Association of Whole-Genome and NETRIN1 Signaling Pathway-Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank.
Association of Whole-Genome and NETRIN1 Signaling Pathway-Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank.
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DOI：
10.1016/j.bpsc.2018.07.006
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Whalley HC
中科院分区：
文献类型：
--
作者：
Barbu MC;Zeng Y;Shen X;Cox SR;Clarke TK;Gibson J;Adams MJ;Johnstone M;Haley CS;Lawrie SM;Deary IJ;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium;23andMe Research Team;McIntosh AM;Whalley HC
重度抑郁障碍是一种具有多基因结构的临床异质性精神障碍。全基因组关联研究已经确定了基因组中一些与风险相关的变异，并报告了越来越多的证据表明NETRIN1途径参与其中。根据NETRIN1途径内的遗传变异对疾病风险进行分层，可能为通过专注于特定过程而识别疾病机制提供重要途径，排除其他途径中与风险相关的异质性变异。在这里，我们试图调查来自NETRIN1信号通路(NETRIN1-PRSS)和整个基因组(不包括NETRIN1途径基因)的重大抑郁障碍多基因风险分数是否与白质微结构有关。在最新的英国生物库神经成像数据发布中，我们使用了两种扩散张量成像指标，分数各向异性(FA)和平均扩散率(MD)(FA：N=6401；MD：N=6390)。我们发现，在丘脑辐射的整体测量中，上纵束的FA显著降低(β=0.035，−=0.029)，MD显著升高(β=0.029，P校正后的β=0.021)，而与NETRIN1-PRS相关的上纵束(β=0.029，Prectedβ=0.043)、丘脑上(β=0.027，Prected F=0.043)和丘脑的前部(LINR=0.025，Prected F=0.043)的MD显著升高。在几个区域中，基因组-粗蛋白还与低FA和高MD相关。我们的发现表明，NETRIN1信号通路的变异可能通过影响许多白质束而增加患抑郁症的风险。
Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). We found significantly lower FA in the superior longitudinal fasciculus (β = −.035, pcorrected = .029) and significantly higher MD in a global measure of thalamic radiations (β = .029, pcorrected = .021), as well as higher MD in the superior (β = .034, pcorrected = .039) and inferior (β = .029, pcorrected = .043) longitudinal fasciculus and in the anterior (β = .025, pcorrected = .046) and superior (β = .027, pcorrected = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.
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DOI：
10.1093/bioinformatics/btu848
发表时间：
2015-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Euesden J;Lewis CM;O'Reilly PF
通讯作者：
O'Reilly PF
影响因子：
10.6
作者：
Hek, Karin;Demirkan, Ayse;Lahti, Jari;Terracciano, Antonio;Teumer, Alexander;Cornelis, Marilyn C.;Amin, Najaf;Bakshis, Erin;Baumert, Jens;Ding, Jingzhong;Liu, Yongmei;Marciante, Kristin;Meirelles, Osorio;Nalls, Michael A.;Sun, Yan V.;Vogelzangs, Nicole;Yu, Lei;Bandinelli, Stefania;Benjamin, Emelia J.;Bennett, David A.;Boomsma, Dorret;Cannas, Alessandra;Coker, Laura H.;de Geus, Eco;De Jager, Philip L.;Diez-Roux, Ana V.;Purcell, Shaun;Hu, Frank B.;Rimm, Eric B.;Hunter, David J.;Jensen, Majken K.;Curhan, Gary;Rice, Kenneth;Penman, Alan D.;Rotter, Jerome I.;Sotoodehnia, Nona;Emeny, Rebecca;Eriksson, Johan G.;Evans, Denis A.;Ferrucci, Luigi;Fornage, Myriam;Gudnason, Vilmundur;Hofman, Albert;Illig, Thomas;Kardia, Sharon;Kelly-Hayes, Margaret;Koenen, Karestan;Kraft, Peter;Kuningas, Maris;Massaro, Joseph M.;Melzer, David;Mulas, Antonella;Mulder, Cornelis L.;Murray, Anna;Oostra, Ben A.;Palotie, Aarno;Penninx, Brenda;Petersmann, Astrid;Pilling, Luke C.;Psaty, Bruce;Rawal, Rajesh;Reiman, Eric M.;Schulz, Andrea;Shulman, Joshua M.;Singleton, Andrew B.;Smith, Albert V.;Sutin, Angelina R.;Uitterlinden, Andre G.;Voelzke, Henry;Widen, Elisabeth;Yaffe, Kristine;Zonderman, Alan B.;Cucca, Francesco;Harris, Tamara;Ladwig, Karl-Heinz;Llewellyn, David J.;Raikkonen, Katri;Tanaka, Toshiko;van Duijn, Cornelia M.;Grabe, Hans J.;Launer, Lenore J.;Lunetta, Kathryn L.;Mosley, Thomas H., Jr.;Newman, Anne B.;Tiemeier, Henning;Murabito, Joanne
通讯作者：
Murabito, Joanne
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
4.6
作者：
Reus, L. M.;Shen, X.;McIntosh, A. M.
通讯作者：
McIntosh, A. M.
DOI：
10.1016/j.jaac.2009.11.005
发表时间：
2010-02-01
影响因子：
13.3
作者：
Cullen, Kathryn R.;Klimes-Dougan, Bonnie;Lim, Kelvin O.
通讯作者：
Lim, Kelvin O.