Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants
Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity. a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 sing...
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| creator | Hinney, Anke Nguyen, Thuy Trang Scherag, André Friedel, Susann Brönner, Günter Müller, Timo Dirk Grallert, Harald Illig, Thomas Wichmann, H-Erich Rief, Winfried Schäfer, Helmut Hebebrand, Johannes |
| description | Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.
a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency > or =10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13 x 10(-7), corrected p = 0.0494; odds ratio (OR)(CT) 1.67, 95% confidence interval (CI) 1.22-2.27; OR(TT) 2.76, 95% CI 1.88-4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p |
| doi_str_mv | 10.1371/journal.pone.0001361 |
| format | Article |
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a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency > or =10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13 x 10(-7), corrected p = 0.0494; odds ratio (OR)(CT) 1.67, 95% confidence interval (CI) 1.22-2.27; OR(TT) 2.76, 95% CI 1.88-4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.
Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0001361</identifier><identifier>PMID: 18159244</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adipose Tissue - metabolism ; Adolescent ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Biometrics ; Body fat ; Body mass index ; Child ; Child & adolescent psychiatry ; Confidence intervals ; Creutzfeldt-Jakob disease ; Diabetes and Endocrinology/Obesity ; Diabetes and Endocrinology/Type 2 Diabetes ; Epidemiology ; Family studies ; Gene frequency ; Genes ; Genetics and Genomics ; Genetics and Genomics/Complex Traits ; Genetics and Genomics/Gene Discovery ; Genetics and Genomics/Genetics of Disease ; Genetics and Genomics/Medical Genetics ; Genome, Human ; Genome-wide association studies ; Genomes ; Heritability ; Humans ; Linkage disequilibrium ; Obesity ; Obesity - genetics ; Offspring ; Organ Size ; Parents ; Polymorphism ; Polymorphism, Single Nucleotide ; Proteins - genetics ; Single-nucleotide polymorphism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Studies</subject><ispartof>PloS one, 2007-12, Vol.2 (12), p.e1361-e1361</ispartof><rights>2007 Hinney et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Hinney et al. 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c642t-93f240d668db0150f2920211a75946ffab0a91c5724794751e569709129e48b73</citedby><cites>FETCH-LOGICAL-c642t-93f240d668db0150f2920211a75946ffab0a91c5724794751e569709129e48b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137937/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137937/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18159244$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hinney, Anke</creatorcontrib><creatorcontrib>Nguyen, Thuy Trang</creatorcontrib><creatorcontrib>Scherag, André</creatorcontrib><creatorcontrib>Friedel, Susann</creatorcontrib><creatorcontrib>Brönner, Günter</creatorcontrib><creatorcontrib>Müller, Timo Dirk</creatorcontrib><creatorcontrib>Grallert, Harald</creatorcontrib><creatorcontrib>Illig, Thomas</creatorcontrib><creatorcontrib>Wichmann, H-Erich</creatorcontrib><creatorcontrib>Rief, Winfried</creatorcontrib><creatorcontrib>Schäfer, Helmut</creatorcontrib><creatorcontrib>Hebebrand, Johannes</creatorcontrib><title>Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.
a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency > or =10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13 x 10(-7), corrected p = 0.0494; odds ratio (OR)(CT) 1.67, 95% confidence interval (CI) 1.22-2.27; OR(TT) 2.76, 95% CI 1.88-4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.
Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.</description><subject>Adipose Tissue - metabolism</subject><subject>Adolescent</subject><subject>Alpha-Ketoglutarate-Dependent Dioxygenase FTO</subject><subject>Biometrics</subject><subject>Body fat</subject><subject>Body mass index</subject><subject>Child</subject><subject>Child & adolescent psychiatry</subject><subject>Confidence intervals</subject><subject>Creutzfeldt-Jakob disease</subject><subject>Diabetes and Endocrinology/Obesity</subject><subject>Diabetes and Endocrinology/Type 2 Diabetes</subject><subject>Epidemiology</subject><subject>Family studies</subject><subject>Gene frequency</subject><subject>Genes</subject><subject>Genetics and Genomics</subject><subject>Genetics and Genomics/Complex Traits</subject><subject>Genetics and Genomics/Gene Discovery</subject><subject>Genetics and Genomics/Genetics of Disease</subject><subject>Genetics and Genomics/Medical Genetics</subject><subject>Genome, Human</subject><subject>Genome-wide association studies</subject><subject>Genomes</subject><subject>Heritability</subject><subject>Humans</subject><subject>Linkage disequilibrium</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Offspring</subject><subject>Organ Size</subject><subject>Parents</subject><subject>Polymorphism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proteins - genetics</subject><subject>Single-nucleotide polymorphism</subject><subject>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</subject><subject>Studies</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1kt1u1DAQhSMEoqXwBggsIaH2YheP_xLfIFUVXSpV6k0Rl5aTTLZZJfZiO4V9Bx6abDctW0SvbHm-OeMzOln2FugceA6fVn4IznbztXc4p5QCV_AsOwTN2Uwxyp_v3Q-yVzGuKJW8UOpldgAFSM2EOMx-L9D5HsnPtkZiY_RVa1PrHTlefD89ITEN9YY0PhC0odsQ7yImgr9SwLHJlxjbtCFxWK99SJGkGyTBd2OlIY1NpB8ViXX1A3k_AWuyRIfk-Pz66oTc2tBal-Lr7EVju4hvpvMo-3b-5frs6-zyanFxdno5q5RgaaZ5wwStlSrqkoKkDdOMMgCbSy1U09iSWg2VzJnItcgloFQ6pxqYRlGUOT_K3u90152PZlpkNKAl5QIKTZ8kWKGBg5RsJC52RO3tyqxD29uwMd625u7Bh6WxIbVVh4bZvKZFiZWWKICJAi0vbINMg8hZWY1an6dpQ9ljXaFLwXaPRB9XXHtjlv7WsDEJmm8NfZwEgv8xYEymb2OFXWcd-iEapWkh2Z2vD_-A_3f_NLW_AbGjquBjDNg8fBio2Ub0vstsI2qmiI5t7_bN_m2aMsn_AE5J4k0</recordid><startdate>20071226</startdate><enddate>20071226</enddate><creator>Hinney, Anke</creator><creator>Nguyen, Thuy Trang</creator><creator>Scherag, André</creator><creator>Friedel, Susann</creator><creator>Brönner, Günter</creator><creator>Müller, Timo Dirk</creator><creator>Grallert, Harald</creator><creator>Illig, Thomas</creator><creator>Wichmann, H-Erich</creator><creator>Rief, Winfried</creator><creator>Schäfer, Helmut</creator><creator>Hebebrand, Johannes</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20071226</creationdate><title>Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants</title><author>Hinney, Anke ; Nguyen, Thuy Trang ; Scherag, André ; Friedel, Susann ; Brönner, Günter ; Müller, Timo Dirk ; Grallert, Harald ; Illig, Thomas ; Wichmann, H-Erich ; Rief, Winfried ; Schäfer, Helmut ; Hebebrand, Johannes</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c642t-93f240d668db0150f2920211a75946ffab0a91c5724794751e569709129e48b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adipose Tissue - metabolism</topic><topic>Adolescent</topic><topic>Alpha-Ketoglutarate-Dependent Dioxygenase FTO</topic><topic>Biometrics</topic><topic>Body fat</topic><topic>Body mass index</topic><topic>Child</topic><topic>Child & adolescent psychiatry</topic><topic>Confidence intervals</topic><topic>Creutzfeldt-Jakob disease</topic><topic>Diabetes and Endocrinology/Obesity</topic><topic>Diabetes and Endocrinology/Type 2 Diabetes</topic><topic>Epidemiology</topic><topic>Family studies</topic><topic>Gene frequency</topic><topic>Genes</topic><topic>Genetics and Genomics</topic><topic>Genetics and Genomics/Complex Traits</topic><topic>Genetics and Genomics/Gene Discovery</topic><topic>Genetics and Genomics/Genetics of Disease</topic><topic>Genetics and Genomics/Medical Genetics</topic><topic>Genome, Human</topic><topic>Genome-wide association studies</topic><topic>Genomes</topic><topic>Heritability</topic><topic>Humans</topic><topic>Linkage disequilibrium</topic><topic>Obesity</topic><topic>Obesity - genetics</topic><topic>Offspring</topic><topic>Organ Size</topic><topic>Parents</topic><topic>Polymorphism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proteins - 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Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.
a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency > or =10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13 x 10(-7), corrected p = 0.0494; odds ratio (OR)(CT) 1.67, 95% confidence interval (CI) 1.22-2.27; OR(TT) 2.76, 95% CI 1.88-4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.
Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>18159244</pmid><doi>10.1371/journal.pone.0001361</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1950341890 |
| source | Open Access: PubMed Central; MEDLINE; Public Library of Science; Full-Text Journals in Chemistry (Open access); DOAJ Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | Adipose Tissue - metabolism Adolescent Alpha-Ketoglutarate-Dependent Dioxygenase FTO Biometrics Body fat Body mass index Child Child & adolescent psychiatry Confidence intervals Creutzfeldt-Jakob disease Diabetes and Endocrinology/Obesity Diabetes and Endocrinology/Type 2 Diabetes Epidemiology Family studies Gene frequency Genes Genetics and Genomics Genetics and Genomics/Complex Traits Genetics and Genomics/Gene Discovery Genetics and Genomics/Genetics of Disease Genetics and Genomics/Medical Genetics Genome, Human Genome-wide association studies Genomes Heritability Humans Linkage disequilibrium Obesity Obesity - genetics Offspring Organ Size Parents Polymorphism Polymorphism, Single Nucleotide Proteins - genetics Single-nucleotide polymorphism Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Studies |
| title | Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T09%3A05%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome%20wide%20association%20(GWA)%20study%20for%20early%20onset%20extreme%20obesity%20supports%20the%20role%20of%20fat%20mass%20and%20obesity%20associated%20gene%20(FTO)%20variants&rft.jtitle=PloS%20one&rft.au=Hinney,%20Anke&rft.date=2007-12-26&rft.volume=2&rft.issue=12&rft.spage=e1361&rft.epage=e1361&rft.pages=e1361-e1361&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0001361&rft_dat=%3Cproquest_plos_%3E1950341890%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1289131552&rft_id=info:pmid/18159244&rft_doaj_id=oai_doaj_org_article_2a7d08bec95e41248ea38afe291472bc&rfr_iscdi=true |