Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits—The Hispanic/Latino Anthropometry Consortium
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Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 100099 |
| Tidsskrift | Human Genetics and Genomics Advances |
| Vol/bind | 3 |
| Udgave nummer | 2 |
| Antal sider | 21 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
S.M.G. and A.M.S. receive funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. All others authors declare no competing interests.
Funding Information:
A.G.L. was supported by NIH (T32 HD091058, P2C HD050924, and P30 AG066615). A.G.T. was supported by NIH (T32HL007055). A.R.L. has been supported by the Leverhulme Trust (F/07 134/DF), the Excellence Initiative of Aix-Marseille University - A?MIDEX (a French ?Investissements d'Avenir? programme), the National Natural Science Foundation of China (#31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), Ministry of Science and Technology of China (2020YFE0201600), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the 111 Project (B13016), and BBSRC (BB/I021213/1). L.F. was supported by NIH (R01CA204797). L.F.-R. was supported by an American Heart Association predoctoral grant (13PRE16100015). M.G. K.L.Y. and K.E.N. were supported by AHA (13GRNT16490017, 15GRNT25880008), R01DK089256, and R01DK101855. L.F.-R. C.A.H. and R.F.J.L. were supported by NIH (R01DK101855). X.R.G. was supported by NIH (R01EY022651). K.E.N. was supported by NIH (R01HD057194, R01DK122503, R01HG010297, R01HL142302, R01HL143885, and R01HG009974). L.G. was supported by NIH (T32 HL129982). Q.Q. was supported by NIH (R01HL060712, R01HL140976, and R01DK119268). S.F.A.G. was supported by the Daniel B. Burke Endowed Chair for Diabetes Research and NIH (R01 HD056465). X.G. M.A.A. Y.-D.I.C. J.Y. and J.I.R. were supported by NIH (EY14684, HL-0767711, HL-0697974, HL-088457, NEI EY11753, UL1-TR-001881). X.L. and K.R. were supported by NIH (R01 HL0767711 and DK-079888). Z.A. T.A.B. J.T. and A.H.X. were supported by HTN-IR funding (HL-0697974) and P.M.G. Y.H. E.I. and K.D.T. were supported by NIH (EY-14684). M.O.G. W.H. K.L. and K.S. were supported by NIH (HL-088457). A.E.J. was supported by NIH (K99/R00 HL130580). E.M.J. was supported by NIH (R01 CA063446, R01 CA077305, DOD RP9590546, and CBCRP 7PB-0068). J.M. was supported by the American Diabetes Association 1-19-ICTS-068 and by U01HG011723. C.W.K.C. was supported by R35GM142783. Study-specific acknowledgments are available as supplemental data. S.M.G. and A.M.S. receive funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. All others authors declare no competing interests.
Funding Information:
A.G.L. was supported by NIH ( T32 HD091058 , P2C HD050924 , and P30 AG066615 ). A.G.T. was supported by NIH ( T32HL007055 ). A.R.L. has been supported by the Leverhulme Trust ( F/07 134/DF ), the Excellence Initiative of Aix-Marseille University - A∗MIDEX (a French “Investissements d’Avenir” programme), the National Natural Science Foundation of China ( #31771393 ), the Scientific and Technology Committee of Shanghai Municipality ( 18490750300 ), Ministry of Science and Technology of China ( 2020YFE0201600 ), Shanghai Municipal Science and Technology Major Project ( 2017SHZDZX01 ), the 111 Project ( B13016 ), and BBSRC ( BB/I021213/1 ). L.F. was supported by NIH ( R01CA204797 ). L.F.-R. was supported by an American Heart Association predoctoral grant ( 13PRE16100015 ). M.G., K.L.Y., and K.E.N. were supported by AHA ( 13GRNT16490017 , 15GRNT25880008 ), R01DK089256 , and R01DK101855 . L.F.-R., C.A.H., and R.F.J.L. were supported by NIH ( R01DK101855 ). X.R.G. was supported by NIH ( R01EY022651 ). K.E.N. was supported by NIH ( R01HD057194 , R01DK122503 , R01HG010297 , R01HL142302 , R01HL143885 , and R01HG009974 ). L.G. was supported by NIH ( T32 HL129982 ). Q.Q. was supported by NIH ( R01HL060712 , R01HL140976 , and R01DK119268 ). S.F.A.G. was supported by the Daniel B. Burke Endowed Chair for Diabetes Research and NIH ( R01 HD056465 ). X.G., M.A.A., Y.-D.I.C., J.Y., and J.I.R. were supported by NIH ( EY14684 , HL-0767711 , HL-0697974 , HL-088457 , NEI EY11753 , UL1-TR-001881 ). X.L. and K.R. were supported by NIH ( R01 HL0767711 and DK-079888 ). Z.A., T.A.B., J.T., and A.H.X. were supported by HTN-IR funding ( HL-0697974 ) and P.M.G., Y.H., E.I., and K.D.T. were supported by NIH ( EY-14684 ). M.O.G., W.H., K.L., and K.S. were supported by NIH ( HL-088457 ). A.E.J. was supported by NIH ( K99/R00 HL130580 ). E.M.J. was supported by NIH ( R01 CA063446 , R01 CA077305 , DOD RP9590546 , and CBCRP 7PB-0068 ). J.M. was supported by the American Diabetes Association 1-19-ICTS-068 and by U01HG011723 . C.W.K.C. was supported by R35GM142783 . Study-specific acknowledgments are available as supplemental data .
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