A Two-Stage Association Study Suggests BRAP as a Susceptibility Gene for Schizophrenia

Zhang, Fuquan; Liu, Chenxing; Xu, Yong; Qi, Guoyang; Gao, Yuan; Zhang, Cheng; Wang, Jidong; Wang, Guoqiang; Wang, Zhiqiang; Zhu, Wei; Zhou, Zhenhe; Zhao, Xiaojia; Tian, Lin; Jin, Chunhui; Yuan, Janmin; Zhang, Guofu; Chen, Ya-Guang; Wang, Lifang; Lu, Tianlan; Yan, Hao; Ruan, Yijun; Yue, Weihua; Zhang, Dai

doi:10.1371/journal.pone.0086037

Cited by 13 publications

(32 citation statements)

References 44 publications

(56 reference statements)

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“…A postmortem study in humans showed that NF-κB is downregulated in the brains of alcoholic patients 36. Similarly, other studies have shown that BRAP silencing via RNA interference inhibits NF-κB activation and that BRAP expression is ~twofold higher due to the genetic variant rs11066001 , which is a tagging SNP of rs3782886 that has a high correlation value ( r 2 =0.81) 31,37,38. Taken together, these findings suggest that changes in BRAP expression induced by genetic variants might affect the NF-κB inflammatory cascade and may be a mechanism by which BRAP affects the risk level of AD.…”

Section: Discussionmentioning

confidence: 93%

“…BRAP is a regulatory protein that binds to several translocation signal proteins in the cytoplasm31 and, based on its functions, can modulate several intracellular signaling pathways. First, BRAP regulates the mitogen-activated protein kinase (MAPK) signaling pathway during CNS development through its function as a ubiquitin ligase 32.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these findings suggest that changes in BRAP expression induced by genetic variants might affect the NF-κB inflammatory cascade and may be a mechanism by which BRAP affects the risk level of AD. However, the direct and/or indirect functional impacts of BRAP on AD remain to be tested because the direct functional impacts of BRAP on several human disorders, including schizophrenia,31 myocardial infarction,39 carotid atherosclerosis,37 and metabolic syndrome,40 are not yet fully understood. However, the function of BRAP as a mediator of the translocation of signaling proteins might be a plausible explanation for the association between BRAP and human diseases with distinct pathophysiologies.…”

Section: Discussionmentioning

confidence: 99%

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Associations of <em>BRAP</em> polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test

Kim

Choe

Shin

et al. 2018

NDT

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BackgroundAlcohol dependence (AD) is a common disorder that is influenced by genetic as well as environmental factors. A previous genome-wide association study (GWAS) of the Korean population performed by our research group identified a number of genes, including BRCA1-associated protein (BRAP) and protein arginine methyltransferase 8 (PRMT8), as novel genetic markers of AD.MethodsThe present investigation was a fine-mapping follow-up study of 459 AD and 455 non-AD subjects of Korean descent to determine the associations between BRAP and PRMT8 polymorphisms and AD. The Alcohol Use Disorders Identification Test (AUDIT) was administered to screen for the degree of AD risk in the subjects and 58 genetic variants, 5 for BRAP and 53 for PRMT8, were genotyped for subsequent association analyses.ResultsIn the present case–control analysis, BRAP rs3782886 showed the most significant association signal with a risk of AD (P=1.29×10−16, Pcorr =7.74×10−16, OR =0.19). There were also significant differences in the overall and subcategory scores for the BRAP genetic variants, including rs3782886 (P=9.94×10−31, Pcorr =5.96×10−30 at rs3782886 for the overall AUDIT score). However, the genetic effects of PRMT8 polymorphisms observed in our previous GWAS were not replicated in the present study (minimum P=0.0005, Pcorr >0.05, OR =0.30 at rs4766139 in the recessive model). Furthermore, the single-nucleotide polymorphisms of PRMT8 were not associated with the overall and subcategory AUDIT scores.ConclusionThe present findings suggest that the genetic variants of BRAP may contribute to a predisposition for an alcohol use disorder.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Associations of <em>BRAP</em> polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test

Kim

Choe

Shin

et al. 2018

NDT

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“…Associations of SNPs with schizophrenia in smallscale studies were found for SNPs in GSK3B 21 , BRAP 19 , DLCK1 20 , MYT1L 22 and BDNF 23 , but not for NTNG1. Some were validations of previous Genome WideAssociation studies (GWAS) results.…”

Section: Neurodevelopmentmentioning

confidence: 84%

Schizophrenia: neuroinflammation, neurodegeneration or neurodevelopment? A genetic overview

Polho¹,

Paula

2017

Rev. Med. (São Paulo)

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Schizophrenia is a devastating mental illness and its etiology is still largely unknown. Several gene mapping studies suggest that schizophrenia is a complex disorder, with a cumulative impact of variable genetic effects coupled with environmental factors. There is evidence that schizophrenia could be a neurodegenerative, neuroinflammatory or neurodevelopmental disorder. Neuropsychological data indicate neurocognitive functions are relatively stable over time after illness onset, whereas morphological data indicate a degenerative process; potential roles of neuroinflammation in the etiology of psychiatric diseases including schizophrenia have also been suggested. Recent research indicates genetic overlap between schizophrenia and syndromes in which psychopathology manifests in childhood and that are often grouped together as 'neurodevelopmental disorders'. These findings challenge the etiological basis of current diagnostic categories and, together with evidence for frequent comorbidity, suggest that we should view the functional psychoses as members of a group that result in part from a combination of genetic and environmental effects on brain development and that are associated with specific and general impairments of cognitive function. The objective was to perform a systematic literature review of articles on genetics of schizophrenia relating to neurodegeneration, neuroinflammation and neurodevelopment. After proper filter, we included 40 studies and reviewed each finding and its relevance to the hypotheses. We can conclude that the evidence points to schizophrenia as a neurodevelopmental disease with the direct presence of factors related to neuroinflammation and neurodegeneration.Keywords: Schizophrenia/genetics; Neurodevelopmental disorders/ genetics; Pantothenate kinase-associated neurodegeneration/ genetics; Neurogenetic inflammation/genetics; Genetics.RESUMO: Esquizofrenia é uma doença mental debilitante e sua etiologia é, em sua maior parte, desconhecida. Alguns estudos de mapeamento genético sugerem que esquizofrenia é uma doença complexa, com impacto acumulativo de fatores genéticos variáveis associados a fatores ambientais. Há evidência de que a esquizofrenia poderia ser uma doença neurodegenerativa, neuroinflamatória ou do neurodesenvolvimento. Dados neuropsicológicos indicam que funções cognitivas são relativamente estáveis no decorrer do tempo após o início da doença, enquanto dados morfológicos indicam processos degenerativos; papéis importantes da neuroinflamação na etiologia de doenças psiquiátricas, incluindo esquizofrenia, também foram sugeridos. Pesquisas recentes indicam sobreposição entre esquizofrenia e síndromes cuja fisiopatologia se manifesta na infância e são em geral agrupadas como "doenças do neurodesenvolvimento". Estes achados desafiam a base etiológica das categorias atuais de diagnóstico e, juntamente com a evidência de comorbidade frequente, sugerem que devemos ver as psicoses como membros do grupo que resulta em parte da combinação de efeitos genéticos e ambientai...

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“…Recently, BRAP has attracted attention because its expression is associated with the prognosis of patients with colorectal cancer [24] and the invasiveness of esophageal squamous cell carcinoma[25]. In addtion, several studies revealed that BRAP is genetic risk factor for coronary artery disease including myocardial infarction, hypertension, metabolic syndrome[26] [27] [28] [29] [30]. In these studies, 5 single nucleotide polymorphisms (SNPs) were reported (rs11066001[chr12:111681367, c.443+270 A>G], rs3782886 [chr12:11672685, c.90 A>G, p.Arg241Arg)], rs11065987 [chr12:111634620, located 9.9 kb upstream of BRAP ], rs1544396 [chr:111625071, located 17 kb upstream of BRAP ] and rs601663 [chr:111685480, c.82+231 T>C]), however all SNPs are located very far from the variant we identified, c.1661 G>T p.Arg554Leu.…”

Section: Discussionmentioning

confidence: 99%

Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension

et al. 2019

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Although mutations in several genes have been reported in pulmonary arterial hypertension (PAH), most of PAH cases do not carry these mutations. This study aimed to identify a novel cause of PAH. To determine the disease-causing variants, direct sequencing and multiplex ligation-dependent probe amplification were performed to analyze 18 families with multiple affected family members with PAH. In one of the 18 families with PAH, no disease-causing variants were found in any of BMPR2, ACVRL1, ENG, SMAD1/4/8, BMPR1B, NOTCH3, CAV1, or KCNK3. In this family, a female proband and her paternal aunt developed PAH in their childhood. Whole-exome next-generation sequencing was performed in the 2 PAH patients and the proband’s healthy mother, and a BRCA1-associated protein (BRAP) gene variant, p.Arg554Leu, was identified in the 2 family members with PAH, but not in the proband’s mother without PAH. Functional analyses were performed using human pulmonary arterial smooth muscle cells (hPASMCs). Knockdown of BRAP via small interfering RNA in hPASMCs induced p53 signaling pathway activation and decreased cell proliferation. Overexpression of either wild-type BRAP or p.Arg554Leu-BRAP cDNA constructs caused cell death confounding these studies, however we observed higher levels of p53 signaling inactivation and hPASMC proliferation in cells expressing p.Arg554Leu-BRAP compared to wild-type BRAP. In addition, p.Arg554Leu-BRAP induced decreased apoptosis of hPASMCs compared with wild-type BRAP. In conclusion, we have identified a novel variant of BRAP in a Japanese family with PAH and our results suggest it could have a gain-of-function. This study sheds light on new mechanism of PAH pathogenesis.

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A Two-Stage Association Study Suggests BRAP as a Susceptibility Gene for Schizophrenia

Cited by 13 publications

References 44 publications

Associations of <em>BRAP</em> polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test

Associations of <em>BRAP</em> polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test

Schizophrenia: neuroinflammation, neurodegeneration or neurodevelopment? A genetic overview

Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension

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