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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

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Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Genome-wide association results for the BMI meta-analysis.(a) Manhattan plot showing the significance of association between all SNPs and BMI in the stage 1 meta-analysis, highlighting SNPs previously reported to show genome-wide significant association with BMI (blue), weight or waist circumference (green) and the 18 new regions described here (red). The 19 SNPs that reached genome-wide significance in stage 1 (13 previously reported and 6 new SNPs) are listed in Table 1. (b) Quantile-quantile plot of SNPs in the stage 1 meta-analysis (black) and after removing any SNPs within 1 Mb of the ten previously reported genome-wide significant hits for BMI (blue), after additionally excluding SNPs from the four loci for waist or weight (green), and after excluding SNPs from all 32 confirmed loci (red). The plot is abridged at the y axis (at P < 10−20) to better visualize the excess of small P values after excluding the 32 confirmed loci (Supplementary shows the full-scale quantile-quantile plot). The shaded region is the 95% concentration band. (c) Plot of effect size (in inverse-normally transformed units (invBMI)) versus effect-allele frequency of newly identified and previously identified BMI variants after stage 1 and stage 2 meta-analysis, including the 10 previously identified BMI loci (blue), the 4 previously identified waist and weight loci (green) and the 18 newly identified BMI loci (blue). The dotted lines represent the minimum effect sizes that could be identified for a given effect-allele frequency with 80% (upper line), 50% (middle line) and 10% (lower line) power, assuming a sample size of 123,000 individuals and an α level of 5 × 10−8.
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Nature GeNetics VOLUME 42 | NUMBER 11 | NOVEMBER 2010 937
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Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci
for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals
with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci
and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near
GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of
these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into
human body weight regulation.
19 loci associated with BMI at P < 5 × 10−8 (Table 1, Fig. 1a and
Supplementary Table 1). These 19 loci included all ten loci from
previous GWAS of BMI6–10, two loci previously associated with body
weight10 (at FAIM2 and SEC16B) and one locus previously associated
with waist circumference14 (near TFAP2B). The remaining six loci,
near GPRC5B, MAP2K5-LBXCOR1, TNNI3K, LRRN6C, FLJ35779-
HMGCR and PRKD1, have not previously been associated with BMI
or other obesity-related traits.
Stage 2 follow up identifies additional new loci for BMI
To identify additional BMI-associated loci and to validate the loci
that reached genome-wide significance in the stage 1 analyses, we
examined SNPs representing 42 independent loci (including the 19
genome-wide significant loci) having a stage 1 P < 5 × 10−6. Variants
were considered to be independent if the pair-wise linkage disequi-
librium (LD, r2) was less than 0.1 and if they were separated by at
least 1 Mb. In stage 2, we examined these 42 SNPs in up to 125,931
additional individuals (79,561 newly genotyped individuals from 16
different studies and 46,370 individuals from 18 additional studies
for which genome-wide association data were available; Table 1,
Supplementary Note and Online Methods). In a joint analysis of
stage 1 and stage 2 results, 32 of the 42 SNPs reached P < 5 × 10−8
(Table 1, Supplementary Table 1 and Supplementary Figs. 1 and 2).
Even after excluding SNPs within the 32 confirmed BMI loci, we still
observed an excess of small P values compared to the distribution
expected under the null hypothesis (Fig. 1b and Supplementary
Fig. 3), suggesting that more BMI loci remain to be uncovered.
The 32 confirmed associations included all 19 loci with P < 5 × 10−8
at stage 1, 12 additional new loci near RBJ-ADCY3-POMC, QPCTL-
GIPR, SLC39A8, TMEM160, FANCL, CADM2, LRP1B, PTBP2, MTIF3-
GTF3A, ZNF608, RPL27A-TUB and NUDT3-HMGA1 and one locus
(in NRXN3) previously associated with waist circumference15 (Table 1,
Supplementary Table 1 and Supplementary Figs. 1 and 2). In all,
our study increased the number of loci robustly associated with BMI
from 10 to 32. Four of the 22 new loci were previously associated
Association analyses of 249,796 individuals reveal
18 new loci associated with body mass index
Obesity is a major and increasingly prevalent risk factor for multiple
disorders, including type 2 diabetes and cardiovascular disease1,2.
Although lifestyle changes have driven its prevalence to epidemic
proportions, heritability studies provide evidence for a substantial
genetic contribution (with heritability estimates (h2) of ~40%–70%)
to obesity risk3,4. BMI is an inexpensive, non-invasive measure of
obesity that predicts the risk of related complications5. Identifying
genetic determinants of BMI could lead to a better understanding of
the biological basis of obesity.
Genome-wide association studies (GWAS) of BMI have previously
identified ten loci with genome-wide significant (P < 5 × 10−8) asso-
ciations6–10 in or near FTO, MC4R, TMEM18, GNPDA2, BDNF,
NEGR1, SH2B1, ETV5, MTCH2 and KCTD15. Many of these genes
are expressed or known to act in the central nervous system, high-
lighting a likely neuronal component in the predisposition to obesity9.
This pattern is consistent with results in animal models and studies
of monogenic human obesity in which neuronal genes, particularly
those expressed in the hypothalamus and involved in regulation of
appetite or energy balance, are known to play a major role in suscep-
tibility to obesity11–13.
The ten previously identified loci account for only a small fraction
of the variation in BMI. Furthermore, power calculations based on the
effect sizes of established variants have suggested that increasing the
sample size would likely lead to the discovery of additional variants9.
To identify additional loci associated with BMI, we expanded the
Genetic Investigation of Anthropometric Traits (GIANT) Consortium
genome-wide association meta-analysis to include a total of 249,796
individuals of European ancestry.
RESULTS
Stage 1 GWAS identifies new loci associated with BMI
We first conducted a meta-analysis of GWAS of BMI and ~2.8 million
imputed or genotyped SNPs using data from 46 studies including
up to 123,865 individuals (Online Methods, Supplementary
Fig. 1 and Supplementar y Note). This stage 1 analysis revealed
A full list of authors and affiliations appear at the end of the paper.
Received 13 May; accepted 15 September; published online 10 October 2010; doi:10.1038/ng.686
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93 8 VOLUME 42 | NUMBER 11 | NOVEMBER 2010 Nature GeNetics
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with body weight10 or waist circumference14,15, whereas 18 new loci
had not previously associated with any obesity-related trait in the gen-
eral population. Although we confirmed all loci previously established
by large-scale GWAS for BMI6–10 and waist circumference14,15, four
loci previously identified in GWAS for early-onset or adult morbid
obesity16,17 (at NPC1, rs1805081, P = 0.0025; MAF, rs1424233, P = 0.25;
PTER, rs10508503, P = 0.64; and TNKS-MSRA, rs473034, P = 0.23)
showed limited or no evidence of association with BMI in our study.
Table 1 Stage 1 and stage 2 results of the 32 SNPs that were associated with BMI at genome-wide significant (P < 5 × 10−8) levels
SNP
Nearest
gene
Other
nearby
genesaChr.
Positionb
(bp)
AllelesbFrequency
effect
allele
Per allele
change
in BMI Explained
variance
(%) Stage 1 PStage 2 P
Stage 1 + 2
Effect Other β (s.e.m.)cn P
Previously identified BMI loci
rs1558902 FTO 16 52,361,075 A T 0.42 0.39 (0.02) 0.34% 2.05 × 10−62 1.01 × 10−60 192,344 4.8 × 10−120
rs2867125 TMEM18 2 612,827 C T 0.83 0.31 (0.03) 0.15% 2.42 × 10−22 4.42 × 10−30 197,806 2.77 × 10−49
rs571312 MC4R (B) 18 55,990,749 A C 0.24 0.23 (0.03) 0.10% 1.82 × 10−22 3.19 × 10−21 203,600 6.43 × 10−42
rs10938397 GNPDA2 4 44,877,284 G A 0.43 0.18 (0.02) 0.08% 4.35 × 10−17 1.45 × 10−15 197,008 3.78 × 10−31
rs10767664 BDNF (B,M) 11 27,682,562 A T 0.78 0.19 (0.03) 0.07% 5.53 × 10−13 1.17 × 10−14 204,158 4.69 × 10−26
rs2815752 NEGR1
(C,Q)
1 72,585,028 A G 0.61 0.13 (0.02) 0.04% 1.17 × 10−14 2.29 × 10−9 198,380 1.61 × 10−22
rs7359397 SH2B1
(Q,B,M)
APOB48R
(Q,M),
SULT1A2
(Q,M),
AC138894.2
(M), ATXN2L
(M), TUFM (Q)
16 28,793,160 T C 0.40 0.15 (0.02) 0.05% 1.75 × 10−10 7.89 × 10−12 204,309 1.88 × 10−20
rs9816226 ETV5 3 187,317,193 T A 0.82 0.14 (0.03) 0.03% 7.61 × 10−14 1.15 × 10−6 196,221 1.69 × 10−18
rs3817334 MTCH2
(Q,M)
NDUFS3 (Q),
CUGBP1 (Q)
11 47,607,569 T C 0.41 0.06 (0.02) 0.01% 4.79 × 10−11 1.10 × 10−3 191,943 1.59 × 10−12
rs29941 KCTD15 19 39,001,372 G A 0.67 0.06 (0.02) 0.00% 1.31 × 10−9 2.40 × 10−2 192,872 3.01 × 10−9
Previously identified waist and weight loci
rs543874 SEC16B 1 176,156,103 G A 0.19 0.22 (0.03) 0.07% 1.66 × 10−13 2.41 × 10−11 179,414 3.56 × 10−23
rs987237 TFAP2B 6 50,911,009 G A 0.18 0.13 (0.03) 0.03% 5.97 × 10−16 2.40 × 10−6 195,776 2.90 × 10−20
rs7138803 FAIM2 12 48,533,735 A G 0.38 0.12 (0.02) 0.04% 3.96 × 10−11 7.82 × 10−8 200,064 1.82 × 10−17
rs10150332 NRXN3 14 79,006,717 C T 0.21 0.13 (0.03) 0.02% 2.03 × 10−7 2.86 × 10−5 183,022 2.75 × 10−11
Newly identified BMI loci
rs713586 RBJ ADCY3 (Q, M),
POMC (Q,B)
2 25,011,512 C T 0.47 0.14 (0.02) 0.06% 1.80 × 10−7 1.44 × 10−16 230,748 6.17 × 10−22
rs12444979 GPRC5B
(C,Q)
IQCK (Q) 16 19,841,101 C T 0.87 0.17 (0.03) 0.04% 4.20 × 10−11 8.13 × 10−12 239,715 2.91 × 10−21
rs2241423 MAP2K5 LBXCOR1 (M) 15 65,873,892 G A 0.78 0.13 (0.02) 0.03% 1.15 × 10−10 1.59 × 10−9 227,950 1.19 × 10−18
rs2287019 QPCTL GIPR (B,M) 19 50,894,012 C T 0.80 0.15 (0.03) 0.04% 3.18 × 10−7 1.40 × 10−10 194,564 1.88 × 10−16
rs1514175 TNNI3K 1 74,764,232 A G 0.43 0.07 (0.02) 0.02% 1.36 × 10–9 7.04 × 10−6 227,900 8.16 × 10−14
rs13107325 SLC39A8
(Q,M)
4 103,407,732 T C 0.07 0.19 (0.04) 0.03% 1.37 × 10−7 1.93 × 10−7 245,378 1.50 × 10−13
rs2112347 FLJ35779
(M)
HMGCR (B) 5 75,050,998 T G 0.63 0.10 (0.02) 0.02% 4.76 × 10−8 8.29 × 10−7 231,729 2.17 × 10−13
rs10968576 LRRN6C 9 28,404,339 G A 0.31 0.11 (0.02) 0.02% 1.88 × 10−8 3.19 × 10−6 216,916 2.65 × 10−13
rs3810291 TMEM160
(Q)
ZC3H4 (Q) 19 52,260,843 A G 0.67 0.09 (0.02) 0.02% 1.04 × 10−7 1.59 × 10−6 233,512 1.64 × 10−12
rs887912 FANCL 2 59,156,381 T C 0.29 0.10 (0.02) 0.03% 2.69 × 10−6 1.72 × 10−7 242,807 1.79 × 10−12
rs13078807 CADM2 3 85,966,840 G A 0.20 0.10 (0.02) 0.02% 9.81 × 10−8 5.32 × 10−5 237,404 3.94 × 10−11
rs11847697 PRKD1 14 29,584,863 T C 0.04 0.17 (0.05) 0.01% 1.11 × 10−8 2.25 × 10−4 241,667 5.76 × 10−11
rs2890652 LRP1B 2 142,676,401 C T 0.18 0.09 (0.03) 0.02% 2.38 × 10−7 9.47 × 10−5 209,068 1.35 × 10−10
rs1555543 PTBP2 1 96,717,385 C A 0.59 0.06 (0.02) 0.01% 7.65 × 10−7 4.48 × 10−5 243,013 3.68 × 10−10
rs4771122 MTIF3 GTF3A (Q) 13 26,918,180 G A 0.24 0.09 (0.03) 0.02% 1.20 × 10−7 8.24 × 10−4 198,577 9.48 × 10−10
rs4836133 ZNF608 5 124,360,002 A C 0.48 0.07 (0.02) 0.01% 7.04 × 10−7 1.88 × 10−4 241,999 1.97 × 10−9
rs4929949 RPL27A TUB (B) 11 8,561,169 C T 0.52 0.06 (0.02) 0.01% 7.57 × 10−8 1.00 × 10−3 249,791 2.80 × 10−9
rs206936 NUDT3 HMGA1 (B) 6 34,410,847 G A 0.21 0.06 (0.02) 0.01% 2.81 × 10−6 7.39 × 10−4 249,777 3.02 × 10−8
Chr., chromosome; Q, association and eQTL data converge to affect gene expression; B, biological candidate; M, BMI-associated variant is in strong LD (r2 0.75) with a missense
variant in the indicated gene; C, CNV.
aGenes within ± 500 kb of the lead SNP. bPositions according to Build 36 and allele coding based on the positive strand. cEffect sizes in kg/m2 obtained from stage 2 cohorts only.
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Nature GeNetics VOLUME 42 | NUMBER 11 | NOVEMBER 2010 939
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As could be expected, the effect sizes of the 18 newly discovered loci
are slightly smaller, for a given minor allele frequency, than those of
the previously identified variants (Table 1 and Fig. 1c). The increased
sample size used here also brought out more signals with low minor
allele frequency. The BMI-increasing allele frequencies for the 18
newly identified variants ranged from 4% to 87%, covering more of
the allele frequency spectrum than previous, smaller GWAS of BMI
(24%–83%)9,10 (Table 1 and Fig. 1c).
We tested for evidence of non-additive (dominant or recessive)
effects, SNP × SNP interaction effects and heterogeneity by sex or
study among the 32 BMI-associated SNPs (Online Methods). We
found no evidence for any such effects (all P > 0.001 and no significant
results were seen after correcting for multiple testing) (Supplementary
Table 1 and Supplementary Note).
Impact of the 32 confirmed loci on BMI, obesity, body size
and other metabolic traits
Together, the 32 confirmed BMI loci explained 1.45% of the inter-
individual variation in BMI in the stage 2 samples, with the FTO
SNP accounting for the largest proportion of the variance (0.34%)
(Table 1). To estimate the cumulative effect of the 32 variants on BMI,
we constructed a genetic susceptibility score that summed the number
of BMI-increasing alleles weighted by the overall stage 2 effect sizes in
the Atherosclerosis Risk in Communities (ARIC) study (n = 8,120),
one of our largest population-based studies (Online Methods). For
each unit increase in the genetic-susceptibility score, which is approxi-
mately equivalent to having one additional risk allele, BMI increased
by 0.17 kg/m2, the equivalent of a 435–551 g gain in body weight in
adults of 160–180 cm in height. The difference in average BMI between
individuals with a high genetic-susceptibility score (defined as having
38 BMI-increasing alleles, comprising 1.5% (n = 124) of the ARIC
sample) and those with a low genetic-susceptibility score (defined
as having 21 BMI-increasing alleles, comprising 2.2% (n = 175) of
the ARIC sample) was 2.73 kg/m2, equivalent to a 6.99–8.85 kg body
weight difference in adults of 160–180 cm in height (Fig. 2a). Still,
we note that the predictive value for obesity risk and BMI of the 32
variants combined was modest, although it was statistically significant
(Fig. 2b and Supplementary Fig. 4). The area under the receiver-
operating characteristic (ROC) curve for prediction of risk of obesity
(BMI 30 kg/m2) using a model including age, age2 and sex only was
0.515 (P = 0.023 compared to the area under the curve (AUC) of 0.50),
which increased to 0.575 (P < 10−5) when the 32 confirmed SNPs were
also included in the model (Fig. 2b). The area under the ROC curve
for the model including the 32 SNPs only was 0.574 (P < 10−5).
All 32 confirmed BMI-increasing alleles showed directionally
consistent effects on the risk of being overweight (BMI 25 kg/m2)
or obese (BMI 30 kg/m2) in the stage 2 samples, with 30 of 32
variants achieving at least nominally significant associations. The
BMI-increasing alleles increased the odds of being overweight by
1.013- to 1.138-fold and the odds of being obese by 1.016- to 1.203-
fold (Supplementary Table 2). In addition, 30 of the 32 loci also
showed directionally consistent effects on the risk of extreme and
early-onset obesity in a meta-analysis of seven case-control studies of
adults and children (binomial sign test P = 1.3 × 10−7) (Supplementary
Table 3). The BMI-increasing allele observed in adults also increased
the BMI in children and adolescents with directionally consistent
effects observed for 23 of the 32 SNPs (binomial sign test P = 0.01).
Furthermore, in family-based studies, the BMI-increasing allele was
over-transmitted to the obese offspring for 24 of the 32 SNPs (bino-
mial sign test P = 0.004) (Supplementary Table 3). As these studies
in extreme obesity cases, children and families were relatively small
(with n ranging from 354 to 15,251 individuals) compared to the
overall meta-analyses, their power was likely insufficient to confirm
association for all 32 loci. Nevertheless, these results show that the
effects are unlikely to reflect population stratification and that they
extend to BMI differences throughout the life course.
Figure 1 Genome-wide association results for
the BMI meta-analysis. (a) Manhattan plot
showing the significance of association between
all SNPs and BMI in the stage 1 meta-analysis,
highlighting SNPs previously reported to show
genome-wide significant association with BMI
(blue), weight or waist circumference (green)
and the 18 new regions described here (red).
The 19 SNPs that reached genome-wide
significance in stage 1 (13 previously reported
and 6 new SNPs) are listed in Table 1.
(b) Quantile-quantile plot of SNPs in the stage 1
meta-analysis (black) and after removing any
SNPs within 1 Mb of the ten previously reported
genome-wide significant hits for BMI (blue),
after additionally excluding SNPs from the
four loci for waist or weight (green), and after
excluding SNPs from all 32 confirmed
loci (red). The plot is abridged at the y axis
(at P < 10−20) to better visualize the excess of
small P values after excluding the 32 confirmed
loci (Supplementary Fig. 3 shows the full-scale
quantile-quantile plot). The shaded region is the
95% concentration band. (c) Plot of effect size
(in inverse-normally transformed units (invBMI))
versus effect-allele frequency of newly identified
and previously identified BMI variants after
stage 1 and stage 2 meta-analysis, including the
10 previously identified BMI loci (blue), the 4 previously identified waist and weight loci (green) and the 18 newly identified BMI loci (blue). The dotted
lines represent the minimum effect sizes that could be identified for a given effect-allele frequency with 80% (upper line), 50% (middle line) and 10%
(lower line) power, assuming a sample size of 123,000 individuals and an
α
level of 5 × 10−8.
70
60
50
Novel loci
Previous waist or weight loci
Previous BMI loci
Novel loci
Excluding SNPs
from 32 confirmed loci
Excluding SNPs
from 14 previous
BMI/waist/weight loci
Excluding SNPs from 10
previously known BMI loci
All SNPs Previous waist or
weight loci
Previous BMI loci
40 NEGR1
TMEM18 GNPDA2
MTCH2 SH2B1
MC4R
NRXN3
FAIM2
TFAP2B
SEC16B
FTO
MAP2K5
GPRC5B
MTIF3
RPL27A
LRRN6C
CADM2
LRP1B
TNNI3K
PTBP2 FANCL
POMC
SLC39A8 NUDT3
ZNF608
FLJ35779
PRKD1
TMEM160
GIPR
KCTD15
BDNF
ETV5
30
20
10
10
15
5
0
0
1 2 3 4 5 6 7
Chromosomes
1 2 3 4 5 60 7
8 9 10 11
0.09
0.08
FTO
0.07
0.06
0.05
0.04
0.03
0.02
0.01
Increase in BMI (InvBMI units)
per additional BMI-increasing allele
0
0% 60%
Allele frequency of BMI-increasing allele
100%80%40%20%
12 13 14 15 16 17 1819 20 2221
–log10 P–log10 P
Expected –log10 P
a
c
b
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All BMI-increasing alleles were associated with increased body
weight, as could be expected from the correlation between BMI and
body weight (Supplementary Table 2). To confirm an effect of the loci
on adiposity rather than general body size, we tested for association
with body fat percentage, for which data was available in a subset of the
stage 2 replication samples (n = 5,359 to n = 28,425) (Supplementary
Table 2). The BMI-increasing allele showed directionally consistent
effects on body fat percentage at 31 of the 32 confirmed loci (binomial
sign test P = 1.54 × 10−8) (Supplementary Table 2).
We also examined the association of the BMI loci with metabolic
traits (type 2 diabetes18, fasting glucose, fasting insulin, indices of
β-cell function (HOMA-B) and insulin resistance (HOMA-IR)19, and
blood lipid levels20) and with height (Supplementary Tables 2 and 4).
Although many nominal associations were expected because of known
correlations between BMI and most of these traits, and because of
overlap in samples, several associations stood out as possible examples
of pleiotropic effects of the BMI-associated variants. Particularly
interesting is the variant in the GIPR locus, where the BMI-increasing
allele is also associated with increased fasting glucose levels and lower
2-h glucose levels (Supplementary Table 4)19,21. The direction of
the effect is opposite to what would be expected due to the correla-
tion between obesity and glucose intolerance but is consistent with
the suggested roles of GIPR in glucose and energy metabolism (see
below)22. Three loci showed strong associations (P < 10−4) with height
(at MC4R, RBJ-ADCY3-POMC and MTCH2-NDUFS3). Because BMI
is weakly correlated with height (and indeed, the BMI-associated vari-
ants as a group show no consistent effect on height), these associations
are also suggestive of pleiotropy. Notably, analogous to the effects of
severe mutations in POMC and MC4R on height and weight23,24, the
BMI-increasing alleles of the variants near these genes were associated
with decreased (POMC) and increased (MC4R) height, respectively
(Supplementary Table 2).
Potential functional roles and pathway analyses
Although associated variants typically implicate genomic regions
rather than individual genes, we note that some of the 32 loci include
candidate genes with established connections to obesity. Several of
the ten previously identified loci are located in or near genes that
encode neuronal regulators of appetite or energy balance, includ-
ing MC4R12,25, BDNF26 and SH2B111,27. Each of these genes has
been tied to obesity, not only in animal models, but also by rare
human variants that disrupt each of these genes and lead to severe
obesity24,28,29. Using the automated literature search program Snipper
(Online Methods), we identified various genes within the newly dis-
covered loci with potential biological links to obesity susceptibility
(Supplementary Note). Among the new loci, the location of rs713586
near POMC provides further support for a role of neuroendocrine
circuits that regulate energy balance in susceptibility to obesity.
POMC encodes several polypeptides, including α-MSH, a ligand of
the MC4R gene product30, and rare mutations in POMC also cause
obesity in humans23,29,31.
In contrast, the locus near GIPR, which encodes a receptor of gastric
inhibitory polypeptide (GIP), suggests a role for peripheral biology
in obesity. GIP, which is expressed in the K cell of the duodenum and
intestine, is an incretin hormone that mediates incremental insulin
secretion in response to oral intake of glucose. The variant associated
with BMI is in strong LD (r2 = 0.83) with a missense SNP in GIPR
(rs1800437, p.Glu354Gln) that has recently been shown to influence
glucose and insulin response to an oral glucose challenge21. Although
no human phenotype is known to be caused by mutations in GIPR,
mice with disruption of Gipr are resistant to diet-induced obesity32.
The association of a variant in GIPR with BMI suggests that there
may be a link between incretins, insulin secretion and body weight
regulation in humans as well.
To systematically identify biological connections among the genes
located near the 32 confirmed SNPs and to potentially identify new
pathways associated with BMI, we performed pathway-based ana-
lyses using MAGENTA33. Specifically, we tested for enrichment of
genetic associations to BMI in biological processes or molecular func-
tions that contain at least one gene from the 32 confirmed BMI loci
(Online Methods). Using annotations from the Kyoto Encyclopedia
of Genes and Genomes (KEGG), Ingenuity, Protein Analysis Through
Evolutionary Relationships (PANTHER) and Gene Ontology data-
bases, we found evidence of enrichment for pathways involved in
platelet-derived growth factor (PDGF) signaling (PANTHER,
P = 0.0008, false discovery rate (FDR) = 0.0061), translation elongation
(PANTHER, P = 0.0008, FDR = 0.0066), hormone or nuclear-hormone
receptor binding (Gene Ontology, P < 0.0005, FDR < 0.0085), homeo-
box transcription (PANTHER, P = 0.0001, FDR = 0.011), regulation of
cellular metabolism (Gene Ontology, P = 0.0002, FDR = 0.031), neuro-
genesis and neuron differentiation (Gene Ontology, P < 0.0002, FDR <
0.034), protein phosphorylation (PANTHER, P = 0.0001, FDR = 0.045)
Figure 2 Combined impact of risk alleles on
BMI and obesity. (a) Combined effect of risk
alleles on average BMI in the population-
based ARIC study (n = 8,120 individuals of
European descent). For each individual, the
number of ‘best guess’ replicated (n = 32)
risk alleles from imputed data (0, 1 or 2) per
SNP was weighted for its relative effect size
estimated from the stage 2 data. Weighted risk
alleles were summed for each individual, and
the overall individual sum was rounded to the
nearest integer to represent the individual’s risk
allele score (ranging from 16 to 44). Along the
x axis, individuals in each risk allele category
are shown (grouped as having 21 risk alleles
and 38 risk alleles at the extremes), and the mean BMI (± s.e.m.) is plotted (y axis on right), with the line representing the regression of the mean BMI
values across the risk-allele scores. The histogram (y axis on left) represents the number of individuals in each risk-score category. (b) The area under
the ROC curve (AUC) of two different models predicting the risk of obesity (BMI 30 kg/m2) in the 8,120 genotyped individuals of European descent in
the ARIC study. Model 1, represented by the solid line, includes age, age2 and sex (AUC = 0.515, P = 0.023 for difference from the null AUC = 0.50).
Model 2, represented by the dashed line, includes age, age2, sex and the 32 confirmed BMI SNPs (AUC = 0.575, P < 10−5 for difference from the null
AUC = 0.50). The difference between both AUCs is significant (P < 10−4).
1,500
ab
29 1.00
0.75
0.50
0.25
0
0 0.25 0.50
1 – specicity
Number of weighted risk alleles
0.75 1.00
28
27
26
25
1,000
Number of individuals
Mean BMI (kg/m2)
Sensitivity
500
21
38
22–23
24–25
26–27
28–29
30–31
32–33
34–35
36–37
0
© 2010 Nature America, Inc. All rights reserved.
Nature GeNetics VOLUME 42 | NUMBER 11 | NOVEMBER 2010 941
ARTICLES
and numerous other pathways related to
growth, metabolism, immune and neuronal
processes (Gene Ontology, P < 0.002, FDR <
0.046) (Supplementary Table 5).
Identifying possible functional variants
We used data from the 1000 Genomes Project
and the HapMap Consortium to explore
whether the 32 confirmed BMI SNPs were in
LD (r2 0.75) with common missense SNPs or copy number variants
(CNVs) (Online Methods). Non-synonymous variants in LD with
our signals were present in BDNF, SLC39A8, FLJ35779-HMGCR,
QPCTL-GIPR, MTCH2, ADCY3 and LBXCOR1. In addition, the
rs7359397 signal was in LD with coding variants in several genes
including SH2B1, ATNX2L, APOB48R, SULT1A2 and AC138894.2
(Table 1, Fig. 3, Supplementary Table 6 and Supplementary Fig. 2).
Furthermore, two SNPs tagged common CNVs. The first CNV has
been previously identified9 and is a 45-kb deletion near NEGR1. The
second CNV is a 21-kb deletion that lies 50 kb upstream of GPRC5B;
the deletion allele is tagged by the T allele of rs12444979 (r2 = 1)
(Fig. 3). Although the correlations with potentially functional vari-
ants do not prove that these variants are indeed causal, they pro-
vide first clues as to which genes and variants at these loci might be
prioritized for fine mapping and functional follow up.
Because many of the 32 BMI loci harbor multiple genes, we exam-
ined whether gene expression quantitative trait loci (eQTL) analyses
could also direct us to positional candidates. Gene expression data
were available for human brain, lymphocyte, blood, subcutaneous
and visceral adipose tissue, and liver34–36 (Online Methods, Table 1
and Supplementary Table 7). Significant cis associations, defined at
the tissue-specific level, were obser ved between 14 BMI-associated
alleles and expression levels (Table 1 and Supplementary Table 7).
In several instances, the BMI-associated SNP was the most significant
SNP or explained a substantial proportion of the association with the
most significant SNP for the gene transcript in conditional analyses
(adjusted P > 0.05). These significant associations included NEGR1,
ZC3H4, TMEM160, MTCH2, NDUFS3, GTF3A, ADCY3, APOB48R,
SH2B1, TUFM, GPRC5B, IQCK, SLC39A8, SULT1A1 and SULT1A2
(Table 1 and Supplementary Table 7), making these genes higher
priority candidates within the associated loci. However, we note that
some BMI-associated variants were correlated with the expression
of multiple nearby genes, making it difficult to determine the most
relevant gene.
Evidence for the existence of additional associated variants
Because the variants identified by this large study explain only 1.45%
of the variance in BMI (2%–4% of genetic variance based on an
estimated heritability of 40%–70%), we considered how much the
explained phenotypic variance could be increased by including more
SNPs at various degrees of significance in a polygene model using
an independent validation set (Online Methods)37. We found that
including SNPs associated with BMI at lower significance levels (up
to P > 0.05) increased the explained phenotypic variance in BMI to
2.5%, or 4%–6% of the genetic variance (Fig. 4a). In a separate ana-
lysis, we estimated the total number of independent BMI-associated
variants that are likely to exist with similar effect sizes as the 32 con-
firmed here (Online Methods)38. Based on the effect size and allele
frequencies of the 32 replicated loci observed in stage 2 and the power
to detect association in stage 1 and stage 2 combined, we estimated
that there are 284 (95% CI 132–510) loci with similar effect sizes as
those currently observed, which together would account for 4.5%
(95% CI 3.1%–6.8%) of the phenotypic variation or 6%–11% of the
genetic variation in BMI (based on an estimated heritability of 40%–
70%) (Supplementary Table 8). In order to detect 95% of these loci,
a sample size of approximately 730,000 subjects would be needed
(Fig. 4b). This method does not account for the potential of loci of
smaller effect than those identified here to explain even more of the
variance and thus provides an estimated lower bound of explained
variance. These two analyses strongly suggest that larger GWAS will
rs2287019
SNPs
10
–log10 P
8
2
4
a
c d
b
6
0
50.4 50.6 50.8 51.0
Position on chr. 19 (Mb)
Recombination rate
(cM/Mb)
51.2
1 gene
omitted
100
80
60
40
20
EXOC3L2
MARK4 RTN2 EML2 DMPK NOVA2 IGFL3
CCDC61
SYMPK
MIR769
IGFL2
PGLYRP1
NANOS2 NCOA1
C2orf79 DNAJC27
TMC5 C16orf62 IQCK GPR139 GP2
UMOD
PDILT
ACSM5
GPRC5BC16orf88
C15orf61
IQCH MAP2K5
LBXCOR1
PIAS1
CALML4
CLN6
FEM1B
GDE1
CP110
POMC MIR1301
CENPO DTNB
ADCY3 EFR3B DNMT3A
FBXO46
SNRPD2
DMWD
IRF2BP1
FOXA3
GIPR
MIR642
QPCTL
MIR330
OPA3
FLJ40125
VASPKLC3
CKM
ERCC2
PPP1R13L
CD3EAP
ERCC1
FOSB GPR4 SIX5 MYPOP IGFL4
0
rs713586
ADCY3GIPR
LBXCOR1 GPRC5B
SNPs
10
–log10 P
8
2
4
6
0
24.6 24.8 25.0 25.2
Position on chr. 2 (Mb)
Recombination rate (cM/Mb)
25.4
100
80
60
40
20
0
rs12444979
Low-BMI haplotype (frequency = 0.87)
High-BMI haplotype (frequency = 0.13)
SNPs
10
–log10 P
8
2
4
6
0
19.4 19.6 19.8 20.0
Position on chr. 16 (Mb)
Recombination rate (cM/Mb)
20.2
100
80
60
40
20
0
rs2241423
p.Trp200Arg
p.Ser107Pro
p.Glu354Gln
SNPs
10
–log10 P
8
2
4
6
0
65.4 65.6 65.8 66.0
Position on chr. 15 (Mb)
Recombination rate (cM/Mb)
66.2
100
80
60
40
20
0
r
2
0.8
0.6
0.4
0.2
r
2
0.8
0.6
0.4
0.2
r
2
0.8
0.6
0.4
0.2
r
2
0.8
0.6
0.4
0.2
Figure 3 Regional plots of selected replicating
BMI loci with missense and CNV variants. SNPs
are plotted by position on the chromosome
against association with BMI (–log10 P). The
SNP name shown on the plot was the most
significant SNP after the stage 1 meta-analysis.
Estimated recombination rates (from HapMap)
are plotted in cyan to reflect the local LD
structure. The SNPs surrounding the most
significant SNP are color coded to reflect
their LD with this SNP (taken from pairwise r2
values from the HapMap CEU data). Genes,
the position of exons and the direction of
transcription from the UCSC genome browser
are noted. Hashmarks represent SNP positions
available in the meta-analysis. (ac) Missense
variants noted with their amino acid change for
the gene listed above the plot. (d) Structural
haplotypes and the BMI association signal in the
GPRC5B region. A 21-kb deletion polymorphism
was associated with four SNPs (r2 = 1.0) that
comprise the best haplogroup associating with
BMI. Plots were generated using LocusZoom
(see URLs).
© 2010 Nature America, Inc. All rights reserved.
94 2 VOLUME 42 | NUMBER 11 | NOVEMBER 2010 Nature GeNetics
ARTICLES
continue to identify additional new associated loci but also indicate
that even extremely large studies focusing on variants with allele fre-
quencies above 5% will not account for a large fraction of the genetic
contribution to BMI.
We examined whether selecting only a single variant from each
locus for follow up led us to underestimate the fraction of phenotypic
variation explained by the associated loci. To search for additional
independent loci at each of the 32 associated BMI loci, we repeated
our genome-wide association meta-analysis conditioning on the 32
confirmed SNPs. Using a significance threshold of P = 5 × 10−6 for
SNPs at known loci, we identified one apparently independent signal
at the MC4R locus; rs7227255 was associated with BMI (P = 6.56 ×
10−7) even after conditioning for the most strongly associated variant
near MC4R (rs571312) (Fig. 5). Notably, rs7227255 is in perfect LD
(r2 = 1) with a relatively rare MC4R missense variant (rs2229616,
p.Val103Ile, minor allele frequency = 1.7%) that has been associ-
ated with BMI in two independent meta-analyses39,40. Furthermore,
mutations at the MC4R locus are known to influence early-onset
obesity24,41, supporting the notion that allelic heterogeneity may be
a frequent phenomenon in the genetic architecture of obesity.
DISCUSSION
Using a two-stage genome-wide association meta-analysis of up
to 249,796 individuals of European descent, we identified 18 addi-
tional loci that are associated with BMI at genome-wide significance,
bringing the total number of such loci to 32. We estimate that more
than 250 common variant loci (that is, 284 predicted loci minus 32
confirmed loci) with effects on BMI similar to those described here
remain to be discovered and that even larger numbers of loci with
smaller effects remain to be identified. A substantial proportion of
these loci should be identifiable through larger GWAS and/or by
targeted follow up of the top signals selected from our stage 1 analysis.
The latter approach is already being implemented through large-scale
genotyping of samples informative for BMI using a custom array (the
Metabochip) designed to support follow up of
thousands of promising variants in hundreds
of thousands of individuals.
The combined effect on BMI of the associ-
ated variants at the 32 loci is modest, and even
when we try to account for as yet undiscovered
variants with similar properties, we estimate
that these common variant signals account
for only 6%–11% of the genetic variation in
BMI. There is a strong expectation that addi-
tional variance and biology will be explained
using complementary approaches that capture
variants not examined in the current study,
such as lower frequency variants and short
insertion-deletion polymorphisms. There is
good reason to believe (based on our find-
ings at MC4R and other loci, such as those at
POMC, BDNF and SH2B1, which feature both
common and rare variant associations) that
a proportion of such low-frequency and rare
causal variation will map to the loci already
identified by GWAS.
A primary goal of human genetic discovery
is to improve understanding of the biology
Figure 4 Phenotypic variance explained by
common variants. (a) The variance explained is
higher when SNPs not reaching genome-wide
significance are included in the prediction
model. The y axis represents the proportion
of variance explained at different P value
thresholds from the stage 1 meta-analysis.
Results are given for three studies (Rotterdam
Study II (RSII), Rotterdam Study III (RSIII),
Queens Institute of Medical Research (QIMR))
which were not included in the meta-analysis,
after exclusion of all samples from The
Netherlands (for RSII and RSIII) and the United
Kingdom (for QIMR) from the discovery analysis
for this sub-analysis. The dotted line represents
the weighted average of the explained variance
of three validation sets. (b) Cumulative number of susceptibility loci expected to be discovered, including those we have already identified and others
that have yet to be detected, by the expected percentage of phenotypic variation explained and the sample size required for a one-stage GWAS assuming
a genomic control correction is used. The projections are based on loci that achieved a significance level of P < 5 × 10−8 in the joint analysis of stage 1
and stage 2 and the distribution of their effect sizes in stage 2. The dotted red line corresponds to the expected phenotypic variance explained by the
22 loci that are expected to be discovered in a one-stage GWAS using the sample size of stage 1 of this study.
a4.0% RSII
RSIII
QIMR
Average
3.0%
2.0%
1.0%
Percentage of variance explained
0%
5
×
10
–8
5
×
10
–7
5
×
10
–6
5
×
10
–5
5
×
10
–4
5
×
10
–3
5
×
10
–2
P threshold
b4.5
4.0
3.0
2.0
0
62 K
122 K
198 K
319 K
512 K
730 K
1.0
Cumulative expected variance
explained (%)
Cumulative expected number of loci
Sample size required
0
0
30
60
90
120
150
180
210
240
270
Figure 5 A second signal at the MC4R locus contributing to BMI. SNPs are plotted by position in
a 1-Mb window of chromosome 18 against association with BMI (–log10 P). (a) Plot highlighting
the most significant SNP in the stage 1 meta-analysis. (b) Plot highlighting the most significant
SNP after conditional analysis, where the model included the most strongly associated SNP as a
covariate. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD
structure. The SNPs surrounding the most significant SNP are color coded to reflect their LD with
this SNP (taken from pairwise r2 values from the HapMap CEU database). Genes, exons and the
direction of transcription from the UCSC genome browser are noted. Hashmarks at the top of the
figure represent the positions of SNPs in the meta-analysis. Regional plots were generated using
LocusZoom.
ab
25 r
2
0.8
0.6
0.4
0.2
rs6567160
SNPs
20
15
–log10 P
10
5
0
55.6 55.8 56.0 56.2
Position on chr. 18 (Mb)
Recombination rate (cM/Mb)
56.4 56.6
100
80
60
40
20
PMAIP1 MC4R
0
25 r
2
0.8
0.6
0.4
0.2
rs7227255
SNPs
20
15
–log10 P
10
5
0
55.6 55.8 56.0 56.2
Position on chr. 18 (Mb)
Recombination rate (cM/Mb)
56.4 56.6
100
80
60
40
20
PMAIP1 MC4R
0
© 2010 Nature America, Inc. All rights reserved.
Nature GeNetics VOLUME 42 | NUMBER 11 | NOVEMBER 2010 943
ARTICLES
of conditions such as obesity42. One particularly noteworthy finding
in this regard is the association between BMI and common variants
near GIPR, which may indicate a causal contribution of variation
in postprandial insulin secretion in the development of obesity. In
most instances, the loci identified by the present study harbor few, if
any, annotated genes with clear connections to the biology of weight
regulation. This reflects our still limited understanding of the biology
of BMI and obesity-related traits and is in striking contrast with the
results from equivalent studies of certain other traits (such as autoim-
mune diseases or lipid levels). Thus, these results suggest that much
of the biology that underlies obesity remains to be uncovered and
that GWAS may provide an important entry point for investigation.
In particular, further examination of the associated loci through a
combination of resequencing and fine mapping to find causal variants
and genomic and experimental studies designed to assign function
could uncover new insights into the biology of obesity.
In conclusion, we performed GWAS in large samples to identify
numerous genetic loci associated with variation in BMI, a common
measure of obesity. Because current lifestyle interventions are largely
ineffective in addressing the challenges of growing obesity43,44, new
insights into the biology of obesity are critically needed to guide the
development and application of future therapies and interventions.
URLs. LocusZoom, http://csg.sph.umich.edu/locuszoom; METAL,
http://www.sph.umich.edu/csg/abecasis/Metal/.
METHODS
Methods and any associated references are available in the online version
of the paper at http://www.nature.com/naturegenetics/.
Note: Supplementary information is available on the Nature Genetics website.
ACKNOWLEDGMENTS
A full list of acknowledgments appears in the Supplementary Note.
Funding was provided by Academy of Finland (10404, 77299, 104781, 114382,
117797, 120315, 121584, 124243, 126775, 126925, 127437, 129255, 129269, 129306,
129494, 129680, 130326, 209072, 210595, 213225, 213506 and 216374); ADA
Mentor-Based Postdoctoral Fellowship; Amgen; Agency for Science, Technology
and Research of Singapore (A*STAR); ALF/LUA research grant in Gothenburg;
Althingi (the Icelandic Parliament); AstraZeneca; Augustinus Foundation;
Australian National Health and Medical Research Council (241944, 389875,
389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485 and 613672);
Australian Research Council (ARC grant DP0770096); Becket Foundation;
Biocenter (Finland); Biomedicum Helsinki Foundation; Boston Obesity Nutrition
Research Center; British Diabetes Association (1192); British Heart Foundation
(97020; PG/02/128); Busselton Population Medical Research Foundation;
Cambridge Institute for Medical Research; Cambridge National Institute of Health
Research (NIHR) Comprehensive Biomedical Research Centre; CamStrad (UK);
Cancer Research UK; Centre for Medical Systems Biology (The Netherlands);
Centre for Neurogenomics and Cognitive Research (The Netherlands); Chief
Scientist Office of the Scottish Government; Contrat Plan Etat Région (France);
Danish Centre for Health Technology Assessment; Danish Diabetes Association;
Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research
Council; Deutsche Forschungsgemeinschaft (DFG; HE 1446/4-1); Department of
Health (UK); Diabetes UK; Diabetes and Inflammation Laboratory; Donald W.
Reynolds Foundation; Dresden University of Technology Funding Grant; Emil and
Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus
University (Rotterdam); European Commission (DG XII; QLG1-CT-2000-01643,
QLG2-CT-2002-01254, LSHC-CT-2005, LSHG-CT-2006-018947, LSHG-CT-2004-
518153, LSH-2006-037593, LSHM-CT-2007-037273, HEALTH-F2-2008-
ENGAGE, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, FP7/2007-
2013, 205419, 212111, 245536, SOC 95201408 05F02 and WLRT-2001-01254);
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01GI0823, 01GI0826, 01GP0209, 01GP0259, 01GS0820, 01GS0823, 01GS0824,
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(33CSCO-122661, 310000-112552 and 3100AO-116323/1); Torsten and Ragnar
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Foundation.
AUTHOR CONTRIBUTIONS
A full list of author contributions appears in the Supplementary Note.
COMPETING FINANCIAL INTERESTS
The authors declare competing financial interests: details accompany the full-text
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Research, Massachusetts General Hospital, Boston, Massachusetts, USA. 18Program in Medical and Population Genetics, Broad Institute of Harvard and
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 19Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts,
USA. 20Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam, The Netherlands. 21Department of Internal Medicine, Erasmus MC, Rotterdam, The
Netherlands. 22Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands. 23Department of
Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. 24Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts,
USA. 25Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 26Queensland Statistical Genetics Laboratory, Queensland
Institute of Medical Research, Queensland, Australia. 27Centre National de la Recherche Scientifique (CNRS) UMR8199-IBL-Institut Pasteur de Lille, Lille, France.
28University Lille Nord de France, Lille, France. 29Estonian Genome Center, University of Tartu, Tartu, Estonia. 30Estonian Biocenter, Tartu, Estonia. 31Institute of
Molecular and Cell Biology, University of Tartu, Tartu, Estonia. 32Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
33Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. 34Swiss Institute of Bioinformatics, Lausanne, Switzerland. 35Department of Twin
Research and Genetic Epidemiology, King’s College London, London, UK. 36Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts, USA. 37Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.
38Icelandic Heart Association, Kopavogur, Iceland. 39University of Iceland, Reykjavik, Iceland. 40Comprehensive Cancer Center East, Nijmegen, The Netherlands.
41Hudson Alpha Institute for Biotechnology, Huntsville, Alabama, USA. 42Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. 43Department of
Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 44Department of Medicine, University of Washington, Seattle,
Washington, USA. 45Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. 46University of Melbourne, Parkville, Australia.
47Department of Primary Industries, Melbourne, Victoria, Australia. 48Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
49Technical University Munich, Chair of Biomathematics, Garching, Germany. 50Department of Biological Psychology, Vrije Universiteit (VU) University Amsterdam,
Amsterdam, The Netherlands. 51Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden. 52Department of Cancer
Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. 53Clinical Pharmacology,
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK. 54Clinical Pharmacology
and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of
London, Charterhouse Square, London, UK. 55Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck
Medical University, Innsbruck, Austria. 56National Heart and Lung Institute, Imperial College London, London, UK. 57Department of Neurology, Boston University
School of Medicine, Boston, Massachusetts, USA. 58National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. 59Institut
für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. 60Institute for
Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 61National Institute for Health and Welfare, Department of Chronic Disease Prevention,
Unit of Public Health Genomics, Helsinki, Finland. 62Hagedorn Research Institute, Gentofte, Denmark. 63MRC Centre for Causal Analyses in Translational
Epidemiology, Department of Social Medicine, Oakfield House, Bristol, UK. 64Department of Oncology, University of Cambridge, Cambridge, UK. 65Department of
Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 66Department of Physiology and Biophysics, Keck
School of Medicine, University of Southern California, Los Angeles, California, USA. 67Department of Biostatistics, Boston University School of Public Health, Boston,
Massachusetts, USA. 68University of Milan, Department of Medicine, Surgery and Dentistry, Milano, Italy. 69Division of Preventive Medicine, Brigham and Women’s
Hospital, Boston, Massachusetts, USA. 70Harvard Medical School, Boston, Massachusetts, USA. 71Centre for Genetic Epidemiology and Biostatistics, University of
Western Australia, Crawley, Western Australia, Australia. 72Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of
Gothenburg, Gothenburg, Sweden. 73University Vita-Salute San Raffaele, Division of Nephrology and Dialysis, Milan, Italy. 74Lund University Diabetes Centre,
Department of Clinical Sciences, Lund University, Malmö, Sweden. 75Department of Biostatistics, University of Washington, Seattle, Washington, USA. 76Collaborative
Health Studies Coordinating Center, Seattle, Washington, USA. 77INSERM Centre de recherche en Epidémiologie et Santé des Populations (CESP) Centre for
Research in Epidemiology and Public Health U1018, Villejuif, France. 78University Paris Sud 11, Unité Mixte de Recherche en Santé (UMRS) 1018, Villejuif, France.
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79Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK.
80Department of Social Medicine, University of Bristol, Bristol, UK. 81Institute of Experimental Paediatric Endocrinology, Charité Universitätsmedizin Berlin, Berlin,
Germany. 82Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK. 83Department of Medicine III, University of
Dresden, Dresden, Germany. 84Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK. 85Division of Endocrinology, Keck
School of Medicine, University of Southern California, Los Angeles, California, USA. 86Istituto di Neurogenetica e Neurofarmacologia del Consiglio Nazionale delle
Ricerche (CNR), Monserrato, Cagliari, Italy. 87Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland, UK. 88University of
Warwick, Warwick Medical School, Coventry, UK. 89Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 90Clinical Trial Service Unit,
Oxford, UK. 91Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK. 92University of
Dundee, Ninewells Hospital and Medical School, Dundee, UK. 93Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands. 94Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 95Northshore University
Healthsystem, Evanston, Illinois, USA. 96The London School of Hygiene and Tropical Medicine, London, UK. 97South Asia Network for Chronic Disease, New Dehli,
India. 98MRC-Health Protection Agency (HPA) Centre for Environment and Health, London, UK. 99Cardiovascular Epidemiology and Genetics, Institut Municipal
D’investigacio Medica and Centro de Investigación Biomédica en Red CIBER Epidemiología y Salud Pública, Barcelona, Spain. 100Department of General Practice and
Primary Health Care, University of Helsinki, Helsinki, Finland. 101National Institute for Health and Welfare, Helsinki, Finland. 102Helsinki University Central Hospital,
Unit of General Practice, Helsinki, Finland. 103Folkhalsan Research Centre, Helsinki, Finland. 104Vasa Central Hospital, Vasa, Finland. 105Institute of Genetic
Medicine, European Academy Bozen-Bolzano (EURAC), Bolzano-Bozen, Italy, Affiliated Institute of the University of Lübeck, Lübeck, Germany. 106Department of
Neurology, General Central Hospital, Bolzano, Italy. 107Department of Internal Medicine B, Ernst-Moritz-Arndt University, Greifswald, Germany. 108Pediatric
Endocrinology, Diabetes and Obesity Unit, Department of Pediatrics and Adolescent Medicine, Ulm, Germany. 109Division of Epidemiology and Community Health,
School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. 110Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Greifswald,
Greifswald, Germany. 111Center for Neurobehavioral Genetics, University of California, Los Angeles, California, USA. 112Department of Medicine, University of
Maryland School of Medicine, Baltimore, Maryland, USA. 113Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington,
Oxford, UK. 114Montreal Heart Institute, Montreal, Quebec, Canada. 115Department of Medicine III, Pathobiochemistry, University of Dresden, Dresden, Germany.
116Merck Research Laboratories, Merck and Co., Inc., Boston, Massachusetts, USA. 117Department of Clinical Sciences, Obstetrics and Gynecology, University of
Oulu, Oulu, Finland. 118National Institute for Health and Welfare, Department of Chronic Disease Prevention, Chronic Disease Epidemiology and Prevention Unit,
Helsinki, Finland. 119MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK. 120Department
of Psychiatry and Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, Missouri, USA. 121Klinik und Poliklinik für Innere
Medizin II, Universität Regensburg, Regensburg, Germany. 122Regensburg University Medical Center, Innere Medizin II, Regensburg, Germany. 123Department of
Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany. 124Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-
University Greifswald, Greifswald, Germany. 125PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands,
Western Australia, Australia. 126Busselton Population Medical Research Foundation Inc., Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
127Division of Research, Kaiser Permanente Northern California, Oakland, California, USA. 128Department of Epidemiology and Biostatistics, University of California,
San Francisco, San Francisco, California, USA. 129Department of Social Services and Health Care, Jakobstad, Finland. 130Core Genotyping Facility, SAIC-Frederick,
Inc., National Cancer Institute (NCI)-Frederick, Frederick, Maryland, USA. 131Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg,
Germany. 132Institut für Epidemiologie und Sozialmedizin, Universität Greifswald, Greifswald, Germany. 133Research Centre for Prevention and Health, Glostrup
University Hospital, Glostrup, Denmark. 134Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark. 135National Institute for Health and Welfare,
Department of Chronic Disease Prevention, Population Studies Unit, Turku, Finland. 136Institute of Health Sciences, University of Oulu, Oulu, Finland. 137Biocenter
Oulu, University of Oulu, Oulu, Finland. 138Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Hospital District of
Helsinki and Uusimaa (HUS), Helsinki, Finland. 139Massachusetts General Hospital (MGH) Weight Center, Massachusetts General Hospital, Boston, Massachusetts,
USA. 140Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. 141Framingham Heart Study of the
National, Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts, USA. 142Department of Medicine, Harvard Medical School, Boston,
Massachusetts, USA. 143National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland. 144Department of Medicine, Stanford University
School of Medicine, Stanford, California, USA. 145Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia. 146Interdisciplinary
Centre for Clinical Research, University of Leipzig, Leipzig, Germany. 147Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio,
Finland. 148Nord-Trøndelag Health Study (HUNT) Research Centre, Department of Public Health and General Practice, Norwegian University of Science and
Technology, Levanger, Norway. 149Finnish Institute of Occupational Health, Oulu, Finland. 150Institut inter-regional pour la santé (IRSA), La Riche, France.
151Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. 152Department of Clinical
Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland. 153Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
154Human Genetics, Genome Institute of Singapore, Singapore, Singapore. 155Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki,
Finland. 156Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 157Department of Public
Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK. 158On behalf of the MAGIC (Meta-Analyses of Glucose and Insulin-
Related Traits Consortium) investigators. 159Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique
des Hôpitaux de Paris, Paris, France. 160Cardiovascular Genetics Research Unit, Université Henri Poincaré-Nancy 1, Nancy, France. 161Genetic Epidemiology
Laboratory, Queensland Institute of Medical Research, Queensland, Australia. 162Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department
of Social Medicine, University of Bristol, Bristol, UK. 163Division of Health, Research Board, An Bord Taighde Sláinte, Dublin, Ireland. 164Institute of Human
Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. 165Institute of Human Genetics, Helmholtz Zentrum München-German
Research Center for Environmental Health, Neuherberg, Germany. 166Department of Clinical Sciences, Lund University, Malmö, Sweden. 167Molecular Epidemiology
Laboratory, Queensland Institute of Medical Research, Queensland, Australia. 168Croatian Centre for Global Health, School of Medicine, University of Split, Split,
Croatia. 169Neurogenetics Laboratory, Queensland Institute of Medical Research, Queensland, Australia. 170National Heart, Lung, and Blood Institute, National
Institutes of Health, Framingham, Massachusetts, USA. 171University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s
Hospital, Cambridge, UK. 172Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. 173Department of Pathology and Molecular Medicine,
McMaster University, Hamilton, Ontario, Canada. 174Amgen, Cambridge, Massachusetts, USA. 175Finnish Twin Cohort Study, Department of Public Health, University
of Helsinki, Helsinki, Finland. 176Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland. 177Department of
Medicine, Levanger Hospital, The Nord-Trøndelag Health Trust, Levanger, Norway. 178Gen-Info Ltd, Zagreb, Croatia. 179National Institute for Health and Welfare, Oulu,
Finland. 180Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. 181Research Centre of Applied and Preventive
Cardiovascular Medicine, University of Turku, Turku, Finland. 182The Department of Clinical Physiology, Turku University Hospital, Turku, Finland. 183Clinical
Psychology and Psychotherapy, University of Marburg, Marburg, Germany. 184Department of Clinical Sciences and Clinical Chemistry, University of Oulu, Oulu,
Finland. 185Ludwig-Maximilians-Universität, Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Munich, Germany. 186South Karelia
Central Hospital, Lappeenranta, Finland. 187Department of Clinical Sciences and Internal Medicine, University of Oulu, Oulu, Finland. 188Institut für Community
Medicine, Greifswald, Germany. 189Christian-Albrechts-University, University Hospital Schleswig-Holstein, Institute for Clinical Molecular Biology and Department of
Internal Medicine I, Kiel, Germany. 190Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany. 191Division of Cardiology, Cardiovascular Laboratory, Helsinki
University Central Hospital, Helsinki, Finland. 192Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA. 193Department of
Psychiatry, Instituut voor Extramuraal Geneeskundig Onderzoek (EMGO) Institute, VU University Medical Center, Amsterdam, The Netherlands. 194Department of
Haematology, University of Cambridge, Cambridge, UK. 195National Health Service (NHS) Blood and Transplant, Cambridge Centre, Cambridge, UK. 196Leicester
NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK. 197Department of Health Sciences, University of Leicester, University
Road, Leicester, UK. 198Department of Medicine, University of Leipzig, Leipzig, Germany. 199Coordination Centre for Clinical Trials, University of Leipzig, Leipzig,
Germany. 200Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. 201Research Program of Molecular Medicine, University of Helsinki,
Helsinki, Finland. 202Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 203Center of Medical Systems Biology, Leiden
University Medical Center, Leiden, The Netherlands. 204Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland. 205INSERM
© 2010 Nature America, Inc. All rights reserved.
94 8 VOLUME 42 | NUMBER 11 | NOVEMBER 2010 Nature GeNetics
Cardiovascular Genetics team, Centre Investigation Clinique (CIC) 9501, Nancy, France. 206Steno Diabetes Center, Gentofte, Denmark. 207Center for Human
Genomics, Wake Forest University, Winston-Salem, North Carolina, USA. 208Department of Physiatrics, Lapland Central Hospital, Rovaniemi, Finland. 209School of
Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia. 210Department of Internal Medicine, University of Oulu,
Oulu, Finland. 211School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. 212Department of Clinical Physiology,
University of Tampere and Tampere University Hospital, Tampere, Finland. 213Stanford University School of Medicine, Stanford, California, USA. 214Department of
Psychiatry and Human Behavior, University of California, Irvine (UCI), Irvine, California, USA. 215Leipziger Interdisziplinärer Forschungs-komplex zu molekularen
Ursachen umwelt- und lebensstilassoziierter Erkrankungen (LIFE) Study Centre, University of Leipzig, Leipzig, Germany. 216Service of Medical Genetics, Centre
Hospitalier Universitaire Vaudois (CHUV) University Hospital, Lausanne, Switzerland. 217Human Genetics Center and Institute of Molecular Medicine, University of
Texas Health Science Center, Houston, Texas, USA. 218Faculty of Health Science, University of Southern Denmark, Odense, Denmark. 219New York University Medical
Center, New York, New York, USA. 220National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Unit for Child and
Adolescent Mental Health, Helsinki, Finland. 221NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK. 222Department of Urology, Radboud
University Nijmegen Medical Centre, Nijmegen, The Netherlands. 223Institute of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. 224Faculty
of Health Science, University of Aarhus, Aarhus, Denmark. 225Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. 226Department
of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands. 227Department of Neurology, University of Lübeck, Lübeck, Germany. 228Institute for
Paediatric Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten-Herdecke, Datteln, Germany. 229Department of Medicine III,
Prevention and Care of Diabetes, University of Dresden, Dresden, Germany. 230Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration
Medical Center, Baltimore, Maryland, USA. 231Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. 232South Ostrobothnia Central
Hospital, Seinajoki, Finland. 233Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) University Hospital, Lausanne, Switzerland. 234The
Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. 235Department of Psychiatry, Harvard Medical School,
Boston, Massachusetts, USA. 236Pacific Biosciences, Menlo Park, California, USA. 237Sage Bionetworks, Seattle, Washington, USA. 238Division of Biostatistics,
Washington University School of Medicine, St. Louis, Missouri, USA. 239Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham
Heart Study, Framingham, Massachusetts, USA. 240Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York,
USA. 241Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. 242Department of Medical Genetics, University of Helsinki, Helsinki,
Finland. 243Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA. 244Division of Community Health Sciences, St. George’s, University of
London, London, UK. 245Klinikum Grosshadern, Munich, Germany. 246Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 247University of Cambridge
Metabolic Research Labs, Institute of Metabolic Science Addenbrooke’s Hospital, Cambridge, UK. 248Carolina Center for Genome Sciences, School of Public Health,
University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA. 249Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
250These authors contributed equally to this work. Correspondence should be addressed to M.B. (boehnke@umich.edu), K. Stefansson (kstefans@decode.is), K.E.N.
(kari_north@unc.edu), M.I.M. (mark.mccarthy@drl.ox.ac.uk), J.N.H. (joelh@broadinstitute.org), E.I. (erik.ingelsson@ki.se) or R.J.F.L. (ruth.loos@mrc-epid.cam.ac.uk).
ARTICLES
© 2010 Nature America, Inc. All rights reserved.
Nature GeNetics
doi:10.1038/ng.686
ONLINE METHODS
Study design. We designed a multistage study (Supplementary Fig. 1) com-
prising a genome-wide association meta-analysis (stage 1) of data on up to
123,865 genotyped individuals from 46 studies and selected 42 SNPs with P <
5 × 10−6 for follow up in stage 2. Stage 2 comprised up to 125,931 additional
genotyped individuals from 42 studies. Meta-analysis of stage 1 and stage 2
summary statistics identified 32 SNPs that reached genome-wide significance
(P < 5 × 10−8).
Stage 1 genome-wide association meta-analysis. Samples and genotyping.
The GIANT consortium currently encompasses 46 studies with up to
123,865 genotyped adult individuals of European ancestry with data on BMI
(Supplementar y Note). The samples from 46 studies, including between 276
and 26,799 individuals each, were genotyped using Affymetrix and Illumina
whole genome genotyping arrays (Supplementary Note). To allow for meta-
analysis across different marker sets, imputation of polymorphic HapMap
European CEU SNPs (Supplementary Note) was performed using MACH45,
IMPUTE46 or BimBam47.
Association analysis with BMI. Each study performed single marker asso-
ciation analyses with BMI using an additive genetic model implemented
in MACH2QTL (Y. Li, C.J.W., P.S. Ding and G.R.A., unpublished data),
Merlin48, SNPTEST46, ProbAbel49, GenABEL50, LME in R or PLINK51. BMI
was adjusted for age, age2 and other appropriate covariates (for example, prin-
cipal components) and inverse normally transformed to a mean of 0 and a
standard deviation of 1. Analyses were stratified by sex and case status (for
samples ascertained for other diseases) (Supplementary Note). To allow for
relatedness in the SardiNIA, Framingham Heart, Amish HAPI Heart and
Family Heart studies, regression coefficients were estimated in the context
of a variance component model that modeled relatedness in men and women
combined with sex as a covariate. Before meta-analyzing the genome-wide
association data for the 46 studies, SNPs with poor imputation quality scores
(r2.hat < 0.3 in MACH, obser ved/expected dosage variance < 0.3 in BimBam
or proper_info < 0.4 in IMPUTE) and those with a minor allele count (MAC =
2 × N × minor allele frequency) of < 6 in each sex- and case-specific stratum
were excluded for each study. All individual GWAS were genomic control cor-
rected before meta-analysis. Individual study-specific genomic control values
ranged from 0.983 to 1.104 (Supplementary Note).
Meta-analysis of stage 1 association results. Next, we performed the stage 1
meta-analysis using the inverse variance method, which is based on β values
and standard errors from each individual GWAS. To ensure consistency of
results, we also performed the stage 1 meta-analysis using the weighted z-score
method, which is based on the direction of association and P values of each of
the individual studies. Both meta-analyses were performed using METAL (see
URLs), and the correlation between the resulting –log10 P values was high (r >
0.99). For the discovery of replicating variants, the results of the inverse vari-
ance meta-analysis were used followed by a final genomic control correction
of the meta-analyzed results. The genomic control value for the meta-analyzed
results before genomic control correction was 1.318.
Selection of SNPs for follow up. Forty-two lead SNPs, representing the forty-two
most significant (P < 5 × 10−6) independent loci, were selected for replication
analyses (stage 2) (Supplementary Table 1). Loci were considered independ-
ent when separated by at least 1 Mb. For some loci, the SNP with the strongest
association could not be genotyped for technical reasons and was substituted
by a proxy SNP that was in high LD with it (r2 > 0.8) according to the HapMap
CEU data (Supplementary Table 1). We tested the association of these 42
SNPs in 16 de novo and 18 in silico replication studies in stage 2.
Stage 2 follow up. Samples and genotyping. Directly genotyped data for the
42 SNPs was available from a total of 79,561 adults of European ancestry from
16 studies using Sequenom iPLEX or TaqMan assays (Supplementary Note).
Samples and SNPs that did not meet the quality control criteria defined by
each individual study were excluded. Minimum genotyping quality control
criteria were defined as Hardy-Weinberg Equilibrium P > 10−6, call rate > 90%
and concordance > 99% in duplicate samples in each of the follow-up studies.
Association results were also obtained for the 42 most significant SNPs from
46,370 individuals of European ancestry from 18 GWAS that had not been
included in the stage 1 analyses (Supplementary Note). Studies included
between 345 and 22,888 individuals and were genotyped using Affymetrix
and Illumina genome-wide genotyping arrays. Autosomal HapMap SNPs were
imputed using either MACH45 or IMPUTE46. SNPs with poor imputation
quality scores from the in silico studies (r2.hat < 0.3 in MACH or proper_info
< 0.4 in IMPUTE), and SNPs with a MAC < 6 in each sex- and case-specific
stratum were excluded.
Association analyses and meta-analysis. We tested the association between
the 42 SNPs and BMI in each in silico and de novo stage 2 study separately as
described for the stage 1 studies. We subsequently meta-analyzed β values and
standard errors from the stage 2 studies using the inverse-variance method.
The meta-analysis using a weighted z-score method was similar (the r between
P values was >0.99) and included up to 249,796 individuals. Data was available
for at least 179,000 individuals for 41 of the 42 SNPs. For one SNP (rs6955651
in KIAA1505), data was only available for 125,672 individuals due to technical
challenges relating to the genotyping and imputation of this SNP. Next, we
meta-analyzed the summary statistics of the stage 1 and stage 2 meta-analyses
using the inverse-variance method in METAL.
Assessment of population stratification. To assess for possible inflation of test
statistics by population stratification, we performed a family-based analysis,
which is immune to stratification, in 5,507 individuals with pedigree informa-
tion from the Framingham Heart Study using that the QFAM–within proce-
dure in PLINK. Effect sizes and directions in the Framingham Heart Study
data are the β statistics reported by PLINK from the within-family analysis,
and the P values are empirical and are based on permutation testing. For
imputed SNPs, only those with r2.hat > 0.3 in MACH were analyzed using
the best-guess genotypes from dosages reported by MACH. For the 32 loci in
general and the 18 new loci in particular, the estimated effect sizes on BMI
were essentially identical in the overall meta-analysis and in the Framingham
Heart Study sample (Supplementary Note), and, as expected in the absence
of substantial stratification, about half of the loci (18 out of 32 loci total and 10
out of 18 new loci) had a larger effect size in the family-based sample. These
results indicate that the genome-wide significant associations in our meta-
analysis are not substantially confounded by stratification.
In addition, we estimated the fixation index (Fst) for all SNPs to test whether
the 32 confirmed BMI SNPs might be false-positive results due to population
stratification. We selected five diverse European populations with relatively
large sample sizes (Northern Finland Birth Cohort (NFBC), British 1958 Birth
Cohort, SardiNIA, CoLaus and DeCODE) for this analysis. The mean Fst value
for the 32 confirmed BMI SNPs was not significantly different from the mean
Fst for 2.1 million non-BMI associated SNPs (t test P = 0.28), suggesting that
the SNPs that are associated with BMI do not appear to have strong allele
frequency differences across the European samples examined.
Follow-up analyses. Subsequently, we performed an extensive series of fol-
low-up analyses to estimate the impact of the 32 confirmed BMI loci in adults
and children and to explore their potential functional roles. These follow-up
analyses are described in detail in the Supplementary Note.
In brief, we estimated the cumulative effe ct of the 32 loci combin ed
on BMI and asse ssed their predictive ability in obesity and BMI in the
ARIC study. Association between the 32 confirmed BMI variants and over-
weight or obese status was assessed in stage 2 samples, and association with
BMI in children and adolescents w as examined in four population-based
studies. Furt hermore, we tested for association between the 32 SNPs and
extreme or early-onset obesity in seven case-control stu dies of extremely
obese adults and extremely obes e children or adolescents. Data on the
association between the 32 SNPs and height and weight were obtained from
the sta ge 2 replication samples, and data on the association with related
traits were extr acte d from previously rep orted genome-wide association
meta-an alyses for type 2 diab etes (Di abetes Geneti cs Replication and
Meta-analysis (DIAGRAM) Consortium 18), lipid levels (the Global Lipids
© 2010 Nature America, Inc. All rights reserved.
Nature GeNetics doi:10.1038/ng.686
Genetics Consortium20) an d glycemic traits (Me ta-Analyses of Glucos e
and Insulin-re lated traits Consor tium (MAGIC)19,21).
To discover potentially new pathways associated with BMI, we tested
whether predefined biological processes or molecular functions that contain
at least one gene within 300 kb of the 32 confirmed BMI SNPs were enriched
for multiple modest BMI associations using MAGENTA33. We identified SNPs
having r2 0.75 with the lead SNP that were likely non-synonymous, nonsense
or which occurred within 5 bp of the exon-intron boundary and also evalu-
ated whether any of the 32 confirmed BMI SNPs tagged common CNVs. We
examined the cis associations between each of the 32 confirmed BMI SNPs
and expression of nearby genes in adipose tissue34,52, whole blood34, lym-
phocytes36,52 and brain35.
We evaluated the amount of phenotypic variance explained by the 32 BMI
loci using a method proposed by the International Schizophrenia Consortium37
and estimated the number of susceptibility loci that are likely to exist using a
new method38 based on the distribution of effect sizes and minor allele fre-
quencies observed for the established BMI loci and the power to detect those
effects in the combined stage 1 and stage 2 analysis.
We performed a conditional genome-wide association analysis to examine
whether any of the 32 confirmed BMI loci harbored additional independent
signals, and we also examined gene-by-gene and gene-by-sex interactions among
the BMI loci. Dominant and recessive analyses were performed for the 32 con-
firmed BMI SNPs to test for non-additive effects.
45. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev.
Genomics Hum. Genet. 10, 387–406 (2009).
46. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint
method for genome-wide association studies by imputation of genotypes. Nat. Genet.
39, 906–913 (2007).
47. Guan, Y. & Stephens, M. Practical issues in imputation-based association mapping.
PLoS Genet. 4, e1000279 (2008).
48. Abecasis, G.R. & Wigginton, J.E. Handling marker-marker linkage disequilibrium:
pedigree analysis with clustered markers. Am. J. Hum. Genet. 77, 754–767
(2005).
49. Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for
genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134
(2010).
50. Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for
genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).
51. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-
based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
52. Zhong, H., Yang, X., Kaplan, L.M., Molony, C. & Schadt, E.E. Integrating pathway
analysis and genetics of gene expression for genome-wide association studies.
Am. J. Hum. Genet. 86, 581–591 (2010).
© 2010 Nature America, Inc. All rights reserved.
... By GWAS studies, glucosamine-6-phosphate deaminase (GNPDA2) was associated with obesity (14) and in a recent article appeared in the present Research Topic of Frontiers in Nutrition, Gutierrez-Aguilar et al. observed in an animal model that, although GNPDA2 seemed not involved in appetite regulation at central level, it may play a role in glucose homeostasis. Also, the fat mass and obesity-related (FTO) variants were extensively investigated due to their association(s) with increased BMI. ...
... Moreover, FTO gene serves various functions in the nervous and cardiovascular systems (44). Studies have shown that high FTO expression is strongly associated with both body mass index (BMI) and obesity (45)(46)(47). The results of several studies indicated that this gene responds to insulin when influenced by environmental factors, such as hunger and nutrition; hence, this gene is Iran J Health Sci 2022; 10(2): 36 associated with insulin sensitivity (48,49). ...
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Thesis
L’obésité est associée à une prévalence élevée de symptômes neuropsychiatriques, notamment émotionnels et cognitifs. Des données récentes suggèrent l’implication de mécanismes immunitaires. L’obésité se caractérise en effet par un état d’inflammation chronique à bas bruit avec production soutenue de facteurs inflammatoires au niveau du tissu adipeux. L’obésité résulte de l’intrication de plusieurs facteurs, notamment alimentaires. Une alimentation obésogène, riche en gras, sucres et sel, favorise l'activation de processus immuno-inflammatoires, et peut accroître la vulnérabilité à des troubles neuropsychiatriques. Néanmoins, être vulnérable peut ne pas être suffisant. Il important que certains mécanismes se mettent en place pour précipiter des individus vulnérables dans un état pathologique ou significatif/manifeste d’un point de vue clinique. Dans ce contexte, des altérations du métabolisme du tryptophane (TRP) apparaissent constituer un mécanisme pertinent. À l'appui de cette notion, l'inflammation est associée à des perturbations du métabolisme du TRP, et un grand nombre de données de la littérature suggèrent une possible implication de ces altérations dans la physiopathologie de la dépression survenant dans des conditions inflammatoires. L’objectif principal de cette thèse est d’évaluer la relation entre inflammation chronique de bas grade, altérations du métabolisme du TRP, et symptômes neuropsychiatriques chez le sujet obèse et de déterminer si les habitudes alimentaires à fort potentiel obésogène et inflammatoire confèrent à des sujets sains une vulnérabilité neuropsychiatrique accrue. Ce travail s’articule en 3 chapitres correspondant à 3 sous-objectifs précis : 1) caractériser les symptômes neuropsychiatriques chez des sujets obèses et déterminer le rôle de l’inflammation et des régimes alimentaires obésogènes dans cette relation; 2) évaluer les relations entre l'inflammation systémique et métabolisme du TRP chez des sujets obèses et non-obèses mais présentant des habitudes obésogènes; 3) évaluer la pertinence de ces processus dans la symptomatologie dépressive des sujets obèses. ii Les résultats du chapitre 1 indiquent que l'obésité est caractérisée par une prévalence accrue de symptômes neuropsychiatriques (dépressifs, cognitifs, fatigue) interdépendants ainsi que par une inflammation chronique de bas niveau qui augmente graduellement avec les classes de l'IMC. Cette relation entre le degré d'adiposité, l'inflammation systémique et l'intensité des altérations neuropsychiatriques est linéaire et n’est pas modulée par les caractéristiques métaboliques de l’individu. Enfin, les résultats exposés dans le chapitre 1 indiquent que les régimes alimentaires obésogènes, avant l’instauration d’un état d'obésité, sont associés à une inflammation systémique à bas bruit et à une altération des performances cognitives lors de l'exposition à un stress psychologique aigu. Les résultats du chapitre 2 montrent une altération des différentes voies du métabolisme du TRP dans l'obésité. En particulier, les sujets obèses présentaient un rapport kynurénine (KYN)/TRP augmenté ainsi que des niveaux de sérotonine et d'indoles diminués, comparativement aux témoins non obèses. De façon intéressante, les altérations des voies de la KYN et des indoles étaient associées à l’inflammation systémique chez le sujet obèse. En revanche, seule la voie des indoles était altérée chez les sujets présentant habitudes alimentaires obésogènes, suggérant que l'adhésion à ce type de régime alimentaire obésogène est suffisante pour perturber cette voie. Les résultats exposés dans le chapitre 3 de cette thèse indiquent que l’activité d’IDO dans l’obésité est plus spécifiquement associée à l’activation de la branche neurotoxique de la voie de la KYN. De façon intéressante, l’activation de cette voie ainsi que des niveaux d’indole-3-carboxaldéhyde étaient significativement associés à la symptomatologie dépressive « sous-syndromique » des individus obèses. [...]
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