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

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.

SUBMITTER: Wang H

PROVIDER: S-EPMC6360325 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Wang Heming H Cade Brian E BE Sofer Tamar T Sands Scott A SA Chen Han H Browning Sharon R SR Stilp Adrienne M AM Louie Tin L TL Thornton Timothy A TA Johnson W Craig WC Below Jennifer E JE Conomos Matthew P MP Evans Daniel S DS Gharib Sina A SA Guo Xiuqing X Wood Alexis C AC Mei Hao H Yaffe Kristine K Loredo Jose S JS Ramos Alberto R AR Barrett-Connor Elizabeth E Ancoli-Israel Sonia S Zee Phyllis C PC Arens Raanan R Shah Neomi A NA Taylor Kent D KD Tranah Gregory J GJ Stone Katie L KL Hanis Craig L CL Wilson James G JG Gottlieb Daniel J DJ Patel Sanjay R SR Rice Ken K Post Wendy S WS Rotter Jerome I JI Sunyaev Shamil R SR Cai Jianwen J Lin Xihong X Purcell Shaun M SM Laurie Cathy C CC Saxena Richa R Redline Susan S Zhu Xiaofeng X

Human molecular genetics 20190201 4

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 ...[more]

PMID: 30403821

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Project description:Systemic Lupus Erythematosus (SLE) disproportionately affects minorities, such as Hispanic Americans (HA). Prevalence of SLE is 3-5 times higher in HA than in European-derived populations and have more active disease at the time of diagnosis, with more serious organ system involvement. HA is an admixed population, it is possible that there is an effect of admixture on the relative risk of the disease. This admixture can create substantial increase of linkage disequilibrium (LD) in both magnitude and range, which can provide a unique opportunity for admixture mapping. The main objectives of this study are to (a) estimate hidden population structure in HA individuals; (b) estimate individual ancestry proportions and its impact on SLE risk; (c) assess impact of admixture on ITGAM association, a recently identified SLE susceptibility gene; and (d) estimate power of admixture mapping in HA. Our dataset contained 1125 individuals, of whom 884 (657 SLE cases and 227 controls) were self-classified as HA. Using 107 unlinked ancestry informative markers (AIMs), we estimated hidden population structure and individual ancestry in HA. Out of 5671 possible pairwise LD, 54% were statistically significant, indicating recent population admixture. The best-fitted model for HA was a four-population model with average ancestry of European (48%), American-Indian (AI) (40%), African (8%) and a fourth population (4%) with unknown ancestry. We also identified significant higher risk associated with AI ancestry (odds ratio (OR)=4.84, P=0.0001, 95% CI (confidence interval)=2.14-10.95) on overall SLE. We showed that ITGAM is associated as a risk factor for SLE (OR=2.06, P=8.74 x 10(-5), 95% CI=1.44-2.97). This association is not affected by population substructure or admixture. We have shown that HA have great potential and are an appropriate population for admixture mapping. As expected, the case-only design is more powerful than case-control design, for any given admixture proportion or ancestry risk ratio.

Dataset Information

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

Publications

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

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