The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.
The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.
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DOI：
10.1002/oby.20147
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发表时间：
2013-01
期刊：
影响因子：
6.9
通讯作者：
Grant, Struan F. A.
中科院分区：
文献类型：
--
作者：
Deliard, Sandra;Panossian, Saarene;Mentch, Frank D.;Kim, Cecilia E.;Hou, Cuiping;Frackelton, Edward C.;Bradfield, Jonathan P.;Glessner, Joseph T.;Zhang, Haitao;Wang, Kai;Sleiman, Patrick M. A.;Chiavacci, Rosetta M.;Berkowitz, Robert I.;Hakonarson, Hakon;Zhao, Jianhua;Grant, Struan F. A.
在携带FTO、MC4R和TMEM 18的基因座处的常见变异一直被报道为在统计学上与肥胖最强相关。我们调查了这些基因座是否也含有罕见的错义变异，这些错义变异赋予非裔美国人（AA）儿童更高的常见儿童肥胖风险。我们在我们的队列的初始子集中，即200名肥胖（BMI≥第95百分位数）和200名瘦AA儿童（BMI≤第5百分位数）中对FTO、MC4R和TMEM 18的外显子进行测序。发现的任何错义外显子变异都将在同一种族的另外768名肥胖和768名瘦（BMI≤第50百分位数）儿童中进行进一步的基因分型。从我们的测序工作中观察到许多外显子变体：FTO中有7个，其中4个是非同义的（A163T、G182A、M400V和A405V），MC4R中有13个，其中6个是非同义的（V103I、N123S、S136A、F202L、N240S和I251L），TMEM18中有4个，其中2个是非同义的（P2S和V113L）。对这些错义变异体的后续基因分型显示，病例和对照之间的等位基因频率仅存在一个显著差异，即MC4R中的N240S（Fisher精确P = 0.0001）。总之，在我们的研究中观察到的FTO、MC4R和TMEM18基因中的中度罕见错义变异并没有赋予非裔美国人常见儿童肥胖症的风险，除了MC4R中一种已知功能丧失变异的证据。
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.
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肥胖相关基因座在全基因组关联研究中鉴定出的作用在小儿BMI的测定中。
影响因子：
6.9
作者：
Zhao, Jianhua;Bradfield, Jonathan P.;Li, Mingyao;Wang, Kai;Zhang, Haitao;Kim, Cecilia E.;Annaiah, Kiran;Glessner, Joseph T.;Thomas, Kelly;Garris, Maria;Frackelton, Edward C.;Otieno, F. George;Shaner, Julie L.;Smith, Ryan M.;Chiavacci, Rosetta M.;Berkowitz, Robert I.;Hakonarson, Hakon;Grant, Struan F. A.
通讯作者：
Grant, Struan F. A.
稀有变体会产生整个基因组的关联。
影响因子：
9.8
作者：
Dickson SP;Wang K;Krantz I;Hakonarson H;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
56.9
作者：
Frayling, Timothy M.;Timpson, Nicholas J.;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
30.8
作者：
Loos, Ruth J. F.;Lindgren, Cecilia M.;Li, Shengxu;Wheeler, Eleanor;Zhao, Jing Hua;Prokopenko, Inga;Inouye, Michael;Freathy, Rachel M.;Attwood, Antony P.;Beckmann, Jacques S.;Berndt, Sonja I.;Bergmann, Sven;Bennett, Amanda J.;Bingham, Sheila A.;Bochud, Murielle;Brown, Morris;Cauchi, Stephane;Connell, John M.;Cooper, Cyrus;Smith, George Davey;Day, Ian;Dina, Christian;De, Subhajyoti;Dermitzakis, Emmanouil T.;Doney, Alex S. F.;Elliott, Katherine S.;Elliott, Paul;Evans, David M.;Farooqi, I. Sadaf;Froguel, Philippe;Ghori, Jilur;Groves, Christopher J.;Gwilliam, Rhian;Hadley, David;Hall, Alistair S.;Hattersley, Andrew T.;Hebebrand, Johannes;Heid, Iris M.;Herrera, Blanca;Hinney, Anke;Hunt, Sarah E.;Jarvelin, Marjo-Riitta;Johnson, Toby;Jolley, Jennifer D. M.;Karpe, Fredrik;Keniry, Andrew;Khaw, Kay-Tee;Luben, Robert N.;Mangino, Massimo;Marchini, Jonathan;McArdle, Wendy L.;McGinnis, Ralph;Meyre, David;Munroe, Patricia B.;Morris, Andrew D.;Ness, Andrew R.;Neville, Matthew J.;Nica, Alexandra C.;Ong, Ken K.;O'Rahilly, Stephen;Owen, Katharine R.;Palmer, Colin N. A.;Papadakis, Konstantinos;Potter, Simon;Pouta, Anneli;Qi, Lu;Randall, Joshua C.;Rayner, Nigel W.;Ring, Susan M.;Sandhu, Manjinder S.;Scherag, Andre;Sims, Matthew A.;Song, Kijoung;Soranzo, Nicole;Speliotes, Elizabeth K.;Syddall, Holly E.;Teichmann, Sarah A.;Timpson, Nicholas J.;Tobias, Jonathan H.;Uda, Manuela;Vogel, Carla I. Ganz;Wallace, Chris;Waterworth, Dawn M.;Weedon, Michael N.;Willer, Cristen J.;Wraight, Vicki L.;Yuan, Xin;Zeggini, Eleftheria;Hirschhorn, Joel N.;Strachan, David P.;Ouwehand, Willem H.;Caulfield, Mark J.;Samani, Nilesh J.;Frayling, Timothy M.;Vollenweider, Peter;Waeber, Gerard;Mooser, Vincent;Deloukas, Panos;McCarthy, Mark I.;Wareham, Nicholas J.;Barroso, Ines
通讯作者：
Barroso, Ines
影响因子：
7.7
作者：
Meyre D;Proulx K;Kawagoe-Takaki H;Vatin V;Gutiérrez-Aguilar R;Lyon D;Ma M;Choquet H;Horber F;Van Hul W;Van Gaal L;Balkau B;Visvikis-Siest S;Pattou F;Farooqi IS;Saudek V;O'Rahilly S;Froguel P;Sedgwick B;Yeo GS
通讯作者：
Yeo GS