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1.  The missense variation landscape of FTO, MC4R and TMEM18 in obese children of African ancestry 
Obesity (Silver Spring, Md.)  2013;21(1):159-163.
Common variation at the loci harboring FTO, MC4R and TMEM18 is consistently reported as being statistically the most strongly associated with obesity. We investigated if these loci also harbor rarer missense variants that confer substantially higher risk of common childhood obesity in African American (AA) children. We sequenced the exons of FTO, MC4R and TMEM18 in an initial subset of our cohort i.e. 200 obese (BMI≥95th percentile) and 200 lean AA children (BMI≤5th percentile). Any missense exonic variants that were uncovered went on to be further genotyped in a further 768 obese and 768 lean (BMI≤50th percentile) children of the same ethnicity. A number of exonic variants were observed from our sequencing effort: seven in FTO, of which four were non-synonymous (A163T, G182A, M400V and A405V), thirteen in MC4R, of which six were non-synonymous (V103I, N123S, S136A, F202L, N240S and I251L) and four in TMEM18, of which two were non-synonymous (P2S and V113L). Follow-up genotyping of these missense variants revealed only one significant difference in allele frequency between cases and controls, namely with N240S in MC4R(Fisher's Exact P = 0.0001). In summary, moderately rare missense variants within the FTO, MC4R and TMEM18 genes observed in our study did not confer risk of common childhood obesity in African Americans except for a degree of evidence for one known loss-of-function variant in MC4R.
doi:10.1002/oby.20147
PMCID: PMC3605748  PMID: 23505181
Obesity; Pediatrics; Genomics
2.  Genetics of Childhood Obesity 
Journal of Obesity  2011;2011:845148.
Obesity is a major health problem and an immense economic burden on the health care systems both in the United States and the rest of the world. The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. Genome-wide association studies (GWAS) have revealed strongly associated genomic variants associated with most common disorders; indeed there is general consensus on these findings from generally positive replication outcomes by independent groups. To date, there have been only a few GWAS-related reports for childhood obesity specifically, with studies primarily uncovering loci in the adult setting instead. It is clear that a number of loci previously reported from GWAS analyses of adult BMI and/or obesity also play a role in childhood obesity.
doi:10.1155/2011/845148
PMCID: PMC3136227  PMID: 21773009
3.  Examination of All Type 2 Diabetes GWAS Loci Reveals HHEX-IDE as a Locus Influencing Pediatric BMI 
Diabetes  2009;59(3):751-755.
OBJECTIVE
A number of studies have found that BMI in early life influences the risk of developing type 2 diabetes later in life. Our goal was to investigate if any type 2 diabetes variants uncovered through genome-wide association studies (GWAS) impact BMI in childhood.
RESEARCH DESIGN AND METHODS
Using data from an ongoing GWAS of pediatric BMI in our cohort, we investigated the association of pediatric BMI with 20 single nucleotide polymorphisms at 18 type 2 diabetes loci uncovered through GWAS, consisting of ADAMTS9, CDC123-CAMK1D, CDKAL1, CDKN2A/B, EXT2, FTO, HHEX-IDE, IGF2BP2, the intragenic region on 11p12, JAZF1, KCNQ1, LOC387761, MTNR1B, NOTCH2, SLC30A8, TCF7L2, THADA, and TSPAN8-LGR5. We randomly partitioned our cohort exactly in half in order to have a discovery cohort (n = 3,592) and a replication cohort (n = 3,592).
RESULTS
Our data show that the major type 2 diabetes risk–conferring G allele of rs7923837 at the HHEX-IDE locus was associated with higher pediatric BMI in both the discovery (P = 0.0013 and survived correction for 20 tests) and replication (P = 0.023) sets (combined P = 1.01 × 10−4). Association was not detected with any other known type 2 diabetes loci uncovered to date through GWAS except for the well-established FTO.
CONCLUSIONS
Our data show that the same genetic HHEX-IDE variant, which is associated with type 2 diabetes from previous studies, also influences pediatric BMI.
doi:10.2337/db09-0972
PMCID: PMC2828649  PMID: 19933996
4.  Examination of Type 2 Diabetes Loci Implicates CDKAL1 as a Birth Weight Gene 
Diabetes  2009;58(10):2414-2418.
OBJECTIVE
A number of studies have found that reduced birth weight is associated with type 2 diabetes later in life; however, the underlying mechanism for this correlation remains unresolved. Recently, association has been demonstrated between low birth weight and single nucleotide polymorphisms (SNPs) at the CDKAL1 and HHEX-IDE loci, regions that were previously implicated in the pathogenesis of type 2 diabetes. In order to investigate whether type 2 diabetes risk–conferring alleles associate with low birth weight in our Caucasian childhood cohort, we examined the effects of 20 such loci on this trait.
RESEARCH DESIGN AND METHODS
Using data from an ongoing genome-wide association study in our cohort of 5,465 Caucasian children with recorded birth weights, we investigated the association of the previously reported type 2 diabetes–associated variation at 20 loci including TCF7L2, HHEX-IDE, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B, and JAZF1 with birth weight.
RESULTS
Our data show that the minor allele of rs7756992 (P = 8 × 10−5) at the CDKAL1 locus is strongly associated with lower birth weight, whereas a perfect surrogate for variation previously implicated for the trait at the same locus only yielded nominally significant association (P = 0.01; r2 rs7756992 = 0.677). However, association was not detected with any of the other type 2 diabetes loci studied.
CONCLUSIONS
We observe association between lower birth weight and type 2 diabetes risk–conferring alleles at the CDKAL1 locus. Our data show that the same genetic locus that has been identified as a marker for type 2 diabetes in previous studies also influences birth weight.
doi:10.2337/db09-0506
PMCID: PMC2750235  PMID: 19592620
5.  Two novel type 2 diabetes loci revealed through integration of TCF7L2 DNA occupancy and SNP association data 
Background
The transcription factor 7-like 2 (TCF7L2) locus is strongly implicated in the pathogenesis of type 2 diabetes (T2D). We previously mapped the genomic regions bound by TCF7L2 using ChIP (chromatin immunoprecipitation)-seq in the colorectal carcinoma cell line, HCT116, revealing an unexpected highly significant over-representation of genome-wide association studies (GWAS) loci associated primarily with endocrine (in particular T2D) and cardiovascular traits.
Methods
In order to further explore if this observed phenomenon occurs in other cell lines, we carried out ChIP-seq in HepG2 cells and leveraged ENCODE data for five additional cell lines. Given that only a minority of the predicted genetic component to most complex traits has been identified to date, plus our GWAS-related observations with respect to TCF7L2 occupancy, we investigated if restricting association analyses to the genes yielded from this approach, in order to reduce the constraints of multiple testing, could reveal novel T2D loci.
Results
We found strong evidence for the continued enrichment of endocrine and cardiovascular GWAS categories, with additional support for cancer. When investigating all the known GWAS loci bound by TCF7L2 in the shortest gene list, derived from HCT116, the coronary artery disease-associated variant, rs46522 at the UBE2Z-GIP-ATP5G1-SNF8 locus, yielded significant association with T2D within DIAGRAM. Furthermore, when we analyzed tag-SNPs (single nucleotide polymorphisms) in genes not previously implicated by GWAS but bound by TCF7L2 within 5 kb, we observed a significant association of rs4780476 within CPPED1 in DIAGRAM.
Conclusions
ChIP-seq data generated with this GWAS-implicated transcription factor provided a biologically plausible method to limit multiple testing in the assessment of genome-wide genotyping data to uncover two novel T2D-associated loci.
doi:10.1136/bmjdrc-2014-000052
PMCID: PMC4250976  PMID: 25469308
Genetic Association; Type 2; Transcription Factor; Gene
6.  New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism 
Horikoshi, Momoko | Yaghootkar, Hanieh | Mook-Kanamori, Dennis O. | Sovio, Ulla | Taal, H. Rob | Hennig, Branwen J. | Bradfield, Jonathan P. | St. Pourcain, Beate | Evans, David M. | Charoen, Pimphen | Kaakinen, Marika | Cousminer, Diana L. | Lehtimäki, Terho | Kreiner-Møller, Eskil | Warrington, Nicole M. | Bustamante, Mariona | Feenstra, Bjarke | Berry, Diane J. | Thiering, Elisabeth | Pfab, Thiemo | Barton, Sheila J. | Shields, Beverley M. | Kerkhof, Marjan | van Leeuwen, Elisabeth M. | Fulford, Anthony J. | Kutalik, Zoltán | Zhao, Jing Hua | den Hoed, Marcel | Mahajan, Anubha | Lindi, Virpi | Goh, Liang-Kee | Hottenga, Jouke-Jan | Wu, Ying | Raitakari, Olli T. | Harder, Marie N. | Meirhaeghe, Aline | Ntalla, Ioanna | Salem, Rany M. | Jameson, Karen A. | Zhou, Kaixin | Monies, Dorota M. | Lagou, Vasiliki | Kirin, Mirna | Heikkinen, Jani | Adair, Linda S. | Alkuraya, Fowzan S. | Al-Odaib, Ali | Amouyel, Philippe | Andersson, Ehm Astrid | Bennett, Amanda J. | Blakemore, Alexandra I.F. | Buxton, Jessica L. | Dallongeville, Jean | Das, Shikta | de Geus, Eco J. C. | Estivill, Xavier | Flexeder, Claudia | Froguel, Philippe | Geller, Frank | Godfrey, Keith M. | Gottrand, Frédéric | Groves, Christopher J. | Hansen, Torben | Hirschhorn, Joel N. | Hofman, Albert | Hollegaard, Mads V. | Hougaard, David M. | Hyppönen, Elina | Inskip, Hazel M. | Isaacs, Aaron | Jørgensen, Torben | Kanaka-Gantenbein, Christina | Kemp, John P. | Kiess, Wieland | Kilpeläinen, Tuomas O. | Klopp, Norman | Knight, Bridget A. | Kuzawa, Christopher W. | McMahon, George | Newnham, John P. | Niinikoski, Harri | Oostra, Ben A. | Pedersen, Louise | Postma, Dirkje S. | Ring, Susan M. | Rivadeneira, Fernando | Robertson, Neil R. | Sebert, Sylvain | Simell, Olli | Slowinski, Torsten | Tiesler, Carla M.T. | Tönjes, Anke | Vaag, Allan | Viikari, Jorma S. | Vink, Jacqueline M. | Vissing, Nadja Hawwa | Wareham, Nicholas J. | Willemsen, Gonneke | Witte, Daniel R. | Zhang, Haitao | Zhao, Jianhua | Wilson, James F. | Stumvoll, Michael | Prentice, Andrew M. | Meyer, Brian F. | Pearson, Ewan R. | Boreham, Colin A.G. | Cooper, Cyrus | Gillman, Matthew W. | Dedoussis, George V. | Moreno, Luis A | Pedersen, Oluf | Saarinen, Maiju | Mohlke, Karen L. | Boomsma, Dorret I. | Saw, Seang-Mei | Lakka, Timo A. | Körner, Antje | Loos, Ruth J.F. | Ong, Ken K. | Vollenweider, Peter | van Duijn, Cornelia M. | Koppelman, Gerard H. | Hattersley, Andrew T. | Holloway, John W. | Hocher, Berthold | Heinrich, Joachim | Power, Chris | Melbye, Mads | Guxens, Mònica | Pennell, Craig E. | Bønnelykke, Klaus | Bisgaard, Hans | Eriksson, Johan G. | Widén, Elisabeth | Hakonarson, Hakon | Uitterlinden, André G. | Pouta, Anneli | Lawlor, Debbie A. | Smith, George Davey | Frayling, Timothy M. | McCarthy, Mark I. | Grant, Struan F.A. | Jaddoe, Vincent W.V. | Jarvelin, Marjo-Riitta | Timpson, Nicholas J. | Prokopenko, Inga | Freathy, Rachel M.
Nature genetics  2012;45(1):76-82.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
doi:10.1038/ng.2477
PMCID: PMC3605762  PMID: 23202124
7.  A genome-wide association meta-analysis identifies new childhood obesity loci 
Bradfield, Jonathan P. | Taal, H. Rob | Timpson, Nicholas J. | Scherag, André | Lecoeur, Cecile | Warrington, Nicole M. | Hypponen, Elina | Holst, Claus | Valcarcel, Beatriz | Thiering, Elisabeth | Salem, Rany M. | Schumacher, Fredrick R. | Cousminer, Diana L. | Sleiman, Patrick M.A. | Zhao, Jianhua | Berkowitz, Robert I. | Vimaleswaran, Karani S. | Jarick, Ivonne | Pennell, Craig E. | Evans, David M. | St. Pourcain, Beate | Berry, Diane J. | Mook-Kanamori, Dennis O | Hofman, Albert | Rivadeinera, Fernando | Uitterlinden, André G. | van Duijn, Cornelia M. | van der Valk, Ralf J.P. | de Jongste, Johan C. | Postma, Dirkje S. | Boomsma, Dorret I. | Gauderman, William J. | Hassanein, Mohamed T. | Lindgren, Cecilia M. | Mägi, Reedik | Boreham, Colin A.G. | Neville, Charlotte E. | Moreno, Luis A. | Elliott, Paul | Pouta, Anneli | Hartikainen, Anna-Liisa | Li, Mingyao | Raitakari, Olli | Lehtimäki, Terho | Eriksson, Johan G. | Palotie, Aarno | Dallongeville, Jean | Das, Shikta | Deloukas, Panos | McMahon, George | Ring, Susan M. | Kemp, John P. | Buxton, Jessica L. | Blakemore, Alexandra I.F. | Bustamante, Mariona | Guxens, Mònica | Hirschhorn, Joel N. | Gillman, Matthew W. | Kreiner-Møller, Eskil | Bisgaard, Hans | Gilliland, Frank D. | Heinrich, Joachim | Wheeler, Eleanor | Barroso, Inês | O'Rahilly, Stephen | Meirhaeghe, Aline | Sørensen, Thorkild I.A. | Power, Chris | Palmer, Lyle J. | Hinney, Anke | Widen, Elisabeth | Farooqi, I. Sadaf | McCarthy, Mark I. | Froguel, Philippe | Meyre, David | Hebebrand, Johannes | Jarvelin, Marjo-Riitta | Jaddoe, Vincent W.V. | Smith, George Davey | Hakonarson, Hakon | Grant, Struan F.A.
Nature Genetics  2012;44(5):526-531.
Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made to establish genetic influences on common early-onset obesity. We performed a North American-Australian-European collaborative meta-analysis of fourteen studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight novel signals yielding association with P < 5×10−6 in to nine independent datasets (n = 2,818 cases and 4,083 controls) we observed two loci that yielded a genome wide significant combined P-value, namely near OLFM4 on 13q14 (rs9568856; P=1.82×10−9; OR=1.22) and within HOXB5 on 17q21 (rs9299; P=3.54×10−9; OR=1.14). Both loci continued to show association when including two extreme childhood obesity cohorts (n = 2,214 cases and 2,674 controls). Finally, these two loci yielded directionally consistent associations in the GIANT meta-analysis of adult BMI1.
doi:10.1038/ng.2247
PMCID: PMC3370100  PMID: 22484627
8.  Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight 
Freathy, Rachel M | Mook-Kanamori, Dennis O | Sovio, Ulla | Prokopenko, Inga | Timpson, Nicholas J | Berry, Diane J | Warrington, Nicole M | Widen, Elisabeth | Hottenga, Jouke Jan | Kaakinen, Marika | Lange, Leslie A | Bradfield, Jonathan P | Kerkhof, Marjan | Marsh, Julie A | Mägi, Reedik | Chen, Chih-Mei | Lyon, Helen N | Kirin, Mirna | Adair, Linda S | Aulchenko, Yurii S | Bennett, Amanda J | Borja, Judith B | Bouatia-Naji, Nabila | Charoen, Pimphen | Coin, Lachlan J M | Cousminer, Diana L | de Geus, Eco J. C. | Deloukas, Panos | Elliott, Paul | Evans, David M | Froguel, Philippe | Glaser, Beate | Groves, Christopher J | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hirschhorn, Joel N | Hofman, Albert | Holly, Jeff M P | Hyppönen, Elina | Kanoni, Stavroula | Knight, Bridget A | Laitinen, Jaana | Lindgren, Cecilia M | McArdle, Wendy L | O'Reilly, Paul F | Pennell, Craig E | Postma, Dirkje S | Pouta, Anneli | Ramasamy, Adaikalavan | Rayner, Nigel W | Ring, Susan M | Rivadeneira, Fernando | Shields, Beverley M | Strachan, David P | Surakka, Ida | Taanila, Anja | Tiesler, Carla | Uitterlinden, Andre G | van Duijn, Cornelia M | Wijga, Alet H | Willemsen, Gonneke | Zhang, Haitao | Zhao, Jianhua | Wilson, James F | Steegers, Eric A P | Hattersley, Andrew T | Eriksson, Johan G | Peltonen, Leena | Mohlke, Karen L | Grant, Struan F A | Hakonarson, Hakon | Koppelman, Gerard H | Dedoussis, George V | Heinrich, Joachim | Gillman, Matthew W | Palmer, Lyle J | Frayling, Timothy M | Boomsma, Dorret I | Smith, George Davey | Power, Chris | Jaddoe, Vincent W V | Jarvelin, Marjo-Riitta | McCarthy, Mark I
Nature genetics  2010;42(5):430-435.
INTRODUCTORY PARAGRAPH
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (N=10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in thirteen replication studies (N=27,591). Rs900400 near LEKR1 and CCNL1 (P=2×10−35), and rs9883204 in ADCY5 (P=7×10−15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and type 2 diabetes susceptibility,1 providing evidence that the well described association between lower birth weight and subsequent type 2 diabetes2,3 has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, the 9% of Europeans with 4 birth weight-lowering alleles were, on average, 113g (95%CI 89-137g) lighter at birth than the 24% with 0 or 1 allele (Ptrend=7×10−30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.4
doi:10.1038/ng.567
PMCID: PMC2862164  PMID: 20372150
9.  The role of obesity-associated loci identified in genome wide association studies in the determination of pediatric BMI 
Obesity (Silver Spring, Md.)  2009;17(12):2254-2257.
The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. A number of genetic determinants of adult BMI have already been established through genome wide association studies. In this study, we examined 25 single nucleotide polymorphisms (SNPs) corresponding to thirteen previously reported genomic loci in 6,078 children with measures of BMI. Fifteen of these SNPs yielded at least nominally significant association to BMI, representing nine different loci including INSIG2, FTO, MC4R, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15 and 1q25. Other loci revealed no evidence for association, namely at MTCH2, SH2B1, 12q13 and 3q27. For the 15 associated variants, the genotype score explained 1.12% of the total variation for BMI z-score. We conclude that among thirteen loci that have been reported to associate with adult BMI, at least nine also contribute to the determination of BMI in childhood as demonstrated by their associations in our pediatric cohort.
doi:10.1038/oby.2009.159
PMCID: PMC2860782  PMID: 19478790

Results 1-9 (9)