Table 4.
Trans-ethnic fixed-effect meta-analysis of 36 BMI loci and Bayesian fine-mapping in up to 101,979 individuals
| FE SNP estimates |
MANTRA Lead SNP estimates
|
Index-Lead SNPS r2 range*****
|
|||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene | Chr | FE Marker Type | rsID | Bp37 | Risk Allele | RAF | Effect (%) | StdErr (%) | P*** | Isq | HetP**** | N | log10BF | HetProb | N | In TE sample | In WHI EA |
| NEGR1 | 1 | Index | rs3101336 | 72,751,185 | C | 0.655 | 0.17 | 0.09 | 6.8E-02 | 69.4 | 2.0E-02 | 101,969 | 0.18 | 0.30 | |||
| Lead | rs1460939 | 72,861,567 | T | 0.868 | 0.47 | 0.13 | 4.3E-04 | 0.6 | 3.9E-01 | 101,976 | 2.3 | 0.022 | 101,976 | ||||
| TNNI3K | 1 | Index, Lead | rs12566985 | 75,002,193 | G | 0.719 | 0.42 | 0.11 | 2.8E-04 | 0 | 5.2E-01 | 75,627 | 1 (same), <0.01 (MANTRA) | 1 (same), <0.01 (MANTRA) | |||
| – | rs76514352 | 75,011,423 | 2.1 | 0.107 | 51,874 | ||||||||||||
| SEC16B | 1 | Index, Lead | rs543874 | 177,889,480 | G | 0.213 | 0.90 | 0.10 | 3.5E-21 | 72.9 | 1.1E-02 | 101,972 | 19.1 | 0.252 | 101,972 | 0.62–1 (same) | 0.96–1 (same) |
| LYPLAL1** | 1 | Index, Lead | rs2820436 | 219,640,680 | A | 0.388 | 0.50 | 0.09 | 3.2E-08 | 0 | 4.7E-01 | 93,721 | 6.0 | 0.006 | 93,721 | 1 (same) | 1 (same) |
| TMEM18 | 2 | Index | rs13021737 | 632,348 | G | 0.873 | 1.05 | 0.12 | 3.0E-18 | 42 | 1.6E-01 | 101,832 | 0.61–0.92 | 0.95 | |||
| Lead | rs6731872 | 624,205 | G | 0.877 | 1.09 | 0.12 | 8.3E-19 | 45.3 | 1.4E-01 | 101,832 | 16.6 | 0.037 | 101,832 | ||||
| BRE* | 2 | Index | rs116612809 | 28,301,171 | G | 0.088 | 1.05 | 0.23 | 8.8E-06 | 87.9 | 2.6E-04 | 68,016 | 5.1 | 0.937 | 68,016 | 0.07 | <0.01 |
| Lead | rs58154175 | 28,604,833 | T | 0.315 | 0.53 | 0.12 | 8.8E-06 | 12.6 | 3.3E-01 | 93,669 | |||||||
| COBLL1* | 2 | Index, Lead | rs10184004 | 165,508,389 | T | 0.452 | 0.52 | 0.10 | 1.3E-07 | 0 | 5.5E-01 | 93,726 | 5.6 | 0.011 | 93,726 | 1 (same) | 1 (same) |
| IRS1* | 2 | Index, Lead | rs2176040 | 227092802 | A | 0.275 | 0.50 | 0.10 | 4.0E-07 | 0 | 5.5E-01 | 93,732 | 5.1 | 0.006 | 93,732 | 1 (same) | 1 (same) |
| CADM2 | 3 | Index | rs13078960 | 85,807,590 | G | 0.857 | 0.00 | 0.15 | 9.8E-01 | 0 | 8.2E-01 | 101,976 | <0.01 | – | |||
| Lead | rs115299727 | 85,843,586 | G | 0.009 | 2.91 | 0.79 | 2.6E-04 | 0 | 1.0E+00 | 51,162 | 2.5 | 0.049 | 51,162 | ||||
| IGF2BP2** | 3 | Index, Lead | rs11927381 | 185,508,591 | T | 0.563 | 0.49 | 0.09 | 1.3E-07 | 0 | 8.4E-01 | 93,626 | 1 (same), 0.81 (MANTRA) | 1 (same), 0.99 (MANTRA) | |||
| – | rs4481184 | 185,505,787 | 5.6 | 0.005 | 93,647 | ||||||||||||
| ETV5 | 3 | Index | rs1516725 | 185,824,004 | C | 0.864 | 0.69 | 0.13 | 1.0E-07 | 0 | 8.7E-01 | 101,811 | 0.34 | 0.57 | |||
| Lead | rs7647305 | 185,834,290 | C | 0.720 | 0.59 | 0.10 | 3.7E-09 | 0 | 5.2E-01 | 101,974 | 7.0 | 0.017 | 101,974 | ||||
| GNPDA2 | 4 | Index | rs10938397 | 45,182,527 | G | 0.325 | 0.60 | 0.08 | 7.3E-13 | 1.7 | 3.8E-01 | 101,782 | 0.38–0.98 | 0.55–1.00 | |||
| Lead | rs12507026 | 45,181,334 | T | 0.325 | 0.61 | 0.08 | 5.3E-13 | 6.7 | 3.6E-01 | 101,974 | 10.8 | 0.011 | 101,974 | ||||
| SLC39A8* | 4 | Index, Lead | rs13107325 | 103,188,709 | T | 0.053 | 1.05 | 0.25 | 3.4E-05 | 0 | 8.7E-01 | 79,090 | 3.2 | 0.015 | 79,090 | 1 (same) | 1 (same) |
| POC5 | 5 | Index | rs2112347 | 75,015,242 | T | 0.531 | 0.28 | 0.08 | 4.3E-04 | 3.3 | 3.8E-01 | 101,972 | 0.17 | 0.57 | |||
| Lead | rs60493905 | 75,038,426 | C | 0.630 | 0.48 | 0.09 | 1.9E-08 | 0 | 7.8E-01 | 101,968 | 6.4 | 0.008 | 101,968 | ||||
| CDKAL1* | 6 | Index | rs9356744 | 20,685,486 | T | 0.562 | 0.42 | 0.08 | 2.6E-07 | 81.2 | 1.2E-03 | 101,966 | 0.24 | 0.48 | |||
| Lead | rs67131976 | 20,686,878 | C | 0.729 | 0.60 | 0.10 | 4.0E-10 | 61.6 | 5.0E-02 | 101,973 | 8.1 | 0.092 | 101,973 | ||||
| TFAP2B | 6 | Index | rs2207139 | 50,845,490 | G | 0.211 | 0.41 | 0.10 | 1.0E-04 | 2 | 3.8E-01 | 101,973 | 0.33 | 0.47 | |||
| Lead | rs2744475 | 50,784,880 | G | 0.352 | 0.56 | 0.08 | 9.9E-12 | 39.1 | 1.8E-01 | 101,763 | 9.7 | 0.015 | 101,763 | ||||
| SLC22A3* | 6 | Index | rs3127574 | 160,791,370 | C | 0.497 | 0.13 | 0.08 | 1.2E-01 | 51.7 | 1.0E-01 | 93,727 | 0.01, 0.03 (MANTRA) | <0.01, <0.01 (MANTRA) | |||
| Lead | rs78739765 | 160,868,121 | G | 0.979 | 1.34 | 0.43 | 1.9E-03 | 0 | 6.4E-01 | 72,083 | |||||||
| - | rs73589298 | 160,804,090 | 1.9 | 0.952 | 57,992 | ||||||||||||
| LINGO2 | 9 | Index | rs10968576 | 28,414,339 | G | 0.217 | 0.52 | 0.10 | 1.1E-07 | 0 | 5.9E-01 | 101,976 | 0.95 | 1.00 | |||
| Lead | rs17770336 | 28,414,625 | T | 0.223 | 0.52 | 0.10 | 9.6E-08 | 0 | 6.3E-01 | 101,930 | 5.8 | 0.013 | 101,930 | ||||
| NT5C2* | 10 | Index | rs11191560 | 104,869,038 | C | 0.204 | 0.54 | 0.11 | 1.8E-06 | 0 | 7.8E-01 | 101,966 | 0.86 | 0.95 | |||
| Lead | rs11191447 | 104,652,323 | T | 0.193 | 0.56 | 0.11 | 3.8E-07 | 0 | 8.4E-01 | 101,919 | 5.2 | 0.008 | 101,919 | ||||
| TCF7L2* | 10 | Index, Lead | rs7903146 | 114,758,349 | C | 0.739 | 0.75 | 0.10 | 2.2E-13 | 54 | 8.9E-02 | 101,975 | 11.2 | 0.063 | 101,975 | 1 (same) | 1 (same) |
| KCNQ1* | 11 | Index | rs2237897 | 2,858,546 | T | 0.237 | 0.66 | 0.12 | 3.3E-08 | 0 | 4.0E-01 | 93,516 | 0.76 | 0.97 | |||
| Lead | rs2237896 | 2,858,440 | A | 0.272 | 0.73 | 0.13 | 3.0E-08 | 0 | 4.6E-01 | 93,196 | 6.2 | 0.014 | 93,196 | ||||
| STK33/TRIM66 | 11 | Index | rs4256980 | 8,673,939 | G | 0.509 | 0.22 | 0.08 | 5.2E-03 | 0 | 5.4E-01 | 101,492 | 0.80 | – | |||
| Lead | rs76876925 | 8,650,183 | G | 0.512 | 0.36 | 0.10 | 1.4E-04 | 0 | 8.7E-01 | 72,292 | 2.7 | 0.008 | 72,292 | ||||
| KCNJ11* | 11 | Index | rs1557765 | 17,403,639 | T | 0.686 | 0.31 | 0.10 | 1.5E-03 | 0 | 5.0E-01 | 93,268 | 0.08–0.09, 0.20–0.21 (MANTRA) | 0.26–0.27, 0.39–0.41 (MANTRA) | |||
| Lead | rs7949405 | 17,085,192 | A | 0.568 | 0.32 | 0.09 | 4.8E-04 | 0 | 5.8E-01 | 86,446 | |||||||
| – | rs214933 | 17,194,584 | 2.2 | 0.005 | 93,270 | ||||||||||||
| BDNF-AS1/BDNF | 11 | Index | rs11030104 | 27,684,517 | A | 0.694 | 0.40 | 0.10 | 7.3E-05 | 79.5 | 2.2E-03 | 101,516 | 0.28–0.40 | 0.13–0.35 | |||
| Lead | rs1519480 | 27,675,712 | C | 0.444 | 0.59 | 0.09 | 1.2E-11 | 44.3 | 1.5E-01 | 101,510 | 9.5 | 0.006 | 101,510 | ||||
| MTCH2 | 11 | Index | rs3817334 | 47,650,993 | T | 0.338 | 0.28 | 0.08 | 6.3E-04 | 0 | 5.0E-01 | 101,940 | 0.03 | 0.09 | |||
| Lead | rs896817 | 47,394,305 | C | 0.713 | 0.46 | 0.09 | 4.3E-07 | 0 | 7.9E-01 | 101,965 | 5.1 | 0.006 | 101,965 | ||||
| FAIM2 | 12 | Index, Lead | rs7138803 | 50,247,468 | A | 0.285 | 0.35 | 0.09 | 9.0E-05 | 0 | 4.8E-01 | 101,969 | 2.9 | 0.003 | 101,969 | 1 (same) | 1 (same) |
| BRAP* | 12 | Index | rs11065987 | 112,072,424 | A | 0.716 | 0.21 | 0.12 | 8.8E-02 | 17.8 | 3.0E-01 | 93,730 | <0.01–0.06 | 0.17–0.18 | |||
| Lead | rs10774631 | 112,023,001 | A | 0.219 | 0.25 | 0.10 | 1.2E-02 | 46.6 | 1.3E-01 | 93,498 | 0.9 | 0.024 | 93,498 | ||||
| PRKD1 | 14 | Index | rs11847697 | 30,515,112 | T | 0.258 | 0.01 | 0.14 | 9.3E-01 | 0 | 9.5E-01 | 93,490 | 0.02 | 0.04 | |||
| Lead | rs1957347 | 30,483,129 | T | 0.303 | 0.27 | 0.09 | 3.4E-03 | 0 | 5.4E-01 | 101,505 | 1.4 | 0.016 | 101,505 | ||||
| MAP2K5 | 15 | Index | rs16951275 | 68,077,168 | T | 0.542 | 0.35 | 0.08 | 2.5E-05 | 27.3 | 2.5E-01 | 101,972 | 0.56–1 (same) | 0.54–1 (same) | |||
| Lead | rs4776970 | 68,080,886 | A | 0.422 | 0.38 | 0.08 | 6.1E-06 | 0 | 9.0E-01 | 101,972 | 4.1 | 0.004 | 101,972 | ||||
| GPRC5B | 16 | Index | rs12446632 | 19,935,389 | G | 0.02, 0.03 (MANTRA) | 0.03, 0.05 (MANTRA) | ||||||||||
| Lead | rs67501351 | 20,006,745 | G | 0.372 | 0.36 | 0.08 | 1.5E-05 | 28.8 | 2.4E-01 | 101,506 | |||||||
| - | rs28461566 | 19,998,311 | 3.5 | 0.021 | 101,498 | ||||||||||||
| ATP2A1 | 16 | Index | rs2650492 | 28,333,411 | A | 0.146 | 0.54 | 0.14 | 9.5E-05 | 26.1 | 2.5E-01 | 99,770 | 0.92 | 0.38–1.00 | |||
| Lead | rs8061590 | 28,895,130 | G | 0.307 | 0.52 | 0.10 | 2.9E-07 | 0 | 3.7E-01 | 84,081 | 5.2 | 0.011 | 84,081 | ||||
| FTO | 16 | Index | rs17817964 | 53,828,066 | T | 0.256 | 1.23 | 0.10 | 7.1E-36 | 0 | 7.1E-01 | 101,976 | 0.94–0.95 | 0.95–0.99 | |||
| Lead | rs3751812 | 53,818,460 | T | 0.242 | 1.34 | 0.10 | 2.3E-42 | 15.6 | 3.1E-01 | 101,974 | 39.9 | 0.010 | 101,974 | ||||
| KCNJ2* | 17 | Index | rs312750 | 68,343,539 | A | 0.638 | 0.09 | 0.09 | 3.4E-01 | 0 | 8.9E-01 | 93,734 | <0.01 | <0.01 | |||
| Lead | rs72868947 | 68,494,065 | T | 0.007 | 2.60 | 0.78 | 9.2E-04 | 52.5 | 1.2E-01 | 74,163 | 1.7 | 0.105 | 74,163 | ||||
| MC4R | 18 | Index, Lead | rs6567160 | 57,829,135 | C | 0.193 | 0.89 | 0.10 | 9.4E-19 | 13.8 | 3.2E-01 | 101,966 | 16.2 | 0.011 | 101,966 | 0.01–1 (same) | <0.01–1 (same) |
| KCTD15 | 19 | Index | rs29941 | 34,309,532 | G | 0.562 | 0.26 | 0.09 | 3.9E-03 | 0 | 6.2E-01 | 101,951 | 0.49 | 0.60 | |||
| Lead | rs368794 | 34,320,452 | A | 0.537 | 0.32 | 0.08 | 1.4E-04 | 0 | 4.0E-01 | 99,796 | 2.7 | 0.012 | 99,796 | ||||
| GIPR* | 19 | Index | rs11671664 | 46,172,278 | G | 0.688 | 0.40 | 0.11 | 1.5E-04 | 79.9 | 1.9E-03 | 101,500 | 0.09–0.88, 0.09–0.88 (MANTRA) | 0.42–0.90, 0.42–0.90 (MANTRA) | |||
| Lead | rs1800437 | 46,181,392 | G | 0.817 | 0.64 | 0.11 | 1.6E-09 | 0 | 8.2E-01 | 101,488 | |||||||
| - | rs11672660 | 46,180,184 | 7.0 | 0.007 | 101,501 | ||||||||||||
Abbreviations: Bp37=base pair Build 37, BF=Bayes Factor, Chr=chromosome, EA=European American women, FE=Fixed-Effect, HetProb=The posterior probability of heterogeneity, MANTRA=Meta-ANalysis of Trans-Ethnic Association studies, RAF=Risk Allele Frequency, RAF=risk allele frequency, SNPs=single nucleotide polymorphisms, TE=Transethnic.
*
Note: Starred genes represent fine-mapped loci, which were associated with BMI after the design of the Metabochip in 2009.
**
Genome-wide significant findings under review (Gong et al., under review at Nature Comm).
***
For GWAS SNPs a Bonferroni correction for multiple tests reflected the number of independent GWAS signals tested (=0.05/166; Supplemental Table 3). For all other SNPs in the fine-mapped BMI regions, we performed a Bonferroni correction for the number of independent SNPs per region (r2<0.2 in ARIC African-Americans; Supplemental Table 1).
****
Locus-specific Bonferroni significant heterogeneity p-values shown in italics.
*****
The range of linkage disequilibrium captures any SNP within the fine-mapped loci (Supplemental Table 3) that represents the index BMI signal or secondary signal (described in European descent populations), or race/ethnic population specific marker. ARIC, HCHS/SOL, and WHI samples were used to represent the linkage disequilibrium for the PAGE trans-ethnic and European descent samples.