Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder.
Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder.
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DOI：
10.1038/s41467-021-23453-w
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发表时间：
2021-06-18
影响因子：
16.6
通讯作者：
Takata A
中科院分区：
文献类型：
--
作者：
Nishioka M;Kazuno AA;Nakamura T;Sakai N;Hayama T;Fujii K;Matsuo K;Komori A;Ishiwata M;Watanabe Y;Oka T;Matoba N;Kataoka M;Alkanaq AN;Hamanaka K;Tsuboi T;Sengoku T;Ogata K;Iwata N;Ikeda M;Matsumoto N;Kato T;Takata A
双相情感障碍是一种严重的精神疾病，其特征是反复发作的躁狂和抑郁发作。为了更好地了解其遗传结构，我们分析了354例双相情感障碍三人组中的超罕见从头突变。对于生殖系新生突变，我们发现限制基因中的功能丧失突变（校正P = 0.0410）和突触前活动区基因中的有害突变（FDR = 0.0415）显著富集。整合单细胞RNA测序数据的分析鉴定了优先表达受有害突变影响的基因的兴奋性神经元的子集，其特征还在于发育障碍基因的高表达。在合子后突变的分析中，我们观察到发育障碍基因中有害基因的显著富集（P = 0.00135），包括两个无关先证者中突变的SRCAP基因。这些数据共同表明生殖系和合子后突变对双相情感障碍风险的贡献，支持发育障碍基因的合子后突变可能导致双相情感障碍的假设。双相情感障碍中罕见和新发变异的意义尚不清楚。在这里，作者分析了来自三人组的全外显子组/基因组数据，以确定与双相情感障碍相关的有害的从头变异。
Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder. The significance of rare and de novo variants in bipolar disorder is not well understood. Here, the authors have analyzed whole exome/genome data from trios to identify deleterious de novo variants associated with bipolar disorder.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
在健康个体中预测急性髓样白血病的风险。
影响因子：
64.8
作者：
Abelson S;Collord G;Ng SWK;Weissbrod O;Mendelson Cohen N;Niemeyer E;Barda N;Zuzarte PC;Heisler L;Sundaravadanam Y;Luben R;Hayat S;Wang TT;Zhao Z;Cirlan I;Pugh TJ;Soave D;Ng K;Latimer C;Hardy C;Raine K;Jones D;Hoult D;Britten A;McPherson JD;Johansson M;Mbabaali F;Eagles J;Miller JK;Pasternack D;Timms L;Krzyzanowski P;Awadalla P;Costa R;Segal E;Bratman SV;Beer P;Behjati S;Martincorena I;Wang JCY;Bowles KM;Quirós JR;Karakatsani A;La Vecchia C;Trichopoulou A;Salamanca-Fernández E;Huerta JM;Barricarte A;Travis RC;Tumino R;Masala G;Boeing H;Panico S;Kaaks R;Krämer A;Sieri S;Riboli E;Vineis P;Foll M;McKay J;Polidoro S;Sala N;Khaw KT;Vermeulen R;Campbell PJ;Papaemmanuil E;Minden MD;Tanay A;Balicer RD;Wareham NJ;Gerstung M;Dick JE;Brennan P;Vassiliou GS;Shlush LI
通讯作者：
Shlush LI
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
6.2
作者：
de Boer, Anneke;Vermeulen, Karlijn;Kleefstra, Tjitske
通讯作者：
Kleefstra, Tjitske