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Genetic Composition of Brazilian Population Samples Based on a Set of Twenty Eight Ancestry Informative SNPs

Ancestry informative SNPs can be useful to estimate individual and population biogeographical ancestry. Brazilian population is characterized by a genetic background of three parental populations (European, African, and Brazilian Native Amerindians) with a wide degree and diverse patterns of admixture. In this work we analyzed the information content of 28 ancestry‐informative SNPs into multiplexed panels using three parental population sources (African, Amerindian, and European) to infer the genetic admixture in an urban sample of the five Brazilian geopolitical regions. The SNPs assigned apart the parental populations from each other and thus can be applied for ancestry estimation in a three hybrid admixed population. Data was used to infer genetic ancestry in Brazilians with an admixture model. Pairwise estimates of Fst among the five Brazilian geopolitical regions suggested little genetic differentiation only between the South and the remaining regions. Estimates of ancestry results are consistent with the heterogeneous genetic profile of Brazilian population, with a major contribution of European ancestry (0.771) followed by African (0.143) and Amerindian contributions (0.085). The described multiplexed SNP panels can be useful tool for bioanthropological studies but it can be mainly valuable to control for spurious results in genetic association studies in admixed populations. Am. J. Hum. Biol., 2010.

Genetic Heterogeneity of Self-Reported Ancestry Groups in an Admixed Brazilian Population

Background Population stratification is the main source of spurious results and poor reproducibility in genetic association findings. Population heterogeneity can be controlled for by grouping individuals in ethnic clusters; however, in admixed populations, there is evidence that such proxies do not provide efficient stratification control. The aim of this study was to evaluate the relation of self-reported with genetic ancestry and the statistical risk of grouping an admixed sample based on self-reported ancestry. Methods A questionnaire that included an item on self-reported ancestry was completed by 189 female volunteers from an admixed Brazilian population. Individual genetic ancestry was then determined by genotyping ancestry informative markers. Results Self-reported ancestry was classified as white, intermediate, and black. The mean difference among self-reported groups was significant for European and African, but not Amerindian, genetic ancestry. Pairwise fixation index analysis revealed a significant difference among groups. However, the increase in the chance of type 1 error was estimated to be 14%. Conclusions Self-reporting of ancestry was not an appropriate methodology to cluster groups in a Brazilian population, due to high variance at the individual level. Ancestry informative markers are more useful for quantitative measurement of biological ancestry.

Lessons from genome-wide association studies findings in Alzheimer's disease.

Alzheimers disease (AD) is the most common neurodegenerative disorder with a complex genetic background. Recent genome‐wide association studies (GWAS) have placed important new contributors into the genetic framework of early‐ and late‐onset forms of this dementia. Besides confirming the major role of classic allelic variants (e.g. apolipoprotein E) in the development of AD, GWAS have thus far implicated over 20 single nucleotide polymorphisms in AD. In this review, we summarize the findings of 16 AD‐based GWAS performed to date whose public registries are available at the National Human Genome Research Institute, with an emphasis on understanding whether the polymorphic markers under consideration support functional implications to the pathophysiological role of the major genetic risk factors unraveled by GWAS.

Population analysis of vitamin D receptor polymorphisms and the role of genetic ancestry in an admixed population

The vitamin D receptor (VDR) is an essential protein related to bone metabolism. Some VDR alleles are differentially distributed among ethnic populations and display variable patterns of linkage disequilibrium (LD). In this study, 200 unrelated Brazilians were genotyped using 21 VDR single nucleotide polymorphisms (SNPs) and 28 ancestry informative markers. The patterns of LD and haplotype distribution were compared among Brazilian and the HapMap populations of African (YRI), European (CEU) and Asian (JPT+CHB) origins. Conditional regression and haplotype-specific analysis were performed using estimates of individual genetic ancestry in Brazilians as a quantitative trait. Similar patterns of LD were observed in the 5′ and 3′ gene regions. However, the frequency distribution of haplotype blocks varied among populations. Conditional regression analysis identified haplotypes associated with European and Amerindian ancestry, but not with the proportion of African ancestry. Individual ancestry estimates were associated with VDR haplotypes. These findings reinforce the need to correct for population stratification when performing genetic association studies in admixed populations.

Allele and haplotype frequency distribution in PTPN22 gene across variable ethnic groups: Implications for genetic association studies for autoimmune diseases

The rs2476601-T allele at the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene has been consistently associated with several autoimmune diseases in European-derived populations. However, little is known about the allele and haplotype frequency distributions in PTPN22 among populations derived from other ethnic groups. In the present study, the allele and haplotype frequency distributions of six single nucleotide polymorphisms (SNPs) in the PTPN22 gene were compared among Brazilian populations and HapMap phase 3 dataset. A total of 10 different population samples were evaluated. Additionally, in admixed populations, individual genetic ancestries were estimated for Native American, African, and European contributions. Estimated individual ancestries were used as quantitative traits in a conditional approach for single-marker and haplotype-specific regression analyses. It was shown that several SNPs and haplotypes have different frequencies among different ethnic populations. Individual genetic ancestries were not associated with the rs2476601-T allele, but were associated with PTPN22 haplotypes in Brazilian, Mexican, and African-American admixed populations. Our results suggest caution in the interpretation of results found in association studies involving PTPN22 polymorphisms in admixed populations. Correction for stratification generated by admixture should be mandatory to minimize or avoid chances of spurious association.

Cytokine gene polymorphisms and Alzheimer's disease in Brazil.

Background: Single-nucleotide polymorphisms in genes encoding immunological mediators can affect the biological activity of these molecules by regulating transcription, translation, or secretion, modulating the genetic risk of inflammatory damage in Alzheimers disease (AD). Nonetheless, the Brazilian contingent is highly admixed, and few association trials performed herein with AD patients have considered genetic ancestry estimates as co-variables when investigating markers for this complex trait. Methods: We analyzed polymorphisms in 10 inflammatory genes and compared the genotype distribution across outpatients with late-onset AD and noncognitively impaired subjects from Midwest Brazil under a strict criterion, and controlling for ancestry heritage and ApoE genotype. Results: Our findings show an almost 40% lower chance of AD (p = 0.004) among homozygotes of the IL10 -1082A allele (rs1800896). Dichotomization to ApoE and mean ancestry levels did not affect protection, except among those with greater European or minor African heritage. Conclusion: The IL10 locus seems to affect the onset of AD in a context sensitive to the genetic ancestry of Brazilian older adults.

TagSNP transferability and relative loss of variability prediction from HapMap to an admixed population

BackgroundThe application of a subset of single nucleotide polymorphisms, the tagSNPs, can be useful in capturing untyped SNPs information in a genomic region. TagSNP transferability from the HapMap dataset to admixed populations is of uncertain value due population structure, admixture, drift and recombination effects. In this work an empirical dataset from a Brazilian admixed sample was evaluated against the HapMap population to measure tagSNP transferability and the relative loss of variability prediction.MethodsThe transferability study was carried out using SNPs dispersed over four genomic regions: the PTPN22, HMGCR, VDR and CETP genes. Variability coverage and the prediction accuracy for tagSNPs in the selected genomic regions of HapMap phase II were computed using a prediction accuracy algorithm. Transferability of tagSNPs and relative loss of prediction were evaluated according to the difference between the Brazilian sample and the pooled and single HapMap population estimates.ResultsEach population presented different levels of prediction per gene. On average, the Brazilian (BRA) sample displayed a lower power of prediction when compared to HapMap and the pooled sample. There was a relative loss of prediction for BRA when using single HapMap populations, but a pooled HapMap dataset generated minor loss of variability prediction and lower standard deviations, except at the VDR locus at which loss was minor using CEU tagSNPs.ConclusionStudies that involve tagSNP selection for an admixed population should not be generally correlated with any specific HapMap population and can be better represented with a pooled dataset in most cases.

A Prospective Screening of Gene Copy Number Variation in Brazilian Admixed Population Sample

Copy number variants (CNVs) represent an important source of variation in the human genome. Some CNVS embedded genes are differently distributed among the human population groups. Therefore, it is important to understand the distribution of CNV within and between populations, especially in those with admixed ancestry, such as the Brazilians. The aim of the study was to investigate the variability of a set of CNV-embedded genes in a sample of the Brazilian population. The CNV-embedded genes were chosen based on data showing that they have differential copy variation distribution between African and Europeans. Four genes (POLR2J4, PCDHB13, NPEPPS and AMY1) were investigated by qPCR in a sample of 96 Brazilians, previously classified by genetic ancestry. The gene AMY1 showed a variable copy numbers in the range of 1 to 8 copies whereas NPEPPS ranged from 1 to 5 copies. A low variability was identified for the POLR2J4 and PCDHB13 genes, showing 2 copies in frequency of 0.875 and 0.917, respectively. Genetic ancestry was not correlated to the number of copies of the AMY1and NPEPPS genes. The results provided an overview of the corresponding frequency of gene copy number variation in a sample of the Brazilian population, serving as reference for further genetic population studies, which may correlate these polymorphisms with other phenotypic features.

Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients

The CTLA-4 protein is expressed in activated T cells and plays an essential role in the immune response through its regulatory effect on T cell activation. Polymorphisms of the CTLA-4 gene have been correlated with autoimmune, neoplastic and infectious illnesses. This work aimed to verify possible associations between single nucleotide polymorphisms (SNPs) in CTLA-4, -318C/T in the promoter and +49A/G in exon 1 and paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis. For this purpose, 66 chronic form PCM patients and 76 healthy controls had their allele, genotype and haplotype frequencies determined. The genetic admixture structure of the patients and controls was evaluated to eliminate ancestral bias. The comparison of frequencies indicated no significant differences between patients and controls that could link the SNPs to PCM. Groups were admixture matched with no difference observed in population ancestry inference, indicating that the absence of association between CTLA-4 polymorphisms and PCM could not be attributed to ancestral bias. This study showed that there was no association between the CTLA-4 SNPs -318 and +49 and the resistance or susceptibility to PCM.

Population Analysis of Pharmacogenetic Polymorphisms Related to Acute Lymphoblastic Leukemia Drug Treatment

This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL), and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes.