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

Author

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, Nicholette D. Palmer, Jennifer E. Below, Jonathan 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 Pulit, Andrea Horimoto, Jose E. Krieger, Marta Guindo-Martínez, Michael Preuss, Claudia Schumann, Roelof A.J. Smit, Gabriela Torres-Mejía, Victor Acuña-Alonzo, Gabriel Bedoya, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Rolando González-José, Giovanni Poletti, Francisco Rothhammer, Hakon Hakonarson, Robert 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 Wagenknecht, Roberta Mckean-Cowdin, Xiaoyi Raymond Gao, Darryl Nousome, David V. Conti, Ye Feng, Matthew 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, Kathryn 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 M. John, Carlos Aguilar-Salinas, Noël P. Burtt, Jose C. Florez, Humberto García-Ortíz, Clicerio González-Villalpando, Josep Mercader, Lorena Orozco, Teresa Tusié-Luna, Estela Blanco, Sheila Gahagan, Nancy J. Cox, Craig 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, Andres Ruiz-Linares, Jerome I. Rotter, Christopher A. Haiman, Esteban J. Parra, Miguel Cruz, Ruth J.F. Loos, and Kari E. North

Subjects
Genetics, QH426-470
Published
2023
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2. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits—The Hispanic/Latino Anthropometry Consortium

Author

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, Nicholette D. Palmer, Jennifer E. Below, Jonathan 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 Pulit, Andrea Horimoto, Jose E. Krieger, Marta Guindo-Martínez, Michael Preuss, Claudia Schumann, Roelof A.J. Smit, Gabriela Torres-Mejía, Victor Acuña-Alonzo, Gabriel Bedoya, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Rolando González-José, Giovanni Poletti, Francisco Rothhammer, Hakon Hakonarson, Robert 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 Wagenknecht, Roberta Mckean-Cowdin, Xiaoyi Raymond Gao, Darryl Nousome, David V. Conti, Ye Feng, Matthew 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, Kathryn 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 M. John, Carlos Aguilar-Salinas, Noël P. Burtt, Jose C. Florez, Humberto García-Ortíz, Clicerio González-Villalpando, Josep Mercader, Lorena Orozco, Teresa Tusié-Luna, Estela Blanco, Sheila Gahagan, Nancy J. Cox, Craig 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, Andres Ruiz-Linares, Jerome I. Rotter, Christopher A. Haiman, Esteban J. Parra, Miguel Cruz, Ruth J.F. Loos, and Kari E. North

Subjects
Hispanic/Latino, anthropometrics, obesity, diversity, trans-ancestral or trans-ethnic, fine-mapping, Genetics, QH426-470
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.

Published
2022
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3. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium

Author

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, Nicholette D. Palmer, Jennifer E. Below, Jonathan 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 Pulit, Andrea Horimoto, Jose E. Krieger, Marta Guindo-Martínez, Michael Preuss, Claudia Schumann, Roelof A.J. Smit, Gabriela Torres-Mejía, Victor Acuña-Alonzo, Gabriel Bedoya, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Rolando González-José, Giovanni Poletti, Francisco Rothhammer, Hakon Hakonarson, Robert 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 Wagenknecht, Roberta Mckean-Cowdin, Xiaoyi Raymond Gao, Darryl Nousome, David V. Conti, Ye Feng, Matthew 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, Kathryn 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 M. John, Carlos Aguilar-Salinas, Noël P. Burtt, Jose C. Florez, Humberto García-Ortíz, Clicerio González-Villalpando, Josep Mercader, Lorena Orozco, Teresa Tusié-Luna, Estela Blanco, Sheila Gahagan, Nancy J. Cox, Craig 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, Andres Ruiz-Linares, Jerome I. Rotter, Christopher A. Haiman, Esteban J. Parra, Miguel Cruz, Ruth J.F. Loos, and Kari E. North

Subjects
obesity, fine-mapping, population stratification, Molecular Medicine, Correction, nutritional and metabolic diseases, anthropometrics, Hispanic/Latino, trans-ancestral or trans-ethnic, Genetics (clinical), diversity
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.

Published
2021
Full Text
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4. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

Author

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

Subjects
Linkage disequilibrium, medicine, Locus (genetics), Genome-wide association study, Anthropometry, Overweight, medicine.symptom, Biology, Population stratification, Body mass index, Demography, Genetic association
Abstract

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 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.

Published
2021
Full Text
View/download PDF

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