The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine
The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine
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3p21.1 处精神疾病的全基因组风险等位基因显示出对 mRNA 表达、认知功能和蘑菇树突棘的趋同效应
DOI：
10.1038/s41380-019-0592-0
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发表时间：
2019-11
影响因子：
11
通讯作者：
Xiao Xiao
中科院分区：
文献类型：
--
作者：
Zhihui Yang;Danyang Zhou;Huijuan Li;Xin Cai;Weipeng Liu;Lu Wang;Hong Chang;Ming Li;Xiao Xiao
精神分裂症和双相情感障碍（BPD）被认为具有共同的临床特征、病因学因素和疾病病理学（例如认知功能受损和树突棘病理学）。与此同时，越来越多的证据表明精神分裂症和BPD之间存在共同的遗传风险，尽管我们对功能风险变异和生物学机制的了解仍然有限。在这里，我们通过结合精神分裂症和BPD的全基因组关联研究（GWAS）的统计数据和人脑背外侧前额叶皮层（DLPFC）组织的多表达数量性状基因座（eQTL）数据集，进行基于汇总数据的孟德尔随机化（SMR）分析。这些综合性研究确定了染色体3p21.1区域的一个主要风险位点，该位点包含多种连锁不平衡（LD）中的单核苷酸多态性（SNP），并包含20多个基因。进一步的分析表明，3p21.1处的许多SNP与精神分裂症和BPD，甚至抑郁症显著相关，并且3p21.1处的精神病风险等位基因与多个基因（如NEK4，GNL3和PBRM 1）的mRNA表达相关。我们还确定了一个335 bp的功能性Alu多态性rs71052682在显着LD与精神GWAS风险SNP rs2251219，并确认这种Alu多态性对转录活性的调节作用。然后，我们探讨了3p21.1位点参与这些疾病的常见临床特征和病因。我们发现，在低到高LD中，3p21.1的精神病风险等位基因始终预测人类认知功能较差，并且操纵与较高遗传风险相关的基因表达（NEK4，GNL3和PBRM 1）可以降低大鼠初级皮层神经元中蘑菇树突棘的密度，反映精神病患者前额叶皮层的棘病理学。我们的研究结果发现，虽然在3p21.1的风险等位基因是在低至中度LD跨越一个大的基因组区域，其潜在的生物学机制在精神疾病可能会收敛。这些结果提供了重要的洞察神经机制的基础上的染色体3p21.1风险位点的共同病理和病因学特征的精神分裂症和BPD。
Schizophrenia and bipolar disorder (BPD) are believed to share clinical features, etiological factors, and disease pathologies (such as impaired cognitive functions and dendritic spine pathology). Meanwhile, there is growing evidence of shared genetic risk between schizophrenia and BPD, despite that our knowledge of the functional risk variations and biological mechanisms is still limited. Here, we conduct summary data-based Mendelian randomization (SMR) analyses through combining the statistical data from genome-wide association studies (GWAS) of both schizophrenia and BPD and multiple expression quantitative trait loci (eQTL) datasets of the human brain dorsolateral prefrontal cortex (DLPFC) tissues. These integrative investigations identify a lead risk locus at the chromosome 3p21.1 region, which contains numerous single-nucleotide polymorphisms (SNPs) in varied linkage disequilibrium (LD) and encompasses more than 20 genes. Further analyses suggest that many SNPs at 3p21.1 are significantly associated with both schizophrenia and BPD, and even depression, and the psychiatric risk alleles at 3p21.1 are correlated with mRNA expression of multiple genes such as NEK4, GNL3, and PBRM1. We also identify a 335-bp functional Alu polymorphism rs71052682 in significant LD with the psychiatric GWAS risk SNP rs2251219, and confirm the regulatory effects of this Alu polymorphism on transcription activities. We then explore the involvement of the 3p21.1 locus in the common clinical features and etiology of these illnesses. We reveal that psychiatric risk alleles at 3p21.1 in low-to-high LD consistently predict worse cognitive functions in humans, and manipulating the gene expression (NEK4, GNL3, and PBRM1) linked with higher genetic risk could reduce the density of mushroom dendritic spines in rat primary cortical neurons, mirroring the spine pathology in the prefrontal cortex of psychiatric patients. Our results find that, although the risk alleles at 3p21.1 are in low-to-moderate LD spanning a large genomic area, their underlying biological mechanisms in psychiatric disorders likely converge. These results provide essential insights into the neural mechanisms underlying the chromosome 3p21.1 risk locus in the shared pathological and etiological features of both schizophrenia and BPD.
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影响因子：
11
作者：
Chang H;Hoshina N;Zhang C;Ma Y;Cao H;Wang Y;Wu DD;Bergen SE;Landén M;Hultman CM;Preisig M;Kutalik Z;Castelao E;Grigoroiu-Serbanescu M;Forstner AJ;Strohmaier J;Hecker J;Schulze TG;Müller-Myhsok B;Reif A;Mitchell PB;Martin NG;Schofield PR;Cichon S;Nöthen MM;Swedish Bipolar Study Group;MooDS Bipolar Consortium;Walter H;Erk S;Heinz A;Amin N;van Duijn CM;Meyer-Lindenberg A;Tost H;Xiao X;Yamamoto T;Rietschel M;Li M
通讯作者：
Li M
综合综合分析确定 GLT8D1 和 CSNK2B 为精神分裂症风险基因
影响因子：
16.6
作者：
Yang CP;Li X;Wu Y;Shen Q;Zeng Y;Xiong Q;Wei M;Chen C;Liu J;Huo Y;Li K;Xue G;Yao YG;Zhang C;Li M;Chen Y;Luo XJ
通讯作者：
Luo XJ
影响因子：
25
作者：
M. Fromer;P. Roussos;S. Sieberts;Jessica S. Johnson;D. Kavanagh;T. Perumal;D. Ruderfer;Edwin C. T. Oh-E
通讯作者：
M. Fromer;P. Roussos;S. Sieberts;Jessica S. Johnson;D. Kavanagh;T. Perumal;D. Ruderfer;Edwin C. T. Oh-E
DOI：
10.1016/b978-0-12-813866-3.00038-2
发表时间：
2020
期刊：
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease
影响因子：
--
作者：
D. Volk;Aaron K. Jenkins;Paven A. Lidstone;D. Lewis
通讯作者：
D. Volk;Aaron K. Jenkins;Paven A. Lidstone;D. Lewis
影响因子：
11
作者：
Hibar, D. P.;Westlye, L. T.;van Erp, T. G. M.;Rasmussen, J.;Leonardo, C. D.;Faskowitz, J.;Haukvik, U. K.;Hartberg, C. B.;Doan, N. T.;Agartz, I.;Dale, A. M.;Gruber, O.;Kraemer, B.;Trost, S.;Liberg, B.;Abe, C.;Ekman, C. J.;Ingvar, M.;Landen, M.;Fears, S. C.;Freimer, N. B.;Bearden, C. E.;Sprooten, E.;Glahn, D. C.;Pearlson, G. D.;Emsell, L.;Kenney, J.;Scanlon, C.;McDonald, C.;Cannon, D. M.;Almeida, J.;Versace, A.;Caseras, X.;Lawrence, N. S.;Phillips, M. L.;Dima, D.;Delvecchio, G.;Frangou, S.;Satterthwaite, T. D.;Wolf, D.;Houenou, J.;Henry, C.;Malt, U. F.;Boen, E.;Elvsashagen, T.;Young, A. H.;Lloyd, A. J.;Goodwin, G. M.;Mackay, C. E.;Bourne, C.;Bilderbeck, A.;Abramovic, L.;Boks, M. P.;van Haren, N. E. M.;Ophoff, R. A.;Kahn, R. S.;Bauer, M.;Pfennig, A.;Alda, M.;Hajek, T.;Mwangi, B.;Soares, J. C.;Nickson, T.;Dimitrova, R.;Sussmann, J. E.;Hagenaars, S.;Whalley, H. C.;McIntosh, A. M.;Thompson, P. M.;Andreassen, O. A.
通讯作者：
Andreassen, O. A.