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

Abstract

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. 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 population-based cohorts from Northeast (Salvador), Southeast (Bambuí) and South (Pelotas) of the country. 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= 2.76 e-06). This variant is very rare in Europeans but with frequencies of ~3% in West Africa, and has one of the stronger female-specific effects ever reported (95%CI: 2.32-5.65 kg/m 2 per each A allele). We replicated this sex-specific association and its strong effect for an adjusted fat-mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São 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 ~9% among morbidly obese women from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least fivetimes the effect size of the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects, and for which we replicated associations in Pelotas. We demonstrate how, after a decade of GWAS mostly performed in European-ancestry populations, non-European and admixed populations are a source of new relevant phenotype-associated genetic variants.

Genomic Regions 10q22.2, 17q21.31, and 2p23.1 Can Contribute to a Lower Lung Function in African Descent Populations

“…The three models were adjusted by age, sex, BMI, and global African ancestry. We used an additive model that considers the number of inferred African, European or Native American ancestry copies (0, 1 or 2) carried by an individual for each window [ 27 ]. We used PLINK software [ 26 ] to perform linear regressions.…”

Genetic Epidemiology in Latin America: Identifying Strong Genetic Proxies for Complex Disease Risk Factors

“…This approach allows not only the validation (or not) of already identified IVs, but most importantly, the discovery of new IVs of relevance in Latin America. In fact, an admixture mapping study carried out on participants of the EPIGEN-Brasil consortium recently reported a low frequency variant of chromosome 13 strongly associated with body mass index (BMI) in females [17]. This variant, very rare in Europeans, exhibited a notably larger effect size in Brazil than that of SNPs in fat mass and obesity-associated gene (FTO), one of the genes with the most compelling association amongst Europeans.…”

“…Third, there was limited mention of confounding by population stratification, despite the well-known admixed background of Brazilians; nonetheless, some studies attempted to take this into account, adjusting for skin color, race, or ethnicity. Only a couple of studies ran models adjusted for principal components [38] or genetic ancestry [17]. Fourth, there is a very uneven, yet not unexpected, distribution of studies throughout the country, with concentration on the south and southeast regions, and on women and children.…”