A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology.
A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology.
复制标题
DOI：
10.1038/s41467-023-40679-y
复制
发表时间：
2023-08-18
影响因子：
16.6
通讯作者：
Astle, William J.
中科院分区：
文献类型：
--
作者：
Akbari, Parsa;Vuckovic, Dragana;Stefanucci, Luca;Jiang, Tao;Kundu, Kousik;Kreuzhuber, Roman;Bao, Erik L.;Collins, Janine H.;Downes, Kate;Grassi, Luigi;Guerrero, Jose A.;Kaptoge, Stephen;Knight, Julian C.;Meacham, Stuart;Sambrook, Jennifer;Seyres, Denis;Stegle, Oliver;Verboon, Jeffrey M.;Walter, Klaudia;Watkins, Nicholas A.;Danesh, John;Roberts, David J.;Di Angelantonio, Emanuele;Sankaran, Vijay G.;Frontini, Mattia;Burgess, Stephen;Kuijpers, Taco;Peters, James E.;Butterworth, Adam S.;Ouwehand, Willem H.;Soranzo, Nicole;Astle, William J.
血细胞含有功能重要的细胞内结构，如颗粒，对免疫和血栓形成至关重要。这些结构的数量变异以前没有进行过大规模的遗传分析。我们在INTERVAL研究的41，515名参与者中对63种流式细胞术衍生的细胞表型进行了全基因组关联研究，包括粒度，核酸含量和反应性的细胞类型特异性测量。我们确定了2172个不同的变异性状协会，包括协会附近的基因编码的蛋白质细胞器中牵连炎症和血栓性疾病。通过整合表观遗传数据，我们表明许多细胞内结构可能在不成熟的前体细胞中确定。通过整合蛋白质组学数据，我们确定转录因子FOG 2作为血小板形成和α粒度的早期调节因子。最后，我们表明，我们与疾病风险信号的关联的共定位可以表明IL2RA和ITGA 4中的病因细胞类型变体分别反映了达克珠单抗在多发性硬化症中的已知作用和Vedolizumab在炎症性肠病中的已知作用。作者在数百个基因中识别出与血细胞内部生物结构特性相关的遗传变异，并展示了这些发现如何用于提高对导致疾病的细胞机制的理解。
Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes—including cell-type specific measures of granularity, nucleic acid content and reactivity—in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types—variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease. The authors identify genetic variation associated with properties of the internal biological structures of blood cells in hundreds of genes and show how such discoveries can be used to improve understanding of cellular mechanisms causing disease.
登录
查看更多内容
影响因子：
30.8
作者：
Demenais F;Margaritte-Jeannin P;Barnes KC;Cookson WOC;Altmüller J;Ang W;Barr RG;Beaty TH;Becker AB;Beilby J;Bisgaard H;Bjornsdottir US;Bleecker E;Bønnelykke K;Boomsma DI;Bouzigon E;Brightling CE;Brossard M;Brusselle GG;Burchard E;Burkart KM;Bush A;Chan-Yeung M;Chung KF;Couto Alves A;Curtin JA;Custovic A;Daley D;de Jongste JC;Del-Rio-Navarro BE;Donohue KM;Duijts L;Eng C;Eriksson JG;Farrall M;Fedorova Y;Feenstra B;Ferreira MA;Australian Asthma Genetics Consortium (AAGC) collaborators;Freidin MB;Gajdos Z;Gauderman J;Gehring U;Geller F;Genuneit J;Gharib SA;Gilliland F;Granell R;Graves PE;Gudbjartsson DF;Haahtela T;Heckbert SR;Heederik D;Heinrich J;Heliövaara M;Henderson J;Himes BE;Hirose H;Hirschhorn JN;Hofman A;Holt P;Hottenga J;Hudson TJ;Hui J;Imboden M;Ivanov V;Jaddoe VWV;James A;Janson C;Jarvelin MR;Jarvis D;Jones G;Jonsdottir I;Jousilahti P;Kabesch M;Kähönen M;Kantor DB;Karunas AS;Khusnutdinova E;Koppelman GH;Kozyrskyj AL;Kreiner E;Kubo M;Kumar R;Kumar A;Kuokkanen M;Lahousse L;Laitinen T;Laprise C;Lathrop M;Lau S;Lee YA;Lehtimäki T;Letort S;Levin AM;Li G;Liang L;Loehr LR;London SJ;Loth DW;Manichaikul A;Marenholz I;Martinez FJ;Matheson MC;Mathias RA;Matsumoto K;Mbarek H;McArdle WL;Melbye M;Melén E;Meyers D;Michel S;Mohamdi H;Musk AW;Myers RA;Nieuwenhuis MAE;Noguchi E;O'Connor GT;Ogorodova LM;Palmer CD;Palotie A;Park JE;Pennell CE;Pershagen G;Polonikov A;Postma DS;Probst-Hensch N;Puzyrev VP;Raby BA;Raitakari OT;Ramasamy A;Rich SS;Robertson CF;Romieu I;Salam MT;Salomaa V;Schlünssen V;Scott R;Selivanova PA;Sigsgaard T;Simpson A;Siroux V;Smith LJ;Solodilova M;Standl M;Stefansson K;Strachan DP;Stricker BH;Takahashi A;Thompson PJ;Thorleifsson G;Thorsteinsdottir U;Tiesler CMT;Torgerson DG;Tsunoda T;Uitterlinden AG;van der Valk RJP;Vaysse A;Vedantam S;von Berg A;von Mutius E;Vonk JM;Waage J;Wareham NJ;Weiss ST;White WB;Wickman M;Widén E;Willemsen G;Williams LK;Wouters IM;Yang JJ;Zhao JH;Moffatt MF;Ober C;Nicolae DL
通讯作者：
Nicolae DL
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
16.6
作者：
Cordell HJ;Han Y;Mells GF;Li Y;Hirschfield GM;Greene CS;Xie G;Juran BD;Zhu D;Qian DC;Floyd JA;Morley KI;Prati D;Lleo A;Cusi D;Canadian-US PBC Consortium;Italian PBC Genetics Study Group;UK-PBC Consortium;Gershwin ME;Anderson CA;Lazaridis KN;Invernizzi P;Seldin MF;Sandford RN;Amos CI;Siminovitch KA
通讯作者：
Siminovitch KA
DOI：
10.1016/s0140-6736(17)31928-1
发表时间：
2017-11-25
期刊：
Lancet (London, England)
影响因子：
--
作者：
Di Angelantonio E;Thompson SG;Kaptoge S;Moore C;Walker M;Armitage J;Ouwehand WH;Roberts DJ;Danesh J;INTERVAL Trial Group
通讯作者：
INTERVAL Trial Group
DOI：
10.1073/pnas.0601335103
发表时间：
2006-04-11
影响因子：
11.1
作者：
Bielekova, B;Catalfamo, M;Martin, R
通讯作者：
Martin, R