Association Analysis of Candidate Variants in Admixed Brazilian Patients With Genetic Generalized Epilepsies.

Genetic generalized epilepsies (GGEs) include well-established epilepsy syndromes with generalized onset seizures: childhood absence epilepsy, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), myoclonic absence epilepsy, epilepsy with eyelid myoclonia (Jeavons syndrome), generalized tonic-clonic seizures, and generalized tonic-clonic seizures alone. Genome-wide association studies (GWASs) and exome sequencing have identified 48 single-nucleotide polymorphisms (SNPs) associated with GGE. However, these studies were mainly based on non-admixed, European, and Asian populations. Thus, it remains unclear whether these results apply to patients of other origins. This study aims to evaluate whether these previous results could be replicated in a cohort of admixed Brazilian patients with GGE. We obtained SNP-array data from 87 patients with GGE, compared with 340 controls from the BIPMed public dataset. We could directly access genotypes of 17 candidate SNPs, available in the SNP array, and the remaining 31 SNPs were imputed using the BEAGLE v5.1 software. We performed an association test by logistic regression analysis, including the first five principal components as covariates. Furthermore, to expand the analysis of the candidate regions, we also interrogated 14,047 SNPs that flank the candidate SNPs (1 Mb). The statistical power was evaluated in terms of odds ratio and minor allele frequency (MAF) by the genpwr package. Differences in SNP frequencies between Brazilian and Europeans, sub-Saharan African, and Native Americans were evaluated by a two-proportion Z-test. We identified nine flanking SNPs, located on eight candidate regions, which presented association signals that passed the Bonferroni correction (rs12726617; rs9428842; rs1915992; rs1464634; rs6459526; rs2510087; rs9551042; rs9888879; and rs8133217; p-values <3.55e-06). In addition, the two-proportion Z-test indicates that the lack of association of the remaining candidate SNPs could be due to different genomic backgrounds observed in admixed Brazilians. This is the first time that candidate SNPs for GGE are analyzed in an admixed Brazilian population, and we could successfully replicate the association signals in eight candidate regions. In addition, our results provide new insights on how we can account for population structure to improve risk stratification estimation in admixed individuals.

Genetic variability in COVID-19-related genes in the Brazilian population.

SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease (TMPRSS2) to infect human lung cells. Previous studies have suggested that different host ACE2 and TMPRSS2 genetic backgrounds might contribute to differences in the rate of SARS-CoV-2 infection or COVID-19 severity. Recent studies have also shown that variants in 15 genes related to type I interferon immunity to influenza virus might predispose patients toward life-threatening COVID-19 pneumonia. Other genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, IL6, CTSL, ABO, and FURIN) and HLA alleles have also been implicated in the response to infection with SARS-CoV-2. Currently, Brazil has recorded the third-highest number of COVID-19 cases worldwide. We aimed to investigate the genetic variation present in COVID-19-related genes in the Brazilian population. We analyzed 27 candidate genes and HLA alleles in 954 admixed Brazilian exomes. We used the information available in two public databases (http://www.bipmed.org and http://abraom.ib.usp.br/) and additional exomes from individuals born in southeast Brazil, the region of the country with the highest number of COVID-19 patients. Variant allele frequencies were compared with the 1000 Genomes Project phase 3 (1KGP) and gnomAD databases. We detected 395 nonsynonymous variants; of these, 325 were also found in the 1KGP and/or gnomAD. Six of these variants were previously reported to influence the rate of infection or clinical prognosis of COVID-19. The remaining 70 variants were identified exclusively in the Brazilian sample, with a mean allele frequency of 0.0025. In silico analysis revealed that seven of these variants are predicted to affect protein function. Furthermore, we identified HLA alleles previously associated with the COVID-19 response at loci DQB1 and DRB1. Our results showed genetic variability common to other populations and rare and ultrarare variants exclusively found in the Brazilian population. These findings might lead to differences in the rate of infection or response to infection by SARS-CoV-2 and should be further investigated in patients with this disease.

The genetic architecture of the human cerebral cortex.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Distribution of local ancestry and evidence of adaptation in admixed populations.

Admixed American populations have different global proportions of European, Sub-Saharan African, and Native-American ancestry. However, individuals who display the same global ancestry could exhibit remarkable differences in the distribution of local ancestry blocks. We studied for the first time the distribution of local ancestry across the genome of 264 Brazilian admixed individuals, ascertained within the scope of the Brazilian Initiative on Precision Medicine. We found a decreased proportion of European ancestry together with an excess of Native-American ancestry on chromosome 8p23.1 and showed that this is due to haplotypes created by chromosomal inversion events. Furthermore, Brazilian non-inverted haplotypes were more similar to Native-American haplotypes than to European haplotypes, in contrast to what was found in other American admixed populations. We also identified signals of recent positive selection on chromosome 8p23.1, and one gene within this locus, PPP1R3B, is related to glycogenesis and has been associated with an increased risk of type 2 diabetes and obesity. These findings point to a selection event after admixture, which is still not entirely understood in recent admixture events.