Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System.
Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System.
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DOI：
10.1001/jamapsychiatry.2022.2742
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发表时间：
2022-09-14
期刊：
影响因子：
25.8
通讯作者：
Roussos, Panos
中科院分区：
文献类型：
--
作者：
Bigdeli, Tim B.;Voloudakis, Georgios;Barr, Peter B.;Gorman, Bryan R.;Genovese, Giulio;Peterson, Roseann E.;Burstein, David E.;Velicu, Vlad, I;Li, Yuli;Gupta, Rishab;Mattheisen, Manuel;Tomasi, Simone;Rajeevan, Nallakkandi;Sayward, Frederick;Radhakrishnan, Krishnan;Natarajan, Sundar;Malhotra, Anil K.;Shi, Yunling;Zhao, Hongyu;Kosten, Thomas R.;Concato, John;O'Leary, Timothy J.;Przygodzki, Ronald;Gleason, Theresa;Pyarajan, Saiju;Brophy, Mary;Huang, Grant D.;Muralidhar, Sumitra;Gaziano, J. Michael;Aslan, Mihaela;Fanous, Ayman H.;Harvey, Philip D.;Roussos, Panos
本横断面研究对退伍军人健康管理局医疗保健系统中当前神经精神多基因风险评分的外显率进行了基准测试，并通过全现象关联研究探讨了多基因风险评分与广泛的人类疾病类别之间的关联。在使用退伍军人健康管理局医疗保健系统的美国退伍军人中，精神分裂症、双相情感障碍和重度抑郁症的多基因风险评分（prs）的外显率是多少？哪些健康问题与较高的多基因负担相关？在这项涉及707299人的横断面研究中，PRSs与曾经接受过相关精神诊断有关，并且在更频繁住院的患者中更丰富。更高的PRSs与许多心理和身体健康诊断的几率增加有关，即使在缺乏正式诊断的个体中也是如此。通过大规模遗传研究获得的个人水平的prs在美国医疗保健系统中是可移植的，并且具有风险分层的新潜力，尽管在不同的祖先中具有不同的特异性。严重的精神疾病，包括精神分裂症、双相情感障碍和抑郁症，是遗传性的、高度多因素的疾病，也是全世界致残的主要原因。在退伍军人健康管理局医疗保健系统中对当前神经精神多基因风险评分（PRS）的外显率进行基准测试，并通过全现象关联研究探索PRS与广泛类别人类疾病之间的关联。从1999年10月到2021年1月，对退伍军人健康管理局的电子健康记录进行了评估，并发现了9378名确诊为精神分裂症或双相情感障碍的个体。比较了百万退伍军人计划中非洲或欧洲血统参与者（约40万人）的精神分裂症、双相情感障碍和重度抑郁症prs的表现，并探讨了基于ICD-9/10计费代码的prs与1650种疾病类别之间的关联。最后，应用基因组结构方程模型推导出新的PRSs，以索引常见和疾病特异性遗传因子。分析时间为2021年1月至2022年1月。将基于面对面结构化临床访谈的诊断与ICD-9/10计费代码进行比较。PRSs是用精神分裂症、双相情感障碍和重度抑郁症全基因组关联研究的汇总统计数据构建的。在707299名入组研究参与者中，459667人在撰写本文时进行了基因分型；84 806人具有广泛的非洲血统（平均[SD]年龄58[12.1]岁），314 909人具有广泛的欧洲血统（平均[SD]年龄66.4[13.5]岁）。在9378例确诊为精神分裂症或双相情感障碍的患者中，8962例（95.6%）使用ICD-9/10编码（2个或以上）被正确识别。在欧洲血统的人群中，PRSs与被诊断为精神分裂症（比值比[OR]， 1.81 [95% CI, 1.76-1.87]; P < 10 - 257）或双相情感障碍（比值比[OR]， 1.42 [95% CI, 1.39-1.44]; P < 10 - 295）显著相关。非洲血统的受试者在精神分裂症（OR, 1.35 [95% CI, 1.29-1.42]; P < 10−38）和双相情感障碍（OR, 1.16 [95% CI, 1.11-1.12]; P < 10−10）上的相应效应值要小得多。神经精神PRSs与一系列精神和身体健康问题的风险增加有关。通过面对面结构化临床访谈和当前神经精神PRSs确认的诊断，证明了美国退伍军人中基于电子健康记录的表型方法的有效性，强调了PRSs在解除生物学和介导性多效性方面的潜力。
This cross-sectional study benchmarks the penetrance of current neuropsychiatric polygenic risk scores in the Veterans Health Administration health care system, and explores associations between polygenic risk scores and broad categories of human disease via phenome-wide association studies. What is the penetrance of polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, and major depression among US veterans who use the Veterans Health Administration health care system and what health problems are associated with having a higher polygenic burden? In this cross-sectional study of 707 299 individuals, PRSs were associated with having ever received a relevant psychiatric diagnosis and were enriched among more frequently hospitalized patients. Higher PRSs were associated with increased odds for numerous mental and physical health diagnoses, even among individuals who lack a formal diagnosis. Individual-level PRSs informed by large-scale genetic studies are portable across US health care systems and have emergent potential for risk stratification, albeit with disparate specificity across ancestries. Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. Extensive Veterans Health Administration’s electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10−257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10−295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10−38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10−10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records–based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.
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影响因子：
--
作者：
Kessler, RC;Berglund, P;Walters, EE
通讯作者：
Walters, EE
DOI：
10.1002/ajmg.b.32242
发表时间：
2014-06-01
影响因子：
2.8
作者：
Harvey, Philip D.;Siever, Larry J.;Concato, John
通讯作者：
Concato, John
影响因子：
9.8
作者：
Hunter-Zinck, Haley;Shi, Yunling;Pyarajan, Saiju
通讯作者：
Pyarajan, Saiju
影响因子：
30.8
作者：
Wray NR;Ripke S;Mattheisen M;Trzaskowski M;Byrne EM;Abdellaoui A;Adams MJ;Agerbo E;Air TM;Andlauer TMF;Bacanu SA;Bækvad-Hansen M;Beekman AFT;Bigdeli TB;Binder EB;Blackwood DRH;Bryois J;Buttenschøn HN;Bybjerg-Grauholm J;Cai N;Castelao E;Christensen JH;Clarke TK;Coleman JIR;Colodro-Conde L;Couvy-Duchesne B;Craddock N;Crawford GE;Crowley CA;Dashti HS;Davies G;Deary IJ;Degenhardt F;Derks EM;Direk N;Dolan CV;Dunn EC;Eley TC;Eriksson N;Escott-Price V;Kiadeh FHF;Finucane HK;Forstner AJ;Frank J;Gaspar HA;Gill M;Giusti-Rodríguez P;Goes FS;Gordon SD;Grove J;Hall LS;Hannon E;Hansen CS;Hansen TF;Herms S;Hickie IB;Hoffmann P;Homuth G;Horn C;Hottenga JJ;Hougaard DM;Hu M;Hyde CL;Ising M;Jansen R;Jin F;Jorgenson E;Knowles JA;Kohane IS;Kraft J;Kretzschmar WW;Krogh J;Kutalik Z;Lane JM;Li Y;Li Y;Lind PA;Liu X;Lu L;MacIntyre DJ;MacKinnon DF;Maier RM;Maier W;Marchini J;Mbarek H;McGrath P;McGuffin P;Medland SE;Mehta D;Middeldorp CM;Mihailov E;Milaneschi Y;Milani L;Mill J;Mondimore FM;Montgomery GW;Mostafavi S;Mullins N;Nauck M;Ng B;Nivard MG;Nyholt DR;O'Reilly PF;Oskarsson H;Owen MJ;Painter JN;Pedersen CB;Pedersen MG;Peterson RE;Pettersson E;Peyrot WJ;Pistis G;Posthuma D;Purcell SM;Quiroz JA;Qvist P;Rice JP;Riley BP;Rivera M;Saeed Mirza S;Saxena R;Schoevers R;Schulte EC;Shen L;Shi J;Shyn SI;Sigurdsson E;Sinnamon GBC;Smit JH;Smith DJ;Stefansson H;Steinberg S;Stockmeier CA;Streit F;Strohmaier J;Tansey KE;Teismann H;Teumer A;Thompson W;Thomson PA;Thorgeirsson TE;Tian C;Traylor M;Treutlein J;Trubetskoy V;Uitterlinden AG;Umbricht D;Van der Auwera S;van Hemert AM;Viktorin A;Visscher PM;Wang Y;Webb BT;Weinsheimer SM;Wellmann J;Willemsen G;Witt SH;Wu Y;Xi HS;Yang J;Zhang F;eQTLGen;23andMe;Arolt V;Baune BT;Berger K;Boomsma DI;Cichon S;Dannlowski U;de Geus ECJ;DePaulo JR;Domenici E;Domschke K;Esko T;Grabe HJ;Hamilton SP;Hayward C;Heath AC;Hinds DA;Kendler KS;Kloiber S;Lewis G;Li QS;Lucae S;Madden PFA;Magnusson PK;Martin NG;McIntosh AM;Metspalu A;Mors O;Mortensen PB;Müller-Myhsok B;Nordentoft M;Nöthen MM;O'Donovan MC;Paciga SA;Pedersen NL;Penninx BWJH;Perlis RH;Porteous DJ;Potash JB;Preisig M;Rietschel M;Schaefer C;Schulze TG;Smoller JW;Stefansson K;Tiemeier H;Uher R;Völzke H;Weissman MM;Werge T;Winslow AR;Lewis CM;Levinson DF;Breen G;Børglum AD;Sullivan PF;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
通讯作者：
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
影响因子：
25.8
作者：
Wang, Meng-Ting;Tsai, Chen-Liang;Lin, Hui-Lan
通讯作者：
Lin, Hui-Lan