Whole-exome sequencing in 415,422 individuals identifies rare variants associated with mitochondrial DNA copy number.
Whole-exome sequencing in 415,422 individuals identifies rare variants associated with mitochondrial DNA copy number.
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DOI：
10.1016/j.xhgg.2022.100147
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发表时间：
2023-01-12
期刊：
影响因子：
--
通讯作者：
Arking, Dan E.
中科院分区：
文献类型：
--
作者：
Pillalamarri, Vamsee;Shi, Wen;Say, Conrad;Yang, Stephanie;Lane, John;Guallar, Eliseo;Pankratz, Nathan;Arking, Dan E.
线粒体基因组拷贝数的个体间差异，称为线粒体 DNA 拷贝数 (mtDNA-CN)，反映了线粒体功能，并与各种衰老相关疾病相关。我们检查了来自英国生物银行的 415,422 个自我报告的白人血统个体的外显子组，并在单个变异水平上并通过聚合变异集测试测试了罕见变异对 mtDNA-CN 的影响。一项针对九个变体集的调查测试了假定因果变体的富集，并确定了 14 个具有实验范围显着性的基因和 3 个具有边缘显着性的基因。其中包括已知 mtDNA 耗竭综合征基因（mtDNA 解旋酶 TWNK，p = 1.1 × 10−30；线粒体转录因子 TFAM，p = 4.3 × 10−15；mtDNA 维持核酸外切酶 MGME1，p = 2.0 × 10−6）和酪氨酸激酶中 V617F 显性功能获得性突变的关联JAK2 (p = 2.7 × 10−17)，与骨髓增生性疾病相关。新基因包括参与线粒体蛋白质组质量的 ATP 依赖性蛋白酶 CLPX (p = 8.4 × 10−9) 和参与造血的线粒体腺苷酸激酶 AK2 (p = 4.7 × 10−8)。最显着的关联是 SAMHD1 中的错义变异 (p = 4.2 × 10−28)，该变异发现于 20 号染色体上罕见的 1.2 Mb 共享祖先单倍型。 SAMHD1 编码参与病毒防御反应和线粒体核苷酸挽救途径的细胞质宿主限制因子，并与 Aicardi-Goutières 综合征 5（一种儿童脑病和慢性脑病）相关。炎症反应障碍。孟德尔 mtDNA 耗竭综合征位点富含罕见变异，这些变异涉及 mtDNA 复制、类核结构形成和维持的核心过程。这些数据表明，核基因组的强效突变有助于 mtDNA-CN 的遗传结构。线粒体DNA拷贝数（mtDNA-CN）是衰老的重要生物标志物。我们在英国生物银行的 415,422 名个体中测试了罕见的核遗传变异与 mtDNA-CN 的关联。罕见的变异揭示了与线粒体生物学和疾病相关的基本过程。
Inter-individual variation in the number of copies of the mitochondrial genome, called mitochondrial DNA copy number (mtDNA-CN), reflects mitochondrial function and has been associated with various aging-related diseases. We examined 415,422 exomes of self-reported White ancestry individuals from the UK Biobank and tested the impact of rare variants, at the level of single variants and through aggregate variant-set tests, on mtDNA-CN. A survey across nine variant sets tested enrichment of putatively causal variants and identified 14 genes at experiment-wide significance and three genes at marginal significance. These included associations at known mtDNA depletion syndrome genes (mtDNA helicase TWNK, p = 1.1 × 10−30; mitochondrial transcription factor TFAM, p = 4.3 × 10−15; mtDNA maintenance exonuclease MGME1, p = 2.0 × 10−6) and the V617F dominant gain-of-function mutation in the tyrosine kinase JAK2 (p = 2.7 × 10−17), associated with myeloproliferative disease. Novel genes included the ATP-dependent protease CLPX (p = 8.4 × 10−9), involved in mitochondrial proteome quality, and the mitochondrial adenylate kinase AK2 (p = 4.7 × 10−8), involved in hematopoiesis. The most significant association was a missense variant in SAMHD1 (p = 4.2 × 10−28), found on a rare, 1.2-Mb shared ancestral haplotype on chromosome 20. SAMHD1 encodes a cytoplasmic host restriction factor involved in viral defense response and the mitochondrial nucleotide salvage pathway, and is associated with Aicardi-Goutières syndrome 5, a childhood encephalopathy and chronic inflammatory response disorder. Rare variants were enriched in Mendelian mtDNA depletion syndrome loci, and these variants implicated core processes in mtDNA replication, nucleoid structure formation, and maintenance. These data indicate that strong-effect mutations from the nuclear genome contribute to the genetic architecture of mtDNA-CN. Mitochondrial DNA copy number (mtDNA-CN) is an important biomarker of aging. We tested rare nuclear genetic variants in 415,422 individuals from the UK Biobank for association with mtDNA-CN. Rare variants reveal fundamental processes related to mitochondrial biology and disease.
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影响因子：
5.8
作者：
Gogarten, Stephanie M.;Sofer, Tamar;Conomos, Matthew P.
通讯作者：
Conomos, Matthew P.
基因集富集分析变得简单。
影响因子：
2.3
作者：
Irizarry RA;Wang C;Zhou Y;Speed TP
通讯作者：
Speed TP
影响因子：
4.5
作者：
Ding J;Sidore C;Butler TJ;Wing MK;Qian Y;Meirelles O;Busonero F;Tsoi LC;Maschio A;Angius A;Kang HM;Nagaraja R;Cucca F;Abecasis GR;Schlessinger D
通讯作者：
Schlessinger D
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J