Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study.
Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study.
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循环蛋白将心血管疾病与认知性能联系起来：孟德尔随机化研究。
DOI：
10.3389/fgene.2023.1124431
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发表时间：
2023
影响因子：
3.7
通讯作者：
Dehghan, Abbas
中科院分区：
文献类型：
--
作者：
Huang, Jian;Gill, Dipender;Zuber, Verena;Matthews, Paul M.;Elliott, Paul;Tzoulaki, Ioanna;Dehghan, Abbas
背景和目的：机制研究表明心血管疾病(CVD)和痴呆病理对认知功能下降有协同作用。针对与心血管疾病和痴呆的共同机制相关的蛋白质的干预也可以用于预防认知损害。方法：我们应用孟德尔随机化(MR)和共定位分析来研究Olink CVD I小组测量的90个CVD相关蛋白与认知特征的因果关系。根据3组标准：1)蛋白质数量性状基因座(PQTL)；2)cis-pQTL(距离编码基因±500 kb的pQTL)；3)脑特异性顺式表达QTL(cis-eQTL)，解释基于GTEx8的编码基因表达。认知绩效的遗传关联来自GWAS：1)使用主成分分析构建的一般认知功能(N=300,486)；或2)使用基因组结构方程模型构建的g因子(N=11,263-331,679)。候选因果蛋白的研究结果在冰岛人(N=35,559)中使用一种单独的蛋白GWAS进行了重复。结果：在不同的遗传工具选择标准下，基因预测的循环髓过氧化物酶(MPO)浓度越高，名义上与更好的认知表现相关(p<；0.05)。尤其是脑特异性cis-eQTL预测的MPO与一般认知功能相关(βwald=0.2 2，pwald=2.4×10−4)。MPO pQTL与g因子共定位的后验概率(PP.H4)为0.577。MPO的研究结果也使用冰岛的全球环境监测系统进行了复制。虽然我们没有发现共定位的证据，但我们发现组织蛋白酶D和CD40的遗传预测浓度越高，认知表现越好，而脑脊液-1的遗传预测浓度越高，认知表现越差。结论：这些蛋白参与了心血管疾病与认知储备或影响认知功能减退的共同途径，提示治疗靶点能够降低心血管疾病的遗传风险。
Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment. Methods: We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD-related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb from the coding gene); and 3) brain-specific cis-expression QTL (cis-eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g Factor constructed using genomic structural equation modelling (N = 11,263–331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559). Results: A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (p < 0.05) using different selection criteria for genetic instruments. Particularly, brain-specific cis-eQTL predicted MPO, which accounts for protein-coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4 × 10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.577. Findings for MPO were replicated using the Icelandic GWAS. Although we did not find evidence for colocalization, we found that higher genetically predicted concentrations of cathepsin D and CD40 were associated with better cognitive performance and a higher genetically predicted concentration of CSF-1 was associated with poorer cognitive performance. Conclusion: We conclude that these proteins are involved in shared pathways between CVD and those for cognitive reserve or affecting cognitive decline, suggesting therapeutic targets able to reduce genetic risks conferred by cardiovascular disease.
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影响因子：
2
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan N;Thompson J
通讯作者：
Thompson J
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
16.6
作者：
Harris, Sarah E.;Cox, Simon R.;Deary, Ian J.
通讯作者：
Deary, Ian J.
影响因子：
4.3
作者：
Kametani F;Hasegawa M
通讯作者：
Hasegawa M
影响因子：
16.6
作者：
Davies G;Lam M;Harris SE;Trampush JW;Luciano M;Hill WD;Hagenaars SP;Ritchie SJ;Marioni RE;Fawns-Ritchie C;Liewald DCM;Okely JA;Ahola-Olli AV;Barnes CLK;Bertram L;Bis JC;Burdick KE;Christoforou A;DeRosse P;Djurovic S;Espeseth T;Giakoumaki S;Giddaluru S;Gustavson DE;Hayward C;Hofer E;Ikram MA;Karlsson R;Knowles E;Lahti J;Leber M;Li S;Mather KA;Melle I;Morris D;Oldmeadow C;Palviainen T;Payton A;Pazoki R;Petrovic K;Reynolds CA;Sargurupremraj M;Scholz M;Smith JA;Smith AV;Terzikhan N;Thalamuthu A;Trompet S;van der Lee SJ;Ware EB;Windham BG;Wright MJ;Yang J;Yu J;Ames D;Amin N;Amouyel P;Andreassen OA;Armstrong NJ;Assareh AA;Attia JR;Attix D;Avramopoulos D;Bennett DA;Böhmer AC;Boyle PA;Brodaty H;Campbell H;Cannon TD;Cirulli ET;Congdon E;Conley ED;Corley J;Cox SR;Dale AM;Dehghan A;Dick D;Dickinson D;Eriksson JG;Evangelou E;Faul JD;Ford I;Freimer NA;Gao H;Giegling I;Gillespie NA;Gordon SD;Gottesman RF;Griswold ME;Gudnason V;Harris TB;Hartmann AM;Hatzimanolis A;Heiss G;Holliday EG;Joshi PK;Kähönen M;Kardia SLR;Karlsson I;Kleineidam L;Knopman DS;Kochan NA;Konte B;Kwok JB;Le Hellard S;Lee T;Lehtimäki T;Li SC;Lill CM;Liu T;Koini M;London E;Longstreth WT Jr;Lopez OL;Loukola A;Luck T;Lundervold AJ;Lundquist A;Lyytikäinen LP;Martin NG;Montgomery GW;Murray AD;Need AC;Noordam R;Nyberg L;Ollier W;Papenberg G;Pattie A;Polasek O;Poldrack RA;Psaty BM;Reppermund S;Riedel-Heller SG;Rose RJ;Rotter JI;Roussos P;Rovio SP;Saba Y;Sabb FW;Sachdev PS;Satizabal CL;Schmid M;Scott RJ;Scult MA;Simino J;Slagboom PE;Smyrnis N;Soumaré A;Stefanis NC;Stott DJ;Straub RE;Sundet K;Taylor AM;Taylor KD;Tzoulaki I;Tzourio C;Uitterlinden A;Vitart V;Voineskos AN;Kaprio J;Wagner M;Wagner H;Weinhold L;Wen KH;Widen E;Yang Q;Zhao W;Adams HHH;Arking DE;Bilder RM;Bitsios P;Boerwinkle E;Chiba-Falek O;Corvin A;De Jager PL;Debette S;Donohoe G;Elliott P;Fitzpatrick AL;Gill M;Glahn DC;Hägg S;Hansell NK;Hariri AR;Ikram MK;Jukema JW;Vuoksimaa E;Keller MC;Kremen WS;Launer L;Lindenberger U;Palotie A;Pedersen NL;Pendleton N;Porteous DJ;Räikkönen K;Raitakari OT;Ramirez A;Reinvang I;Rudan I;Dan Rujescu;Schmidt R;Schmidt H;Schofield PW;Schofield PR;Starr JM;Steen VM;Trollor JN;Turner ST;Van Duijn CM;Villringer A;Weinberger DR;Weir DR;Wilson JF;Malhotra A;McIntosh AM;Gale CR;Seshadri S;Mosley TH Jr;Bressler J;Lencz T;Deary IJ
通讯作者：
Deary IJ