Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways.
Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways.
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DOI：
10.1371/journal.pone.0182778
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Magri C
中科院分区：
文献类型：
--
作者：
Giacopuzzi E;Gennarelli M;Minelli A;Gardella R;Valsecchi P;Traversa M;Bonvicini C;Vita A;Sacchetti E;Magri C
近亲繁殖是隐性孟德尔疾病的一个已知风险因素，以前的研究表明，它也可能在复杂的疾病中发挥作用，如精神疾病。最近的近亲繁殖导致基因组沿着存在长的纯合性（ROH），其也被定义为同源性区域。这些区域的遗传变异有两个等位基因，它们在血统上是相同的，因此增加了由于纯合状态而产生罕见隐性有害突变的几率。最近的一项研究表明，精神分裂症患者中长ROH的暗示性富集，表明最近的近亲繁殖可能在疾病中发挥作用。为了更好地了解同源性对精神分裂症风险的影响，我们从180名意大利患者的队列中选择了7名受试者，这些受试者具有极高数量的大ROH，这些ROH可能是由于最近的近亲繁殖，并使用全外显子组测序和基因集富集分析来表征其ROH内的突变景观。我们确定了一个显着的重叠（17%;经验p值= 0.0171）基因内的ROH受影响的低频功能纯合变异（107个基因）和一组最有前途的候选基因突变的精神分裂症。此外，在4名患者中，我们发现了参与神经发育（MEGF 8）和GABA/神经元突触传递（GAD 1，FMN 1，ANO 2）的基因中的新型和极其罕见的损伤性突变。这些结果提供了对罕见的隐性突变和近亲繁殖作为精神分裂症的危险因素的贡献的见解。可能是由于最近近亲繁殖导致的ROH含有易患病的低频变异和对疾病所涉及的关键生物学途径具有高度影响的极其罕见的变异的组合。此外，这项研究证实，关注高水平纯合性患者可能是发现遗传复杂疾病中新的高影响突变的有用优先策略。
Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders.
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影响因子：
5.3
作者：
Stoehr, Heidi;Heisig, Julia B.;Schulz, Heidi L.
通讯作者：
Schulz, Heidi L.
影响因子：
9.8
作者：
Szpiech, Zachary A.;Xu, Jishu;Li, Jun Z.
通讯作者：
Li, Jun Z.
影响因子：
3.8
作者：
Bersani, G;Maddalena, F;Pancheri, P
通讯作者：
Pancheri, P
影响因子：
64.8
作者：
Ripke, Stephan;Neale, Benjamin M.;Corvin, Aiden;Walters, James T. R.;Farh, Kai-How;Holmans, Peter A.;Lee, Phil;Bulik-Sullivan, Brendan;Collier, David A.;Huang, Hailiang;Pers, Tune H.;Agartz, Ingrid;Agerbo, Esben;Albus, Margot;Alexander, Madeline;Amin, Farooq;Bacanu, Silviu A.;Begemann, Martin;Belliveau, Richard A., Jr.;Bene, Judit;Bergen, Sarah E.;Bevilacqua, Elizabeth;Bigdeli, Tim B.;Black, Donald W.;Bruggeman, Richard;Buccola, Nancy G.;Buckner, Randy L.;Byerley, William;Cahn, Wiepke;Cai, Guiqing;Campion, Dominique;Cantor, Rita M.;Carr, Vaughan J.;Carrera, Noa;Catts, Stanley V.;Chambert, Kimberly D.;Chan, Raymond C. K.;Chen, Ronald Y. L.;Chen, Eric Y. H.;Cheng, Wei;Cheung, Eric F. C.;Chong, Siow Ann;Cloninger, C. 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Hong;Legge, Sophie E.;Lerer, Bernard;Li, Miaoxin;Li, Tao;Liang, Kung-Yee;Lieberman, Jeffrey;Limborska, Svetlana;Loughland, Carmel M.;Lubinski, Jan;Lonnqvist, Jouko;Macek, Milan, Jr.;Magnusson, Patrik K. E.;Maher, Brion S.;Maier, Wolfgang;Mallet, Jacques;Marsal, Sara;Mattheisen, Manuel;Mattingsdal, Morten;McCarley, Robert W.;McDonald, Colm;McIntosh, Andrew M.;Meier, Sandra;Meijer, Carin J.;Melegh, Bela;Melle, Ingrid;Mesholam-Gately, Raquelle I.;Metspalu, Andres;Michie, Patricia T.;Milani, Lili;Milanova, Vihra;Mokrab, Younes;Morris, Derek W.;Mors, Ole;Murphy, Kieran C.;Murray, Robin M.;Myin-Germeys, Inez;Mueller-Myhsok, Bertram;Nelis, Mari;Nenadic, Igor;Nertney, Deborah A.;Nestadt, Gerald;Nicodemus, Kristin K.;Nikitina-Zake, Liene;Nisenbaum, Laura;Nordin, Annelie;O'Callaghan, Eadbhard;O'Dushlaine, Colm;O'Neill, F. 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Scott;Subramaniam, Mythily;Suvisaari, Jaana;Svrakic, Dragan M.;Szatkiewicz, Jin P.;Soderman, Erik;Thirumalai, Srinivas;Toncheva, Draga;Tosato, Sarah;Veijola, Juha;Waddington, John;Walsh, Dermot;Wang, Dai;Wang, Qiang;Webb, Bradley T.;Weiser, Mark;Wildenauer, Dieter B.;Williams, Nigel M.;Williams, Stephanie;Witt, Stephanie H.;Wolen, Aaron R.;Wong, Emily H. M.;Wormley, Brandon K.;Xi, Hualin Simon;Zai, Clement C.;Zheng, Xuebin;Zimprich, Fritz;Wray, Naomi R.;Stefansson, Kari;Visscher, Peter M.;Adolfsson, Rolf;Andreassen, Ole A.;Blackwood, Douglas H. 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通讯作者：
O'Donovan, Michael C.
影响因子：
4.5
作者：
Chahrour MH;Yu TW;Lim ET;Ataman B;Coulter ME;Hill RS;Stevens CR;Schubert CR;ARRA Autism Sequencing Collaboration;Greenberg ME;Gabriel SB;Walsh CA
通讯作者：
Walsh CA