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

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 (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.

SUBMITTER: Fernandez-Rhodes L

PROVIDER: S-EPMC8990175 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Fernández-Rhodes Lindsay L Graff Mariaelisa M Buchanan Victoria L VL Justice Anne E AE Highland Heather M HM Guo Xiuqing X Zhu Wanying W Chen Hung-Hsin HH Young Kristin L KL Adhikari Kaustubh K Palmer Nicholette D ND Below Jennifer E JE Bradfield Jonathan J Pereira Alexandre C AC Glover LáShauntá L Kim Daeeun D Lilly Adam G AG Shrestha Poojan P Thomas Alvin G AG Zhang Xinruo X Chen Minhui M Chiang Charleston W K CWK Pulit Sara S Horimoto Andrea A Krieger Jose E JE Guindo-Martínez Marta M Preuss Michael M Schumann Claudia C Smit Roelof A J RAJ Torres-Mejía Gabriela G Acuña-Alonzo Victor V Bedoya Gabriel G Bortolini Maria-Cátira MC Canizales-Quinteros Samuel S Gallo Carla C González-José Rolando R Poletti Giovanni G Rothhammer Francisco F Hakonarson Hakon H Igo Robert R Adler Sharon G SG Iyengar Sudha K SK Nicholas Susanne B SB Gogarten Stephanie M SM Isasi Carmen R CR Papnicolaou George G Stilp Adrienne M AM Qi Qibin Q Kho Minjung M Smith Jennifer A JA Langefeld Carl D CD Wagenknecht Lynne L Mckean-Cowdin Roberta R Gao Xiaoyi Raymond XR Nousome Darryl D Conti David V DV Feng Ye Y Allison Matthew A MA Arzumanyan Zorayr Z Buchanan Thomas A TA Ida Chen Yii-Der YD Genter Pauline M PM Goodarzi Mark O MO Hai Yang Y Hsueh Willa W Ipp Eli E Kandeel Fouad R FR Lam Kelvin K Li Xiaohui X Nadler Jerry L JL Raffel Leslie J LJ Roll Kathryn K Sandow Kevin K Tan Jingyi J Taylor Kent D KD Xiang Anny H AH Yao Jie J Audirac-Chalifour Astride A de Jesus Peralta Romero Jose J Hartwig Fernando F Horta Bernando B Blangero John J Curran Joanne E JE Duggirala Ravindranath R Lehman Donna E DE Puppala Sobha S Fejerman Laura L John Esther M EM Aguilar-Salinas Carlos C Burtt Noël P NP Florez Jose C JC García-Ortíz Humberto H González-Villalpando Clicerio C Mercader Josep J Orozco Lorena L Tusié-Luna Teresa T Blanco Estela E Gahagan Sheila S Cox Nancy J NJ Hanis Craig C Butte Nancy F NF Cole Shelley A SA Comuzzie Anthony G AG Voruganti V Saroja VS Rohde Rebecca R Wang Yujie Y Sofer Tamar T Ziv Elad E Grant Struan F A SFA Ruiz-Linares Andres A Rotter Jerome I JI Haiman Christopher A CA Parra Esteban J EJ Cruz Miguel M Loos Ruth J F RJF North Kari E KE

HGG advances 20220311 2

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 conduc ...[more]

PMID: 35399580

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Project description:Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Dataset Information

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

Publications

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

Similar Datasets

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