respiratory disturbances, and further, identified three novel regions in genes related iron-metabolism which associated with OSA, which were different by ancestry. These findings are important because they suggest (1) that individuals with African ancestry should be informed about, and monitored for, the development of OSA in the presence of other OSA risk factors; and (2) further examination of the role of iron/heme pathways (a topic of growing interest due to associations with diabetes, and obesity - both risk factors for OSA) as a potential mechanisms related to OSA is warranted.

Technical 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 oxyhemoglobin saturation 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<5.7x10-5), 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<8x10-6). 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.