Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size

Vineet Agrawal; Ali Manouchehri; Nataraja S. Vaitinadin; Mingjian Shi; Minoo Bagheri; Deepak K. Gupta; Iftikhar J. Kullo; Yuan Luo; Elizabeth M. Mcnally; Megan J. Puckelwartz; Jane F. Ferguson; Quinn S. Wells; Jonathan D. Mosley

doi:10.1161/CIRCHEARTFAILURE.123.010557

Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size

Vineet Agrawal, Ali Manouchehri, Nataraja S. Vaitinadin, Mingjian Shi, Minoo Bagheri, Deepak K. Gupta, Iftikhar J. Kullo, Yuan Luo, Elizabeth M. Mcnally, Megan J. Puckelwartz, Jane F. Ferguson, Quinn S. Wells, Jonathan D. Mosley^*

^*Corresponding author for this work

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

1 Scopus citations

Abstract

BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code-based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code-based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.

Original language	English (US)
Pages (from-to)	E010557
Journal	Circulation: Heart Failure
Volume	17
Issue number	1
DOIs	https://doi.org/10.1161/CIRCHEARTFAILURE.123.010557
State	Published - Jan 1 2024

Funding

The authors acknowledge the expert technical support of the VANTAGE (Vanderbilt Technologies for Advanced Genomics) and VANGARD (Vanderbilt Technologies for Advanced Genomics Analysis and Research Design) core facilities, supported in part by the Vanderbilt-Ingram Cancer Center and the Vanderbilt Vision Center. Data on coronary artery disease/myocardial infarction have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG . This work was funded by National Institutes of Health (NIH) R01 HL142856 (Dr Ferguson and Dr Mosley); R01 GM130791 (Dr Mosley); K08 HL153956, American Heart Association Career Development Award 35310194, and IK2BX005828 (Dr Agrawal); NIH T32-HL007411 (Dr Manouchehri); NIH T32 HG008341 (Dr Bagheri); NIH K24 HL137010 (Dr Kullo); American Heart Association Strategic Focused Research Network (Dr McNally and Dr Puckelwartz); and NIH R01HL128075 (Dr McNally and Dr Puckelwartz). The BioVU resource of Vanderbilt University Medical Center is supported by numerous sources: institutional funding, private agencies, and federal grants, including the NIH-funded Shared Instrumentation Grant S10RR025141 and Clinical and Translational Science Award grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711; additional funding sources are listed at https://victr.vanderbilt.edu/pub/biovu/ . This Electronic Medical Records and Genomics Network (phase III) was initiated and funded by the National Human Genomics Research Institute through the following grants: U01HG8657 (Group Health Cooperative/University of Washington), U01HG8685 (Brigham and Women’s Hospital), U01HG8672 (Vanderbilt University Medical Center), U01HG8666 (Cincinnati Children’s Hospital Medical Center), U01HG6379 (Mayo Clinic), U01HG8679 (Geisinger Clinic), U01HG8680 (Columbia University Health Sciences), U01HG8684 (Children’s Hospital of Philadelphia), U01HG8673 (Northwestern University), U01HG8701 (Vanderbilt University Medical Center serving as the coordinating center), U01HG8676 (Partners Healthcare/Broad Institute), U01HG8664 (Baylor College of Medicine), U01HG006385 (Vanderbilt University Medical Center serving as the coordinating center), U01HG004438 (Center for Inherited Diseases Research serving as genotyping center), and U01HG004424 (the Broad Institute serving as genotyping center). This work was funded by National Institutes of Health R01 HL142856 (Dr Ferguson and Dr Mosley); R01 GM130791 (Dr Mosley); K08 HL153956, American Heart Association Career Development Award 35310194, and IK2BX005828 (Dr Agrawal); NIH T32-HL007411 (Dr Manouchehri); NIH T32 HG008341 (Dr Bagheri); NIH K24 HL137010 (Dr Kullo); American Heart Association Strategic Focused Research Network (Dr McNally and Dr Puckelwartz); and NIH R01HL128075 (Dr McNally and Dr Puckelwartz). The BioVU resource of Vanderbilt University Medical Center is supported by numerous sources: institutional funding, private agencies, and federal grants, including the NIH-funded Shared Instrumentation Grant S10RR025141 and Clinical and Translational Science Award grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711; additional funding sources are listed at https://victr.vanderbilt.edu/pub/biovu/. This Electronic Medical Records and Genomics Network (phase III) was initiated and funded by the National Human Genomics Research Institute through the following grants: U01HG8657 (Group Health Cooperative/University of Washington), U01HG8685 (Brigham and Women's Hospital), U01HG8672 (Vanderbilt University Medical Center), U01HG8666 (Cincinnati Children's Hospital Medical Center), U01HG6379 (Mayo Clinic), U01HG8679 (Geisinger Clinic), U01HG8680 (Columbia University Health Sciences), U01HG8684 (Children's Hospital of Philadelphia), U01HG8673 (Northwestern University), U01HG8701 (Vanderbilt University Medical Center serving as the coordinating center), U01HG8676 (Partners Healthcare/Broad Institute), U01HG8664 (Baylor College of Medicine), U01HG006385 (Vanderbilt University Medical Center serving as the coordinating center), U01HG004438 (Center for Inherited Diseases Research serving as genotyping center), and U01HG004424 (the Broad Institute serving as genotyping center).

Keywords

Mendelian randomization analysis
atrial fibrillation
body mass index
coronary artery disease
genotype

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

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

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10.1161/CIRCHEARTFAILURE.123.010557

Cite this

Agrawal, V., Manouchehri, A., Vaitinadin, N. S., Shi, M., Bagheri, M., Gupta, D. K., Kullo, I. J., Luo, Y., Mcnally, E. M., Puckelwartz, M. J., Ferguson, J. F., Wells, Q. S., & Mosley, J. D. (2024). Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size. Circulation: Heart Failure, 17(1), E010557. https://doi.org/10.1161/CIRCHEARTFAILURE.123.010557

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title = "Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size",

abstract = "BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code-based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code-based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.",

keywords = "Mendelian randomization analysis, atrial fibrillation, body mass index, coronary artery disease, genotype",

author = "Vineet Agrawal and Ali Manouchehri and Vaitinadin, {Nataraja S.} and Mingjian Shi and Minoo Bagheri and Gupta, {Deepak K.} and Kullo, {Iftikhar J.} and Yuan Luo and Mcnally, {Elizabeth M.} and Puckelwartz, {Megan J.} and Ferguson, {Jane F.} and Wells, {Quinn S.} and Mosley, {Jonathan D.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Heart Association, Inc.",

year = "2024",

month = jan,

day = "1",

doi = "10.1161/CIRCHEARTFAILURE.123.010557",

language = "English (US)",

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pages = "E010557",

journal = "Circulation: Heart Failure",

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Agrawal, V, Manouchehri, A, Vaitinadin, NS, Shi, M, Bagheri, M, Gupta, DK, Kullo, IJ, Luo, Y , Mcnally, EM , Puckelwartz, MJ, Ferguson, JF, Wells, QS & Mosley, JD 2024, 'Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size', Circulation: Heart Failure, vol. 17, no. 1, pp. E010557. https://doi.org/10.1161/CIRCHEARTFAILURE.123.010557

TY - JOUR

T1 - Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size

AU - Agrawal, Vineet

AU - Manouchehri, Ali

AU - Vaitinadin, Nataraja S.

AU - Shi, Mingjian

AU - Bagheri, Minoo

AU - Gupta, Deepak K.

AU - Kullo, Iftikhar J.

AU - Luo, Yuan

AU - Mcnally, Elizabeth M.

AU - Puckelwartz, Megan J.

AU - Ferguson, Jane F.

AU - Wells, Quinn S.

AU - Mosley, Jonathan D.

PY - 2024/1/1

Y1 - 2024/1/1

N2 - BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code-based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code-based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.

AB - BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code-based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code-based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.

KW - Mendelian randomization analysis

KW - atrial fibrillation

KW - body mass index

KW - coronary artery disease

KW - genotype

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Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size

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