Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, As...
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| Veröffentlicht in: | Cell genomics 2022-01, Vol.2 (1), p.100084 |
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| creator | Taub, Margaret A Conomos, Matthew P Keener, Rebecca Iyer, Kruthika R Weinstock, Joshua S Yanek, Lisa R Lane, John Miller-Fleming, Tyne W Brody, Jennifer A Raffield, Laura M McHugh, Caitlin P Jain, Deepti Gogarten, Stephanie M Laurie, Cecelia A Keramati, Ali Arvanitis, Marios Smith, Albert V Heavner, Benjamin Barwick, Lucas Becker, Lewis C Bis, Joshua C Blangero, John Bleecker, Eugene R Burchard, Esteban G Celedón, Juan C Chang, Yen Pei C Custer, Brian Darbar, Dawood de Las Fuentes, Lisa DeMeo, Dawn L Freedman, Barry I Garrett, Melanie E Gladwin, Mark T Heckbert, Susan R Hidalgo, Bertha A Irvin, Marguerite R Islam, Talat Johnson, W Craig Kaab, Stefan Launer, Lenore Lee, Jiwon Liu, Simin Moscati, Arden North, Kari E Peyser, Patricia A Rafaels, Nicholas Seidman, Christine Weeks, Daniel E Wen, Fayun Wheeler, Marsha M Williams, L Keoki Yang, Ivana V Zhao, Wei Aslibekyan, Stella Auer, Paul L Bowden, Donald W Cade, Brian E Chen, Zhanghua Cho, Michael H Cupples, L Adrienne Curran, Joanne E Daya, Michelle Deka, Ranjan Eng, Celeste Fingerlin, Tasha E Guo, Xiuqing Hou, Lifang Hwang, Shih-Jen Johnsen, Jill M Kenny, Eimear E Levin, Albert M Liu, Chunyu Minster, Ryan L Naseri, Take Nouraie, Mehdi Reupena, Muagututi'a Sefuiva Sabino, Ester C Smith, Jennifer A Smith, Nicholas L Lasky-Su, Jessica Taylor, 6th, James G Telen, Marilyn J Tiwari, Hemant K Tracy, Russell P White, Marquitta J Zhang, Yingze Wiggins, Kerri L Weiss, Scott T Vasan, Ramachandran S Taylor, Kent D Sinner, Moritz F Silverman, Edwin K Shoemaker, M Benjamin Sheu, Wayne H-H Sciurba, Frank Schwartz, David A Rotter, Jerome I Roden, Daniel Redline, Susan Raby, Benjamin A |
| description | Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10
) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes. |
| doi_str_mv | 10.1016/j.xgen.2021.100084 |
| format | Article |
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Martinez on behalf of the NHLBI CARE Network ; TOPMed Structural Variation Working Group ; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</creatorcontrib><description>Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10
) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.</description><identifier>EISSN: 2666-979X</identifier><identifier>DOI: 10.1016/j.xgen.2021.100084</identifier><identifier>PMID: 38170873</identifier><language>eng</language><publisher>United States</publisher><ispartof>Cell genomics, 2022-01, Vol.2 (1), p.100084</ispartof><rights>Copyright © 2021. 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Martinez on behalf of the NHLBI CARE Network</creatorcontrib><creatorcontrib>TOPMed Structural Variation Working Group</creatorcontrib><creatorcontrib>NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</creatorcontrib><title>Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed</title><title>Cell genomics</title><addtitle>Cell Genom</addtitle><description>Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10
) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.</description><issn>2666-979X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNo1T91KwzAYDYK4MfcCXkgewM4vX9M2uZShU5jMiwnejTT5unW06WwydW9vRb06cP44h7ErATMBIr_dz7625GcIKAYCQMkzNsY8zxNd6LcRm4awH2hUg1ikF2yUKlGAKtIxqxfkKdaWO4rUt7U3PgbeVTxS07XUE2_Ib-OOV33XcgH6RiBy4y2F2JumOXFXf1AfiH_uuoaSYccQ44Hej_Rj4rXn69XLM7lLdl6ZJtD0Dyfs9eF-PX9MlqvF0_xumRwEqJi41Dqs0GJuQZGmzCptNWSVrrICEI2Usigh0zLHTEgrSVtnQUpEUFCadMKuf3sPx7Iltzn0dWv60-b_c_oND3hY2Q</recordid><startdate>20220112</startdate><enddate>20220112</enddate><creator>Taub, Margaret A</creator><creator>Conomos, Matthew P</creator><creator>Keener, Rebecca</creator><creator>Iyer, Kruthika R</creator><creator>Weinstock, Joshua S</creator><creator>Yanek, Lisa R</creator><creator>Lane, John</creator><creator>Miller-Fleming, Tyne 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Garrett, Melanie E ; Gladwin, Mark T ; Heckbert, Susan R ; Hidalgo, Bertha A ; Irvin, Marguerite R ; Islam, Talat ; Johnson, W Craig ; Kaab, Stefan ; Launer, Lenore ; Lee, Jiwon ; Liu, Simin ; Moscati, Arden ; North, Kari E ; Peyser, Patricia A ; Rafaels, Nicholas ; Seidman, Christine ; Weeks, Daniel E ; Wen, Fayun ; Wheeler, Marsha M ; Williams, L Keoki ; Yang, Ivana V ; Zhao, Wei ; Aslibekyan, Stella ; Auer, Paul L ; Bowden, Donald W ; Cade, Brian E ; Chen, Zhanghua ; Cho, Michael H ; Cupples, L Adrienne ; Curran, Joanne E ; Daya, Michelle ; Deka, Ranjan ; Eng, Celeste ; Fingerlin, Tasha E ; Guo, Xiuqing ; Hou, Lifang ; Hwang, Shih-Jen ; Johnsen, Jill M ; Kenny, Eimear E ; Levin, Albert M ; Liu, Chunyu ; Minster, Ryan L ; Naseri, Take ; Nouraie, Mehdi ; Reupena, Muagututi'a Sefuiva ; Sabino, Ester C ; Smith, Jennifer A ; Smith, Nicholas L ; Lasky-Su, Jessica ; Taylor, 6th, James G ; Telen, Marilyn J ; Tiwari, Hemant K ; Tracy, Russell P ; White, Marquitta J ; Zhang, Yingze ; Wiggins, Kerri L ; Weiss, Scott T ; Vasan, Ramachandran S ; Taylor, Kent D ; Sinner, Moritz F ; Silverman, Edwin K ; Shoemaker, M Benjamin ; Sheu, Wayne H-H ; Sciurba, Frank ; Schwartz, David A ; Rotter, Jerome I ; Roden, Daniel ; Redline, Susan ; Raby, Benjamin A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p108t-d3cd2f2c26c08e9e5c89c905f9f57022a4447b059462514c4e9cdc04422080ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Taub, Margaret A</creatorcontrib><creatorcontrib>Conomos, Matthew P</creatorcontrib><creatorcontrib>Keener, Rebecca</creatorcontrib><creatorcontrib>Iyer, Kruthika R</creatorcontrib><creatorcontrib>Weinstock, Joshua S</creatorcontrib><creatorcontrib>Yanek, Lisa R</creatorcontrib><creatorcontrib>Lane, John</creatorcontrib><creatorcontrib>Miller-Fleming, Tyne W</creatorcontrib><creatorcontrib>Brody, Jennifer A</creatorcontrib><creatorcontrib>Raffield, Laura M</creatorcontrib><creatorcontrib>McHugh, Caitlin P</creatorcontrib><creatorcontrib>Jain, Deepti</creatorcontrib><creatorcontrib>Gogarten, Stephanie M</creatorcontrib><creatorcontrib>Laurie, Cecelia A</creatorcontrib><creatorcontrib>Keramati, Ali</creatorcontrib><creatorcontrib>Arvanitis, Marios</creatorcontrib><creatorcontrib>Smith, Albert V</creatorcontrib><creatorcontrib>Heavner, Benjamin</creatorcontrib><creatorcontrib>Barwick, Lucas</creatorcontrib><creatorcontrib>Becker, Lewis C</creatorcontrib><creatorcontrib>Bis, Joshua C</creatorcontrib><creatorcontrib>Blangero, John</creatorcontrib><creatorcontrib>Bleecker, Eugene R</creatorcontrib><creatorcontrib>Burchard, Esteban G</creatorcontrib><creatorcontrib>Celedón, Juan C</creatorcontrib><creatorcontrib>Chang, Yen Pei C</creatorcontrib><creatorcontrib>Custer, Brian</creatorcontrib><creatorcontrib>Darbar, Dawood</creatorcontrib><creatorcontrib>de Las Fuentes, Lisa</creatorcontrib><creatorcontrib>DeMeo, Dawn L</creatorcontrib><creatorcontrib>Freedman, Barry I</creatorcontrib><creatorcontrib>Garrett, Melanie E</creatorcontrib><creatorcontrib>Gladwin, Mark T</creatorcontrib><creatorcontrib>Heckbert, Susan R</creatorcontrib><creatorcontrib>Hidalgo, Bertha A</creatorcontrib><creatorcontrib>Irvin, Marguerite R</creatorcontrib><creatorcontrib>Islam, Talat</creatorcontrib><creatorcontrib>Johnson, W Craig</creatorcontrib><creatorcontrib>Kaab, Stefan</creatorcontrib><creatorcontrib>Launer, Lenore</creatorcontrib><creatorcontrib>Lee, Jiwon</creatorcontrib><creatorcontrib>Liu, Simin</creatorcontrib><creatorcontrib>Moscati, Arden</creatorcontrib><creatorcontrib>North, Kari E</creatorcontrib><creatorcontrib>Peyser, Patricia A</creatorcontrib><creatorcontrib>Rafaels, Nicholas</creatorcontrib><creatorcontrib>Seidman, Christine</creatorcontrib><creatorcontrib>Weeks, Daniel E</creatorcontrib><creatorcontrib>Wen, Fayun</creatorcontrib><creatorcontrib>Wheeler, Marsha M</creatorcontrib><creatorcontrib>Williams, L Keoki</creatorcontrib><creatorcontrib>Yang, Ivana V</creatorcontrib><creatorcontrib>Zhao, Wei</creatorcontrib><creatorcontrib>Aslibekyan, Stella</creatorcontrib><creatorcontrib>Auer, Paul L</creatorcontrib><creatorcontrib>Bowden, Donald W</creatorcontrib><creatorcontrib>Cade, Brian E</creatorcontrib><creatorcontrib>Chen, Zhanghua</creatorcontrib><creatorcontrib>Cho, Michael H</creatorcontrib><creatorcontrib>Cupples, L Adrienne</creatorcontrib><creatorcontrib>Curran, Joanne E</creatorcontrib><creatorcontrib>Daya, Michelle</creatorcontrib><creatorcontrib>Deka, Ranjan</creatorcontrib><creatorcontrib>Eng, Celeste</creatorcontrib><creatorcontrib>Fingerlin, Tasha E</creatorcontrib><creatorcontrib>Guo, Xiuqing</creatorcontrib><creatorcontrib>Hou, Lifang</creatorcontrib><creatorcontrib>Hwang, Shih-Jen</creatorcontrib><creatorcontrib>Johnsen, Jill M</creatorcontrib><creatorcontrib>Kenny, Eimear E</creatorcontrib><creatorcontrib>Levin, Albert M</creatorcontrib><creatorcontrib>Liu, Chunyu</creatorcontrib><creatorcontrib>Minster, Ryan L</creatorcontrib><creatorcontrib>Naseri, Take</creatorcontrib><creatorcontrib>Nouraie, Mehdi</creatorcontrib><creatorcontrib>Reupena, Muagututi'a Sefuiva</creatorcontrib><creatorcontrib>Sabino, Ester C</creatorcontrib><creatorcontrib>Smith, Jennifer A</creatorcontrib><creatorcontrib>Smith, Nicholas L</creatorcontrib><creatorcontrib>Lasky-Su, Jessica</creatorcontrib><creatorcontrib>Taylor, 6th, James G</creatorcontrib><creatorcontrib>Telen, Marilyn J</creatorcontrib><creatorcontrib>Tiwari, Hemant K</creatorcontrib><creatorcontrib>Tracy, Russell P</creatorcontrib><creatorcontrib>White, Marquitta J</creatorcontrib><creatorcontrib>Zhang, Yingze</creatorcontrib><creatorcontrib>Wiggins, Kerri L</creatorcontrib><creatorcontrib>Weiss, Scott T</creatorcontrib><creatorcontrib>Vasan, Ramachandran S</creatorcontrib><creatorcontrib>Taylor, Kent D</creatorcontrib><creatorcontrib>Sinner, Moritz F</creatorcontrib><creatorcontrib>Silverman, Edwin K</creatorcontrib><creatorcontrib>Shoemaker, M Benjamin</creatorcontrib><creatorcontrib>Sheu, Wayne H-H</creatorcontrib><creatorcontrib>Sciurba, Frank</creatorcontrib><creatorcontrib>Schwartz, David A</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>Roden, Daniel</creatorcontrib><creatorcontrib>Redline, Susan</creatorcontrib><creatorcontrib>Raby, Benjamin A</creatorcontrib><creatorcontrib>TOPMed Hematology and Hemostasis Working Group</creatorcontrib><creatorcontrib>Fernando D. Martinez on behalf of the NHLBI CARE Network</creatorcontrib><creatorcontrib>TOPMed Structural Variation Working Group</creatorcontrib><creatorcontrib>NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</creatorcontrib><collection>PubMed</collection><jtitle>Cell genomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Taub, Margaret A</au><au>Conomos, Matthew P</au><au>Keener, Rebecca</au><au>Iyer, Kruthika R</au><au>Weinstock, Joshua S</au><au>Yanek, Lisa R</au><au>Lane, John</au><au>Miller-Fleming, Tyne W</au><au>Brody, Jennifer A</au><au>Raffield, Laura M</au><au>McHugh, Caitlin P</au><au>Jain, Deepti</au><au>Gogarten, Stephanie M</au><au>Laurie, Cecelia A</au><au>Keramati, Ali</au><au>Arvanitis, Marios</au><au>Smith, Albert V</au><au>Heavner, Benjamin</au><au>Barwick, Lucas</au><au>Becker, Lewis C</au><au>Bis, Joshua C</au><au>Blangero, John</au><au>Bleecker, Eugene R</au><au>Burchard, Esteban G</au><au>Celedón, Juan C</au><au>Chang, Yen Pei C</au><au>Custer, Brian</au><au>Darbar, Dawood</au><au>de Las Fuentes, Lisa</au><au>DeMeo, Dawn L</au><au>Freedman, Barry I</au><au>Garrett, Melanie E</au><au>Gladwin, Mark T</au><au>Heckbert, Susan R</au><au>Hidalgo, Bertha A</au><au>Irvin, Marguerite R</au><au>Islam, Talat</au><au>Johnson, W Craig</au><au>Kaab, Stefan</au><au>Launer, Lenore</au><au>Lee, Jiwon</au><au>Liu, Simin</au><au>Moscati, Arden</au><au>North, Kari E</au><au>Peyser, Patricia A</au><au>Rafaels, Nicholas</au><au>Seidman, Christine</au><au>Weeks, Daniel E</au><au>Wen, Fayun</au><au>Wheeler, Marsha M</au><au>Williams, L Keoki</au><au>Yang, Ivana V</au><au>Zhao, Wei</au><au>Aslibekyan, Stella</au><au>Auer, Paul L</au><au>Bowden, Donald W</au><au>Cade, Brian E</au><au>Chen, Zhanghua</au><au>Cho, Michael H</au><au>Cupples, L Adrienne</au><au>Curran, Joanne E</au><au>Daya, Michelle</au><au>Deka, Ranjan</au><au>Eng, Celeste</au><au>Fingerlin, Tasha E</au><au>Guo, Xiuqing</au><au>Hou, Lifang</au><au>Hwang, Shih-Jen</au><au>Johnsen, Jill M</au><au>Kenny, Eimear E</au><au>Levin, Albert M</au><au>Liu, Chunyu</au><au>Minster, Ryan L</au><au>Naseri, Take</au><au>Nouraie, Mehdi</au><au>Reupena, Muagututi'a Sefuiva</au><au>Sabino, Ester C</au><au>Smith, Jennifer A</au><au>Smith, Nicholas L</au><au>Lasky-Su, Jessica</au><au>Taylor, 6th, James G</au><au>Telen, Marilyn J</au><au>Tiwari, Hemant K</au><au>Tracy, Russell P</au><au>White, Marquitta J</au><au>Zhang, Yingze</au><au>Wiggins, Kerri L</au><au>Weiss, Scott T</au><au>Vasan, Ramachandran S</au><au>Taylor, Kent D</au><au>Sinner, Moritz F</au><au>Silverman, Edwin K</au><au>Shoemaker, M Benjamin</au><au>Sheu, Wayne H-H</au><au>Sciurba, Frank</au><au>Schwartz, David A</au><au>Rotter, Jerome I</au><au>Roden, Daniel</au><au>Redline, Susan</au><au>Raby, Benjamin A</au><aucorp>TOPMed Hematology and Hemostasis Working Group</aucorp><aucorp>Fernando D. Martinez on behalf of the NHLBI CARE Network</aucorp><aucorp>TOPMed Structural Variation Working Group</aucorp><aucorp>NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed</atitle><jtitle>Cell genomics</jtitle><addtitle>Cell Genom</addtitle><date>2022-01-12</date><risdate>2022</risdate><volume>2</volume><issue>1</issue><spage>100084</spage><pages>100084-</pages><eissn>2666-979X</eissn><abstract>Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10
) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.</abstract><cop>United States</cop><pmid>38170873</pmid><doi>10.1016/j.xgen.2021.100084</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 2666-979X |
| ispartof | Cell genomics, 2022-01, Vol.2 (1), p.100084 |
| issn | 2666-979X |
| language | eng |
| recordid | cdi_pubmed_primary_38170873 |
| source | DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| title | Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T14%3A31%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genetic%20determinants%20of%20telomere%20length%20from%20109,122%20ancestrally%20diverse%20whole-genome%20sequences%20in%20TOPMed&rft.jtitle=Cell%20genomics&rft.au=Taub,%20Margaret%20A&rft.aucorp=TOPMed%20Hematology%20and%20Hemostasis%20Working%20Group&rft.date=2022-01-12&rft.volume=2&rft.issue=1&rft.spage=100084&rft.pages=100084-&rft.eissn=2666-979X&rft_id=info:doi/10.1016/j.xgen.2021.100084&rft_dat=%3Cpubmed%3E38170873%3C/pubmed%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/38170873&rfr_iscdi=true |