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

Heming Wang, Brian E. Cade, Tamar Sofer, Scott A. Sands, Han Chen, Sharon R. Browning, Adrienne M. Stilp, Tin L. Louie, Timothy A. Thornton, W. Craig Johnson, Jennifer E. Below, Matthew P. Conomos, Daniel S. Evans, Sina A. Gharib, Xiuqing Guo, Alexis C. Wood, Hao Mei, Kristine Yaffe, Jose S. Loredo, Alberto R. RamosElizabeth Barrett-Connor, Sonia Ancoli-Israel, Phyllis C Zee, Raanan Arens, Neomi A. Shah, Kent D. Taylor, Gregory J. Tranah, Katie L. Stone, Craig L. Hanis, James G. Wilson, Daniel J. Gottlieb, Sanjay R. Patel, Ken Rice, Wendy S. Post, Jerome I. Rotter, Shamil R. Sunyaev, Jianwen Cai, Xihong Lin, Shaun M. Purcell, Cathy C. Laurie, Richa Saxena, Susan Redline*, Xiaofeng Zhu

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)675-687
Number of pages13
JournalHuman molecular genetics
Volume28
Issue number4
DOIs
StatePublished - Jan 1 2019

Fingerprint

Obstructive Sleep Apnea
Hispanic Americans
Apnea
Iron
Ferrochelatase
Oxyhemoglobins
Heme
Genetic Markers
Single Nucleotide Polymorphism
Linear Models
Cardiovascular Diseases
Joints
Genome
Mortality
Population

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Wang, H., Cade, B. E., Sofer, T., Sands, S. A., Chen, H., Browning, S. R., ... Zhu, X. (2019). Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. Human molecular genetics, 28(4), 675-687. https://doi.org/10.1093/hmg/ddy387
Wang, Heming ; Cade, Brian E. ; Sofer, Tamar ; Sands, Scott A. ; Chen, Han ; Browning, Sharon R. ; Stilp, Adrienne M. ; Louie, Tin L. ; 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 ; Loredo, Jose S. ; Ramos, Alberto R. ; Barrett-Connor, Elizabeth ; Ancoli-Israel, Sonia ; 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. ; Rice, Ken ; 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. / Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. In: Human molecular genetics. 2019 ; Vol. 28, No. 4. pp. 675-687.
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title = "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.",
author = "Heming Wang and Cade, {Brian E.} and Tamar Sofer and Sands, {Scott A.} and Han Chen and Browning, {Sharon R.} and Stilp, {Adrienne M.} and Louie, {Tin L.} and Thornton, {Timothy A.} and Johnson, {W. Craig} and Below, {Jennifer E.} and Conomos, {Matthew P.} and Evans, {Daniel S.} and Gharib, {Sina A.} and Xiuqing Guo and Wood, {Alexis C.} and Hao Mei and Kristine Yaffe and Loredo, {Jose S.} and Ramos, {Alberto R.} and Elizabeth Barrett-Connor and Sonia Ancoli-Israel and Zee, {Phyllis C} and Raanan Arens and Shah, {Neomi A.} and Taylor, {Kent D.} and Tranah, {Gregory J.} and Stone, {Katie L.} and Hanis, {Craig L.} and Wilson, {James G.} and Gottlieb, {Daniel J.} and Patel, {Sanjay R.} and Ken Rice and Post, {Wendy S.} and Rotter, {Jerome I.} and Sunyaev, {Shamil R.} and Jianwen Cai and Xihong Lin and Purcell, {Shaun M.} and Laurie, {Cathy C.} and Richa Saxena and Susan Redline and Xiaofeng Zhu",
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Wang, H, Cade, BE, Sofer, T, Sands, SA, Chen, H, Browning, SR, Stilp, AM, Louie, TL, Thornton, TA, Johnson, WC, Below, JE, Conomos, MP, Evans, DS, Gharib, SA, Guo, X, Wood, AC, Mei, H, Yaffe, K, Loredo, JS, Ramos, AR, Barrett-Connor, E, Ancoli-Israel, S, Zee, PC, Arens, R, Shah, NA, Taylor, KD, Tranah, GJ, Stone, KL, Hanis, CL, Wilson, JG, Gottlieb, DJ, Patel, SR, Rice, K, Post, WS, Rotter, JI, Sunyaev, SR, Cai, J, Lin, X, Purcell, SM, Laurie, CC, Saxena, R, Redline, S & Zhu, X 2019, 'Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans', Human molecular genetics, vol. 28, no. 4, pp. 675-687. https://doi.org/10.1093/hmg/ddy387

Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. / Wang, Heming; Cade, Brian E.; Sofer, Tamar; Sands, Scott A.; Chen, Han; Browning, Sharon R.; Stilp, Adrienne M.; Louie, Tin L.; 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; Loredo, Jose S.; Ramos, Alberto R.; Barrett-Connor, Elizabeth; Ancoli-Israel, Sonia; 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.; Rice, Ken; 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.

In: Human molecular genetics, Vol. 28, No. 4, 01.01.2019, p. 675-687.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans

AU - Wang, Heming

AU - Cade, Brian E.

AU - Sofer, Tamar

AU - Sands, Scott A.

AU - Chen, Han

AU - Browning, Sharon R.

AU - Stilp, Adrienne M.

AU - Louie, Tin L.

AU - Thornton, Timothy A.

AU - Johnson, W. Craig

AU - Below, Jennifer E.

AU - Conomos, Matthew P.

AU - Evans, Daniel S.

AU - Gharib, Sina A.

AU - Guo, Xiuqing

AU - Wood, Alexis C.

AU - Mei, Hao

AU - Yaffe, Kristine

AU - Loredo, Jose S.

AU - Ramos, Alberto R.

AU - Barrett-Connor, Elizabeth

AU - Ancoli-Israel, Sonia

AU - Zee, Phyllis C

AU - Arens, Raanan

AU - Shah, Neomi A.

AU - Taylor, Kent D.

AU - Tranah, Gregory J.

AU - Stone, Katie L.

AU - Hanis, Craig L.

AU - Wilson, James G.

AU - Gottlieb, Daniel J.

AU - Patel, Sanjay R.

AU - Rice, Ken

AU - Post, Wendy S.

AU - Rotter, Jerome I.

AU - Sunyaev, Shamil R.

AU - Cai, Jianwen

AU - Lin, Xihong

AU - Purcell, Shaun M.

AU - Laurie, Cathy C.

AU - Saxena, Richa

AU - Redline, Susan

AU - Zhu, Xiaofeng

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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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