De novo variation in bipolar disorder.
De novo variation in bipolar disorder.
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DOI：
10.1038/s41380-019-0611-1
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发表时间：
2021-08
影响因子：
11
通讯作者：
Pulver, Ann E.
中科院分区：
文献类型：
--
作者：
Goes, Fernando S.;Pirooznia, Mehdi;Tehan, Martin;Zandi, Peter P.;McGrath, John;Wolyniec, Paula;Nestadt, Gerald;Pulver, Ann E.
双相情感障碍（BD）是一种常见的高度遗传性疾病，影响世界人口的1-2%。迄今为止，大多数遗传研究的BD集中在常见的基因变异，虽然已经确定了强大的相关位点，遗传力的很大一部分仍然失踪，可能部分归因于罕见的变异。在这项研究中，我们应用从头范式在BD中，以确定尚未经历自然选择的新出现的变种，可能代表高致病性的变种。我们对97个德系犹太血统的三人组进行了全基因组测序，选择了没有BD家族史和早期发病的“单纯”家族。我们共发现了6，882个新发变异（平均70.9 ± 12.9 S.D.）。每三个变体），包括蛋白质编码基因内的107个变体。我们将我们的外显子变异与79个先前发表的BD三重基因的结果相结合，确定了BD中的20个功能丧失（LoF）和77个错义破坏性从头变异。这些变体显示出受约束基因和位于突触后密度（PSD）的基因的显著富集（所有Bonferonni校正的p < 0.05）。途径分析显示了几种途径的富集，包括“磷酸肌醇（PI）及其下游靶点”（Bonferroni p = 4.2 x 10−6），这是锂的假设作用机制中的一个突出特征。此外，虽然我们在我们的全样本中发现了BD常见变异多基因风险传播的总体证据（pTDT p =2.21x 10−4），但具有LoF变异的特定三联体显示没有多基因传播的证据。总之，我们的研究结果支持从头范式作为BD的遗传结构的贡献者，并提供证据表明，受约束的基因，以及PSD和PI途径内的基因具有与BD相关的罕见变异。
Bipolar Disorder (BD) is a common, highly heritable disorder that affects 1-2% of the world’s population. To date, most genetic studies of BD have focused on common gene variation, and, while robustly associated loci have been identified, a substantial proportion of the heritability remains missing and could be partially attributable to rare variation. In this study, we apply a de novo paradigm in BD to identify newly arisen variants that have yet to undergo natural selection and may represent highly pathogenic variants. We performed whole genome sequencing of 97 trios of Ashkenazi Jewish descent, selecting “simplex” families with no family history of BD and an early age of onset. We found a total of 6,882 de novo variants (an average of 70.9 ± 12.9 S.D. variants per trio), including 107 variants within protein coding genes. We combined our exonic variations with the results of 79 previously published BD trios, identifying 20 Loss of Function (LoF) and 77 missense damaging de novo variants in BD. These variants showed significant enrichment for constrained genes and for genes located to the post-synaptic density (PSD) (all Bonferonni corrected p < 0.05). Pathway analyses showed enrichment in several pathways, including “Phosphoinositides (PI) and their downstream targets” (Bonferroni p = 4.2 x 10−6), a pathway prominently featured in lithium’s hypothesized mechanism of action. Additionally, while we found overall evidence for transmission of common variant polygenic risk of BD in our full sample (pTDT p =2.21x 10−4), specific trios with LoF variants showed no evidence of polygenic transmission. In sum, our findings support the de novo paradigm as a contributor to the genetic architecture of BD and provide evidence that constrained genes, as well as genes within the PSD and PI pathway harbor rare variation associated with BD.
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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
影响因子：
12.3
作者：
Acuna-Hidalgo R;Veltman JA;Hoischen A
通讯作者：
Hoischen A
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
9.8
作者：
Fallin, MD;Lasseter, VK;Pulver, AE
通讯作者：
Pulver, AE