TY - JOUR
T1 - Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans
AU - Salinas, Yasmmyn D.
AU - Wang, Leyao
AU - DeWan, Andrew T.
N1 - Funding Information:
Dr. DeWan is supported by grant 1R01HL116742 from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. Ms. Salinas is supported by a Diversity Supplement to grant 1R01HL116742. Dr. Wang is supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health and a Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship (F32; award number 1F32AI114097-01A1). Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, and CTSA UL1-RR-024156. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. The WHI program is funded by the National Heart, Lung, and Blood Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding for WHI SHARe genotyping was provided by NHLBI contract N02-HL-64278. The MESA and MESA SHARe project are conducted and supported by the NHLBI in collaboration with the MESA investigators. None of the funding institutions listed above played any role in the design, analysis or preparation of the manuscript. In addition, this manuscript was not prepared in collaboration with either the MESA or WHI investigators and does not necessarily reflect the opinions of the MESA or WHI investigators or the NHLBI.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/6/13
Y1 - 2016/6/13
N2 - Background: Genome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women's Health Initiative (WHI). Results: We identified a genome-wide significant association in MESA Hispanics-rs12253976 in KLF6 (beta = 5.792 kg/m2 per-allele, 95 % confidence interval (CI): 3.885, 7.698; p = 3.43 × 10-9)-and suggestive SNPs with p < 5 × 10-6 in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta = -1.111 kg/m2, 95 % CI: -1.578, -0.645; p = 3.33 × 10-6) and WHI Hispanics (beta = -0.304 kg/m2, 95 % CI: -0.613, 0.006; p = 0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10-3) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta = 1.104 kg/m2, 95 % CI: 0.643, 1.564; p = 2.85 × 10-6) and WHI African Americans (beta = 0.219 kg/m2, 95 % CI: -0.021, 0.460; p = 0.074). Conclusions: Two BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.
AB - Background: Genome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women's Health Initiative (WHI). Results: We identified a genome-wide significant association in MESA Hispanics-rs12253976 in KLF6 (beta = 5.792 kg/m2 per-allele, 95 % confidence interval (CI): 3.885, 7.698; p = 3.43 × 10-9)-and suggestive SNPs with p < 5 × 10-6 in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta = -1.111 kg/m2, 95 % CI: -1.578, -0.645; p = 3.33 × 10-6) and WHI Hispanics (beta = -0.304 kg/m2, 95 % CI: -0.613, 0.006; p = 0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10-3) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta = 1.104 kg/m2, 95 % CI: 0.643, 1.564; p = 2.85 × 10-6) and WHI African Americans (beta = 0.219 kg/m2, 95 % CI: -0.021, 0.460; p = 0.074). Conclusions: Two BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.
KW - Body mass index
KW - Ethnic differences
KW - Genetic epidemiology
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=84978115994&partnerID=8YFLogxK
U2 - 10.1186/s12863-016-0387-0
DO - 10.1186/s12863-016-0387-0
M3 - Article
C2 - 27296613
AN - SCOPUS:84978115994
SN - 1471-2156
VL - 17
JO - BMC genetics
JF - BMC genetics
IS - 1
M1 - 78
ER -