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

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.; Ida Chen, Yii-Der; 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. and North., Kari E. (2022). Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium. Human Genetics and Genomics Advances (Early Access).

DOI: https://doi.org/10.1016/j.xhgg.2022.100099

Abstract

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 (HISLA 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 three secondary signals for BMI, 28 for height, and two 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.

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