Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

Fernandez-Rhodes, L.; Graff, M.; Buchanan, V. L.; Justice, A. E.; Highland, H. M.; Guo, X.; Young, K. L.; Adhikari, K.; Allred, N. P.; Below, J. E.; Bradfield, J.; Pereira, A. C.; Glover, L.; Kim, D.; Lilly, A. G.; Shrestha, P.; Thomas, A. G.; Zhang, X.; Chen, M.; Chiang, C.; Pulit, S.; Horimoto, A.; Krieger, J. E.; Guindo-Martinez, M.; Preuss, M.; Schumann, C.; Smit, R. A. J.; Torres-Mejia, G.; Acuna-Alonzo, V.; Bedoya, G.; Bortolini, M.-C.; Canizales-Quinteros, S.; Gallo, C.; Gonzalez-Jose, R.; Poletti, G.; Rothhammer, F.; Hakonarson, H.; Adler, S. G.; Igo, R.; Iyengar, S.; Nicholas, S. B.

doi:10.1101/2021.05.27.445969

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bioRxiv · 10.1101/2021.05.27.445969

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

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Abstract

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite notable anthropometric variability with ancestry proportions, and a high burden of growth stunting and overweight/obesity in Hispanic/Latino populations. This address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults, to identify and fine-map common 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=59,769) and validated our findings in 9 additional studies (HISLA Stage 2, n=9,336). We conducted a trans-ethnic 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 novel BMI locus, as well two novel BMI signals and another novel height signal, each within established anthropometric loci. In our trans-ethnic meta- analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI. We replicated >60 established anthropometric loci in Hispanic/Latino populations at genome-wide significance--representing up to 30% of previously-reported index SNP anthropometric associations. Trans-ethnic meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our novel findings demonstrate that future studies may also benefit from leveraging differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

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Fernandez-Rhodes, L., Graff, M., Buchanan, V. L., Justice, A. E., Highland, H. M., Guo, X., Young, K. L., Adhikari, K., Allred, N. P., Below, J. E., Bradfield, J., Pereira, A. C., Glover, L., Kim, D., Lilly, A. G., Shrestha, P., Thomas, A. G., Zhang, X., Chen, M., Chiang, C., Pulit, S., Horimoto, A., Krieger, J. E., Guindo-Martinez, M., Preuss, M., Schumann, C., Smit, R. A. J., Torres-Mejia, G., Acuna-Alonzo, V., Bedoya, G., Bortolini, M.-C., Canizales-Quinteros, S., Gallo, C., Gonzalez-Jose, R., Poletti, G., Rothhammer, F., Hakonarson, H., Adler, S. G., Igo, R., Iyengar, S., Nicholas, S. B.. 2021-05-29. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium. https://doi.org/10.1101/2021.05.27.445969

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