Candidate loci shared among periodontal disease, diabetes and bone density.
Candidate loci shared among periodontal disease, diabetes and bone density.
复制标题
候选基因座在牙周病、糖尿病和骨密度中共有。
DOI：
10.3389/fendo.2022.1016373
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发表时间：
2022
影响因子：
5.2
通讯作者：
Chasman, Daniel I. I.
中科院分区：
文献类型：
--
作者：
Yu, Yau-Hua;Steffensen, Bjorn;Ridker, Paul M. M.;Buring, Julie E. E.;Chasman, Daniel I. I.
关键词：
虽然牙周病（PD）与2型糖尿病（T2D）和骨质疏松症相关，但这些关联的潜在遗传机制在很大程度上仍然未知。本研究的目的是通过评估两两遗传相关性和寻找共享多态性，应用交叉性状遗传分析来研究PD、T2D和骨密度（BMD）之间潜在的共享生物学。我们利用全基因组关联研究（GWAS）汇总统计数据进行了跨性状遗传分析：来自UKBB/GLIDE联盟的牙周炎/松动牙（PerioLT， N=506594），来自DIAGRAM联盟的T2D (Neff=228825)，以及来自GEFOS联盟的骨密度（N=426824）。在这三个品种中，用连锁不平衡（LD）评分回归估计成对遗传相关。对GWAS进行多性状荟萃分析（MTAG）和共定位分析，以发现共享的全基因组显著变异（pMTAG <5 × 10-8）。为了复制，我们在女性基因组健康研究（WGHS）中进行了独立的遗传分析，这是一项前瞻性队列研究，其中14711名中年妇女提供了自我报告的牙周病诊断、口腔健康测量和牙周危险因素数据，包括T2D事件。PerioLT/T2D （Rg=0.23； SE=0.04; p=7.4e-09）与T2D/BMD （Rg=0.09； SE=0.02; p=9.8e-06）具有显著的遗传相关性。通过MTAG鉴定出21个独立的多效性变异（所有性状的pMTAG均<5 × 10-8）。在这些变体中，PerioLT和T2D的遗传信号共定位于一个候选变体（rs17522122; ProbH4 = 0.58），这是AKAP6的一个3'UTR变体。T2D/BMD和原始PerioLT GWAS p值之间的共定位表明有14个额外的位点。在独立的WGHS样本中，包括对PD监测的有效口腔健康问卷的应答，主要的共享候选（rs17522122）与较少使用牙线相关[OR(95%CI)= 0.92 (0.87-0.98), p=0.007]，这一应答与PD状况较差相关。此外，另外4个候选变异间接支持以下相关性：较少使用牙线[rs75933965, 1.17(1.04-1.31), p=0.008]、较少看牙[rs77464186, 0.82(0.75-0.91), p=0.0002]、较少进行牙科预防[rs67111375, 0.91(0.83-0.99), p=0.03；Rs77464186, 0.80(0.72-0.89), p=3.8e-05]，或牙齿周围骨质流失[rs8047395, 1.09(1.03-1.15), p=0.005]。这种综合方法通过比较PD、T2D和BMD的影响，确定了T2D和PD/口腔健康之间共有的一个共定位位点和14个候选位点。未来的研究需要独立验证我们的发现。
While periodontal disease (PD) has been associated with type 2 diabetes (T2D) and osteoporosis, the underlying genetic mechanisms for these associations remain largely unknown. The aim of this study is to apply cross-trait genetic analyses to investigate the potentially shared biology among PD, T2D, and bone mineral density (BMD) by assessing pairwise genetic correlations and searching for shared polymorphisms. We applied cross-trait genetic analyses leveraging genome-wide association study (GWAS) summary statistics for: Periodontitis/loose teeth from the UKBB/GLIDE consortium (PerioLT, N=506594), T2D from the DIAGRAM consortium (Neff=228825), and BMD from the GEFOS consortium (N=426824). Among all three, pair-wise genetic correlations were estimated with linkage disequilibrium (LD) score regression. Multi-trait meta-analysis of GWAS (MTAG) and colocalization analyses were performed to discover shared genome-wide significant variants (pMTAG <5x10-8). For replication, we conducted independent genetic analyses in the Women’s Genome Health Study (WGHS), a prospective cohort study of middle-aged women of whom 14711 provided self-reported periodontal disease diagnosis, oral health measures, and periodontal risk factor data including incident T2D. Significant genetic correlations were identified between PerioLT/T2D (Rg=0.23; SE=0.04; p=7.4e-09) and T2D/BMD (Rg=0.09; SE=0.02; p=9.8e-06). Twenty-one independent pleiotropic variants were identified via MTAG (pMTAG<5x10-8 across all traits). Of these variants, genetic signals for PerioLT and T2D colocalized at one candidate variant (rs17522122; ProbH4 = 0.58), a 3’UTR variant of AKAP6. Colocalization between T2D/BMD and the original PerioLT GWAS p-values suggested 14 additional loci. In the independent WGHS sample, which includes responses to a validated oral health questionnaire for PD surveillance, the primary shared candidate (rs17522122) was associated with less frequent dental flossing [OR(95%CI)= 0.92 (0.87-0.98), p=0.007], a response that is correlated with worse PD status. Moreover, 4 additional candidate variants were indirectly supported by associations with less frequent dental flossing [rs75933965, 1.17(1.04-1.31), p=0.008], less frequent dental visits [rs77464186, 0.82(0.75-0.91), p=0.0002], less frequent dental prophylaxis [rs67111375, 0.91(0.83-0.99), p=0.03; rs77464186, 0.80(0.72-0.89), p=3.8e-05], or having bone loss around teeth [rs8047395, 1.09(1.03-1.15), p=0.005]. This integrative approach identified one colocalized locus and 14 additional candidate loci that are shared between T2D and PD/oral health by comparing effects across PD, T2D and BMD. Future research is needed to independently validate our findings.
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影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
16.2
作者：
Demmer RT;Holtfreter B;Desvarieux M;Jacobs DR Jr;Kerner W;Nauck M;Völzke H;Kocher T
通讯作者：
Kocher T
影响因子：
30.8
作者：
Mahajan A;Taliun D;Thurner M;Robertson NR;Torres JM;Rayner NW;Payne AJ;Steinthorsdottir V;Scott RA;Grarup N;Cook JP;Schmidt EM;Wuttke M;Sarnowski C;Mägi R;Nano J;Gieger C;Trompet S;Lecoeur C;Preuss MH;Prins BP;Guo X;Bielak LF;Below JE;Bowden DW;Chambers JC;Kim YJ;Ng MCY;Petty LE;Sim X;Zhang W;Bennett AJ;Bork-Jensen J;Brummett CM;Canouil M;Ec Kardt KU;Fischer K;Kardia SLR;Kronenberg F;Läll K;Liu CT;Locke AE;Luan J;Ntalla I;Nylander V;Schönherr S;Schurmann C;Yengo L;Bottinger EP;Brandslund I;Christensen C;Dedoussis G;Florez JC;Ford I;Franco OH;Frayling TM;Giedraitis V;Hackinger S;Hattersley AT;Herder C;Ikram MA;Ingelsson M;Jørgensen ME;Jørgensen T;Kriebel J;Kuusisto J;Ligthart S;Lindgren CM;Linneberg A;Lyssenko V;Mamakou V;Meitinger T;Mohlke KL;Morris AD;Nadkarni G;Pankow JS;Peters A;Sattar N;Stančáková A;Strauch K;Taylor KD;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tuomilehto J;Witte DR;Dupuis J;Peyser PA;Zeggini E;Loos RJF;Froguel P;Ingelsson E;Lind L;Groop L;Laakso M;Collins FS;Jukema JW;Palmer CNA;Grallert H;Metspalu A;Dehghan A;Köttgen A;Abecasis GR;Meigs JB;Rotter JI;Marchini J;Pedersen O;Hansen T;Langenberg C;Wareham NJ;Stefansson K;Gloyn AL;Morris AP;Boehnke M;McCarthy MI
通讯作者：
McCarthy MI
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：
7.6
作者：
Eke, P. I.;Dye, B. A.;Genco, R. J.
通讯作者：
Genco, R. J.