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

2022; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês

10.1016/j.xhgg.2022.100099

2666-2477

Lindsay Fernández‐Rhodes, Mariaelisa Graff, Victoria L. Buchanan, Anne E. Justice, Heather M. Highland, Xiuqing Guo, Wanying Zhu, Hung‐Hsin Chen, Kristin L. Young, Kaustubh Adhikari, Colin N. A. Palmer, Jennifer E. Below, Jonathan P. Bradfield, Alexandre C. Pereira, LáShauntá Glover, Daeeun Kim, Adam G. Lilly, Poojan Shrestha, Alvin G. Thomas, Xinruo Zhang, Minhui Chen, Charleston W. K. Chiang, Sara L. Pulit, A.R.V.R. Horimoto, José Eduardo Krieger, Marta Guindo-Martínez, Michael Preuß, Claudia Schumann, Roelof A. J. Smit, Gabriela Torres-Mejı́a, Víctor Acuña-Alonzo, Gabriel Bedoya, María Cátira Bortolini, Samuel Canizales‐Quinteros, Carla Gallo, Rolando González‐José, Giovanni Poletti, Francisco Rothhammer, Hákon Hákonarson, Robert P. Igo, Sharon G. Adler, Sudha K. Iyengar, Susanne B. Nicholas, Stephanie M. Gogarten, Carmen R. Isasi, George Papnicolaou, Adrienne M. Stilp, Qibin Qi, Minjung Kho, Jennifer A. Smith, Carl D. Langefeld, Lynne E. Wagenknecht, Roberta McKean‐Cowdin, Xiaoyi Gao, Darryl Nousome, David V. Conti, Ye Feng, Matthew Allison, Zorayr Arzumanyan, Thomas A. Buchanan, Yii‐Der Ida Chen, Pauline Genter, Mark O. Goodarzi, Yang Hai, Willa A. Hsueh, Eli Ipp, Fouad Kandeel, Kelvin Lam, Xiaohui Li, Jerry L. Nadler, Leslie J. Raffel, Kathryn Roll, Kevin Sandow, Jingyi Tan, Kent D. Taylor, Anny H. Xiang, Jie Yao, Astride Audirac-Chalifour, Jesús Peralta‐Romero, Fernando Pires Hartwig, Bernando Horta, John Blangero, Joanne E. Curran, Ravindranath Duggirala, Donna M. Lehman, Sobha Puppala, Laura Fejerman, Esther M. John, Carlos A. Aguilar‐Salinas, Noël P. Burtt, José C. Florez, Humberto Garcia‐Ortíz, Clicerio González‐Villalpando, Josep M. Mercader, Lorena Orozco, Teresa Tusié‐Luna, Estela Blanco, Sheila Gahagan, Nancy J. Cox, Craig L. Hanis, Nancy F. Butte, Shelley A. Cole, Anthony G. Comuzzie, V. Saroja Voruganti, Rebecca Rohde, Yujie Wang, Tamar Sofer, Elad Ziv, Struan F.A. Grant, Andrés Ruiz‐Linares, Jerome I. Rotter, Christopher A. Haiman, Esteban J. Parra, Miguel Cruz, Ruth J. F. Loos, Kari E. North,

Genetic Mapping and Diversity in Plants and Animals

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.