المؤلفون: van der Wijst, Monique G. P., de Vries, Dylan H., Groot, Hilde E., Trynka, Gosia, Hon, Chung-Chau, Nawijn, Martijn C., Idaghdour, Youssef, van der Harst, Pim, Ye, Chun J., Powell, Joseph, Theis, Fabian J., Mahfouz, Ahmed, Heinig, Matthias, Franke, Lude

مصطلحات موضوعية: Quantitative Biology - Genomics, Quantitative Biology - Molecular Networks, Quantitative Biology - Populations and Evolution

الوصف: In recent years, functional genomics approaches combining genetic information with bulk RNA-sequencing data have identified the downstream expression effects of disease-associated genetic risk factors through so-called expression quantitative trait locus (eQTL) analysis. Single-cell RNA-sequencing creates enormous opportunities for mapping eQTLs across different cell types and in dynamic processes, many of which are obscured when using bulk methods. The enormous increase in throughput and reduction in cost per cell now allow this technology to be applied to large-scale population genetics studies. Therefore, we have founded the single-cell eQTLGen consortium (sc-eQTLGen), aimed at pinpointing disease-causing genetic variants and identifying the cellular contexts in which they affect gene expression. Ultimately, this information can enable development of personalized medicine. Here, we outline the goals, approach, potential utility and early proofs-of-concept of the sc-eQTLGen consortium. We also provide a set of study design considerations for future single-cell eQTL studies.
Comment: 26 pages, 5 figures, position paper of sc-eQTLGen consortium

الوصول الحر: http://arxiv.org/abs/1909.12550Test

المؤلفون: Young, William J, Lahrouchi, Najim, Isaacs, Aaron, Duong, ThuyVy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A, Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Repetto, Linda, Concas, Maria Pina, van den Berg, Marten E, Weiss, Stefan, Baldassari, Antoine R, Bartz, Traci M, Cook, James P, Evans, Daniel S, Freudling, Rebecca, Hines, Oliver, Isaksen, Jonas L, Lin, Honghuang, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Qian, Yong, Richmond, Anne, Roselli, Carolina, Ryan, Kathleen A, Tarazona-Santos, Eduardo, Thériault, Sébastien, van Duijvenboden, Stefan, Warren, Helen R, Yao, Jie, Raza, Dania, Aeschbacher, Stefanie, Ahlberg, Gustav, Alonso, Alvaro, Andreasen, Laura, Bis, Joshua C, Boerwinkle, Eric, Campbell, Archie, Catamo, Eulalia, Cocca, Massimiliano, Cutler, Michael J, Darbar, Dawood, De Grandi, Alessandro, De Luca, Antonio, Ding, Jun, Ellervik, Christina, Ellinor, Patrick T, Felix, Stephan B, Froguel, Philippe, Fuchsberger, Christian, Gögele, Martin, Graff, Claus, Graff, Mariaelisa, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Huang, Paul L, Huikuri, Heikki V, Hutri-Kähönen, Nina, Ikram, M Arfan, Jackson, Rebecca D, Junttila, Juhani, Kavousi, Maryam, Kors, Jan A, Leal, Thiago P, Lemaitre, Rozenn N, Lin, Henry J, Lind, Lars, Linneberg, Allan, Liu, Simin, MacFarlane, Peter W, Mangino, Massimo, Meitinger, Thomas, Mezzavilla, Massimo, Mishra, Pashupati P, Mitchell, Rebecca N, Mononen, Nina, Montasser, May E, Morrison, Alanna C, Nauck, Matthias, Nauffal, Victor, Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K, Pelliccione, Giulia, Pittman, Alan, Porteous, David J, Pramstaller, Peter P, Preuss, Michael H, Raitakari, Olli T, Reiner, Alexander P, Ribeiro, Antonio Luiz P, Rice, Kenneth M, Risch, Lorenz, Schlessinger, David, Schotten, Ulrich, Schurmann, Claudia, Shen, Xia, Shoemaker, M Benjamin, Sinagra, Gianfranco, Sinner, Moritz F, Soliman, Elsayed Z, Stoll, Monika, Strauch, Konstantin, Tarasov, Kirill, Taylor, Kent D, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A, Wilson, James G, Avery, Christy L, Conen, David, Correa, Adolfo, Cucca, Francesco, Dörr, Marcus, Gharib, Sina A, Girotto, Giorgia, Grarup, Niels, Hayward, Caroline, Jamshidi, Yalda, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kääb, Stefan, Kähönen, Mika, Kanters, Jørgen K, Kooperberg, Charles, Lehtimäki, Terho, Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J.F, Lubitz, Steven A, Mook-Kanamori, Dennis O, Morris, Andrew P, O'Connell, Jeffrey R, Olesen, Morten Salling, Orini, Michele, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Psaty, Bruce M, Rotter, Jerome I, Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James F, Arking, Dan E, Ramírez, Julia, Lambiase, Pier D, Sotoodehnia, Nona, Mifsud, Borbala, Newton-Cheh, Christopher, Munroe, Patricia B

المصدر: Young , W J , Lahrouchi , N , Isaacs , A , Duong , T , Foco , L , Ahmed , F , Brody , J A , Salman , R , Noordam , R , Benjamins , J-W , Haessler , J , Lyytikäinen , L-P , Repetto , L , Concas , M P , van den Berg , M E , Weiss , S , Baldassari , A R , Bartz , T M , Cook , J P , Evans , D S , Freudling , R , Hines , O , Isaksen ....

مصطلحات موضوعية: genetic and genomic medicine

الوصف: The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

العلاقة: https://vbn.aau.dk/da/publications/5a5487d2-76a1-400b-962e-72e76412ad5cTest

الإتاحة: https://doi.org/10.1101/2021.11.04.21265866Test
https://vbn.aau.dk/da/publications/5a5487d2-76a1-400b-962e-72e76412ad5cTest

المؤلفون: Pekayvaz, Kami, Losert, Corinna, Knottenberg, Viktoria, van Blokland, Irene V., Oelen, Roy, Groot, Hilde E., Benjamins, Jan Walter, Brambs, Sophia, Kaiser, Rainer, Eivers, Luke, Polewka, Vivien, Escaig, Raphael, Joppich, Markus, Janjic, Aleksandar, Popp, Oliver, Petzold, Tobias, Zimmer, Ralf, Enard, Wolfgang, Saar, Kathrin, Mertins, Philipp, Huebner, Norbert, van der Harst, Pim, Franke, Lude H., van der Wijst, Monique G. P., Massberg, Steffen, Heinig, Matthias, Nicolai, Leo, Stark, Konstantin

المصدر: Pekayvaz , K , Losert , C , Knottenberg , V , van Blokland , I V , Oelen , R , Groot , H E , Benjamins , J W , Brambs , S , Kaiser , R , Eivers , L , Polewka , V , Escaig , R , Joppich , M , Janjic , A , Popp , O , Petzold , T , Zimmer , R , Enard , W , Saar , K , Mertins , P , Huebner , N , van der Harst , P , Franke , L H , ....

الوصف: Acute and chronic coronary syndromes (ACS and CCS) are leading causes of mortality. Inflammation is considered to be a key pathogenic driver, but immune states in humans and their clinical implications remain poorly understood. We hypothesized that Multi-Omic blood analysis combined with Multi-Omic Factor Analysis (MOFA) might uncover hidden sources of variance providing pathophysiological insights linked to clinical needs. Here, we compile a single cell longitudinal dataset of the circulating immune states in ACS & CCS (13x103 clinical & Multi-Omic variables, n=117 subjects, n=838 analyzed samples) from two independent cohorts. Using MOFA, we identify multilayered factors, characterized by distinct classical monocyte and CD4+ & CD8+ T cell states that explain a large proportion of inter-patient variance. Three factors either reflect disease course or predict outcome in coronary syndromes. The diagnostic performance of these factors reaches beyond established biomarkers highlighting the potential use of MOFA as a novel tool for multilayered patient risk stratification.

العلاقة: https://research.rug.nl/en/publications/f53df71a-fd63-46bf-a5ac-5b592b18489fTest

الإتاحة: https://doi.org/10.1101/2023.05.02.23289392Test
https://hdl.handle.net/11370/f53df71a-fd63-46bf-a5ac-5b592b18489fTest
https://research.rug.nl/en/publications/f53df71a-fd63-46bf-a5ac-5b592b18489fTest

المؤلفون: van Blokland, Irene V., Oelen, Roy, Groot, Hilde E., Benjamins, Jan Walter, Pekayvaz, Kami, Losert, Corinna, Knottenberg, Viktoria, Heinig, Matthias, Nicolai, Leo, Stark, Konstantin, van der Harst, Pim, Franke, Lude H., van der Wijst, Monique G. P.

المصدر: van Blokland , I V , Oelen , R , Groot , H E , Benjamins , J W , Pekayvaz , K , Losert , C , Knottenberg , V , Heinig , M , Nicolai , L , Stark , K , van der Harst , P , Franke , L H & van der Wijst , M G P 2023 ' Single-cell dissection of the immune response after acute myocardial infarction ' MedRxiv . https://doi.org/10.1101/2023.05.02.23289370Test

الوصف: Background: The role of the immune system in the context of acute myocardial infarction (MI), and its response to such event are poorly characterized, but is thought to be an important driver of myocardial remodeling, thromboinflammation, and exacerbation of atherosclerosis - triggering recurrent cardiovascular events. So far, anti-inflammatory approaches drugs have shown promising effects on the prevention of recurrent cardiovascular events or myocardial salvage after myocardial infarction. However, they broadly impair the immune system and some are associated with increased infectious side effects. Therefore, a more detailed understanding of the immune response to myocardial infarction is needed to tailor anti-inflammatory therapeutic approaches in MI patients. Methods: To gain such detailed longitudinal understanding of the immune response in ST-elevated myocardial infarction (STEMI) patients, we compared peripheral blood mononuclear cell (PBMCs) single-cell RNA-sequencing (scRNA-seq) expression and plasma protein profiles over time and in comparison to age- and sex-balanced controls in 38 STEMI patients at hospital admission, 24 hours (acute phase) and 6-8 weeks (chronic phase) after STEMI. Results: In total, 95,995 diseased and 33,878 control PBMCs were analyzed. Compared to controls, we observed a relative increase in the number of classical monocytes and a decrease in the number of CD56dim natural killer cells in STEMI patients at admission, and these differences persisted until 24 hours after STEMI. The monocytes also showed the largest gene expression changes in STEMI patients compared to controls, and in STEMI patients over time. These were associated with changes in the activity of toll-like receptors, IFN and IL-1 signaling. Subsequent differential cell-cell communication analysis suggested that these monocytes are mainly involved in the outgoing differential communication in the first 24h after a STEMI, whereas in the next 6-8 weeks they become mostly involved in the incoming differential ...

العلاقة: https://research.rug.nl/en/publications/958df779-89c6-4b95-af82-1d70c1f5bb41Test

الإتاحة: https://doi.org/10.1101/2023.05.02.23289370Test
https://hdl.handle.net/11370/958df779-89c6-4b95-af82-1d70c1f5bb41Test
https://research.rug.nl/en/publications/958df779-89c6-4b95-af82-1d70c1f5bb41Test

المؤلفون: Melissa Bateson, Aviv, Abraham, Bendix, Laila, Benetos, Athanase, Ben-Shlomo, Yoav, Bojesen, Stig E., Cooper, Cyrus, Cooper, Rachel, Deary, Ian J., Hägg, Sara, Harris, Sarah E., Kark, Jeremy D., Kronenberg, Florian, Kuh, Diana, Labat, Carlos, Martin-Ruiz, Carmen M., Meyer, Craig, Nordestgaard, Børge G., Penninx, Brenda WJH, Pepper, Gillian V, Révész, Dóra, Said, M Abdullah, Starr, John M, Syddall, Holly, Thompson, William Murray, van der Harst, Pim, Whooley, Mary, von Zglinicki, Thomas, Willeit, Peter, Zhan, Yiqiang, Nettle, Daniel

مصطلحات موضوعية: biological age, telomere length, telomere attrition, smoking, longitudinal

الوصف: Preprint of mansuscript currently submitted for publication. Abstract: Smoking is associated with shorter leukocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking accelerates LTL attrition. However, an alternative hypothesis is that individuals with shorter telomeres are more likely to start smoking. Both hypotheses predict a cross-sectional difference in LTL between smokers and non-smokers, but the acceleration hypothesis additionally predicts an association between smoking and LTL attrition. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12,579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 78.83 bp shorter in smokers (95% CI: 21.09 to 136.58). However, LTL attrition was a negligible 0.44 bp/year faster in smokers than in non-smokers (95% CI: -1.83 to 0.95), a difference that equates to only 1.23% of the estimated age-related loss of 35.71 bp/year. Assuming a linear effect of smoking, at least 177 years of smoking would be required to generate the observed cross-sectional difference in LTL. It is therefore unlikely that smoking causes the difference in LTL between smokers and non-smokers.

العلاقة: info:eu-repo/grantAgreement/EC/H2020/666669/; https://zenodo.org/record/1463972Test; https://doi.org/10.5281/zenodo.1463972Test; oai:zenodo.org:1463972

الإتاحة: https://doi.org/10.5281/zenodo.1463972Test
https://doi.org/10.5281/zenodo.1240964Test
https://doi.org/10.5281/zenodo.1463971Test
https://zenodo.org/record/1463972Test

المؤلفون: Walsh, Kyle M, Codd, Veryan, Smirnov, Ivan V, Rice, Terri, Decker, Paul A, Hansen, Helen M, Kollmeyer, Thomas, Kosel, Matthew L, Molinaro, Annette M, McCoy, Lucie S, Bracci, Paige M, Cabriga, Belinda S, Pekmezci, Melike, Zheng, Shichun, Wiemels, Joseph L, Pico, Alexander R, Tihan, Tarik, Berger, Mitchell S, Chang, Susan M, Prados, Michael D, Lachance, Daniel H, O'Neill, Brian Patrick, Sicotte, Hugues, Eckel-Passow, Jeanette E, van der Harst, Pim, Wiencke, John K, Samani, Nilesh J, Jenkins, Robert B, Wrensch, Margaret R

المصدر: Nat Genet ; ISSN:1546-1718 ; Volume:46 ; Issue:7

الوصف: Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

العلاقة: https://doi.org/10.1038/ng.3004Test; https://pubmed.ncbi.nlm.nih.gov/24908248Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074274Test/

الإتاحة: https://doi.org/10.1038/ng.3004Test
https://pubmed.ncbi.nlm.nih.gov/24908248Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074274Test/

المؤلفون: Köttgen, Anna, Albrecht, Eva, Teumer, Alexander, Vitart, Veronique, Krumsiek, Jan, Hundertmark, Claudia, Pistis, Giorgio, Ruggiero, Daniela, O'Seaghdha, Conall M, Haller, Toomas, Yang, Qiong, Tanaka, Toshiko, Johnson, Andrew D, Kutalik, Zoltán, Smith, Albert V, Shi, Julia, Struchalin, Maksim, Middelberg, Rita P S, Brown, Morris J, Gaffo, Angelo L, Pirastu, Nicola, Li, Guo, Hayward, Caroline, Zemunik, Tatijana, Huffman, Jennifer, Yengo, Loic, Zhao, Jing Hua, Demirkan, Ayse, Feitosa, Mary F, Liu, Xuan, Malerba, Giovanni, Lopez, Lorna M, van der Harst, Pim, Li, Xinzhong, Kleber, Marcus E, Hicks, Andrew A, Nolte, Ilja M, Johansson, Asa, Murgia, Federico, Wild, Sarah H, Bakker, Stephan J L, Peden, John F, Dehghan, Abbas, Steri, Maristella, Tenesa, Albert, Lagou, Vasiliki, Salo, Perttu, Mangino, Massimo, Rose, Lynda M, Lehtimäki, Terho, Woodward, Owen M, Okada, Yukinori, Tin, Adrienne, Müller, Christian, Oldmeadow, Christopher, Putku, Margus, Czamara, Darina, Kraft, Peter, Frogheri, Laura, Thun, Gian Andri, Grotevendt, Anne, Gislason, Gauti Kjartan, Harris, Tamara B, Launer, Lenore J, McArdle, Patrick, Shuldiner, Alan R, Boerwinkle, Eric, Coresh, Josef, Schmidt, Helena, Schallert, Michael, Martin, Nicholas G, Montgomery, Grant W, Kubo, Michiaki, Nakamura, Yusuke, Tanaka, Toshihiro, Munroe, Patricia B, Samani, Nilesh J, Jacobs, David R, Liu, Kiang, D'Adamo, Pio, Ulivi, Sheila, Rotter, Jerome I, Psaty, Bruce M, Vollenweider, Peter, Waeber, Gerard, Campbell, Susan, Devuyst, Olivier, Navarro, Pau, Kolcic, Ivana, Hastie, Nicholas, Balkau, Beverley, Froguel, Philippe, Esko, Tõnu, Salumets, Andres, Khaw, Kay Tee, Langenberg, Claudia, Wareham, Nicholas J, Isaacs, Aaron, Kraja, Aldi, Zhang, Qunyuan, Wild, Philipp S, Scott, Rodney J, Holliday, Elizabeth G, Org, Elin, Viigimaa, Margus, Bandinelli, Stefania, Metter, Jeffrey E, Lupo, Antonio, Trabetti, Elisabetta, Sorice, Rossella, Döring, Angela, Lattka, Eva, Strauch, Konstantin, Theis, Fabian, Waldenberger, Melanie, Wichmann, H-Erich, Davies, Gail, Gow, Alan J, Bruinenberg, Marcel, Stolk, Ronald P, Kooner, Jaspal S, Zhang, Weihua, Winkelmann, Bernhard R, Boehm, Bernhard O, Lucae, Susanne, Penninx, Brenda W, Smit, Johannes H, Curhan, Gary, Mudgal, Poorva, Plenge, Robert M, Portas, Laura, Persico, Ivana, Kirin, Mirna, Wilson, James F, Mateo Leach, Irene, van Gilst, Wiek H, Goel, Anuj, Ongen, Halit, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G, Imboden, Medea, von Eckardstein, Arnold, Cucca, Francesco, Nagaraja, Ramaiah, Piras, Maria Grazia, Nauck, Matthias, Schurmann, Claudia, Budde, Kathrin, Ernst, Florian, Farrington, Susan M, Theodoratou, Evropi, Prokopenko, Inga, Stumvoll, Michael, Jula, Antti, Perola, Markus, Salomaa, Veikko, Shin, So-Youn, Spector, Tim D, Sala, Cinzia, Ridker, Paul M, Kähönen, Mika, Viikari, Jorma, Hengstenberg, Christian, Nelson, Christopher P, Meschia, James F, Nalls, Michael A, Sharma, Pankaj, Singleton, Andrew B, Kamatani, Naoyuki, Zeller, Tanja, Burnier, Michel, Attia, John, Laan, Maris, Klopp, Norman, Hillege, Hans L, Kloiber, Stefan, Choi, Hyon, Pirastu, Mario, Tore, Silvia, Probst-Hensch, Nicole M, Völzke, Henry, Gudnason, Vilmundur, Parsa, Afshin, Schmidt, Reinhold, Whitfield, John B, Fornage, Myriam, Gasparini, Paolo, Siscovick, David S, Polašek, Ozren, Campbell, Harry, Rudan, Igor, Bouatia-Naji, Nabila, Metspalu, Andres, Loos, Ruth J F, van Duijn, Cornelia M, Borecki, Ingrid B, Ferrucci, Luigi, Gambaro, Giovanni, Deary, Ian J, Wolffenbuttel, Bruce H R, Chambers, John C, März, Winfried, Pramstaller, Peter P, Snieder, Harold, Gyllensten, Ulf, Wright, Alan F, Navis, Gerjan, Watkins, Hugh, Witteman, Jacqueline C M, Sanna, Serena, Schipf, Sabine, Dunlop, Malcolm G, Tönjes, Anke, Ripatti, Samuli, Soranzo, Nicole, Toniolo, Daniela, Chasman, Daniel I, Raitakari, Olli, Kao, W H Linda, Ciullo, Marina, Fox, Caroline S, Caulfield, Mark, Bochud, Murielle, Gieger, Christian

المصدر: Nat Genet ; ISSN:1546-1718 ; Volume:45 ; Issue:2

الوصف: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

العلاقة: https://doi.org/10.1038/ng.2500Test; https://pubmed.ncbi.nlm.nih.gov/23263486Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663712Test/

الإتاحة: https://doi.org/10.1038/ng.2500Test
https://pubmed.ncbi.nlm.nih.gov/23263486Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663712Test/