Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5

Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it...
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Autor*in:	Hunt, Lilian E. [verfasserIn] Noyvert, Boris Bhaw-Rosun, Leena Sesay, Abdul K. Paternoster, Lavinia Nohr, Ellen A. Davey Smith, George Tommerup, Niels Sørensen, Thorkild I. A. Elgar, Greg

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2015

Schlagwörter:	Linkage Disequilibrium Block Complete Linkage Disequilibrium Family Wise Error Rate IRX3 Gene Linkage Disequilibrium Region

Anmerkung:	© Hunt et al. 2015

Übergeordnetes Werk:	Enthalten in: Genome medicine - London : BioMed Central, 2009, 7(2015), 1 vom: 07. Dez.
Übergeordnetes Werk:	volume:7 ; year:2015 ; number:1 ; day:07 ; month:12

Links:	Volltext

DOI / URN:	10.1186/s13073-015-0250-3

Katalog-ID:	SPR03063461X

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520			\|a Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci.
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allfields	10.1186/s13073-015-0250-3 doi (DE-627)SPR03063461X (SPR)s13073-015-0250-3-e DE-627 ger DE-627 rakwb eng Hunt, Lilian E. verfasserin aut Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Hunt et al. 2015 Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. Linkage Disequilibrium Block (dpeaa)DE-He213 Complete Linkage Disequilibrium (dpeaa)DE-He213 Family Wise Error Rate (dpeaa)DE-He213 IRX3 Gene (dpeaa)DE-He213 Linkage Disequilibrium Region (dpeaa)DE-He213 Noyvert, Boris aut Bhaw-Rosun, Leena aut Sesay, Abdul K. aut Paternoster, Lavinia aut Nohr, Ellen A. aut Davey Smith, George aut Tommerup, Niels aut Sørensen, Thorkild I. A. aut Elgar, Greg aut Enthalten in Genome medicine London : BioMed Central, 2009 7(2015), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:7 year:2015 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-015-0250-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2015 1 07 12
spelling	10.1186/s13073-015-0250-3 doi (DE-627)SPR03063461X (SPR)s13073-015-0250-3-e DE-627 ger DE-627 rakwb eng Hunt, Lilian E. verfasserin aut Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Hunt et al. 2015 Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. Linkage Disequilibrium Block (dpeaa)DE-He213 Complete Linkage Disequilibrium (dpeaa)DE-He213 Family Wise Error Rate (dpeaa)DE-He213 IRX3 Gene (dpeaa)DE-He213 Linkage Disequilibrium Region (dpeaa)DE-He213 Noyvert, Boris aut Bhaw-Rosun, Leena aut Sesay, Abdul K. aut Paternoster, Lavinia aut Nohr, Ellen A. aut Davey Smith, George aut Tommerup, Niels aut Sørensen, Thorkild I. A. aut Elgar, Greg aut Enthalten in Genome medicine London : BioMed Central, 2009 7(2015), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:7 year:2015 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-015-0250-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2015 1 07 12
allfields_unstemmed	10.1186/s13073-015-0250-3 doi (DE-627)SPR03063461X (SPR)s13073-015-0250-3-e DE-627 ger DE-627 rakwb eng Hunt, Lilian E. verfasserin aut Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Hunt et al. 2015 Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. Linkage Disequilibrium Block (dpeaa)DE-He213 Complete Linkage Disequilibrium (dpeaa)DE-He213 Family Wise Error Rate (dpeaa)DE-He213 IRX3 Gene (dpeaa)DE-He213 Linkage Disequilibrium Region (dpeaa)DE-He213 Noyvert, Boris aut Bhaw-Rosun, Leena aut Sesay, Abdul K. aut Paternoster, Lavinia aut Nohr, Ellen A. aut Davey Smith, George aut Tommerup, Niels aut Sørensen, Thorkild I. A. aut Elgar, Greg aut Enthalten in Genome medicine London : BioMed Central, 2009 7(2015), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:7 year:2015 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-015-0250-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2015 1 07 12
allfieldsGer	10.1186/s13073-015-0250-3 doi (DE-627)SPR03063461X (SPR)s13073-015-0250-3-e DE-627 ger DE-627 rakwb eng Hunt, Lilian E. verfasserin aut Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Hunt et al. 2015 Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. Linkage Disequilibrium Block (dpeaa)DE-He213 Complete Linkage Disequilibrium (dpeaa)DE-He213 Family Wise Error Rate (dpeaa)DE-He213 IRX3 Gene (dpeaa)DE-He213 Linkage Disequilibrium Region (dpeaa)DE-He213 Noyvert, Boris aut Bhaw-Rosun, Leena aut Sesay, Abdul K. aut Paternoster, Lavinia aut Nohr, Ellen A. aut Davey Smith, George aut Tommerup, Niels aut Sørensen, Thorkild I. A. aut Elgar, Greg aut Enthalten in Genome medicine London : BioMed Central, 2009 7(2015), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:7 year:2015 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-015-0250-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2015 1 07 12
allfieldsSound	10.1186/s13073-015-0250-3 doi (DE-627)SPR03063461X (SPR)s13073-015-0250-3-e DE-627 ger DE-627 rakwb eng Hunt, Lilian E. verfasserin aut Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Hunt et al. 2015 Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. Linkage Disequilibrium Block (dpeaa)DE-He213 Complete Linkage Disequilibrium (dpeaa)DE-He213 Family Wise Error Rate (dpeaa)DE-He213 IRX3 Gene (dpeaa)DE-He213 Linkage Disequilibrium Region (dpeaa)DE-He213 Noyvert, Boris aut Bhaw-Rosun, Leena aut Sesay, Abdul K. aut Paternoster, Lavinia aut Nohr, Ellen A. aut Davey Smith, George aut Tommerup, Niels aut Sørensen, Thorkild I. A. aut Elgar, Greg aut Enthalten in Genome medicine London : BioMed Central, 2009 7(2015), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:7 year:2015 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-015-0250-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2015 1 07 12
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spellingShingle	Hunt, Lilian E. misc Linkage Disequilibrium Block misc Complete Linkage Disequilibrium misc Family Wise Error Rate misc IRX3 Gene misc Linkage Disequilibrium Region Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5
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topic_title	Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5 Linkage Disequilibrium Block (dpeaa)DE-He213 Complete Linkage Disequilibrium (dpeaa)DE-He213 Family Wise Error Rate (dpeaa)DE-He213 IRX3 Gene (dpeaa)DE-He213 Linkage Disequilibrium Region (dpeaa)DE-He213
topic	misc Linkage Disequilibrium Block misc Complete Linkage Disequilibrium misc Family Wise Error Rate misc IRX3 Gene misc Linkage Disequilibrium Region
topic_unstemmed	misc Linkage Disequilibrium Block misc Complete Linkage Disequilibrium misc Family Wise Error Rate misc IRX3 Gene misc Linkage Disequilibrium Region
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title	Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5
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title_full	Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5
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author_browse	Hunt, Lilian E. Noyvert, Boris Bhaw-Rosun, Leena Sesay, Abdul K. Paternoster, Lavinia Nohr, Ellen A. Davey Smith, George Tommerup, Niels Sørensen, Thorkild I. A. Elgar, Greg
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title_sort	complete re-sequencing of a 2mb topological domain encompassing the fto/irxb genes identifies a novel obesity-associated region upstream of irx5
title_auth	Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5
abstract	Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. © Hunt et al. 2015
abstractGer	Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. © Hunt et al. 2015
abstract_unstemmed	Background Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. Conclusions Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. © Hunt et al. 2015
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title_short	Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5
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However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. Methods Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. Results We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. 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Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5

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