Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.
Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.
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DOI：
10.1038/s41380-020-01006-9
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发表时间：
2021-09
影响因子：
11
通讯作者：
Scott LJ
中科院分区：
文献类型：
--
作者：
Jia X;Goes FS;Locke AE;Palmer D;Wang W;Cohen-Woods S;Genovese G;Jackson AU;Jiang C;Kvale M;Mullins N;Nguyen H;Pirooznia M;Rivera M;Ruderfer DM;Shen L;Thai K;Zawistowski M;Zhuang Y;Abecasis G;Akil H;Bergen S;Burmeister M;Chapman S;DelaBastide M;Juréus A;Kang HM;Kwok PY;Li JZ;Levy SE;Monson ET;Moran J;Sobell J;Watson S;Willour V;Zöllner S;Adolfsson R;Blackwood D;Boehnke M;Breen G;Corvin A;Craddock N;DiFlorio A;Hultman CM;Landen M;Lewis C;McCarroll SA;Richard McCombie W;McGuffin P;McIntosh A;McQuillin A;Morris D;Myers RM;O'Donovan M;Ophoff R;Boks M;Kahn R;Ouwehand W;Owen M;Pato C;Pato M;Posthuma D;Potash JB;Reif A;Sklar P;Smoller J;Sullivan PF;Vincent J;Walters J;Neale B;Purcell S;Risch N;Schaefer C;Stahl EA;Zandi PP;Scott LJ
双相情感障碍（BD）是一种严重的精神疾病，具有相当大的共同变异遗传。然而，罕见的编码变异在BD中的作用还没有很好地确定。我们检查了来自双极测序联盟（BSC）的4个队列中的3，987名BD无关个体和5，322名主要欧洲血统的对照的蛋白质编码（外显子）序列。我们评估了罕见的，蛋白质改变，单核苷酸变异分类为致病性或可能致病性（P-LP）的负担，这两个外显子组范围内和几组基因与BD的表型或生物相容性。虽然我们观察到在3,987例BD病例中，165个被鉴定为BD GWAS区域的基因内罕见编码P-LP变异的负担增加，（荟萃分析OR = 1.9，95% CI = 1.3-2.8，单侧p = 6.0 × 10−4），这种富集在另外9，929例BD病例和14，018例对照中没有重复（OR = 0.9，单侧p = 0.70）。虽然BD与精神分裂症具有共同的变异遗传性，但在BSC样本中，我们没有观察到SCZ GWAS基因、与SCZ相关的两类神经元突触基因（RBFOX 2和FMRP）或功能丧失不耐受基因中P-LP变异的显著富集。在这项研究中，BD外显子变异的最大分析，BD个体在外显子组或具有生物可变性的几组基因中的任何一组中都没有携带可复制的罕见P-LP变体富集。此外，尽管BD和SCZ之间通过共同的遗传变异具有很强的共同易感性，但我们没有观察到BD风险与已知调节SCZ风险的基因中的罕见P-LP编码变体之间的关联。
Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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影响因子：
64.8
作者：
Fuchsberger, Christian;Flannick, Jason;Teslovich, Tanya M.;Mahajan, Anubha;Agarwala, Vineeta;Gaulton, Kyle J.;Ma, Clement;Fontanillas, Pierre;Moutsianas, Loukas;McCarthy, Davis J.;Rivas, Manuel A.;Perry, John R. B.;Sim, Xueling;Blackwell, Thomas W.;Robertson, Neil R.;Rayner, N. William;Cingolani, Pablo;Locke, Adam E.;Tajes, Juan Fernandez;Highland, Heather M.;Dupuis, Josee;Chines, Peter S.;Lindgren, Cecilia M.;Hartl, Christopher;Jackson, Anne U.;Chen, Han;Huyghe, Jeroen R.;van de Bunt, Martijn;Pearson, Richard D.;Kumar, Ashish;Mueller-Nurasyid, Martina;Grarup, Niels;Stringham, Heather M.;Gamazon, Eric R.;Lee, Jaehoon;Chen, Yuhui;Scott, Robert A.;Below, Jennifer E.;Chen, Peng;Huang, Jinyan;Go, Min Jin;Stitzel, Michael L.;Pasko, Dorota;Parker, Stephen C. J.;Varga, Tibor V.;Green, Todd;Beer, Nicola L.;Day-Williams, Aaron G.;Ferreira, Teresa;Fingerlin, Tasha;Horikoshi, Momoko;Hu, Cheng;Huh, Iksoo;Ikram, Mohammad Kamran;Kim, Bong-Jo;Kim, Yongkang;Kim, Young Jin;Kwon, Min-Seok;Lee, Juyoung;Lee, Selyeong;Lin, Keng-Han;Maxwell, Taylor J.;Nagai, Yoshihiko;Wang, Xu;Welch, Ryan P.;Yoon, Joon;Zhang, Weihua;Barzilai, Nir;Voight, Benjamin F.;Han, Bok-Ghee;Jenkinson, Christopher P.;Kuulasmaa, Teemu;Kuusisto, Johanna;Manning, Alisa;Ng, Maggie C. Y.;Palmer, Nicholette D.;Balkau, Beverley;Stancakova, Alena;Abboud, Hanna E.;Boeing, Heiner;Giedraitis, Vilmantas;Prabhakaran, Dorairaj;Gottesman, Omri;Scott, James;Carey, Jason;Kwan, Phoenix;Grant, George;Smith, Joshua D.;Neale, Benjamin M.;Purcell, Shaun;Butterworth, Adam S.;Howson, Joanna M. M.;Lee, Heung Man;Lu, Yingchang;Kwak, Soo-Heon;Zhao, Wei;Danesh, John;Lam, Vincent K. L.;Park, Kyong Soo;Saleheen, Danish;So, Wing Yee;Tam, Claudia H. T.;Afzal, Uzma;Aguilar, David;Arya, Rector;Aung, Tin;Chan, Edmund;Navarro, Carmen;Cheng, Ching-Yu;Palli, Domenico;Correa, Adolfo;Curran, Joanne E.;Rybin, Denis;Farook, Vidya S.;Fowler, Sharon P.;Freedman, Barry I.;Griswold, Michael;Hale, Daniel Esten;Hicks, Pamela J.;Khor, Chiea-Chuen;Kumar, Satish;Lehne, Benjamin;Thuillier, Dorothee;Lim, Wei Yen;Liu, Jianjun;van der Schouw, Yvonne T.;Loh, Marie;Musani, Solomon K.;Puppala, Sobha;Scott, William R.;Yengo, Loic;Tan, Sian-Tsung;Taylor, Herman A., Jr.;Thameem, Farook;Wilson, Gregory, Sr.;Wong, Tien Yin;Njolstad, Pal Rasmus;Levy, Jonathan C.;Mangino, Massimo;Bonnycastle, Lori L.;Schwarzmayr, Thomas;Fadista, Joao;Surdulescu, Gabriela L.;Herder, Christian;Groves, Christopher J.;Wieland, Thomas;Bork-Jensen, Jette;Brandslund, Ivan;Christensen, Cramer;Koistinen, Heikki A.;Doney, Alex S. F.;Kinnunen, Leena;Esko, Tonu;Farmer, Andrew J.;Hakaste, Liisa;Hodgkiss, Dylan;Kravic, Jasmina;Lyssenko, Valeriya;Hollensted, Mette;Jorgensen, Marit E.;Jorgensen, Torben;Ladenvall, Claes;Justesen, Johanne Marie;Karajamaki, Annemari;Kriebel, Jennifer;Rathmann, Wolfgang;Lannfelt, Lars;Lauritzen, Torsten;Narisu, Narisu;Linneberg, Allan;Melander, Olle;Milani, Lili;Neville, Matt;Orho-Melander, Marju;Qi, Lu;Qi, Qibin;Roden, Michael;Rolandsson, Olov;Swift, Amy;Rosengren, Anders H.;Stirrups, Kathleen;Wood, Andrew R.;Mihailov, Evelin;Blancher, Christine;Carneiro, Mauricio O.;Maguire, Jared;Poplin, Ryan;Shakir, Khalid;Fennell, Timothy;DePristo, Mark;de Angelis, Martin Hrabe;Deloukas, Panos;Gjesing, Anette P.;Jun, Goo;Nilsson, Peter;Murphy, Jacquelyn;Onofrio, Robert;Thorand, Barbara;Hansen, Torben;Meisinger, Christa;Hu, Frank B.;Isomaa, Bo;Karpe, Fredrik;Liang, Liming;Peters, Annette;Huth, Cornelia;O'Rahilly, Stephen P.;Palmer, Colin N. A.;Pedersen, Oluf;Rauramaa, Rainer;Tuomilehto, Jaakko;Salomaa, Veikko;Watanabe, Richard M.;Syvanen, Ann-Christine;Bergman, Richard N.;Bharadwaj, Dwaipayan;Bottinger, Erwin P.;Cho, Yoon Shin;Chandak, Giriraj R.;Chan, Juliana C. N.;Chia, Kee Seng;Daly, Mark J.;Ebrahim, Shah B.;Langenberg, Claudia;Elliott, Paul;Jablonski, Kathleen A.;Lehman, Donna M.;Jia, Weiping;Ma, Ronald C. W.;Pollin, Toni I.;Sandhu, Manjinder;Tandon, Nikhil;Froguel, Philippe;Barroso, Ines;Teo, Yik Ying;Zeggini, Eleftheria;Loos, Ruth J. F.;Small, Kerrin S.;Ried, Janina S.;DeFronzo, Ralph A.;Grallert, Harald;Glaser, Benjamin;Metspalu, Andres;Wareham, Nicholas J.;Walker, Mark;Banks, Eric;Gieger, Christian;Ingelsson, Erik;Im, Hae Kyung;Illig, Thomas;Franks, Paul W.;Buck, Gemma;Trakalo, Joseph;Buck, David;Prokopenko, Inga;Magi, Reedik;Lind, Lars;Farjoun, Yossi;Owen, Katharine R.;Gloyn, Anna L.;Strauch, Konstantin;Tuomi, Tiinamaija;Kooner, Jaspal Singh;Lee, Jong-Young;Park, Taesung;Donnelly, Peter;Morris, Andrew D.;Hattersley, Andrew T.;Bowden, Donald W.;Collins, Francis S.;Atzmon, Gil;Chambers, John C.;Spector, Timothy D.;Laakso, Markku;Strom, Tim M.;Bell, Graeme I.;Blangero, John;Duggirala, Ravindranath;Tai, E. Shyong;McVean, Gilean;Hanis, Craig L.;Wilson, James G.;Seielstad, Mark;Frayling, Timothy M.;Meigs, James B.;Cox, Nancy J.;Sladek, Rob;Lander, Eric S.;Gabriel, Stacey;Burtt, Noel P.;Mohlke, Karen L.;Meitinger, Thomas;Groop, Leif;Abecasis, Goncalo;Florez, Jose C.;Scott, Laura J.;Morris, Andrew P.;Kang, Hyun Min;Boehnke, Michael;Altshuler, David;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
17.7
作者：
Kieseppä, T;Partonen, T;Lönnqvist, J
通讯作者：
Lönnqvist, J
DOI：
10.1016/j.psc.2015.10.004
发表时间：
2016-03
期刊：
The Psychiatric clinics of North America
影响因子：
--
作者：
Goes FS
通讯作者：
Goes FS
影响因子：
14.5
作者：
Koutsouleris, Nikolaos;Meisenzahl, Eva M.;Davatzikos, Christos
通讯作者：
Davatzikos, Christos
DOI：
10.1073/pnas.1424958112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Ament, Seth A.;Szelinger, Szabolcs;Roach, Jared C.
通讯作者：
Roach, Jared C.