Polygenic risk alters the penetrance of monogenic kidney disease.
Polygenic risk alters the penetrance of monogenic kidney disease.
复制标题
多基因风险改变单基因肾病的外显率。
DOI：
10.1038/s41467-023-43878-9
复制
发表时间：
2023-12-14
影响因子：
16.6
通讯作者：
Kiryluk, Krzysztof
中科院分区：
文献类型：
--
作者：
Khan, Atlas;Shang, Ning;Nestor, Jordan G.;Weng, Chunhua;Hripcsak, George;Harris, Peter C.;Gharavi, Ali G.;Kiryluk, Krzysztof
慢性肾病（CKD）是由单基因、多基因和环境风险的相互作用决定的。常染色体显性遗传性多囊肾病（ADPKD）和COL 4A相关肾病（COL 4A-AN）是单基因肾病的最常见形式。这些疾病有不完全的遗传和可变的表达，我们假设多基因因素解释了这种变异性。通过结合SNP阵列、外显子组/基因组序列和来自英国生物库和All-of-Us队列的电子健康记录数据，我们证明全基因组多基因评分（GPS）可显著预测ADPKD单基因变异携带者中的CKD。与非携带者GPS的中间三分位数相比，顶部三分位数的ADPKD变异携带者的CKD风险增加54倍，而底部三分位数的ADPKD变异携带者的CKD风险仅增加3倍。类似地，GPS显著预测COL 4A-AN携带者中的CKD。GPS顶部三分位数的携带者患CKD的风险高2.5倍，而底部三分位数的携带者的风险与平均人群风险没有差异。这些结果表明，考虑到多基因的风险改善了单基因肾病的风险分层。多基因因素可以部分解释观察到的单基因疾病发病率的变异性。在这里，作者表明，慢性肾脏疾病的多基因风险评分与两种最常见的单基因形式的肾脏疾病的肾功能障碍风险较高显著相关，这表明考虑多基因因素可改善单基因肾脏疾病的风险分层。
Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease. Polygenic factors may partially explain the observed variability in the penetrance of monogenic diseases. Here, the authors show that a polygenic risk score for chronic kidney disease is significantly associated with a higher risk of renal dysfunction in the two most common monogenic forms of kidney disease, suggesting that accounting for polygenic factors improves risk stratification in monogenic kidney disease.
登录
查看更多内容
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：
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：
30.8
作者：
Huyghe, Jeroen R.;Bien, Stephanie A.;Peters, Ulrike
通讯作者：
Peters, Ulrike
影响因子：
30.8
作者：
Ehret, Georg B.;Ferreira, Teresa;Chasman, Daniel I.;Jackson, Anne U.;Schmidt, Ellen M.;Johnson, Toby;Thorleifsson, Gudmar;Luan, Jian'an;Donnelly, Louise A.;Kanoni, Stavroula;Petersen, Ann -Kristin;Pihurl, Vasyl;Strawbridge, Rona J.;Shungin, Dmitry;Hughes, Maria F.;Meirelles, Osorio;Kaakinen, Marika;Bouatia-Naji, Nabila;Kristiansson, Kati;Shah, Sonia;Kleber, Marcus E.;Guo, Xiuqing;Lyytikainen, Leo-Pekka;Fava, Cristiano;Eriksson, Nidas;Nolte, Ilja M.;Magnusson, Patrik K.;Salfati, Elias L.;Rallidis, Loukianos S.;Theusch, Elizabeth;Smith, Andrew J. P.;Folkersen, Lasse;Witkowska, Kate;Pers, Tune H.;Joehanes, Roby;Kim, Stuart K.;Lataniotis, Lazaros;Jansen, Rick;Johnson, Andrew D.;Warren, Helen;Kim, Young Jin;Zhao, Wei;Wu, Ying;Tayo, Bamidele O.;Bochud, Murielle;Absher, Devin;Adair, Linda S.;Amin, Najaf;Arkingl, Dan E.;Axelsson, Tomas;Baldassarre, Damian;Balkau, Beverley;Bandinelli, Stefania;Barnes, Michael R.;Barroso, Ines;Bevan, Stephen;Bis, Joshua C.;Bjornsdottir, Gyda;Boehnke, Michael;Boerwinkle, Eric;Bonnycastle, Lori L.;Boomsma, Dorret I.;Bornstein, Stefan R.;Brown, Morris J.;Burnier, Michel;Cabrera, Claudia P.;Chambers, John C.;Chang, I-Shou;Cheng, Ching-Yu;Chines, Peter S.;Chung, Ren-Hua;Collins, Francis S.;Connell, John M.;Doring, Angela;Dallongeville, Jean;Danesh, John;de Faire, Ulf;Delgado, Graciela;Dominiczak, Anna F.;Doney, Alex S. F.;Drenos, Fotios;Edkins, Sarah;Eicher, John D.;Elosua, Roberto;Enroth, Stefan;Erdmann, Jeanette;Eriksson, Per;Esko, Tonu;Evangelou, Evangelos;Evans, Alun;Fai, Tove;Farra, Martin;Felixl, Janine F.;Ferrieres, Jean;Ferrucci, Luigi;Fornage, Myriam;Forrester, Terrence;Franceschinil, Nora;Franco, Oscar H.;Franco-Cereceda, Anders;Fraser, Ross M.;Ganesh, Santhi K.;Gao, He;Gertow, Karl;Gianfagna, Francesco;Gigante, Bruna;Giulianini, Franco;Goe, Anuj;Goodall, Alison H.;Goodarzi, Mark;Gorski, Mathias;Grassler, Jurgen;Groves, Christopher J.;Gudnason, Vilmundur;Gyllensten, Ulf;Hallmans, Goran;Hartikainen, Anna-Liisa;Hassinen, Maija;Havulinna, Aki S.;Hayward, Caroline;Hercberg, Serge;Herzig, Karl-Heinz;Hicks, Andrew A.;Hingorani, Aroon D.;Hirschhorn, Joel N.;Hofmanl, Albert;Holmen, Jostein;Holmen, Oddgeir Lingaas;Hottenga, Jouke-Jan;Howard, Phil;Hsiung, Chao A.;Hunt, Steven C.;Ikram, M. Arfan;Illig, Thomas;Iribarren, Carlos;Jensen, Richard A.;Kahonen, Mika;Kang, Hyun Min;Kathiresan, Sekar;Keating, Brendan J.;Khaw, Kay-Tee;Kim, Yun Kyoung;Kim, Eric;Kivimaki, Mika;Klopp, Norman;Kolovou, Genovefa;Komulainen, Pirjo;Kooner, Jaspal S.;Kosova, Gulum;Krauss, Ronald M.;Kuh, Diana;Kutalik, Zoltan;Kuusisto, Johanna;Kvaloy, Kirsti;Lakka, Timo A.;Lee, Nanette R.;Lee, I-Te;Lee, Wen-Jane;Levy, Daniel;Li, Xiaohui;Liang, Kae-Woei;Lin, Honghuang;Lin, Li;Lindstrom, Jaana;Lobbens, Stephane;Mannisto, Satu;Muller, Gabriele;Muller-Nurasyid, Martina;Mach, Francois;Markus, Hugh S.;Marouli, Eirini;McCarthy, Mark I.;McKenzie, Colin A.;Meneton, Pierre;Menni, Cristina;Metspalu, Andres;Mijatovic, Vladan;Moilanen, Leena;Montasser, May E.;Morris, Andrew D.;Morrison, Alanna C.;Mulas, Antonella;Nagaraja, Ramaiah;Narisu, Narisu;Nikus, Kjell;O'Donnell, Christopher J.;O'Reilly, Paul F.;Ong, Ken K.;Paccaud, Fred;Palmer, Cameron D.;Parsa, Afshin;Pedersen, Nancy L.;Penninx, Brenda W.;Perola, Markus;Peters, Annette;Poulter, Neil;Pramstaller, Peter P.;Psaty, Bruce M.;Quertermous, Thomas;Rao, Dabeeru C.;Rasheed, Asif;Rayner, N. William;Renstrom, Frida;Rettig, Rainer;Rice, Kenneth M.;Roberts, Robert;Rose, Lynda M.;Rossouw, Jacques;Samani, Nilesh J.;Sanna, Serena;Saramies, Jouko;Schunkert, Heribert;Sebert, Sylvain;Sheu, Wayne H-H;Shin, Young-Ah;Sim, Xueling;Smit, Johannes H.;Smith, Albert V.;Sosa, Maria X.;Spector, Tim D.;Stancakova, Alena;Stanton, Alice V.;Stirrups, Kathleen E.;Stringham, Heather M.;Sundstrom, Johan;Swift, Amy J.;Syvanen, Ann-Christine;Tai, E-Shyong;Tanaka, Toshiko;Tarasov, Kirill V.;Teumer, Alexander;Thorsteinsdottir, Unnur;Tobin, Martin D.;Tremoli, Elena;Uitterlinden, Andre G.;Uusitupa, Matti;Vaez, Ahmad;Vaidya, Dhananjay;van Duijn, Cornelia M.;van Iperen, Erik P. A.;Vasan, Ramachandran S.;Verwoert, Germaine C.;Virtamo, Jarmo;Vitart, Veronique;Voight, Benjamin F.;Vollenweider, Peter;Wagner, Aline;Wain, Louise V.;Wareham, Nicholas J.;Watldns, Hugh;Weder, Alan B.;Westra, Harm Jan;Wilks, Rainford;Wilsgaard, Tom;Wilson, James F.;Wong, Tien Y.;Yang, Tsun-Po;Yao, Jie;Yengo, Loic;Zhang, Weihua;Zhao, Jing Hua;Zhu, Xiaofeng;Bovet, Pascal;Cooper, Richard S.;Mohlke, Karen L.;Saleheen, Danish;Lee, Jong-Young;Elliott, Paul;Gierman, Hinco J.;Willer, Cristen J.;Franke, Lude;Hovingh, G. Kees;Taylor, Kent D.;Dedoussis, George;Sever, Peter;Wong, Andrew;Lind, Lars;Assimes, Themistocles L.;Njolstad, Inger;Schwarz, Peter E. H.;Langenberg, Claudia;Snieder, Harold;Caulfield, Mark J.;Melander, E.;Laakso, Markku;Saltevo, Juha;Rauramaa, Rainer;Tuomilehto, Jaakko;Ingelsson, Erik;Lehtimaki, Terho;Hveem, Kristian;Palmas, Walter;Marz, Winfried;Kumar, Meena;Salomaa, Veikko;Chen, Yii-Der I.;Rotter, Jerome I.;Froguel, Philippe;Jarvelin, Marjo-Riitta;Lakatta, Edward G.;Kuulasmaa, Kari;Franks, Paul W.;Hamsten, Anders;Wichmann, H-Erich;Palmer, Colin N. A.;Stefansson, Kari;Ridker, Paul M.;Loos, Ruth J. F.;Chalcravarti, Aravinda;Deloukas, Panos;Morris, Andrew P.;Newton-Cheh, Christopher;Munroe, Patricia B.
通讯作者：
Munroe, Patricia B.
影响因子：
23.4
作者：
Aly, Markus;Wiklund, Fredrik;Xu, Jianfeng;Isaacs, William B.;Eklund, Martin;D'Amato, Mauro;Adolfsson, Jan;Gronberg, Henrik
通讯作者：
Gronberg, Henrik