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Research Project: Childhood Obesity Prevention

Location: Children's Nutrition Research Center

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

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

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.