脑源性神经营养因子基因和神经营养性酪氨酸激酶受体Ⅱ型基因交互作用与青年自杀未遂行为的关系
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摘要
目的探讨脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)基因与神经营养性酪氨酸激酶受体2型(neurotrophic tyrosine kinase receptor type 2,NTRK2)基因交互作用与青年自杀未遂行为的关系。方法使用IMLDR~(tm)多重SNP分型技术对病例组(70例自杀未遂青年人)和对照组(112例健康青年人)的BDNF基因1个多态性位点rs1491851和NTRK2基因3个多态性位点rs1147198、rs11140800、rs1565445进行分型,采用广义多因子降维法(generalized multifactor dimensionality reduction,GMDR)分析基因-基因交互作用。结果在病例组与对照组中,BDNF rs1491851、NTRK2 rs1147198、rs11140800、rs1565445基因型频率与等位基因频率的分布差异均无统计学意义(P>0.05)。GMDR分析结果显示,BDNF基因与NTRK2基因的2～4阶交互作用,分别为两位点模型(rs1491851、rs1147198)、三位点模型(rs1491851、rs1147198、rs11140800)和四位点模型(rs1491851、rs1147198、rs11140800、rs1565445)。其中四位点模型(rs1491851、rs1147198、rs11140800、rs1565445,测试样本精度为0.632 5,交叉一致性检验为10/10,1 000次置换检验P值为0.032～0.033)为最佳模型。结论 BDNF基因与NTRK2基因存在交互作用,可能与青年自杀未遂行为相关。
Objective To investigate the association of the interaction between brain-derived neurotrophic factor(BDNF) gene and neurotrophic tyrosine kinase receptor type 2(NTRK2) gene with suicide attempt in adolescents. Methods One single nucleotide polymorphism(SNP) of BDNF gene(rs1491851) and 3 SNPs of NTRK2(rs1147198, rs11140800, rs1565445) were tested by IMLDR~(tm) multiplex SNP typing in 70 suicide attempters(15～24 years old) and 111 healthy young individuals(control). Analysis on gene-gene interaction was conducted by generalized multifactor dimensionality reduction(GMDR). Results No significant differences were found in genotype frequencies and allele frequencies between the attempters and controls at 4 SNPs(BDNF rs1491851, and NTRK2 rs1147198, rs1140800, rs1565445)(P>0.05). GMDR analysis indicated the interactions between BDNF gene and NTRK2 gene included a two-locus combination(rs1491851, rs1147198), a three-locus combination(rs1491851, rs1147198, rs11140800) and four-locus combination(rs1491851, rs1147198, rs11140800, rs1565445). The four-locus combination was identified as the best model(Bal. Acc. CV test: 0.632 5, CVC consistency: 10/10, permutation test: P=0.032～0.033). Conclusion There are interactions between BDNF gene and NTRK2 gene, which may be associated with suicide attempt in adolescents.
Objective To investigate the association of the interaction between brain-derived neurotrophic factor(BDNF) gene and neurotrophic tyrosine kinase receptor type 2(NTRK2) gene with suicide attempt in adolescents. Methods One single nucleotide polymorphism(SNP) of BDNF gene(rs1491851) and 3 SNPs of NTRK2(rs1147198, rs11140800, rs1565445) were tested by IMLDR~(tm) multiplex SNP typing in 70 suicide attempters(15～24 years old) and 111 healthy young individuals(control). Analysis on gene-gene interaction was conducted by generalized multifactor dimensionality reduction(GMDR). Results No significant differences were found in genotype frequencies and allele frequencies between the attempters and controls at 4 SNPs(BDNF rs1491851, and NTRK2 rs1147198, rs1140800, rs1565445)(P>0.05). GMDR analysis indicated the interactions between BDNF gene and NTRK2 gene included a two-locus combination(rs1491851, rs1147198), a three-locus combination(rs1491851, rs1147198, rs11140800) and four-locus combination(rs1491851, rs1147198, rs11140800, rs1565445). The four-locus combination was identified as the best model(Bal. Acc. CV test: 0.632 5, CVC consistency: 10/10, permutation test: P=0.032～0.033). Conclusion There are interactions between BDNF gene and NTRK2 gene, which may be associated with suicide attempt in adolescents.
引文
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[2] TURECKI G,BRENT D A.Suicide and suicidal behaviour[J].Lancet,2016,387(10024):1227-1239.DOI:10.1016/S0140-6736(15)00234-2.
[3] BATTY G D,KIVIM?KI M,BELL S,et al.Psychosocial characteristics as potential predictors of suicide in adults:An overview of the evidence with new results from prospective cohort studies[J].Transl Psychiatry,2018,8(1):22.DOI:10.1038/s41398-017-0072-8.
[4] SARKISIAN K L,VAN HULLE C A,HILL GOLDSMITH H.Brooding,inattention,and impulsivity as predictors of adolescent suicidal ideation[J].J Abnorm Child Psychol,2019,47(2):333-344.DOI:10.1007/s10802-018-0435-5.
[5] BALDESSARINI R J,HENNEN J.Genetics of suicide:An overview[J].Harv Rev Psychiatry,2004,12(1):1-13.
[6] CHEN J,YU J.Sex differences in genetic and environmental influences on adolescent depressive symptoms:A meta-analytic review[J].Depress Res Treat,2015,2015:476238.DOI:10.1155/2015/476238.
[7] 操军,王俊,况利,等.抑郁症自杀未遂患者血浆脑源性神经营养因子水平及相关分析[J].中国神经精神疾病杂志,2013,39(10):597-601.DOI:10.3969/j.issn.1002-0152.2013.10.005.CAO J,WANG J,KUANG L,et al.Plasma level of brain-derived neurotrophic factor and the related analysis in depressive patients with suicide attempt[J].Chin J Nerv Mental Dis,2013,39(10):597-601.DOI:10.3969/j.issn.1002-0152.2013.10.005.
[8] YOUSSEF M M,UNDERWOOD M D,HUANG Y Y,et al.Association of BDNF Val66Met polymorphism and brain BDNF levels with major depression and suicide[J].Int J Neuropsychopharmacol,2018,21(6):528-538.DOI:10.1093/ijnp/pyy008.
[9] PARK S,LEE H B,LEE J K,et al.Associations between the brain-derived neurotrophic factor Val66Met polymorphisms and suicide in patients with cancer[J].Psychiatr Genet,2018,28(4):71-72.DOI:10.1097/YPG.00000000000 00199.
[10] B?LC M I,VULTURAR R,CHI? A,et al.Childhood trauma and emotion regulation:The moderator role of BDNF Val66Met[J].Neurosci Lett,2018,685:7-11.DOI:10.1016/j.neulet.2018.07.018.
[11] URSINI G,CAVALLERI T,FAZIO L,et al.BDNF rs6265 methylation and genotype interact on risk for schizophrenia[J].Epigenetics,2016,11(1):11-23.DOI:10.1080/15592294.2015.1117736.
[12] TSAI S J.Critical issues in BDNF Val66Met genetic studies of neuropsychiatric disorders[J].Front Mol Neurosci,2018,11:156.DOI:10.3389/fnmol.2018.00156.
[13] KOHLI M A,SALYAKINA D,PFENNIG A,et al.Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients[J].Arch Gen Psychiatry,2010,67(4):348-359.DOI:10.1001/archgenpsychiatry.2009.201.
[14] DEFLESSELLE E,COLLE R,RIGAL L,et al.The TRKB rs2289656 genetic polymorphism is associated with acute suicide attempts in depressed patients:A transversal case control study[J].PLoS ONE,2018,13(10):e0205648.DOI:10.1371/journal.pone.0205648.
[15] 胡春荣,杜欣娜,李凤君,等.脑源性神经营养因子相互作用蛋白质间的相互作用网络及功能[J].中国老年学杂志,2018,38(7):1707-1709.DOI:10.3969/j.issn.1005-9202.2018.07.073.HU C R,DU X N,LI F J,et al.Protein-protein interaction network and function of brain-derived neurotrophic factor[J].Chin J Gerontol,2018,38(7):1707-1709.DOI:10.3969/j.issn.1005-9202.2018.07.073.
[16] BANERJEE R,GHOSH A K,GHOSH B,et al.Decreased mRNA and protein expression of BDNF,NGF,and their receptors in the hippocampus from suicide:an analysis in human postmortem brain[J].Clin Med Insights Pathol,2013,6:1-11.DOI:10.4137/CMPath.S12530.
[17] ROPRET S,ZUPANC T,KOMEL R,et al.Data in support of association study of the brain-derived neurotrophic factor gene SNPs and completed suicide in the Slovenian sample[J].Data Brief,2015 ,4:529-533.DOI:10.1016/j.dib.2015.07.015.
[18] SCHOSSER A,CARLBERG L,CALATI R,et al.The impact of BDNF polymorphisms on suicidality in treatment-resistant major depressive disorder:A European multicenter study[J].Int J Neuropsychopharmacol,2017,20(10):782-787.DOI:10.1093/ijnp/pyx028.
[19] VOEGELI G,RAMOZ N,SHEKHTMAN T,et al.Neurotrophin genes and antidepressant-worsening suicidal ideation:A prospective case-control study[J].Int J Neuropsychopharmacol,2016,19(11):pyw059.DOI:10.1093/ijnp/pyw059.
[20] MIRKOVIC B,LAURENT C,PODLIPSKI M A,et al.Genetic association studies of suicidal behavior:A review of the past 10 years,progress,limitations,and future directions[J].Front Psychiatry,2016,7:158.DOI:10.3389/fpsyt.2016.00158.
[21] RITCHIE M D,HAHN L W,ROODI N,et al.Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer[J].Am J Hum Genet,2001,69(1):138-147.DOI:10.1086/321276.
[22] LOU X Y,CHEN G B,YAN L,et al.A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence[J].Am J Hum Genet,2007,80(6):1125-1137.DOI:10.1086/518312.
[23] YU P P,JIAO J,CHEN G S,et al.Effect of GRM7 polymorphisms on the development of noise-induced hearing loss in Chinese Han workers:A nested case-control study[J].BMC Med Genet,2018,19(1):4.DOI:10.1186/s12881-017-0515-3.
[24] YI X Y,LIN J,LUO H,et al.Interactions among variants in TXA2R,P2Y12 and GPIIIa are associated with carotid plaque vulnerability in Chinese population[J].Oncotarget,2018,9(25):17597-17607.DOI:10.18632/oncotarget.24801.
[25] FRANKS P W,PEARSON E,FLOREZ J C.Gene-environment and gene-treatment interactions in type 2 diabetes:progress,pitfalls,and prospects[J].Diabetes Care,2013,36(5):1413-1421.DOI:10.2337/dc12-2211.
[26] F?SSBERG M M,VAN ORDEN K A,DUBERSTEIN P,et al.A systematic review of social factors and suicidal behavior in older adulthood[J].Int J Environ Res Public Health,2012,9(3):722-745.DOI:10.3390/ijerph9030722.
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