Genome-wide discovery for diabetes-dependent triglycerides-associated loci.
Genome-wide discovery for diabetes-dependent triglycerides-associated loci.
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DOI：
10.1371/journal.pone.0275934
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
我们旨在发现2型糖尿病（T2 D）背景下与甘油三酯（TG）水平相关的基因座。我们在英国生物库（UKB）的424，120名具有T2 D状态和TG水平的基因型参与者中进行了全基因组关联研究（GWAS）。我们根据T2 D状态对队列进行分层，并对每个层中具有至少20个次要等位基因计数（MAC）的遗传变异的TG水平进行关联分析。通过Cochran的Q检验确定T2 D状态的遗传变异的效应差异，并且我们在马萨诸塞州总布里格姆生物库（MGBB）中验证了显著相关的变异。在来自UKB的21，176个T2 D和402，944个非T2 D样本中，分层的GWAS分别确定了19个和315个与TG水平显著相关的基因组风险位点。只有chr6p21.32表现出全基因组显著异质性（I2 = 98.4%; p异质性= 2.1x10-15），T2 D和非T2 D的log（TG）效应估计值分别为-0.066（95%CI：-0.082，-0.050）和0.002（95%CI：-0.002，0.006）。前导变体rs 9274619：A（等位基因频率0.095）位于HLA-DQB 1基因上游2Kb处，在HLA-DQB 1和HLA-DQA 2基因之间。我们在25，137例MGBB参与者（6，951例T2 D病例）中重复了这一发现（p异质性= 9.5x10-3）。全表型相互作用关联分析显示，先导变体与1型糖尿病（T1 D）的伴随诊断以及糖尿病相关并发症密切相关。总之，我们确定了HLA-DQB 1/DQA 2附近的基因间变异仅在T2 D患者中与甘油三酯降低显著相关，并突出了与T1 D的免疫重叠。
We aimed to discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). We conducted a genome-wide association study (GWAS) in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels. We stratified the cohort based on T2D status and conducted association analyses of TG levels for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochran’s Q-test and we validated the significantly associated variants in the Mass General Brigham Biobank (MGBB). Among 21,176 T2D and 402,944 non-T2D samples from UKB, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2 = 98.4%; pheterogeneity = 2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: -0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene, between HLA-DQB1 and HLA-DQA2 genes. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity = 9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications. In conclusion, we identified an intergenic variant near HLA-DQB1/DQA2 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.
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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
影响因子：
16.2
作者：
Cousminer DL;Ahlqvist E;Mishra R;Andersen MK;Chesi A;Hawa MI;Davis A;Hodge KM;Bradfield JP;Zhou K;Guy VC;Åkerlund M;Wod M;Fritsche LG;Vestergaard H;Snyder J;Højlund K;Linneberg A;Käräjämäki A;Brandslund I;Kim CE;Witte D;Sørgjerd EP;Brillon DJ;Pedersen O;Beck-Nielsen H;Grarup N;Pratley RE;Rickels MR;Vella A;Ovalle F;Melander O;Harris RI;Varvel S;Grill VER;Bone Mineral Density in Childhood Study;Hakonarson H;Froguel P;Lonsdale JT;Mauricio D;Schloot NC;Khunti K;Greenbaum CJ;Åsvold BO;Yderstræde KB;Pearson ER;Schwartz S;Voight BF;Hansen T;Tuomi T;Boehm BO;Groop L;Leslie RD;Grant SFA
通讯作者：
Grant SFA
影响因子：
7.7
作者：
Buzzetti R;Tuomi T;Mauricio D;Pietropaolo M;Zhou Z;Pozzilli P;Leslie RD
通讯作者：
Leslie RD
影响因子：
16.2
作者：
Oram, Richard A.;Sharp, Seth A.;Dabelea, Dana
通讯作者：
Dabelea, Dana
影响因子：
16.6
作者：
Huang J;Howie B;McCarthy S;Memari Y;Walter K;Min JL;Danecek P;Malerba G;Trabetti E;Zheng HF;UK10K Consortium;Gambaro G;Richards JB;Durbin R;Timpson NJ;Marchini J;Soranzo N
通讯作者：
Soranzo N