A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program
Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and g...
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| Veröffentlicht in: | PLoS genetics 2022-06, Vol.18 (6), p.e1010193 |
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| creator | Raghavan, Sridharan Huang, Jie Tcheandjieu, Catherine Huffman, Jennifer E Litkowski, Elizabeth Liu, Chang Ho, Yuk-Lam A Hunter-Zinck, Haley Zhao, Hongyu Marouli, Eirini North, Kari E Lange, Ethan Lange, Leslie A Voight, Benjamin F Gaziano, J Michael Pyarajan, Saiju Hauser, Elizabeth R Tsao, Philip S Wilson, Peter W F Chang, Kyong-Mi Cho, Kelly O'Donnell, Christopher J Sun, Yan V Assimes, Themistocles L |
| description | Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.
Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.
We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study. |
| doi_str_mv | 10.1371/journal.pgen.1010193 |
| format | Article |
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Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.
We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1010193</identifier><identifier>PMID: 35653334</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Atrial Fibrillation ; Biobanks ; Biology and Life Sciences ; Body height ; Body mass index ; Cardiac arrhythmia ; Cardiovascular disease ; Cardiovascular diseases ; Coronary artery disease ; Diabetes mellitus ; Electronic medical records ; Estimates ; Ethnicity ; Fibrillation ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomes ; Health care ; Heart diseases ; Hispanic people ; Humans ; Hyperlipidemia ; Hypertension ; Hypertension - epidemiology ; Hypertension - genetics ; Medicine and Health Sciences ; Peripheral neuropathy ; Physical Sciences ; Pleiotropy ; Polymorphism, Single Nucleotide - genetics ; Population studies ; Research and Analysis Methods ; Risk factors ; Veterans</subject><ispartof>PLoS genetics, 2022-06, Vol.18 (6), p.e1010193</ispartof><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 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To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.
Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.
We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.</description><subject>Adult</subject><subject>Atrial Fibrillation</subject><subject>Biobanks</subject><subject>Biology and Life Sciences</subject><subject>Body height</subject><subject>Body mass index</subject><subject>Cardiac arrhythmia</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Coronary artery disease</subject><subject>Diabetes mellitus</subject><subject>Electronic medical records</subject><subject>Estimates</subject><subject>Ethnicity</subject><subject>Fibrillation</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Health care</subject><subject>Heart diseases</subject><subject>Hispanic 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multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program</title><author>Raghavan, Sridharan ; Huang, Jie ; Tcheandjieu, Catherine ; Huffman, Jennifer E ; Litkowski, Elizabeth ; Liu, Chang ; Ho, Yuk-Lam A ; Hunter-Zinck, Haley ; Zhao, Hongyu ; Marouli, Eirini ; North, Kari E ; Lange, Ethan ; Lange, Leslie A ; Voight, Benjamin F ; Gaziano, J Michael ; Pyarajan, Saiju ; Hauser, Elizabeth R ; Tsao, Philip S ; Wilson, Peter W F ; Chang, Kyong-Mi ; Cho, Kelly ; O'Donnell, Christopher J ; Sun, Yan V ; Assimes, Themistocles L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-1ccb86fb11734cc55873f12808c965414e60844d65138d12a5bd225e5ac2b4333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adult</topic><topic>Atrial Fibrillation</topic><topic>Biobanks</topic><topic>Biology and Life Sciences</topic><topic>Body 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Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Raghavan, Sridharan</au><au>Huang, Jie</au><au>Tcheandjieu, Catherine</au><au>Huffman, Jennifer E</au><au>Litkowski, Elizabeth</au><au>Liu, Chang</au><au>Ho, Yuk-Lam A</au><au>Hunter-Zinck, Haley</au><au>Zhao, Hongyu</au><au>Marouli, Eirini</au><au>North, Kari E</au><au>Lange, Ethan</au><au>Lange, Leslie A</au><au>Voight, Benjamin F</au><au>Gaziano, J Michael</au><au>Pyarajan, Saiju</au><au>Hauser, Elizabeth R</au><au>Tsao, Philip S</au><au>Wilson, Peter W F</au><au>Chang, Kyong-Mi</au><au>Cho, Kelly</au><au>O'Donnell, Christopher J</au><au>Sun, Yan V</au><au>Assimes, Themistocles L</au><aucorp>VA Million Veteran Program</aucorp><aucorp>the VA Million Veteran Program</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2022-06-01</date><risdate>2022</risdate><volume>18</volume><issue>6</issue><spage>e1010193</spage><pages>e1010193-</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.
Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.
We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>35653334</pmid><doi>10.1371/journal.pgen.1010193</doi><orcidid>https://orcid.org/0000-0003-1195-9607</orcidid><orcidid>https://orcid.org/0000-0003-0367-9189</orcidid><orcidid>https://orcid.org/0000-0001-5853-3668</orcidid><orcidid>https://orcid.org/0000-0001-7274-9318</orcidid><orcidid>https://orcid.org/0000-0003-3305-3830</orcidid><orcidid>https://orcid.org/0000-0002-2838-1824</orcidid><orcidid>https://orcid.org/0000-0003-1727-7076</orcidid><orcidid>https://orcid.org/0000-0002-7079-696X</orcidid><orcidid>https://orcid.org/0000-0002-9441-4698</orcidid><orcidid>https://orcid.org/0000-0002-5653-7056</orcidid><orcidid>https://orcid.org/0000-0002-2667-8624</orcidid><orcidid>https://orcid.org/0000-0001-9559-4339</orcidid><orcidid>https://orcid.org/0000-0002-9047-3762</orcidid><orcidid>https://orcid.org/0000-0001-6179-1609</orcidid><orcidid>https://orcid.org/0000-0001-6811-9364</orcidid><orcidid>https://orcid.org/0000-0003-2349-0009</orcidid><orcidid>https://orcid.org/0000-0002-8918-7224</orcidid><orcidid>https://orcid.org/0000-0003-0643-4873</orcidid><orcidid>https://orcid.org/0000-0002-9672-2491</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2022-06, Vol.18 (6), p.e1010193 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_2690721984 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | Adult Atrial Fibrillation Biobanks Biology and Life Sciences Body height Body mass index Cardiac arrhythmia Cardiovascular disease Cardiovascular diseases Coronary artery disease Diabetes mellitus Electronic medical records Estimates Ethnicity Fibrillation Genetic Predisposition to Disease Genome-Wide Association Study Genomes Health care Heart diseases Hispanic people Humans Hyperlipidemia Hypertension Hypertension - epidemiology Hypertension - genetics Medicine and Health Sciences Peripheral neuropathy Physical Sciences Pleiotropy Polymorphism, Single Nucleotide - genetics Population studies Research and Analysis Methods Risk factors Veterans |
| title | A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program |
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