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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (2) : 146-161     DOI: 10.1007/s11684-014-0373-8
REVIEW |
Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies
Tao Wang,Weiping Jia,Cheng Hu()
Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
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Abstract  

Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.

Keywords obesity      genetics      genome-wide association studies      body mass index      fat mass- and obesity-associated gene     
Corresponding Authors: Cheng Hu   
Just Accepted Date: 24 October 2014   Online First Date: 30 December 2014    Issue Date: 22 May 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0373-8     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I2/146
Date Nearest GENE SNP Chr Position Risk allele EAF (%) Traits Effect size P value N (GWAS) N (follow-up) Reference
2007 FTO rs9939609 16 52 378 028 A 39 BMI 0.40 1.20E-29 4862 38 759 5
2008 MC4R rs17782313 18 56 002 077 C 21 BMI 0.22 2.80E-15 16 876 75 981 6
2009 TMEM18 rs6548238 2 624 905 C 84 BMI 0.26 3.20E-26 32 387 59 082 7
2009 GNPDA2 rs10938397 4 45 023 455 G 45 BMI 0.19 3.40E-16 32 387 59 082 7
2009 SH2B1 rs7498665 16 28 790 742 G 41 BMI 0.15 2.20E-14 32 387 59 082 7
2009 MTCH2 rs10838738 11 47 619 625 G 34 BMI 0.07 1.90E-11 32 387 59 082 7
2009 KCTD15 rs11084753 19 39 013 977 G 67 BMI 0.06 4.50E-12 32 387 59 082 7
2009 NEGR1 rs2815752 1 72 524 461 A 62 BMI 0.1 1.00E-12 32 387 59 082 7
2009 ETV5 rs7647305 3 187 316 984 C 77 BMI 0.04 7.20E-11 34 416 43 651 8
2009 FAIM2 rs7138803 12 48 533 735 A 43 BMI NR 1.20E-07 34 416 43 651 8
2009 BDNF rs4923461 11 27 613 486 A 84 BMI 0.04 3.20E-11 34 416 43 651 8
2009 SEC16B rs10913469 1 176 180 142 C 41 BMI 0.15 6.20E-08 34 416 43 651 8
2010 RBJ rs713586 2 25 011 512 C 47 BMI 0.14 6.17E-22 123 865 125931 9
2010 GPRC5B rs12444979 16 19 841 101 C 87 BMI 0.17 2.91E-21 123 865 125 931 9
2010 MAP2K5 rs2241423 15 65 873 892 G 78 BMI 0.13 1.19E-18 123 865 125 931 9
2010 QPCTL rs2287019 19 50 894 012 C 80 BMI 0.15 1.88E-16 123 865 125 931 9
2010 TNNI3K rs1514175 1 74 764 232 A 43 BMI 0.07 8.16E-14 123 865 125 931 9
2010 SLC39A8 rs13107325 4 103 407 732 T 7 BMI 0.19 1.50E-13 123 865 125 931 9
2010 FLJ35779 rs2112347 5 75 050 998 T 63 BMI 0.10 2.17E-13 123 865 125 931 9
2010 LRRN6C rs10968576 9 28 404 339 G 31 BMI 0.11 2.65E-13 123 865 125 931 9
2010 TMEM160 rs3810291 19 52 260 843 A 67 BMI 0.09 1.64E-12 123 865 125 931 9
2010 FANCL rs887912 2 59 156 381 T 29 BMI 0.10 1.79E-12 123 865 125 931 9
2010 CADM2 rs13078807 3 85 966 840 G 20 BMI 0.10 3.94E-11 123 865 125 931 9
2010 PRKD1 rs11847697 14 29 584 863 T 4 BMI 0.17 5.76E-11 123 865 125 931 9
2010 LRP1B rs2890652 2 142 676 401 C 18 BMI 0.09 1.35E-10 123 865 125 931 9
2010 PTBP2 rs1555543 1 96 717 385 C 59 BMI 0.06 3.68E-10 123 865 125 931 9
2010 MTIF3 rs4771122 13 26 918 180 G 24 BMI 0.09 9.48E-10 123 865 125 931 9
2010 ZNF608 rs4836133 5 124 360 002 A 48 BMI 0.07 1.97E-09 123 865 125 931 9
2010 RPL27A rs4929949 11 8 561 169 C 52 BMI 0.06 2.80E-09 123 865 125 931 9
2010 NUDT3 rs206936 6 34 410 847 G 21 BMI 0.06 3.02E-08 123 865 125 931 9
2010 NRXN3 rs10150332 14 79 006 717 C 21 BMI 0.13 2.75E-11 123 865 125 931 9
2010 TFAP2B rs987237 6 50 911 009 G 18 BMI 0.03 2.90E-20 123 865 125 931 9
2011 FTO rs8050136 16 52 373 776 C 60 Body fat percentage 0.33 2.70E- 26 36 626 39 576 20
2011 IRS1 rs2943650 2 226 814 165 T 64 Body fat percentage 0.16 3.80E-11 36 626 39 576 20
2011 SPRY2 rs534870 13 79 857 208 A 68 Body fat percentage 0.14 6.50E- 08 36 626 39 576 20
2009 FTO rs1558902 16 52 361 075 A 45 WC 0.73 4.64E-19 31 373 38 641 24
2009 MC4R rs489693 18 56 033 767 A 41 WC 0.37 3.54E-07 31 373 38 641 24
2009 NRXN3 rs10146997 14 79 014 915 G 25 WC 0.65 5.30E-08 31 373 38 641 24
2009 TFAP2B rs987237 6 50 835 337 G 16 WC 0.035 4.54E-09 38 580 70 639 25
2009 MSRA rs545854 8 10 002 570 G 18 WC 0.04 1.20E-08 38 580 70 639 25
2009 LYPLAL1 rs2605100 1 219 470 882 G 69 WHR 0.018 2.55E-08* 38 580 70 639 25
2010 RSPO3 rs9491696 6 127 494 332 G 52 WHR 0.042 1.84E-40 77 167 113 636 27
2010 VEGFA rs6905288 6 43 866 851 A 56 WHR 0.036 5.88E-25 77 167 113 636 27
2010 TBX15-WARS2 rs984222 1 119 305 366 G 37 WHR 0.034 8.69E-25 77 167 113 636 27
2010 NFE2L3 rs1055144 7 25 837 634 T 21 WHR 0.04 9.97E-25 77 167 113 636 27
2010 GRB14 rs10195252 2 165 221 337 T 60 WHR 0.033 2.09E-24 77 167 113 636 27
2010 DNM3-PIGC rs1011731 1 170 613 171 G 57 WHR 0.028 9.51E-18 77 167 113 636 27
2010 ITPR2-SSPN rs718314 12 26 344 550 G 74 WHR 0.03 1.14E-17 77 167 113 636 27
2010 LY86 rs1294421 6 6 688 148 G 39 WHR 0.028 1.75E-17 77 167 113 636 27
2010 HOXC13 rs1443512 12 52 628 951 A 24 WHR 0.031 6.38E-17 77 167 113 636 27
2010 ADAMTS9 rs6795735 3 64 680 405 C 41 WHR 0.025 9.79E-14 77 167 113 636 27
2010 ZNRF3-KREMEN1 rs4823006 22 27 781 671 A 57 WHR 0.023 1.10E-11 77 167 113 636 27
2010 NISCH-STAB1 rs6784615 3 52 481 466 T 94 WHR 0.043 3.84E-10 77 167 113 636 27
2010 CPEB4 rs6861681 5 173 295 064 A 34 WHR 0.022 1.91E-09 77 167 113 636 27
2013 MAP3K1 rs11743303 5 55 895 709 G 21 WC 0.031 2.69E-11* 73 137 74 657 28
2013 HSD17B4 rs10478424 5 118 816 919 A 78 WHR 0.039 3.45E-09* 73 137 74 657 28
2013 PPARG rs4684854 3 12 463 882 C 42 WHR 0.037 4.17E-14* 73 137 74 657 28
2012 LYPLAL1 rs11118316 1 217 723 786 G 58 VFA\SFA NR 3.16E-09 10 557 70 877–107 300 35
2012 THNSL2 rs1659258 2 88 440 703 A 86 VFA NR 1.60E-08* 10 557 70 877–107 300 35
Tab.1  Susceptibility of obesity-related traits in European populations
Date Nearest GENE SNP Chr Position Risk allele EAF (%) Traits Effect size P value Populations N (GWAS) N (follow-up) Reference
2012 CDKAL1 rs2206734 6 20 802 863 C 59 BMI 0.039 1.40E-11 East Asian 26 620 35 625 14
2012 KLF9 rs11142387 9 72 188 152 C 46 BMI 0.04 1.30E-09 East Asian 26 620 35 625 14
2012 PCSK1 rs261967 5 96 514 546 C 41 BMI 0.04 5.13E-09 East Asian 27 715 55 333 15
2012 GP2 rs12597579 16 20 246 545 C 80 BMI 0.04 1.02E-08 East Asian 27 715 55 333 15
2013 GALNT10 rs7708584 5 153 543 466 A 32 BMI 0.04 3.37E-11 African 39 144 32 268 19
2013 MIR148A-NFE2L3 rs10261878 7 25 917 070 C 44 BMI 0.032 1.23E-10 African 39 144 32 268 19
2014 KCNQ1 rs2237892 11 2 818 521 T 36 BMI 0.03 9.29E-13 East Asian 86 756 7488–47 352 16
2014 ALDH2 rs671 12 111 803 962 G 76 BMI 0.038 3.40E-11 East Asian 86 756 7488–47 352 16
2014 ITIH4 rs2535633 3 52 825 614 G 42 BMI 0.029 3.40E-11 East Asian 86 756 7488–47 352 16
2014 NT5C2 rs11191580 10 103 146 454 C 27 BMI 0.03 3.83E-08 East Asian 86 756 7488–47 352 16
2008 MC4R rs12970134 18 56 035 730 A 36 WC 0.88 1.70E-09 Indian Asian 2 684 11 955 29
2009 ALDH2-HECTD4 rs2074356 12 112 207 597 C 15 WHR 0.006 7.80E-12 East Asian 8 842 7 861 30
2013 LHX2 rs2075064 9 125 823 668 C 13 WC 0.07 2.20E-08 African 23 564 10 027 31
2013 RREB1 rs6931262 6 7 162 516 T 25 WHR 0.06 2.50E-08 African 23 564 10 027 31
Tab.2  Susceptibility loci of obesity-related traits in non-European populations
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