The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses

Kurt R Taylor; Nancy S Mcbride; Jian Zhao; Sam Oddie; Rafaq Azad; John Wright; Ole Andreassen; Isobel Stewart; Claudia Langenberg; Maria C Magnus; Maria C Borges; Massimo Caputo; Debbie A Lawlor

doi:10.3390/jcdd9080237

The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses

Kurt R Taylor, Nancy S Mcbride, Jian Zhao, Sam Oddie, Rafaq Azad, John Wright, Ole Andreassen, Isobel Stewart, Claudia Langenberg, Maria C Magnus, Maria C Borges, Massimo Caputo, Debbie A Lawlor

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Abstract

Background: It is plausible that maternal pregnancy metabolism influences the risk of offspring congenital heart disease (CHD). We sought to explore this through a systematic approach using different methods and data. Methods: We undertook multivariable logistic regression of the odds of CHD for 923 mass spectrometry (MS)-derived metabolites in a sub-sample of a UK birth cohort (Born in Bradford (BiB); N = 2605, 46 CHD cases). We considered metabolites reaching a p-value threshold <0.05 to be suggestively associated with CHD. We sought validation of our findings, by repeating the multivariable regression analysis within the BiB cohort for any suggestively associated metabolite that was measured by nuclear magnetic resonance (NMR) or clinical chemistry (N = 7296, 87 CHD cases), and by using genetic risk scores (GRS: weighted genetic risk scores of single nucleotide polymorphisms (SNPs) that were associated with any suggestive metabolite) in Mendelian randomization (MR) analyses. The MR analyses were performed in BiB and two additional European birth cohorts (N = 38,662, 319 CHD cases). Results: In the main multivariable analyses, we identified 44 metabolites suggestively associated with CHD, including those from the following super pathways: amino acids, lipids, co-factors and vitamins, xenobiotics, nucleotides, energy, and several unknown molecules. Of these 44, isoleucine and leucine were available in the larger BiB cohort (NMR), and for these the results were validated. The MR analyses were possible for 27/44 metabolites and for 11 there was consistency with the multivariable regression results. Conclusions: In summary, we have used complimentary data sources and statistical techniques to construct layers of evidence. We found that pregnancy amino acid metabolism, androgenic steroid lipids, and levels of succinylcarnitine could be important contributing factors for CHD.

Original language	English
Article number	237
Number of pages	19
Journal	Journal of Cardiovascular Development and Disease
Volume	9
Issue number	8
DOIs	https://doi.org/10.3390/jcdd9080237
Publication status	Published - 27 Jul 2022

Bibliographical note

Funding Information:
This study was funded by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/(grant agreement No 669545), US National Institute of Health (R01 DK10324) British Heart Foundation (CS/16/4/32482 and AA/18/7/34219) Taylor is supported by a British Heart Foundation Doctoral Training Program (FS/17/60/33474). Taylor, McBride, Borges, and Lawlor work in a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). Lawlor’s contribution is also supported by a British Heart Foundation Chair in Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003) and a NIHR Senior Investigator (NF-0616-10102). Caputo is supported by the British Heart Foundation Chair in Congenital Heart Disease (CH/1/32804). Magnus has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 947684). This research was also supported by the Research Council of Norway through its Centres of Excellence funding scheme (Project No. 262700). M.C. Borges is supported by a Vice Chancellor’s fellowship from the University of Bristol. The BiB study has received core support from Wellcome Trust (223601/Z/21/Z and WT101597MA), a joint grant from the UK Medical Research Council and UK Economic and Social Science Research Council (MR/N024397/1), the British Heart Foundation (CS/16/4/32482), and the NIHR Applied Research Collaboration Yorkshire and Humber (NIHR200166) and Clinical Research Network. Core funding for ALSPAC is provided by the UK Medical Research Council and Wellcome (217065/Z/19/) and the University of Bristol. Many grants have supported different data collections, including for some of the data used in this publication, and a comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf) GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 MC-UU_12015/1 and MC_UU_00006/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372.

Funding Information:
The BiB (Born in Bradford) study is only possible because of the enthusiasm and commitment of the children and parents. We are grateful to all the participants, practitioners, and researchers who have made the BiB study happen. We are extremely grateful to all the families who took part in The Avon Longitudinal Study of Parents and Children (ALSPAC) study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ( [email protected] ). This study does not necessarily reflect the position or policy of the Norwegian Research Council. We are grateful to all the participants who have been part of the EPIC-Norfolk metabolomics project and to the many members of the study teams at the University of Cambridge who have enabled this research.

Publisher Copyright:
© 2022 by the authors.

Keywords

metabolites
congenital heart disease
Born in Bradford
ALSPAC
MoBa

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Taylor, K. R., Mcbride, N. S., Zhao, J., Oddie, S., Azad, R., Wright, J., Andreassen, O., Stewart, I., Langenberg, C., Magnus, M. C., Borges, M. C., Caputo, M., & Lawlor, D. A. (2022). The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses. Journal of Cardiovascular Development and Disease , 9(8), Article 237. https://doi.org/10.3390/jcdd9080237

@article{5da7fb22ce7f4dbeae4360effffc1289,

title = "The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses",

abstract = "Background: It is plausible that maternal pregnancy metabolism influences the risk of offspring congenital heart disease (CHD). We sought to explore this through a systematic approach using different methods and data. Methods: We undertook multivariable logistic regression of the odds of CHD for 923 mass spectrometry (MS)-derived metabolites in a sub-sample of a UK birth cohort (Born in Bradford (BiB); N = 2605, 46 CHD cases). We considered metabolites reaching a p-value threshold <0.05 to be suggestively associated with CHD. We sought validation of our findings, by repeating the multivariable regression analysis within the BiB cohort for any suggestively associated metabolite that was measured by nuclear magnetic resonance (NMR) or clinical chemistry (N = 7296, 87 CHD cases), and by using genetic risk scores (GRS: weighted genetic risk scores of single nucleotide polymorphisms (SNPs) that were associated with any suggestive metabolite) in Mendelian randomization (MR) analyses. The MR analyses were performed in BiB and two additional European birth cohorts (N = 38,662, 319 CHD cases). Results: In the main multivariable analyses, we identified 44 metabolites suggestively associated with CHD, including those from the following super pathways: amino acids, lipids, co-factors and vitamins, xenobiotics, nucleotides, energy, and several unknown molecules. Of these 44, isoleucine and leucine were available in the larger BiB cohort (NMR), and for these the results were validated. The MR analyses were possible for 27/44 metabolites and for 11 there was consistency with the multivariable regression results. Conclusions: In summary, we have used complimentary data sources and statistical techniques to construct layers of evidence. We found that pregnancy amino acid metabolism, androgenic steroid lipids, and levels of succinylcarnitine could be important contributing factors for CHD.",

keywords = "metabolites, congenital heart disease, Born in Bradford, ALSPAC, MoBa",

author = "Taylor, \{Kurt R\} and Mcbride, \{Nancy S\} and Jian Zhao and Sam Oddie and Rafaq Azad and John Wright and Ole Andreassen and Isobel Stewart and Claudia Langenberg and Magnus, \{Maria C\} and Borges, \{Maria C\} and Massimo Caputo and Lawlor, \{Debbie A\}",

note = "Funding Information: This study was funded by the European Research Council under the European Union{\textquoteright}s Seventh Framework Programme (FP/2007–2013)/(grant agreement No 669545), US National Institute of Health (R01 DK10324) British Heart Foundation (CS/16/4/32482 and AA/18/7/34219) Taylor is supported by a British Heart Foundation Doctoral Training Program (FS/17/60/33474). Taylor, McBride, Borges, and Lawlor work in a unit that is supported by the University of Bristol and UK Medical Research Council (MC\_UU\_00011/6). Lawlor{\textquoteright}s contribution is also supported by a British Heart Foundation Chair in Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003) and a NIHR Senior Investigator (NF-0616-10102). Caputo is supported by the British Heart Foundation Chair in Congenital Heart Disease (CH/1/32804). Magnus has received funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement No 947684). This research was also supported by the Research Council of Norway through its Centres of Excellence funding scheme (Project No. 262700). M.C. Borges is supported by a Vice Chancellor{\textquoteright}s fellowship from the University of Bristol. The BiB study has received core support from Wellcome Trust (223601/Z/21/Z and WT101597MA), a joint grant from the UK Medical Research Council and UK Economic and Social Science Research Council (MR/N024397/1), the British Heart Foundation (CS/16/4/32482), and the NIHR Applied Research Collaboration Yorkshire and Humber (NIHR200166) and Clinical Research Network. Core funding for ALSPAC is provided by the UK Medical Research Council and Wellcome (217065/Z/19/) and the University of Bristol. Many grants have supported different data collections, including for some of the data used in this publication, and a comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf) GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 MC-UU\_12015/1 and MC\_UU\_00006/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC\_PC\_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. Funding Information: The BiB (Born in Bradford) study is only possible because of the enthusiasm and commitment of the children and parents. We are grateful to all the participants, practitioners, and researchers who have made the BiB study happen. We are extremely grateful to all the families who took part in The Avon Longitudinal Study of Parents and Children (ALSPAC) study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ( [email protected] ). This study does not necessarily reflect the position or policy of the Norwegian Research Council. We are grateful to all the participants who have been part of the EPIC-Norfolk metabolomics project and to the many members of the study teams at the University of Cambridge who have enabled this research. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = jul,

day = "27",

doi = "10.3390/jcdd9080237",

language = "English",

volume = "9",

journal = "Journal of Cardiovascular Development and Disease ",

issn = "2308-3425",

publisher = "MDPI AG",

number = "8",

}

Taylor, KR, Mcbride, NS, Zhao, J, Oddie, S, Azad, R, Wright, J, Andreassen, O, Stewart, I, Langenberg, C, Magnus, MC, Borges, MC , Caputo, M & Lawlor, DA 2022, 'The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses', Journal of Cardiovascular Development and Disease , vol. 9, no. 8, 237. https://doi.org/10.3390/jcdd9080237

The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses. / Taylor, Kurt R; Mcbride, Nancy S; Zhao, Jian et al.
In: Journal of Cardiovascular Development and Disease , Vol. 9, No. 8, 237, 27.07.2022.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease

T2 - Results from Multivariable and Mendelian Randomization Analyses

AU - Taylor, Kurt R

AU - Mcbride, Nancy S

AU - Zhao, Jian

AU - Oddie, Sam

AU - Azad, Rafaq

AU - Wright, John

AU - Andreassen, Ole

AU - Stewart, Isobel

AU - Langenberg, Claudia

AU - Magnus, Maria C

AU - Borges, Maria C

AU - Caputo, Massimo

AU - Lawlor, Debbie A

N1 - Funding Information: This study was funded by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/(grant agreement No 669545), US National Institute of Health (R01 DK10324) British Heart Foundation (CS/16/4/32482 and AA/18/7/34219) Taylor is supported by a British Heart Foundation Doctoral Training Program (FS/17/60/33474). Taylor, McBride, Borges, and Lawlor work in a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). Lawlor’s contribution is also supported by a British Heart Foundation Chair in Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003) and a NIHR Senior Investigator (NF-0616-10102). Caputo is supported by the British Heart Foundation Chair in Congenital Heart Disease (CH/1/32804). Magnus has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 947684). This research was also supported by the Research Council of Norway through its Centres of Excellence funding scheme (Project No. 262700). M.C. Borges is supported by a Vice Chancellor’s fellowship from the University of Bristol. The BiB study has received core support from Wellcome Trust (223601/Z/21/Z and WT101597MA), a joint grant from the UK Medical Research Council and UK Economic and Social Science Research Council (MR/N024397/1), the British Heart Foundation (CS/16/4/32482), and the NIHR Applied Research Collaboration Yorkshire and Humber (NIHR200166) and Clinical Research Network. Core funding for ALSPAC is provided by the UK Medical Research Council and Wellcome (217065/Z/19/) and the University of Bristol. Many grants have supported different data collections, including for some of the data used in this publication, and a comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf) GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 MC-UU_12015/1 and MC_UU_00006/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. Funding Information: The BiB (Born in Bradford) study is only possible because of the enthusiasm and commitment of the children and parents. We are grateful to all the participants, practitioners, and researchers who have made the BiB study happen. We are extremely grateful to all the families who took part in The Avon Longitudinal Study of Parents and Children (ALSPAC) study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ( [email protected] ). This study does not necessarily reflect the position or policy of the Norwegian Research Council. We are grateful to all the participants who have been part of the EPIC-Norfolk metabolomics project and to the many members of the study teams at the University of Cambridge who have enabled this research. Publisher Copyright: © 2022 by the authors.

PY - 2022/7/27

Y1 - 2022/7/27

N2 - Background: It is plausible that maternal pregnancy metabolism influences the risk of offspring congenital heart disease (CHD). We sought to explore this through a systematic approach using different methods and data. Methods: We undertook multivariable logistic regression of the odds of CHD for 923 mass spectrometry (MS)-derived metabolites in a sub-sample of a UK birth cohort (Born in Bradford (BiB); N = 2605, 46 CHD cases). We considered metabolites reaching a p-value threshold <0.05 to be suggestively associated with CHD. We sought validation of our findings, by repeating the multivariable regression analysis within the BiB cohort for any suggestively associated metabolite that was measured by nuclear magnetic resonance (NMR) or clinical chemistry (N = 7296, 87 CHD cases), and by using genetic risk scores (GRS: weighted genetic risk scores of single nucleotide polymorphisms (SNPs) that were associated with any suggestive metabolite) in Mendelian randomization (MR) analyses. The MR analyses were performed in BiB and two additional European birth cohorts (N = 38,662, 319 CHD cases). Results: In the main multivariable analyses, we identified 44 metabolites suggestively associated with CHD, including those from the following super pathways: amino acids, lipids, co-factors and vitamins, xenobiotics, nucleotides, energy, and several unknown molecules. Of these 44, isoleucine and leucine were available in the larger BiB cohort (NMR), and for these the results were validated. The MR analyses were possible for 27/44 metabolites and for 11 there was consistency with the multivariable regression results. Conclusions: In summary, we have used complimentary data sources and statistical techniques to construct layers of evidence. We found that pregnancy amino acid metabolism, androgenic steroid lipids, and levels of succinylcarnitine could be important contributing factors for CHD.

AB - Background: It is plausible that maternal pregnancy metabolism influences the risk of offspring congenital heart disease (CHD). We sought to explore this through a systematic approach using different methods and data. Methods: We undertook multivariable logistic regression of the odds of CHD for 923 mass spectrometry (MS)-derived metabolites in a sub-sample of a UK birth cohort (Born in Bradford (BiB); N = 2605, 46 CHD cases). We considered metabolites reaching a p-value threshold <0.05 to be suggestively associated with CHD. We sought validation of our findings, by repeating the multivariable regression analysis within the BiB cohort for any suggestively associated metabolite that was measured by nuclear magnetic resonance (NMR) or clinical chemistry (N = 7296, 87 CHD cases), and by using genetic risk scores (GRS: weighted genetic risk scores of single nucleotide polymorphisms (SNPs) that were associated with any suggestive metabolite) in Mendelian randomization (MR) analyses. The MR analyses were performed in BiB and two additional European birth cohorts (N = 38,662, 319 CHD cases). Results: In the main multivariable analyses, we identified 44 metabolites suggestively associated with CHD, including those from the following super pathways: amino acids, lipids, co-factors and vitamins, xenobiotics, nucleotides, energy, and several unknown molecules. Of these 44, isoleucine and leucine were available in the larger BiB cohort (NMR), and for these the results were validated. The MR analyses were possible for 27/44 metabolites and for 11 there was consistency with the multivariable regression results. Conclusions: In summary, we have used complimentary data sources and statistical techniques to construct layers of evidence. We found that pregnancy amino acid metabolism, androgenic steroid lipids, and levels of succinylcarnitine could be important contributing factors for CHD.

KW - metabolites

KW - congenital heart disease

KW - Born in Bradford

KW - ALSPAC

KW - MoBa

U2 - 10.3390/jcdd9080237

DO - 10.3390/jcdd9080237

M3 - Article (Academic Journal)

C2 - 36005401

SN - 2308-3425

VL - 9

JO - Journal of Cardiovascular Development and Disease

JF - Journal of Cardiovascular Development and Disease

IS - 8

M1 - 237

ER -

The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses

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