Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens.

Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens.
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DOI:
10.1126/science.adh7699
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发表时间:
2023-05-19
期刊:
影响因子:
56.9
通讯作者:
Sanjana, Neville E.
Sanjana, Neville E.
中科院分区:
综合性期刊1区
文献类型:
--
作者:
Morris, John A.;Caragine, Christina;Daniloski, Zharko;Domingo, Julia;Barry, Timothy;Lu, Lu;Davis, Kyrie;Ziosi, Marcello;Glinos, Dafni A.;Hao, Stephanie;Mimitou, Eleni P.;Smibert, Peter;Roeder, Kathryn;Katsevich, Eugene;Lappalainen, Tuuli;Sanjana, Neville E.

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全基因组关联研究(GWAS)发现的与复杂性状和疾病相关的大多数变异都映射到基因组的非编码区,影响未知。使用祖先多样的生物库规模GWAS数据,大规模并行CRISPR筛选以及单细胞转录组和蛋白质组测序,我们发现了91个非编码血液性状GWAS基因座的124个顺式靶基因。通过碱基编辑使用精确的变体插入,我们将特定的变体与基因表达变化联系起来。我们还确定了当顺式靶基因编码转录因子或microRNA时非编码位点的反式效应网络。网络本身富含GWAS变体,并表现出对复杂性状的多基因贡献。该平台能够并行表征顺式和反式人类非编码变体的靶基因和机制。高通量单细胞CRISPR筛选可了解血细胞性状的非编码人类遗传变体。
Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown effects. Using ancestrally diverse biobank-scale GWAS data, massively parallel CRISPR screens, and single cell transcriptomic and proteomic sequencing, we discovered 124 cis-target genes of 91 noncoding blood trait GWAS loci. Using precise variant insertion via base editing, we connected specific variants with gene expression changes. We also identified trans-effect networks of noncoding loci when cis target genes encoded transcription factors or microRNAs. Networks were themselves enriched for GWAS variants and demonstrated polygenic contributions to complex traits. This platform enables massively-parallel characterization of the target genes and mechanisms of human noncoding variants in both cis and trans. High-throughput single cell CRISPR screens to understand noncoding human genetic variants for blood cell traits.
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发表时间: 2022-04
期刊: NATURE GENETICS
影响因子: 30.8
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Bellenguez, Celine;Kucukali, Fahri;Jansen, Iris E.;Kleineidam, Luca;Moreno-Grau, Sonia;Amin, Najaf;Naj, Adam C.;Campos-Martin, Rafael;Grenier-Boley, Benjamin;Andrade, Victor;Holmans, Peter A.;Boland, Anne;Damotte, Vincent;van der Lee, Sven J.;Costa, Marcos R.;Kuulasmaa, Teemu;Yang, Qiong;De Rojas, Itziar;Bis, Joshua C.;Yaqub, Amber;Prokic, Ivana;Chapuis, Julien;Ahmad, Shahzad;Giedraitis, Vilmantas;Aarsland, Dag;Garcia-Gonzalez, Pablo;Abdelnour, Carla;Alarcon-Martin, Emilio;Alcolea, Daniel;Alegret, Montserrat;Alvarez, Ignacio;Alvarez, Victoria;Armstrong, Nicola J.;Tsolaki, Anthoula;Antunez, Carmen;Appollonio, Ildebrando;Arcaro, Marina;Archetti, Silvana;Arias Pastor, Alfonso;Arosio, Beatrice;Athanasiu, Lavinia;Bailly, Henri;Banaj, Nerisa;Baquero, Miquel;Barral, Sandra;Beiser, Alexa;Pastor, Ana Belen;Below, Jennifer E.;Benchek, Penelope;Benussi, Luisa;Berr, Claudine;Besse, Celine;Bessi, Valentina;Binetti, Giuliano;Bizarro, Alessandra;Blesa, Rafael;Boada, Merce;Boerwinkle, Eric;Borroni, Barbara;Boschi, Silvia;Bossu, Paola;Brathen, Geir;Bressler, Jan;Bresner, Catherine;Brodaty, Henry;Brookes, Keeley J.;Ignacio Brusco, Luis;Buiza-Rueda, Dolores;Burger, Katharina;Burholt, Vanessa;Bush, William S.;Calero, Miguel;Cantwell, Laura B.;Chene, Genevieve;Chung, Jaeyoon;Cuccaro, Michael L.;Cecchetti, Roberta;Cervera-Carles, Laura;Charbonnier, Camille;Chen, Hung-Hsin;Chillotti, Caterina;Ciccone, Simona;Claassen, Jurgen A. 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