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

By Lindsay Fernandez-Rhodes, Mariaelisa Graff, Victoria L. Buchanan, Anne E. Justice, Heather M Highland, Xiuqing Guo, Kristin L. Young, Kaustubh Adhikari, Nicholette Palmer Allred, Jennifer E Below, Jonathan Bradfield, Alexandre C Pereira, LaShaunta Glover, Daeeun Kim, Adam G. Lilly, Poojan Shrestha, Alvin G Thomas, Xinruo Zhang, Minhui Chen, Charleston Chiang, Sara Pulit, Andrea Horimoto, Jose E Krieger, Marta Guindo-Martinez, Michael Preuss, Claudia Schumann, Roelof A.J. Smit, Gabriela Torres-Mejia, Victor Acuna-Alonzo, Gabriel Bedoya, Maria-Catira Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Rolando Gonzalez-Jose, Giovanni Poletti, Francisco Rothhammer, Hakon Hakonarson, Sharon G. Adler, Robert Igo, Sudha Iyengar, Susanne B. Nicholas, Stephanie M Gogarten, Carmen R. Isasi, George Papnicolaou, Adrienne M Stilp, Qibin Qi, Minjung Kho, Jennifer A. Smith, Carl Langfeld, Lynne Wagenknecht, Roberta Mckean-Cowdin, Raymond Gao, Darryl Nousome, David V Conti, Ye Feng, Mattew A. Allison, Zorayr Arzumanyan, Thomas A Buchanan, Yii-Der Ida Chen, Pauline M. Genter, Mark O Goodarzi, Yang Hai, Willa Hsueh, Eli Ipp, Fouad R. Kandeel, Kelvin Lam, Xiaohui Li, Jerry L. Nadler, Leslie J Raffel, Kaye Roll, Kevin Sandow, Jingyi Tan, Kent D. Taylor, Anny H. Xiang, Jie Yao, Astride Audirac-Chalifour, Jose de Jesus Peralta Romero, Fernando Hartwig, Bernando Horta, John Blangero, Joanne E. Curran, Ravindranath Duggirala, Donna E. Lehman, Sobha Puppala, Laura Fejerman, Esther John, Carlos Aguilar-Salinas, Noel P Burtt, Jose C. Florez, Clicerio Gonzalez-Villalpando, Josep M Mercader, Lorena Orozco, Teresa Tusie, Estela Blanco, Sheila Gahagan, Nancy J. Cox, Craig Hanis, Nancy F. Butte, Shelley A Cole, Anthony G. Commuzzie, Venkata Saroja Voruganti, Rebecca Rohde, Yujie Wang, Tamar Sofer, Elad Ziv, Struan F. A. Grant, Esteban J Parra, Miguel Cruz, Andres Ruiz-Linares, Jerome I. Rotter, Christopher A. Haiman, Ruth J F Loos, Kari E North

Posted 29 May 2021
bioRxiv DOI: 10.1101/2021.05.27.445969

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 adult 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, two novel signals in established loci for BMI, and one secondary signal in an established locus for height. 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, 29 for height, and two for WHRadjBMI. We replicated 64 established anthropometric loci in Hispanic/Latino populations at genome-wide significance (28% 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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