Genetic comparison of sickle cell anaemia cohorts from Brazil and\xa0the United States reveals high levels of divergence

Pedro R S Cruz,Aderson S Araújo,Fernando F Costa,Mônica Barbosa De Melo,Milena Simioni,Igor F Domingos,Farid Menaa,Hakon Hakonarson,Renata Pellegrino,Vera Lucia Gil-Da-Silva-Lopes,Marcos A C Bezerra,Galina Ananina

doi:10.1038/s41598-019-47313-2

Abstract

Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, particularly to avoid population stratification biases. The point mutation responsible for sickle cell anaemia codes for a variant hemoglobin, sickle hemoglobin or HbS, whose presence drives the pathophysiology of disease. Here we propose to explore ancestry and population structure in a genome-wide study with particular emphasis on chromosome 11 in two SCA admixed cohorts obtained from urban populations of Brazil (Pernambuco and São Paulo) and the United States (Pennsylvania). Ancestry inference showed different proportions of European, African and American backgrounds in the composition of our samples. Brazilians were more admixed, had a lower African background (43% vs. 78% on the genomic level and 44% vs. 76% on chromosome 11) and presented a signature of positive selection and Iberian introgression in the HbS region, driving a high differentiation of this locus between the two cohorts. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels.

Highlights

Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, to avoid population stratification biases
We evaluated the genetic structure at the genome-wide and chromosomal level by comparing Sickle cell anaemia (SCA) cohorts from the United States and Brazil, along with 19 worldwide populations from the African, European, American and Asian continents
principal component analysis (PCA) and FST were concordant in depicting SCA patients from the US and Brazil as closer to each other (FST = 0.017) than to Europeans

Summary

Introduction

Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, to avoid population stratification biases. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels. We aim to further describe the ancestry of SCA patients from Brazil, who have been explored relatively little compared to US patients To achieve these goals, we propose to compare genetic structures of two populations at the genome-wide and local levels, through the analysis of a North American cohort (from the Children’s Hospital of Philadelphia-PA) and a Brazilian SCA cohort (from the Haematology-Haemotherapy Centre in Campinas-SP, HEMOCENTRO, and Haematology and Haemotherapy Foundation of Pernambuco-PE, HEMOPE), using high-density genome-wide microarrays (Genome-Wide Human SNP Array 6.0, Affymetrix Inc., CA, USA)

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