Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea

Jingjing Liang; Heming Wang; Brian E. Cade; Nuzulul Kurniansyah; Karen Y. He; Jiwon Lee; Scott A. Sands; Jennifer A Brody; Han Chen; Daniel J. Gottlieb; Daniel S. Evans; Xiuqing Guo; Sina A. Gharib; Lauren Hale; David R. Hillman; Pamela L. Lutsey; Sutapa Mukherjee; Heather M. Ochs-Balcom; Lyle J. Palmer; Shaun Purcell; Richa Saxena; Sanjay R. Patel; Katie L. Stone; Gregory J. Tranah; Eric Boerwinkle; Xihong Lin; Yongmei Liu; Bruce M. Psaty; Ramachandran S. Vasan; Ani Manichaikul; Stephen S. Rich; Jerome I. Rotter; Tamar Sofer; Susan Redline; Xiaofeng Zhu; TOPMed Sleep Working Group

doi:10.1164/rccm.202203-0618OC

Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea

Jingjing Liang, Heming Wang, Brian E. Cade, Nuzulul Kurniansyah, Karen Y. He, Jiwon Lee, Scott A. Sands, Jennifer A Brody, Han Chen, Daniel J. Gottlieb, Daniel S. Evans, Xiuqing Guo, Sina A. Gharib, Lauren Hale, David R. Hillman, Pamela L. Lutsey, Sutapa Mukherjee, Heather M. Ochs-Balcom, Lyle J. Palmer, Shaun PurcellRicha Saxena, Sanjay R. Patel, Katie L. Stone, Gregory J. Tranah, Eric Boerwinkle, Xihong Lin, Yongmei Liu, Bruce M. Psaty, Ramachandran S. Vasan, Ani Manichaikul, Stephen S. Rich, Jerome I. Rotter, Tamar Sofer, Susan Redline, Xiaofeng Zhu, TOPMed Sleep Working Group

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea–hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 3 10 ²⁸). These noncoding variants together significantly contributed to the linkage evidence (P, 10 ²³). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

Original language	English
Pages (from-to)	1271-1280
Number of pages	10
Journal	American journal of respiratory and critical care medicine
Volume	206
Issue number	10
DOIs	https://doi.org/10.1164/rccm.202203-0618OC
Publication status	Published - 1 Nov 2022

Keywords

apnea–hypopnea index
caveolin-1
genetic association analysis
obstructive sleep apnea
rare variants

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1164/rccm.202203-0618OCLicence: In Copyright

Cite this

Liang, J., Wang, H., Cade, B. E., Kurniansyah, N., He, K. Y., Lee, J., Sands, S. A., A Brody, J., Chen, H., Gottlieb, D. J., Evans, D. S., Guo, X., Gharib, S. A., Hale, L., Hillman, D. R., Lutsey, P. L., Mukherjee, S., Ochs-Balcom, H. M., Palmer, L. J., ... TOPMed Sleep Working Group (2022). Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. American journal of respiratory and critical care medicine, 206(10), 1271-1280. https://doi.org/10.1164/rccm.202203-0618OC

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title = "Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea",

abstract = "Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea–hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 3 10 28). These noncoding variants together significantly contributed to the linkage evidence (P, 10 23). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.",

keywords = "apnea–hypopnea index, caveolin-1, genetic association analysis, obstructive sleep apnea, rare variants",

author = "Jingjing Liang and Heming Wang and Cade, {Brian E.} and Nuzulul Kurniansyah and He, {Karen Y.} and Jiwon Lee and Sands, {Scott A.} and {A Brody}, Jennifer and Han Chen and Gottlieb, {Daniel J.} and Evans, {Daniel S.} and Xiuqing Guo and Gharib, {Sina A.} and Lauren Hale and Hillman, {David R.} and Lutsey, {Pamela L.} and Sutapa Mukherjee and Ochs-Balcom, {Heather M.} and Palmer, {Lyle J.} and Shaun Purcell and Richa Saxena and Patel, {Sanjay R.} and Stone, {Katie L.} and Tranah, {Gregory J.} and Eric Boerwinkle and Xihong Lin and Yongmei Liu and Psaty, {Bruce M.} and Vasan, {Ramachandran S.} and Ani Manichaikul and Rich, {Stephen S.} and Rotter, {Jerome I.} and Tamar Sofer and Susan Redline and Xiaofeng Zhu and {TOPMed Sleep Working Group}",

year = "2022",

month = nov,

day = "1",

doi = "10.1164/rccm.202203-0618OC",

language = "English",

volume = "206",

pages = "1271--1280",

journal = "American journal of respiratory and critical care medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

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Liang, J, Wang, H, Cade, BE, Kurniansyah, N, He, KY, Lee, J, Sands, SA, A Brody, J, Chen, H, Gottlieb, DJ, Evans, DS, Guo, X, Gharib, SA, Hale, L, Hillman, DR, Lutsey, PL, Mukherjee, S, Ochs-Balcom, HM, Palmer, LJ, Purcell, S, Saxena, R, Patel, SR, Stone, KL, Tranah, GJ, Boerwinkle, E, Lin, X, Liu, Y, Psaty, BM, Vasan, RS, Manichaikul, A, Rich, SS, Rotter, JI, Sofer, T, Redline, S, Zhu, X & TOPMed Sleep Working Group 2022, 'Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea', American journal of respiratory and critical care medicine, vol. 206, no. 10, pp. 1271-1280. https://doi.org/10.1164/rccm.202203-0618OC

TY - JOUR

T1 - Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea

AU - Liang, Jingjing

AU - Wang, Heming

AU - Cade, Brian E.

AU - Kurniansyah, Nuzulul

AU - He, Karen Y.

AU - Lee, Jiwon

AU - Sands, Scott A.

AU - A Brody, Jennifer

AU - Chen, Han

AU - Gottlieb, Daniel J.

AU - Evans, Daniel S.

AU - Guo, Xiuqing

AU - Gharib, Sina A.

AU - Hale, Lauren

AU - Hillman, David R.

AU - Lutsey, Pamela L.

AU - Mukherjee, Sutapa

AU - Ochs-Balcom, Heather M.

AU - Palmer, Lyle J.

AU - Purcell, Shaun

AU - Saxena, Richa

AU - Patel, Sanjay R.

AU - Stone, Katie L.

AU - Tranah, Gregory J.

AU - Boerwinkle, Eric

AU - Lin, Xihong

AU - Liu, Yongmei

AU - Psaty, Bruce M.

AU - Vasan, Ramachandran S.

AU - Manichaikul, Ani

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Sofer, Tamar

AU - Redline, Susan

AU - Zhu, Xiaofeng

AU - TOPMed Sleep Working Group

PY - 2022/11/1

Y1 - 2022/11/1

N2 - Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea–hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 3 10 28). These noncoding variants together significantly contributed to the linkage evidence (P, 10 23). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

AB - Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea–hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 3 10 28). These noncoding variants together significantly contributed to the linkage evidence (P, 10 23). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

KW - apnea–hypopnea index

KW - caveolin-1

KW - genetic association analysis

KW - obstructive sleep apnea

KW - rare variants

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U2 - 10.1164/rccm.202203-0618OC

DO - 10.1164/rccm.202203-0618OC

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C2 - 35822943

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SN - 1073-449X

VL - 206

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