FTO Genetic Variation and Association With Obesity inWest Africans and African AmericansAdebowale Adeyemo, Guanjie Chen, Jie Zhou, Daniel Shriner, Ayo Doumatey, Hanxia Huang, and

Charles Rotimi

OBJECTIVE—The FTO gene is one of the most consistentlyreplicated loci for obesity. However, data from populations ofAfrican ancestry are limited. We evaluated genetic variation inthe FTO gene and investigated associations with obesity in WestAfricans and African Americans.

RESEARCH DESIGN AND METHODS—The study samplescomprised 968 African Americans (59% female, mean age 49years, mean BMI 30.8 kg/m2) and 517 West Africans (58% female,mean age 54 years, mean BMI 25.5 kg/m2). FTO genetic variationwas evaluated by genotyping 262 tag single nucleotide polymor-phisms (SNPs) across the entire gene. Association of each SNPwith BMI, waist circumference, and percent fat mass was inves-tigated under an additive model.

RESULTS—As expected, both African-ancestry samplesshowed weaker linkage disequilibrium (LD) patterns comparedwith other continental (e.g., European) populations. Severalintron 8 SNPs, in addition to intron 1 SNPs, showed significantassociations in both study samples. The combined effect size forBMI for the top SNPs from meta-analysis was 0.77 kg/m2 (P �0.009, rs9932411) and 0.70 kg/m2 (P � 0.006, rs7191513). Twopreviously reported associations with intron 1 SNPs (rs1121980and rs7204609, r2 � 0.001) were replicated among the WestAfricans.

CONCLUSIONS—The FTO gene shows significant differencesin allele frequency and LD patterns in populations of Africanancestry compared with other continental populations. Despitethese differences, we observed evidence of associations withobesity in African Americans and West Africans, as well asevidence of heterogeneity in association. More studies of FTO inmultiple ethnic groups are needed. Diabetes 59:1549–1554,2010

The fat mass and obesity associated gene (FTO)(GeneID: 79068) is currently the most consis-tently replicated gene for obesity in humans. Thefirst studies establishing this association were

published in 2007 (1–3); since then, multiple studies havebeen done to confirm the epidemiological association andelucidate the physiological role played by the proteinproduct of the gene (4). While the epidemiological evi-dence for the association of FTO with obesity is quite

strong, it has not been consistently replicated in allpopulations studied, and there remain multiple popula-tions for which data are scarce or absent.

Data on FTO genetic variation and association withobesity in African ancestry populations are quite scarce.Populations with a majority of African ancestry are inter-esting with respect to obesity because they show widevariation in the prevalence of obesity across levels ofindustrialization (for example, across West Africa, theCaribbean, and the U.S.) (5,6). At the same time, they oftenexhibit significant disparities compared with other ethnicgroups within the same country, for example, AfricanAmericans when compared with other ethnic groups in theU.S. (7). Given the greater genetic diversity and differentlinkage disequilibrium (LD) structure exhibited by African-ancestry populations, understanding genetic variation inthe FTO gene in African populations promises to providenovel insights into its association with obesity.

We have evaluated FTO genetic variation in two popu-lations of African ancestry, African Americans and WestAfricans, and tested the association of FTO variants withobesity (as measured by BMI, waist circumference [WC],and percent fat mass [PFM]) in an effort to replicateprevious findings and to search for novel associations ofFTO variants with obesity in populations of Africanancestry.

RESEARCH DESIGN AND METHODS

The study included two sets of participants: 1) 968 unrelated AfricanAmericans (estimated African ancestry 0.78 � 0.11) enrolled from theWashington, D.C., metropolitan area in the U.S. as part of the HowardUniversity Family Study, and 2) 517 unrelated West Africans enrolled ascontrol subjects as part of the Africa-America Diabetes Mellitus (AADM)Study. After obtaining written informed consent, participants underwent aninterview followed by a physical examination during which weight, height,and WC were measured using standard methods. BMI was computed asweight (measured in kilograms) divided by the square of the height (measuredin meters). Body composition was estimated using bioelectric impedanceanalysis with validated population-specific equations as previously described(8). PFM was calculated as (fat mass/weight)*100. DNA was extracted frombuffy coats using PureGene kits (Gentra).

Based on the International HapMap Project (HapMap) YRI data, tag singlenucleotide polymorphisms (SNPs) at a pairwise r2 �0.8 and with a minorallele frequency (MAF) �0.02 were selected for genotyping. The resulting 273SNPs were genotyped as part of a custom Illumina panel using the IlluminaGoldenGate Assay. Of the 273 SNPs, 264 were successfully genotyped, givinga locus success rate of 96.7%. The genotype call rate was 99.32%. Theconcordance rate for blind duplicates was 99.98%. Two SNPs deviatedsignificantly (P � 0.001) from Hardy-Weinberg equilibrium and were excludedfrom further analysis, leaving 262 SNPs.

MAFs were computed and LD visualized using Haploview (9). Associationwith obesity traits was tested under an additive model with adjustment for ageand sex using PLINK version 1.06. Potential population stratification wasaccounted for in each sample by adjusting for the first principal componentderived from a set of 142 ancestry-informative SNPs genotyped in the AfricanAmerican subjects and by adjusting for ethnic group among the West Africansubjects. Each sample was analyzed separately. Then, combined analysis wasdone using a meta-analysis technique that computes weighted statistics for

From the Center for Research on Genomics and Global Health, NationalHuman Genome Research Institute, National Institutes of Health, Bethesda,Maryland.

Corresponding author: Adebowale Adeyemo, adeyemoa@mail.nih.gov.Received 24 August 2009 and accepted 4 March 2010. Published ahead of print

at http://diabetes.diabetesjournals.org on 18 March 2010. DOI:10.2337/db09-1252.

© 2010 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit,and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page

charges. This article must therefore be hereby marked “advertisement” in accordance

with 18 U.S.C. Section 1734 solely to indicate this fact.

BRIEF REPORT

diabetes.diabetesjournals.org DIABETES, VOL. 59, JUNE 2010 1549

association and tests for heterogeneity, implemented in METAL (Meta Anal-ysis Helper, available through the University of Michigan). Previous Europeanstudies have estimated that the FTO variant explains �1% of the phenotypicvariance in BMI (1–3). The present study has �88% power (for the AfricanAmerican sample) and �63% power (for West African sample) to explain �1%of the variance in BMI for a SNP with an MAF of at least 0.05 at a two-tailed� level of 0.05.

Given the strong prior information about the role of FTO variation inobesity, we considered our evaluation of the association between intron 1SNPs and obesity a replication study; thus, nominal P values �0.05 wereconsidered significant. For SNPs in the rest of the gene, tests of associationscould be considered discovery rather than replication for which a Bonferroni-corrected P value threshold of 0.0002 (0.05/209 SNPs) would be significant.

RESULTS

The characteristics of the study subjects are shown inTable 1. The African Americans weighed significantlymore and had higher BMI, WC, and PFM than the WestAfricans. MAFs were generally similar between the twosamples (supplementary Table 1, available in an onlineappendix at http://care.diabetesjournals.org.cgi/content/full/db09-1252/DC1). However, seven (2.7%) SNPs showeda difference (�) in allele frequencies �0.1, and 88 (33.6%)SNPs showed a � � 0.05 (supplementary Fig. 1).

The LD structure across the gene in both study samplesis shown in Fig. 1. Using the CI method of Gabriel et al.(10) to construct haplotype blocks, the African Americansample had 59 haplotype blocks with 138 SNPs outsideblocks while the West African sample had 58 blocks with142 SNPs outside blocks. The LD structure in the twostudy samples is more fragmented than European or Asiancontinental populations (represented by the HapMap CEUand JPT/CHB samples, respectively) (Fig. 1 and supple-mentary Fig. 2). This pattern of low LD was also observedfor the intron 1 region surrounding rs9939609, the mostconsistently reported obesity-associated FTO SNP (sup-plementary Fig. 3). Using a common set of polymorphicSNPs, the proportion of SNPs exceeding specific r2 thresh-olds of 0.2, 0.4, 0.6, and 0.8, respectively, in the HapMapCEU, CHB, and JPT samples were approximately threefoldhigher than those in the present study and the HapMap YRIsample (P � 0.0001, supplementary Fig. 2, and supplemen-tary Table 2). In contrast, there were no significant differ-ences in these proportions between the West African andAfrican American samples in the present study or betweenthese and the HapMap YRI sample.

Table 2 shows the SNPs displaying P � 0.01 in eitherstudy population or in the meta-analysis. The top scoringSNPs for BMI were in intron 8 (Fig 2). For WC and PFM,the most significantly associated SNPs were in intron 8 orintron 1 (Table 2, Fig 2). The effect sizes for BMI were0.9–1.7 kg/m2 in West Africans, �1–1.6 kg/m2 in African

Americans, and �0.8 kg/m2 in the meta-analysis for thetwo significant SNPs showing consistent direction of ef-fect. The effect sizes for WC and PFM are shown in Table2. Some SNPs (one for BMI, one for WC, and three forPFM) showed significant heterogeneity of association be-tween the two study samples (Table 2). Haplotype analysisaround these top-scoring SNPs showed that none of thehaplotypes had a stronger association with any of thetraits than the single SNPs they contained (data notshown). The only nonsynonymous coding SNP, rs16952624(A405V), in this study (MAF 0.041 in West Africans, 0.024in African Americans) showed no association with any ofthe obesity phenotypes in the West African (P 0.52–0.70)or African American sample (P 0.18–0.67). We note thatnone of the discovery SNPs in intron 8 reached statisticalsignificance at a P value threshold of 0.0002 after correct-ing for multiple comparisons using the conservative Bon-ferroni-correction method.

We tested SNPs in the FTO gene previously reported tobe associated with obesity in populations of Europeanancestry, including rs9939609, rs1121980, rs17817449, andrs7204609. The minor allele frequencies in our samplesand the P values for association are shown in Table 2. Wereplicated the association with obesity for both rs1121980and rs7204609 at P � 0.05 in the West African sample butnot in the African American sample. Similarly, we lookedfor association in the set of 16 SNPs tested in the onlypublished African sample to date (11) and found thatrs7204609, rs17817288 and rs12447107 showed significantassociation with PFM in our West African sample (supple-mentary Table 4). As in the Gambian study (11), theseSNPs did not show association with BMI in this study.

One of the potential advantages of studying an Africanpopulation is the opportunity to fine-map loci that havebeen identified in populations with stronger LD. We there-fore looked for evidence of association of SNPs with anr2 � 0.2 with the strongest reported FTO variant(rs9939609) in the HapMap CEU. Only one of 13 such SNPs(rs8055197, r2 � 0.58 in HapMap CEU) showed a smallP value in the present study (P � 0.012 for BMI and P �0.015 for WC, both in African Americans). Conversely,none of the SNPs in Table 1 showed strong LD withrs9939609 in the present study (maximum r2 � 0.337among West Africans, 0.223 among African Americans,(supplementary Table 5).

DISCUSSION

The FTO gene is one of the few genes to show consistentassociation with human obesity, particularly in popula-tions of European ancestry (1,12–16), with few exceptions(17). In contrast, evidence from studies of other continen-tal populations has been less consistent. Some studies ofmultiple Asian populations did not confirm this associa-tion (18–20) while other studies did (21,22). There are fewstudies from populations of African origin, and the datafrom such studies have been largely negative. In the firststudy that included African Americans, Scuteri et al. (1)did not replicate the FTO association with obesity in asample of 1,100 African Americans, neither did two otherstudies (11,23). The first study that found associationbetween FTO variants and obesity in an African-ancestrypopulation was a study of childhood obesity (24). Morerecently, Wing et al. (25) showed that rs8050136 andrs9939609 were associated with BMI and WC amongAfrican Americans in the Insulin Resistance Atherosclero-

TABLE 1Characteristics of the 968 African American and 517 West Africanstudy participants

African Americans West AfricansMen Women Men Women

n 401 567 219 298Age (years) 49.0 � 10.8 49.4 � 12.5 56.1 � 12.8 52.0 � 12.9Weight (kg) 88.9 � 24.1 85.8 � 24.0 69.4 � 15.2 68.8 � 16.3Height (cm) 175.6 � 7.5 163.1 � 7.2 170.0 � 6.8 160.7 � 6.6BMI (kg/m2) 28.8 � 7.5 32.3 � 8.8 23.9 � 4.8 26.6 � 6.1WC (cm) 96.3 � 17.1 97.7 � 17.1 87.3 � 12.1 89.2 � 12.9PFM 28.7 � 9.7 41.4 � 8.5 18.5 � 10.3 32.8 � 12.0

Data are mean � SD.

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1550 DIABETES, VOL. 59, JUNE 2010 diabetes.diabetesjournals.org

sis Study (IRAS) Family Study. The only study so far of asub-Saharan African population (11) was negative. Poten-tial explanations for these differences between popula-tions include differences in sample size, allele frequencydifferences, different LD patterns, and heterogeneity (asdemonstrated for a few variants in this study).

In the present study, we tagged the entire span of theFTO gene (not just previously associated intron 1 SNPs) intwo populations of African ancestry (African Americansand West Africans) to investigate association with obesityin these populations. To our knowledge, the set of 262 tagSNPs we studied is the largest set of SNPs to be directlygenotyped in the FTO gene in any single study to date.Multiple SNPs in intron 8 (in addition to intron 1 SNPs)

showed significant nominal association with the obesityphenotypes in the present study. This finding is significantbecause, to date, the focus on FTO variants associatedwith obesity has been, for the most part, on the specificSNPs or other intron 1 SNPs reported in the initialgenome-wide association study. When significant associa-tions are found within a gene, replication studies in otherpopulations (especially those of a different continentalancestry) that scan the entire gene (rather than just one ora few SNPs) may lead to the discovery of other importantgenetic variants. Consistent with expectations, we foundthat both the West African and African American studysamples showed weaker LD patterns across the gene whencompared with other continental (e.g., European and

African Americans (present study) West Africans (present study)

HapMap CHB HapMap JPT

HapMap CEU HapMap YRI

1 2 5 6 7 8 10 11 12 13 14 15 18 21 22 23 24 25 27 28 30 31 32 33 34 35 36 37 39 40 42 44 45 46 47 48 49 50 51 52 53 54 57 58 59 60 62 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 96 97 98 99 100 101 102 104 105 106 107 110 111 112 113 114 115 116 117 118 119 120 121 122 125 126 127 128 129 130 131 133 134 136 137 138 139 141 142 143 145 146 147 149 150 151 152 153 154 155 156 157 158 159 160 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 191 192 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 218 219 221 222 224 225 227 228 231 232 233 234 235 236 237 238 239 241 242 244 245 246 247 248 249 250 251 253 254 255 256 258 259 260 261 262Block 1 (14 kb) Block 2 (15 kb) Block 3 (10 kb) Block 4 (0 kb) Block 5 (18 kb) Block 6 (16 kb) Block 7 (1 kb) Block 8 (0 kb) Block 9 (2 kb) Block 10 (3 kb) Block 11 (7 kb) Block 12 (3 kb) Block 13 (8 kb) Block 14 (8 kb) Block 15 (1 kb) Block 16 (6 kb) Block 17 (8 kb) Block 18 (5 kb) Block 19 (0 kb) Block 20 (13 kb) Block 21 (22 kb) Block 22 (10 kb) Block 23 (17 kb) Block 24 (3 kb)

1 2 5 6 7 8 10 11 12 13 14 16 17 18 21 22 23 24 25 27 28 30 31 32 33 34 35 36 37 39 40 42 44 45 46 47 49 50 51 52 53 54 57 58 59 60 62 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 90 94 95 96 97 98 99 103 105 111 112 113 114 115 116 117 118 119 120 123 124 125 126 127 128 129 131 134 135 136 137 139 140 141 143 144 145 147 148 149 150 151 152 153 157 158 160 162 163 164 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 185 186 187 189 190 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 208 209 210 211 212 213 214 215 216 217 219 220 222 223 226 229 230 231 232 233 234 235 236 237 239 240 242 243 244 245 246 247 248 249 251 252 253 254 256 257 258 259 260Block 1 (20 kb) Block 2 (10 kb) Block 3 (7 kb) Block 4 (0 kb) Block 5 (5 kb) Block 6 (0 kb) Block 7 (4 kb) Block 8 (11 kb) Block 9 (9 kb) Block 10 (14 kb) Block 11 (8 kb) Block 12 (18 kb) Block 13 (42 kb) Block 14 (10 kb) Block 15 (2 kb) Block 16 (3 kb) Block 17 (1 kb)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 12 1 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 2 06 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 24 8 249 250 251 252 253 254 255 256 257 258 259 260 261 262Bloc k 1 (4 kb) Block 2 (0 kb) Block 3 (8 kb ) Block 4 (1 kb) Block 5 (9 kb) Block 6 (1 kb ) Bloc k 7 (0 kb ) Block 8 (1 kb ) Block 9 (5 kb) Block 10 (3 kb) Bloc k 11 (4 kb) Block 12 (11 kb) Block 13 (3 kb ) Block 14 (2 kb) Block 15 (8 kb) Block 16 (0 kb) Block 17 (4 kb) Bloc k 18 (1 kb) Block 19 (1 2 kb) Block 20 (0 kb) Block 21 (3 kb) Block 22 (7 kb) Block 23 (3 kb) Block 24 (0 kb) Block 25 (1 kb ) Block 26 (0 kb) Block 27 (3 kb ) Block 28 (5 kb ) Block 29 (2 kb) Block 30 (0 kb) Block 31 (1 kb) Block 32 (0 kb ) Block 33 (0 kb) Bloc k 34 (1 kb ) Block 35 (9 kb ) Bloc k 36 (1 kb) Block 37 (0 kb) Block 38 (0 kb) Block 39 (1 kb) Bloc k 40 (1 kb ) Block 41 (3 kb) Block 42 (6 kb) Block 43 (0 kb) Block 44 (2 kb) Bloc k 45 (0 kb ) Block 46 (0 kb ) Block 47 (7 kb) Block 48 (3 kb) Block 49 (1 kb) Block 50 (0 kb) Block 51 (4 kb) Block 52 (3 kb) Block 53 (0 kb) Block 54 (1 kb) Block 55 (3 kb) Block 56 (1 kb ) Block 57 (1 kb) Block 58 (8 kb ) Block 59 (1 kb)

1 2 6 7 8 10 11 12 13 14 16 17 18 21 22 23 24 25 27 28 30 31 32 33 3 4 35 3 6 37 39 4 0 42 4 4 4 5 4 6 4 7 4 9 5 0 5 1 5 2 5 3 5 4 5 7 5 8 5 9 6 0 6 2 6 4 6 5 6 6 6 7 6 8 6 9 7 0 7 1 7 2 7 3 7 4 7 5 7 6 7 7 7 8 7 9 8 0 8 1 8 2 8 384 85 86 87 88 90 94 95 96 97 98 99 100 102 103 105 10 8 10 9 1 10 111 1 1 2 1 1 3 1 1 4 1 1 6 1 1 7 1 1 8 1 1 9 1 2 0 1 2 3 1 2 7 1 2 9 1 3 1 1 3 4 1 3 5 1 3 6 1 3 7 1 3 9 1 4 0 1 4 1 1 4 3 1 4 5 1 4 7 1 4 8 1 4 9 1 5 0 1 5 1 152 153 154 157 158 160 161 162 163 164 165 166 1 67 1 6 8 1 6 9 1 7 0 1 7 1 1 7 2 1 7 3 1 7 4 1 7 5 1 7 6 1 7 7 1 7 8 1 7 9 1 8 0 1 8 1 1 8 2 1 8 3 1 8 5 1 8 6 1 8 7 1 8 9 1 9 0 1 9 2 1 9 3 1 9 4 1 9 5 1 9 6 1 9 7 1 9 8 1 9 9 2 00 201 202 203 204 205 206 208 209 210 211 212 2 13 21 4 21 5 21 6 2 1 7 2 1 9 2 2 0 2 2 2 2 2 3 2 2 6 2 2 9 2 3 0 2 3 1 2 3 2 2 3 3 2 3 4 2 3 5 2 3 6 2 3 7 2 3 9 2 4 0 2 4 2 2 4 3 2 4 4 2 4 5 2 4 6 2 4 7 2 4 8 2 4 9 2 5 1 2 5 2253 254 256 257 258 259 260Block 1 (2 kb) Block 2 (15 kb) Block 3 (10 kb) Block 4 (7 kb) Block 5 (9 kb) Block 6 (0 kb) Block 7 (18 kb) Block 8 (0 kb) Block 9 (4 kb) Block 10 (8 kb) Block 11 (9 kb) Block 12 (3 kb) Block 13 (3 kb) Block 14 (3 kb) Block 15 (6 kb) Block 16 (44 kb) Block 17 (2 kb) Block 18 (8 kb) Block 19 (10 kb) Block 20 (9 kb) Block 21 (1 kb)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 12 1 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 2 06 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 24 8 249 250 251 252 253 254 255 256 257 258 259 260 261 262Block 1 (4 kb) Block 2 (0 kb) Block 3 (8 kb) Block 4 (8 kb) Block 5 (1 kb) Block 6 (5 kb) Block 7 (3 kb) Block 8 (4 kb) Block 9 (2 kb) Block 10 (10 kb) Block 11 (1 kb) Block 12 (3 kb) Block 13 (1 kb) Block 14 (8 kb) Block 15 (0 kb) Block 16 (4 kb) Block 17 (1 kb) Block 18 (12 kb) Block 19 (7 kb) Block 20 (5 kb) Block 21 (0 kb) Block 22 (1 kb) Block 23 (3 kb) Block 24 (0 kb) Block 25 (1 kb) Block 26 (5 kb) Block 27 (5 kb) Block 28 (0 kb) Block 29 (2 kb) Block 30 (3 kb) Block 31 (1 kb) Block 32 (0 kb) Block 33 (2 kb) Block 34 (0 kb) Block 35 (1 kb) Block 36 (1 kb) Block 37 (2 kb) Block 38 (2 kb) Block 39 (2 kb) Block 40 (6 kb) Block 41 (0 kb) Block 42 (2 kb) Block 43 (0 kb) Block 44 (0 kb) Block 45 (7 kb) Block 46 (3 kb) Block 47 (1 kb) Block 48 (0 kb) Block 49 (0 kb) Block 50 (0 kb) Block 51 (0 kb) Block 52 (3 kb) Block 53 (1 kb) Block 54 (3 kb) Block 55 (1 kb) Block 56 (1 kb) Block 57 (9 kb) Block 58 (1 kb)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2 1 22 23 24 25 26 27 2 8 29 30 3 1 3 2 3 3 3 4 3 5 3 6 3 7 3 8 3 9 4 0 4 1 4 2 4 3 4 4 4 5 4 6 4 7 4 8 4 9 5 0 5 1 5 2 5 3 5 4 5 5 5 6 5 7 5 8 5 9 6 0 6 1 6 2 6 3 6 4 6 5 6 6 6 7 6 869 70 71 72 73 74 75 76 77 78 79 80 81 82 8 4 8 5 8 6 87 88 89 90 91 92 93 94 9 5 9 6 9 7 9 8 9 9 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7 1 0 8 1 0 9 1 1 0 1 1 1 1 1 2 1 1 3 1 1 4 1 1 5 1 1 6 1 1 7 1 1 8 1 1 9 1 2 0 1 2 1 122 123 124 125 126 127 128 129 130 1 31 1 32 133 134 135 136 137 138 13 9 14 0 1 4 1 1 4 2 1 4 3 1 4 4 1 4 5 1 4 6 1 4 7 1 4 8 1 4 9 1 5 0 1 5 1 1 5 2 1 5 3 1 5 4 1 5 5 1 5 6 1 5 7 1 5 8 1 5 9 1 6 0 1 6 1 1 6 2 1 6 3 1 64 165 166 167 168 169 170 171 172 173 174 175 176 177 17 8 17 9 1 80 1 81 1 8 2 18 3 1 8 4 18 5 1 8 6 1 8 7 1 8 8 1 8 9 1 9 0 1 9 1 1 9 2 1 9 3 1 9 4 1 9 5 1 9 6 1 9 7 1 9 8 1 9 9 2 0 0 2 0 1 2 0 2 2 0 3 2 0 4 2 0 5 2 0 6207 208 209 210 211 212 213 214 215 21 6 21 7 2 18 2 19 220 221 2 22 22 3 224 225 226 2 2 7 2 2 8 2 2 9 2 3 0 2 3 1 2 3 2 2 3 3 2 3 4 2 3 5 2 3 6 2 3 7 2 3 8 2 3 9 2 4 0 2 4 1 2 4 2 2 4 3 2 4 4 2 4 5 2 4 6 2 4 7 2 4 8 249 250 251 252 253 25 4 255 2 56 2 57 258 259 260 261 262Block 1 (0 kb) Block 2 (5 kb) Block 3 (2 kb) Block 4 (2 kb) Block 5 (2 kb) Block 6 (6 kb) Block 7 (0 kb) Block 8 (5 kb) Block 9 (4 kb) Block 10 (0 kb) Block 11 (1 kb) Block 12 (1 kb) Block 13 (0 kb) Block 14 (2 kb) Block 15 (5 kb) Block 16 (0 kb) Block 17 (0 kb) Block 18 (1 kb) Block 19 (0 kb ) Block 20 (2 kb) Block 21 (1 kb)

FIG. 1. LD patterns across the FTO gene in the two study samples (African Americans and West Africans) and in four HapMap population samples(European, CEU; East Asian, CHB and JPT; and African, YRI). (A high-quality digital representation of this figure is available in the online issue.)

A. ADEYEMO AND ASSOCIATES

diabetes.diabetesjournals.org DIABETES, VOL. 59, JUNE 2010 1551

Asian) populations. Studying populations of different an-cestries (especially those with smaller LD) could helpfine-map disease or trait loci. However, since thers9939609 association in intron 1 of FTO reported inEuropeans did not replicate in this study (as well asseveral other studies of African ancestry populations),African populations may not be the optimum choice tofine-map this locus.

The overall evidence from this study of populations witha majority of African ancestry adds to the growing body ofknowledge supporting the role of FTO variants in obesityacross multiple human populations. The location of mostof these significant SNPs in intron 8 and the downstreamregion (rather than intron 1) suggests that there may be

more than one genetic variant within FTO influencingobesity in humans. Further studies are needed to confirm,refine, and extend these findings.

ACKNOWLEDGMENTS

The Howard University Family Study (HUFS) was sup-ported by grants S06GM008016-380111 to A.A. andS06GM008016-320107 to C.R., both from the NIGMS/MBRS/SCORE Program. Support for the Africa-AmericaDiabetes Mellitus (AADM) study was provided by NationalInstitutes of Health (NIH) Grant 3T37TW0041-03S2 fromthe National Center for Minority Health and Health Dis-parities, as well as other NIH institutes (NHGRI and

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FIG. 2. Association analysis plots for BMI, waist circumference and percent fat mass in the two study samples of African Americans and WestAfricans.

FTO AND OBESITY IN AFRICANS AND AFRICAN AMERICANS

1552 DIABETES, VOL. 59, JUNE 2010 diabetes.diabetesjournals.org

NIDDK through grant DK-54001). Participant enrollmentfor the HUFS was carried out at the Howard UniversityGeneral Clinical Research Center, which is supported bygrant 2M01RR010284 from the National Center for Re-search Resources (NCRR), a component of the NIH. Thisresearch was supported in part by the Intramural ResearchProgram of the Center for Research on Genomics andGlobal Health (CRGGH). The CRGGH is supported by theNHGRI, the NIDDK, the Center for Information Tech-nology, and the Office of the Director at the NIH(Z01HG200362).

The funders had no role in study design, data collectionand analysis, decision to publish, or preparation of themanuscript.

No potential conflicts of interest relevant to this articlewere reported.

Parts of this study were presented in abstract form atthe 59th American Society of Human Genetics Meeting,Honolulu, Hawaii, 24 October 2009.

The authors thank participants, physicians, and investi-gators in the HUFS and Africa America Diabetes Mellitus(AADM) study.

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TABLE 2Best evidence* for association of FTO variants with the obesity-related traits among West Africans and African Americans and onmeta-analysis

SNP Location A1

West Africans African Americans Meta-Analysis

P �L95�

U95� MAF P �

L95�

U95� MAF P �

SE(�) Dir

P

(Het)

BMI (kg/m2)rs708262 INTRON 8 T 0.005 0.99 0.30 1.67 0.40 0.040 0.84 1.65 0.04 0.38 0.412 0.22 0.27 0.001rs11076022 3�_UTR G 0.005 1.66 2.82 0.50 0.09 0.765 0.17 1.26 0.93 0.15 0.033 0.87 0.41 0.067rs9932411 INTRON 8 T 0.034 0.90 0.07 1.72 0.21 0.109 0.66 0.15 1.46 0.31 0.009 0.77 0.29 0.687rs7191513 INTRON 8 G 0.202 0.45 0.24 1.13 0.42 0.008 0.97 0.25 1.69 0.48 0.006 0.70 0.25 0.300rs11076017 INTRON 8 T 0.950 0.03 1.04 1.11 0.12 0.003 1.55 0.54 2.55 0.20 0.024 0.84 0.37 0.044

WC (cm)rs16953075 3�_UTR T 0.005 2.57 0.77 4.38 0.23 0.587 0.58 1.51 2.67 0.15 0.013 1.72 0.70 0.157rs16952987 INTRON 8 A 0.008 2.48 4.29 0.66 0.21 0.292 0.99 2.82 0.85 0.23 0.008 1.74 0.66 0.257rs9933611 INTRON 1 G 0.028 3.18 5.99 0.36 0.08 0.073 2.87 5.99 0.26 0.06 0.004 3.04 1.07 0.885rs2689269 INTRON 8 A 0.030 1.71 3.26 0.17 0.46 0.043 1.60 3.14 0.05 0.49 0.003 1.65 0.56 0.918rs8055197 INTRON 1 G 0.190 1.27 3.17 0.63 0.20 0.015 2.25 4.06 0.44 0.28 0.008 1.78 0.67 0.465rs11076017 INTRON 8 T 0.631 0.58 2.93 1.77 0.12 0.001 3.60 1.54 5.66 0.20 0.024 1.78 0.79 0.009

PFM (%)rs16952725 INTRON 8 C 0.002 4.01 6.59 1.42 0.05 0.925 0.09 1.86 2.05 0.04 0.078 1.40 0.80 0.013rs9932411 INTRON 8 T 0.003 2.05 0.69 3.41 0.21 0.075 0.78 0.08 1.65 0.31 0.002 1.15 0.37 0.125rs7204609 INTRON 1 C 0.006 1.59 2.71 0.46 0.44 0.683 0.18 0.68 1.03 0.36 0.176 0.47 0.35 0.014rs17817288 INTRON 1 G 0.006 1.61 0.46 2.75 0.40 0.704 0.16 0.66 0.97 0.40 0.057 0.64 0.34 0.043rs11076022 3�_UTR G 0.009 2.56 4.47 0.65 0.09 0.598 0.32 0.86 1.49 0.15 0.355 0.47 0.51 0.012rs16952520 INTRON 1 G 0.026 1.36 0.17 2.56 0.32 0.129 0.74 0.21 1.69 0.26 0.010 0.98 0.38 0.425rs7191513 INTRON 8 G 0.125 0.89 0.24 2.02 0.42 0.011 1.00 0.23 1.77 0.48 0.003 0.96 0.33 0.879

*All SNPs with association P values �0.01 using an additive model in either sample or the meta-analysis.

A. ADEYEMO AND ASSOCIATES

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