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 language | English (US) |
|---|---|
| Pages (from-to) | 675-687 |
| Number of pages | 13 |
| Journal | Human molecular genetics |
| Volume | 28 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 15 2019 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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In: Human molecular genetics, Vol. 28, No. 4, 15.02.2019, p. 675-687.
Research output: Contribution to journal › Article › peer-review
}
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
N1 - Funding Information: The Framingham Heart Study is conducted and supported by NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the Framingham Sleep Heart Health Study was provided by NIH/NHLBI grant U01 HL 53941. Funding Information: The baseline examination of the Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236) and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Neurological Disorders and Stroke (NINDS) and NIH Institution Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Provision of genotyping services was supported in part by the National Center for Advancing Translational Sciences (NCATS) CTSI grant UL1TR000124 and NIDDK DRC grant DK063491. Funding Information: The Sleep Reading Center of Brigham and Women's Hospital has been supported by National Institutes of Health grants (5-R01- HL046380-15 and 5-KL2-RR024990-05). The baseline examination of the Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01- HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236) and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Neurological Disorders and Stroke (NINDS) and NIH Institution Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Provision of genotyping services was supported in part by the National Center for Advancing Translational Sciences (NCATS) CTSI grant UL1TR000124 and NIDDK DRC grant DK063491. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100 007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011 00010C, HHSN268201100011C and HHSN268201100012C). The Framingham Heart Study is conducted and supported by NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL- 64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the Framingham Sleep Heart Health Study was provided by NIH/NHLBI grant U01 HL 53941. The Jackson Heart Study (JHS) is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN2682013000 48C, HHSN268201300049C, HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Dr Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences.We thank the JHS participants and staff for their contributions to this work. The Multi Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA). Funding support for the Sleep Polysomnography dataset was provided by grant HL56984. Provision of genotyping services supported in part by NCATS CTSI grant UL1-TR-001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Osteoporotic Fractures inMen (MrOS) Study is supported by NIH funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NCATS and NIH Roadmap for Medical Research under the following grant numbers U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160 and UL1 TR000128. The NHLBI provides funding for the MrOS Sleep ancillary study 'Outcomes of Sleep Disorders in Older Men' under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838 and R01 HL070839. The NIAMS provides funding for the MrOS ancillary study 'Replication of candidate gene associations and bone strength phenotype in MrOS' under the grant number R01 AR051124. The NIAMS provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number RC2 AR058973. The Starr County Health Studies is supported in part by grants R01 DK073541, U01 DK085501, R01 AI085014 and R01 HL102830 from the National Institutes of Health, and funds from The University of Texas Health Science Center at Houston. Graeme I. Bell was supported in part by grant P30 DK020595 and a gift from the Kovler Family Foundation. The Cardiovascular Health Study (CHS) was supported by contract numbers N01-HC- 85079, N01-HC-85080, N01-HC- 85081, N01-HC-85082, N01-HC-85083, N01-HC- 85084, N01- HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC- 55222, N01-HC-75150, N01-HC-45133, N01-HC-85239 and HHSN268201200036C; grant numbers U01 HL080295 from NHLBI and R01 AG-023629 from NIA, with additional contribution from NINDS. Support for the Whole Genome Study was provided by NHLBI grant HL087652. Additional support for infrastructure was provided by HL105756 and additional genotyping among the African-American cohort was supported in part by HL085251. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by National Center for Research Resources grant UL1RR033176, now at NCATS CTSI grant UL1TR000124; in addition to NIDDK grant DK063491 to the Southern California Diabetes Endocrinology Research Center. National Institutes of Health, the National Heart, Lung, Blood Institute (R01HL113338 to S.R., R35HL135818 to S.R., R01HL098433 to S.R., R01HL46380 to S.R. and K01HL135405 to B.E.C); National Human Genome Research Institute (HG003054 to X.Z. B.E.C. K01 award is fromNHLBI); Sleep Research Society Foundation Career Development Award 018-JP-18 (to H.W.); American Thoracic Society Foundation Unrestricted Grant for Sleep (to B.E.C.). Funding Information: The Cardiovascular Health Study (CHS) was supported by contract numbers N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239 and HHSN268201200036C; grant numbers U01 HL080295 from NHLBI and R01 AG-023629 from NIA, with additional contribution from NINDS. Support for the Whole Genome Study was provided by NHLBI grant HL087652. Additional support for infrastructure was provided by HL105756 and additional genotyping among the African-American cohort was supported in part by HL085251. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by National Center for Research Resources grant UL1RR033176, now at NCATS CTSI grant UL1TR000124; in addition to NIDDK grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: National Institutes of Health, the National Heart, Lung, Blood Institute (R01HL113338 to S.R., R35HL135818 to S.R., R01HL098433 to S.R., R01HL46380 to S.R. and K01HL135405 to B.E.C); National Human Genome Research Institute (HG003054 to X.Z. B.E.C. K01 award is from NHLBI); Sleep Research Society Foundation Career Development Award 018-JP-18 (to H.W.); American Thoracic Society Foundation Unrestricted Grant for Sleep (to B.E.C.). Funding Information: The Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NCATS and NIH Roadmap for Medical Research under the following grant numbers U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160 and UL1 TR000128. The NHLBI provides funding for the MrOS Sleep ancillary study ‘Outcomes of Sleep Disorders in Older Men’ under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838 and R01 HL070839. The NIAMS provides funding for the MrOS ancillary study ‘Replication of candidate gene associations and bone strength phenotype in MrOS’ under the grant number R01 AR051124. The NIAMS provides funding for the MrOS ancillary study ‘GWAS in MrOS and SOF’ under the grant number RC2 AR058973. The Starr County Health Studies is supported in part by grants R01 DK073541, U01 DK085501, R01 AI085014 and R01 HL102830 from the National Institutes of Health, and funds from The University of Texas Health Science Center at Houston. Graeme I. Bell was supported in part by grant P30 DK020595 and a gift from the Kovler Family Foundation. Funding Information: The Jackson Heart Study (JHS) is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN2682013000 48C, HHSN268201300049C, HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Dr Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. We thank the JHS participants and staff for their contributions to this work. Funding Information: The Multi Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA). Funding support for the Sleep Polysomnography dataset was provided by grant HL56984. Provision of genotyping services supported in part by NCATS CTSI grant UL1-TR-001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: The Sleep Reading Center of Brigham and Women’s Hospital has been supported by National Institutes of Health grants (5-R01-HL046380-15 and 5-KL2-RR024990-05). Publisher Copyright: © The Author(s) 2018.
PY - 2019/2/15
Y1 - 2019/2/15
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.
UR - http://www.scopus.com/inward/record.url?scp=85060970546&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060970546&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddy387
DO - 10.1093/hmg/ddy387
M3 - Article
C2 - 30403821
AN - SCOPUS:85060970546
SN - 0964-6906
VL - 28
SP - 675
EP - 687
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 4
ER -