RESUMO
Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25-38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.
Assuntos
Transtorno Bipolar/genética , Proteína Inibidora do Complemento C1/genética , Exoma , Redes Reguladoras de Genes , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Alelos , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/fisiopatologia , Cuba , Família , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Linhagem , Penetrância , Risco , Sequenciamento do ExomaRESUMO
BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is among the most frequently occurring congenital malformations worldwide. The number of genetic loci identified as being involved in NSCL/P etiology was recently increased by a large genome-wide meta-analysis of European and Asian samples. This meta-analysis confirmed all six previously recognized genetic susceptibility loci and identified six novel ones. METHODS: To investigate which of these 12 loci contribute to NSCL/P risk in an independent sample of distinct ethnicity, we performed a case-control association analysis in a sample of the Mesoamerican population. A total of 153 individuals with NSCL/P (cases) and 337 unaffected controls were included. Top single-nucleotide polymorphisms (SNPs) at 8 of the 12 loci (1p22.1, 1p36, 2p21, 3p11.1, 8q21.3, 13q31.1, 15q22, and 20q12) were analyzed using mass spectroscopy and restriction-length-fragment polymorphism analyses. In a previous study, we had analyzed the remaining four NSCL/P susceptibility regions (IRF6, 8q24, 10q25, and 17q22) in the same sample. RESULTS: Single-marker association analyses applying allelic, dominant, and recessive models revealed nominal significant associations for four of the eight loci, with two additional loci showing at least a trend of association in the hypothesized direction. CONCLUSION: In combination with results from our previous study using the same sample, our data suggest that the majority of the known NSCL/P susceptibility regions identified to date also confer risk for this malformation in the Mesoamerican population. Birth Defects Research (Part A) 100:43-47, 2014. © 2013 Wiley Periodicals, Inc.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Loci Gênicos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Fenda Labial/etnologia , Fenda Labial/patologia , Fissura Palatina/etnologia , Fissura Palatina/patologia , Feminino , Frequência do Gene , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Indígenas Sul-Americanos , Padrões de Herança , Masculino , Espectrometria de Massas , México , Modelos Genéticos , Polimorfismo de Fragmento de Restrição , RiscoRESUMO
Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital malformations and has a multifactorial etiology. Findings in mice suggest that the v-ski sarcoma viral oncogene homolog (SKI) gene is a candidate gene for orofacial clefting. In humans, a significant association between rs2843159 within SKI and NSCL/P has been reported in patients from the Philippines and South America. In the South American patients, the association was driven by the subgroup of patients with non-syndromic cleft lip only (NSCLO). Here we investigated the association with rs2843159 in a Mayan Mesoamerican population (172 NSCL/P patients and 366 controls). In addition, we analyzed the phenotypic subgroups NSCLO and non-syndromic cleft of lip and palate (NSCLP). A trend towards association between rs2843159 and NSCL/P was observed in the Mayan cohort (P = 0.097), and we found a stronger association in the NSCLP subgroup (P = 0.072) despite a limited sample size. To investigate whether other common variants within the SKI gene contribute to NSCL/P susceptibility in European and Asian populations, we also analyzed genotypic data from two recent genome-wide association studies using set-based statistical approaches. These analyses detected a trend toward association in the European population. Our data provide limited support for the hypothesis that common SKI variants are susceptibility factors for NSCL/P.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Ligação a DNA/genética , Indígenas Norte-Americanos/genética , Proteínas Proto-Oncogênicas/genética , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , México , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
OBJECTIVE: To identify genetic and nongenetic risk factors that contribute to the severity of the bladder exstrophy-epispadias complex (BEEC). STUDY DESIGN: Patients with BEEC from North America (n = 167) and Europe (n = 274) were included. The following data were collected: associated anomalies, parental age at conception, mode of conception, periconceptional folic acid supplementation, maternal risk factors during pregnancy, and environmental risk factors. The patients were divided into 3 subgroups according to phenotype severity: (i) mild, epispadias (n = 43); (ii) intermediate, classic bladder exstrophy (n = 366); and (iii) severe, cloacal exstrophy (n = 31). These subgroups then were compared with identify factors that contribute to phenotype severity. RESULTS: Males were overrepresented in all subgroups. A relatively high prevalence of cleft lip, with or without cleft palate, was observed. Maternal smoking and medical radiation during the first trimester were associated with the severe cloacal exstrophy phenotype. Compliance with periconceptional folic acid supplementation was associated with the mildest phenotype (epispadias). CONCLUSIONS: Periconceptional folic acid supplementation appears to prevent the development of the severe phenotype of BEEC.
Assuntos
Extrofia Vesical/epidemiologia , Epispadia/epidemiologia , Adulto , Antiácidos/uso terapêutico , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Fertilização in vitro/estatística & dados numéricos , Ácido Fólico/uso terapêutico , Humanos , Masculino , Idade Materna , Pessoa de Meia-Idade , América do Norte/epidemiologia , Idade Paterna , Fenótipo , Gravidez , Primeiro Trimestre da Gravidez , Cuidado Pré-Natal , Radiografia/estatística & dados numéricos , Fatores de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Fumar/epidemiologia , Injeções de Esperma Intracitoplásmicas/estatística & dados numéricos , Inquéritos e Questionários , Complexo Vitamínico B/uso terapêuticoRESUMO
INTRODUCTION: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all birth defects. NSCL/P has a multifactorial etiology that includes both genetic and environmental factors. The IRF6 gene and three further susceptibility loci at 8q24, 10q25, and 17q22, which were identified by a recent genome-wide association scan (GWAS), are confirmed genetic risk factors for NSCL/P in patients of European descent. METHODS: A case-control association study was performed to investigate whether these four risk loci contribute to NSCL/P in a Mesoamerican population using four single nucleotide polymorphisms to represent IRF6 and the three novel susceptibility loci. A total of 149 NSCL/P patients and 303 controls of Mayan origin were included. RESULTS: Single marker analysis revealed a significant association between NSCL/P and risk variants in IRF6 and the 8q24 and 10q25 loci. In contrast to previous findings, the association at the 8q24 locus was driven solely by homozygote carriers of the risk allele. This suggests that this locus might act in a recessive manner in the Mayan population. No evidence for association was found at the 17q22 locus. This may have been attributable to the limited power of the sample. CONCLUSION: These results suggest that IRF6 and the 10q25 and 8q24 loci confer a risk for the development of NSCL/P in persons of Mayan origin.