Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.
Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic...
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Public Library of Science (PLoS)
2015-10-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1005573&type=printable |
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| author | Hagit Hochner Catherine Allard Einat Granot-Hershkovitz Jinbo Chen Colleen M Sitlani Sandra Sazdovska Thomas Lumley Barbara McKnight Kenneth Rice Daniel A Enquobahrie James B Meigs Pui Kwok Marie-France Hivert Ingrid B Borecki Felicia Gomez Ting Wang Cornelia van Duijn Najaf Amin Jerome I Rotter John Stamatoyannopoulos Vardiella Meiner Orly Manor Josée Dupuis Yechiel Friedlander David S Siscovick |
| author_facet | Hagit Hochner Catherine Allard Einat Granot-Hershkovitz Jinbo Chen Colleen M Sitlani Sandra Sazdovska Thomas Lumley Barbara McKnight Kenneth Rice Daniel A Enquobahrie James B Meigs Pui Kwok Marie-France Hivert Ingrid B Borecki Felicia Gomez Ting Wang Cornelia van Duijn Najaf Amin Jerome I Rotter John Stamatoyannopoulos Vardiella Meiner Orly Manor Josée Dupuis Yechiel Friedlander David S Siscovick |
| author_sort | Hagit Hochner |
| collection | DOAJ |
| description | Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits. |
| format | Article |
| id | doaj-art-feaa2cfb39d74a1babfb20cd693b93fe |
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| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2015-10-01 |
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| series | PLoS Genetics |
| spelling | doaj-art-feaa2cfb39d74a1babfb20cd693b93fe2025-08-20T02:34:12ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-10-011110e100557310.1371/journal.pgen.1005573Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.Hagit HochnerCatherine AllardEinat Granot-HershkovitzJinbo ChenColleen M SitlaniSandra SazdovskaThomas LumleyBarbara McKnightKenneth RiceDaniel A EnquobahrieJames B MeigsPui KwokMarie-France HivertIngrid B BoreckiFelicia GomezTing WangCornelia van DuijnNajaf AminJerome I RotterJohn StamatoyannopoulosVardiella MeinerOrly ManorJosée DupuisYechiel FriedlanderDavid S SiscovickLoci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1005573&type=printable |
| spellingShingle | Hagit Hochner Catherine Allard Einat Granot-Hershkovitz Jinbo Chen Colleen M Sitlani Sandra Sazdovska Thomas Lumley Barbara McKnight Kenneth Rice Daniel A Enquobahrie James B Meigs Pui Kwok Marie-France Hivert Ingrid B Borecki Felicia Gomez Ting Wang Cornelia van Duijn Najaf Amin Jerome I Rotter John Stamatoyannopoulos Vardiella Meiner Orly Manor Josée Dupuis Yechiel Friedlander David S Siscovick Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults. PLoS Genetics |
| title | Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults. |
| title_full | Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults. |
| title_fullStr | Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults. |
| title_full_unstemmed | Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults. |
| title_short | Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults. |
| title_sort | parent of origin effects of the apob gene on adiposity in young adults |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1005573&type=printable |
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