Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium
Authors: Fernández-Rhodes Lindsay , Graff Mariaelisa , Buchanan Victoria L. , Justice Anne E. , Highland Heather M. , Guo Xiuqing , Zhu Wanying , Chen Hung-Hsin , Young Kristin L. , Adhikari Kaustubh , Allred Nicholette (Palmer) , Below Jennifer E. , Bradfield Jonathan , Pereira Alexandre C. , Glover LáShauntá , Kim Daeeun , Lilly Adam G. , Shrestha Poojan , Thomas Alvin G. , Zhang Xinruo , Chen Minhui , Chiang Charleston W. K. , Pulit Sara , Horimoto Andrea , Krieger Jose E. , Guindo-Martinez Marta , Preuss Michael , Schumann Claudia , Smit Roelof A.J. , Torres-Mejía Gabriela , Acuña-Alonzo Victor , Bedoya Gabriel , Bortolini Maria-Cátira , Canizales-Quinteros Samuel , Gallo Carla , González-José Rolando , Poletti Giovanni , Rothhammer Francisco , Hakonarson Hakon , Igo Robert , Adler Sharon G , Iyengar Sudha K. , Nicholas Susanne B. , Gogarten Stephanie M. , Isasi Carmen R. , Papnicolaou George , Stilp Adrienne M. , Qi Qibin , Kho Minjung , Smith Jennifer A. , Langfeld Carl , Wagenknecht Lynne , Mckean-Cowdin Roberta , Gao Xiaoyi Raymond , Nousome Darryl , Conti David V. , Feng Ye , Allison Matthew A. , Arzumanyan Zorayr , Buchanan Thomas A. , Chen Yii-Der Ida , Genter Pauline M. , Goodarzi Mark O. , Hai Yang , Hsueh Willa , Ipp Eli , Kandeel Fouad R. , Lam Kelvin , Li Xiaohui , Nadler Jerry L. , Raffel Leslie J. , Roll Kaye , Sandow Kevin , Tan Jingyi , Taylor Kent D. , Xiang Anny H. , Yao Jie , Audirac-Chalifour Astride , de Jesus Peralta Romero Jose , Hartwig Fernando , Horta Bernando , Blangero John , Curran Joanne E. , Duggirala Ravindranath , Lehman Donna E. , Puppala Sobha , Fejerman Laura , John Esther , Aguilar-Salinas Carlos , Burtt Noël P. , Florez Jose C. , García-Ortíz Humberto , González-Villalpando Clicerio , Mercader Josep , Orozco Lorena , Tusié Teresa , Blanco Estela , Gahagan Sheila , Cox Nancy J. , Hanis Craig , Butte Nancy F. , Cole Shelley A. , Commuzzie Anthony G. , Voruganti V. Saroja , Rohde Rebecca , Wang Yujie , Sofer Tamar , Ziv Elad , Grant Struan F.A. , Ruiz-Linares Andres , Rotter Jerome I. , Haiman Christopher A. , Parra Esteban J. , Cruz Miguel , Loos Ruth J.F. , North Kari E. 
Published: May 2021

ABSTRACTHispanic/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.