Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes

Author(s):Show less -

Scliar, Marilia O. ^{[1, 2]} ; Sant'Anna, Hanaisa P. ^{[3, 1]} ; Santolalla, Meddly L. ^{[1, 4]} ; Leal, Thiago P. ^{[5, 1]} ; Araujo, Nathalia M. ^{[1, 6]} ; Alvim, Isabela ^{[3, 1]} ; Borda, Victor ^{[1, 7]} ; Magalhaes, Wagner C. S. ^{[1, 8]} ; Gouveia, Mateus H. ^{[1, 6, 9]} ; Lyra, Ricardo ^[1] ; Machado, Moara ^[1] ; Michelin, Lucas ^[1] ; Rodrigues, Maira R. ^{[10, 1]} ; Araujo, Gilderlanio S. ^[11] ; Kehdy, Fernanda S. G. ^{[1, 12]} ; Zolini, Camila ^{[1, 13, 14]} ; Peixoto, Sergio V. ^{[6, 15]} ; Luizon, Marcelo R. ^[1] ; Lobo, Francisco ^[1] ; Naslavsky, Michel S. ^[2] ; Yamamoto, Guilherme L. ^{[2, 16]} ; Duarte, Yeda A. O. ^{[17, 18]} ; Hansen, Matthew E. B. ^{[19, 20]} ; Norris, Shane A. ^[21] ; Gilman, Robert H. ^{[4, 22]} ; Guio, Heinner ^[23] ; Hsing, Ann W. ^[24] ; Mbulaiteye, Sam M. ^[25] ; Mensah, James ^[26] ; Dutil, Julie ^[27] ; Yeager, Meredith ^[28] ; Yeboah, Edward ^[26] ; Tishkoff, Sarah A. ^{[19, 20]} ; Choudhury, Ananyo ^[29] ; Ramsay, Michele ^{[29, 30, 31]} ; Passos-Bueno, Maria Rita ^[2] ; Zatz, Mayana ^[2] ; O'Connor, Timothy D. ^{[32, 33, 34]} ; Pereira, Alexandre C. ^[35] ; Barreto, Mauricio L. ^{[36, 37]} ; Lima-Costa, Maria Fernanda ^[6] ; Horta, Bernardo L. ^[38] ; Tarazona-Santos, Eduardo ^{[39, 1, 14, 40]}

Affiliation:Show less -

^[1] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Genet Ecol & Evoluc, Belo Horizonte, MG - Brazil

^[2] Univ Sao Paulo, Inst Biociencias, Human Genome & Stem Cell Res Ctr, Sao Paulo, SP - Brazil

^[3] Univ Melbourne, Melbourne Integrat Genom, Melbourne, Vic - Australia

^[4] Univ Peruana Cayetano Heredia, Sch Publ Hlth & Adm, Emerge Emerging Dis & Climate Change Res Unit, Lima - Peru

^[5] Univ Fed Minas Gerais, Dept Estat, Belo Horizonte, MG - Brazil

^[6] Fundacao Oswaldo Cruz, Inst Pesquisas Rene Rachou, Belo Horizonte, MG - Brazil

^[7] Lab Nacl Computac Cient LNCC, Lab Bioinformat, LABINFO, Petropolis, RJ - Brazil

^[8] Inst Mario Penna, Nucleo Ensino & Pesquisa, Belo Horizonte, MG - Brazil

^[9] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 - USA

^[10] Univ Sao Paulo, Dept Genet & Biol Evolut, Sao Paulo, SP - Brazil

^[11] Univ Fed Para, Inst Ciencias Biol, Lab Genet Humana & Med, Programa Posgrad Genet & Biol Mol, Campus Guama, Belem, PA - Brazil

^[12] Fundacao Oswaldo Cruz, Lab Hanseniase, Inst Oswaldo Cruz, Rio De Janeiro, RJ - Brazil

^[13] Beagle, Belo Horizonte, MG - Brazil

^[14] Univ Fed Minas Gerais, Mosaico Translat Genom Initiat, Belo Horizonte, MG - Brazil

^[15] Univ Fed Minas Gerais, Dept Gestao Saude, Escola Enfermagem, Belo Horizonte, MG - Brazil

^[16] Univ Sao Paulo, Dept Clin Genet, Childrens Hosp, Med Sch, Sao Paulo, SP - Brazil

^[17] Univ Sao Paulo, Sch Nursing, Sao Paulo, SP - Brazil

^[18] Univ Sao Paulo, Publ Hlth Sch, Dept Epidemiol, Sao Paulo, SP - Brazil

^[19] Univ Penn, Dept Biol, Philadelphia, PA 19104 - USA

^[20] Univ Penn, Dept Genet, Philadelphia, PA 19104 - USA

^[21] Univ Witwatersrand, Fac Hlth Sci, SAMRC Wits Dev Pathways Hlth Res Unit, Johannesburg - South Africa

^[22] Johns Hopkins Sch Publ Hlth, Dept Int Hlth, Baltimore, MD - USA

^[23] Inst Nacl Salud, Lima - Peru

^[24] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 - USA

^[25] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 - USA

^[26] Univ Ghana, Med Sch, Accra - Ghana

^[27] Ponce Hlth Sci Univ, Ponce Res Inst, Canc Biol Div, Ponce, PR - USA

^[28] Frederick Natl Lab Canc Res, Leidos Biomed Res, Canc Genom Res Lab, Frederick, MD - USA

^[29] Univ Witwatersrand, Fac Hlth Sci, Sydney Brenner Inst Mol Biosci, Johannesburg - South Africa

^[30] Univ Witwatersrand, Fac Hlth Sci, Div Human Genet, Natl Hlth Lab Serv, Johannesburg - South Africa

^[31] Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, Johannesburg - South Africa

^[32] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 - USA

^[33] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 - USA

^[34] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 - USA

^[35] Univ Sao Paulo, Inst Coracao, Sao Paulo, SP - Brazil

^[36] Univ Fed Bahia, Inst Saude Colet, Salvador, BA - Brazil

^[37] Fundacao Oswaldo Cruz, Inst Goncalo Muniz, Ctr Data & Knowledge Integrat Hlth, Salvador, BA - Brazil

^[38] Univ Fed Pelotas, Programa Posgrad Epidemiol, Pelotas, RS - Brazil

^[39] Univ Peruana Cayetano Heredia, Lima - Peru

^[40] Univ Fed Minas Gerais, Inst Estudos Avancados Transdisciplinares, Belo Horizonte, MG - Brazil

• Document type: Journal article
• Source: International Journal of Obesity; v. 45, n. 5, p. 1017-1029, MAY 2021.
• Web of Science Citations: 0

Abstract

Background/objectives Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. Subjects/methods Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambui), and South (Pelotas). Results We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of similar to 3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m(2) per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from Sao Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains similar to 9% among women with morbid obesity from Pelotas, Sao Paulo, and Bambui. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects. Conclusions We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants. (AU)

• FAPESP's process: 19/19998-8 - Development of pipeline for copy number variation (CNVs) analysis
• Grantee: Marília de Oliveira Scliar
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training