Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity
Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide as...
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| Veröffentlicht in: | The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2024-04, Vol.79 (4) |
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| container_title | The journals of gerontology. Series A, Biological sciences and medical sciences |
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| creator | Xu, Qian Zhao, Qi-Gang Ma, Xin-Ling Yan, Shan-Shan Han, Bai-Xue Song, Zi-Tong Bu, Fan Li, Kuan Zhang, Lei Pei, Yu-Fang |
| description | Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR] = 1.15, 95% confidence interval [CI] = [1.11-1.19], p = 1.75 × 10-14) that was significantly associated with SO at the exome-wide significance level (p |
| doi_str_mv | 10.1093/gerona/glae025 |
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Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR] = 1.15, 95% confidence interval [CI] = [1.11-1.19], p = 1.75 × 10-14) that was significantly associated with SO at the exome-wide significance level (p < 1 × 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (p < 4.3 × 10-6): PDE3B (OR = 2.48, p = 1.10 × 10-6), MYOZ3 (OR = 25.49, p = 1.41 × 10-7), SLC15A3 (OR = 4.75, p = 6.82 × 10-7), RNF130 (OR = 25.83, p = 4.07 × 10-6), and TNK2 (OR = 4.25, p = 8.75 × 10-8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO.</description><identifier>ISSN: 1079-5006</identifier><identifier>EISSN: 1758-535X</identifier><identifier>DOI: 10.1093/gerona/glae025</identifier><identifier>PMID: 38267387</identifier><language>eng</language><publisher>United States</publisher><subject>Exome - genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Obesity - genetics ; Polymorphism, Single Nucleotide ; Protein-Tyrosine Kinases - genetics ; Sarcopenia - genetics</subject><ispartof>The journals of gerontology. Series A, Biological sciences and medical sciences, 2024-04, Vol.79 (4)</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38267387$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Duque, Gustavo</contributor><creatorcontrib>Xu, Qian</creatorcontrib><creatorcontrib>Zhao, Qi-Gang</creatorcontrib><creatorcontrib>Ma, Xin-Ling</creatorcontrib><creatorcontrib>Yan, Shan-Shan</creatorcontrib><creatorcontrib>Han, Bai-Xue</creatorcontrib><creatorcontrib>Song, Zi-Tong</creatorcontrib><creatorcontrib>Bu, Fan</creatorcontrib><creatorcontrib>Li, Kuan</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Pei, Yu-Fang</creatorcontrib><title>Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity</title><title>The journals of gerontology. Series A, Biological sciences and medical sciences</title><addtitle>J Gerontol A Biol Sci Med Sci</addtitle><description>Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR] = 1.15, 95% confidence interval [CI] = [1.11-1.19], p = 1.75 × 10-14) that was significantly associated with SO at the exome-wide significance level (p < 1 × 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (p < 4.3 × 10-6): PDE3B (OR = 2.48, p = 1.10 × 10-6), MYOZ3 (OR = 25.49, p = 1.41 × 10-7), SLC15A3 (OR = 4.75, p = 6.82 × 10-7), RNF130 (OR = 25.83, p = 4.07 × 10-6), and TNK2 (OR = 4.25, p = 8.75 × 10-8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO.</description><subject>Exome - genetics</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Obesity - genetics</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein-Tyrosine Kinases - genetics</subject><subject>Sarcopenia - genetics</subject><issn>1079-5006</issn><issn>1758-535X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtPwkAQhzdGI4hePZoevRT20e3jSAgiCQkHVIyXZh9TXNNucXebyH9vCehcZpL55pfMh9A9wWOCCzbZgWutmOxqAZjyCzQkGc9jzvj7ZT_jrIg5xukA3Xj_hY_F6TUasJymGcuzIfqY_7QNxFujIdrAdwdWGbuLNqHTh2ipwQZTGdDRAiwEo6I34YywwUdT71tlROh3WxM-o41wqt2D7Zm1BG_C4RZdVaL2cHfuI_T6NH-ZPcer9WI5m65iRTkOMaWKFzKVOpOJyhIAyiEXmUgroaTmSaGF1FUuCMMJpxpnBIgUmnIhgScEsxF6POXuXds_4EPZGK-groWFtvMlLUjOCUkp69HxCVWu9d5BVe6daYQ7lASXR5_lyWd59tkfPJyzO9mA_sf_BLJfyaB1EA</recordid><startdate>20240401</startdate><enddate>20240401</enddate><creator>Xu, Qian</creator><creator>Zhao, Qi-Gang</creator><creator>Ma, Xin-Ling</creator><creator>Yan, Shan-Shan</creator><creator>Han, Bai-Xue</creator><creator>Song, Zi-Tong</creator><creator>Bu, Fan</creator><creator>Li, Kuan</creator><creator>Zhang, Lei</creator><creator>Pei, Yu-Fang</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20240401</creationdate><title>Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity</title><author>Xu, Qian ; Zhao, Qi-Gang ; Ma, Xin-Ling ; Yan, Shan-Shan ; Han, Bai-Xue ; Song, Zi-Tong ; Bu, Fan ; Li, Kuan ; Zhang, Lei ; Pei, Yu-Fang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c250t-22c59b6bd7b4c74ee25e8a7a6facbd549dabdf8a130452d071e1bad25abe54103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Exome - genetics</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-Wide Association Study</topic><topic>Humans</topic><topic>Obesity - genetics</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein-Tyrosine Kinases - genetics</topic><topic>Sarcopenia - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Qian</creatorcontrib><creatorcontrib>Zhao, Qi-Gang</creatorcontrib><creatorcontrib>Ma, Xin-Ling</creatorcontrib><creatorcontrib>Yan, Shan-Shan</creatorcontrib><creatorcontrib>Han, Bai-Xue</creatorcontrib><creatorcontrib>Song, Zi-Tong</creatorcontrib><creatorcontrib>Bu, Fan</creatorcontrib><creatorcontrib>Li, Kuan</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Pei, Yu-Fang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The journals of gerontology. Series A, Biological sciences and medical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Qian</au><au>Zhao, Qi-Gang</au><au>Ma, Xin-Ling</au><au>Yan, Shan-Shan</au><au>Han, Bai-Xue</au><au>Song, Zi-Tong</au><au>Bu, Fan</au><au>Li, Kuan</au><au>Zhang, Lei</au><au>Pei, Yu-Fang</au><au>Duque, Gustavo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity</atitle><jtitle>The journals of gerontology. Series A, Biological sciences and medical sciences</jtitle><addtitle>J Gerontol A Biol Sci Med Sci</addtitle><date>2024-04-01</date><risdate>2024</risdate><volume>79</volume><issue>4</issue><issn>1079-5006</issn><eissn>1758-535X</eissn><abstract>Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR] = 1.15, 95% confidence interval [CI] = [1.11-1.19], p = 1.75 × 10-14) that was significantly associated with SO at the exome-wide significance level (p < 1 × 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (p < 4.3 × 10-6): PDE3B (OR = 2.48, p = 1.10 × 10-6), MYOZ3 (OR = 25.49, p = 1.41 × 10-7), SLC15A3 (OR = 4.75, p = 6.82 × 10-7), RNF130 (OR = 25.83, p = 4.07 × 10-6), and TNK2 (OR = 4.25, p = 8.75 × 10-8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO.</abstract><cop>United States</cop><pmid>38267387</pmid><doi>10.1093/gerona/glae025</doi></addata></record> |
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| subjects | Exome - genetics Genetic Predisposition to Disease Genome-Wide Association Study Humans Obesity - genetics Polymorphism, Single Nucleotide Protein-Tyrosine Kinases - genetics Sarcopenia - genetics |
| title | Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity |
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