{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T10:02:38Z","timestamp":1760781758879},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"S3","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Interactions among genomic loci (also known as epistasis) have been suggested as one of the potential sources of missing heritability in single locus analysis of genome-wide association studies (GWAS). The computational burden of searching for interactions is compounded by the extremely low threshold for identifying significant p-values due to multiple hypothesis testing corrections. Utilizing prior biological knowledge to restrict the set of candidate SNP pairs to be tested can alleviate this problem, but systematic studies that investigate the relative merits of integrating different biological frameworks and GWAS data have not been conducted.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We developed four biologically based frameworks to identify pairwise interactions among candidate SNP pairs as follows: (1) for each human protein-coding gene, a set of SNPs associated with that gene was constructed providing a gene-based interaction model, (2) for each known biological pathway, a set of SNPs associated with the genes in the pathway was constructed providing a pathway-based interaction model, (3) a set of SNPs associated with genes in a disease-related subnetwork provides a network-based interaction model, and (4) a framework is based on the function of SNPs. The last approach uses expression SNPs (eSNPs or eQTLs), which are SNPs or loci that have defined effects on the abundance of transcripts of other genes. We constructed pairs of eSNPs and SNPs located in the target genes whose expression is regulated by eSNPs. For all four frameworks the SNP sets were exhaustively tested for pairwise interactions within the sets using a traditional logistic regression model after excluding genes that were previously identified to associate with the trait. Using previously published GWAS data for type 2 diabetes (T2D) and the biologically based pair-wise interaction modeling, we identify twelve genes not seen in the previous single locus analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>We present four approaches to detect interactions associated with complex diseases. The results show our approaches outperform the traditional single locus approaches in detecting genes that previously did not reach significance; the results also provide novel drug targets and biomarkers relevant to the underlying mechanisms of disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-6-s3-s15","type":"journal-article","created":{"date-parts":[[2013,6,24]],"date-time":"2013-06-24T14:32:50Z","timestamp":1372084370000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Gene, pathway and network frameworks to identify epistatic interactions of single nucleotide polymorphisms derived from GWAS data"],"prefix":"10.1186","volume":"6","author":[{"given":"Yu","family":"Liu","sequence":"first","affiliation":[]},{"given":"Sean","family":"Maxwell","sequence":"additional","affiliation":[]},{"given":"Tao","family":"Feng","sequence":"additional","affiliation":[]},{"given":"Xiaofeng","family":"Zhu","sequence":"additional","affiliation":[]},{"given":"Robert C","family":"Elston","sequence":"additional","affiliation":[]},{"given":"Mehmet","family":"Koyut\u00fcrk","sequence":"additional","affiliation":[]},{"given":"Mark R","family":"Chance","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2012,12,17]]},"reference":[{"issue":"7145","key":"1000_CR1","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nature05911","volume":"447","author":"WTCCC","year":"2007","unstructured":"WTCCC: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007, 447 (7145): 661-678. 10.1038\/nature05911.","journal-title":"Nature"},{"issue":"5","key":"1000_CR2","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nrg2344","volume":"9","author":"MI McCarthy","year":"2008","unstructured":"McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, Hirschhorn JN: Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature reviews Genetics. 2008, 9 (5): 356-369. 10.1038\/nrg2344.","journal-title":"Nature reviews Genetics"},{"issue":"5","key":"1000_CR3","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1056\/NEJMoa072366","volume":"357","author":"NJ Samani","year":"2007","unstructured":"Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann HE: Genomewide association analysis of coronary artery disease. The New England journal of medicine. 2007, 357 (5): 443-453. 10.1056\/NEJMoa072366.","journal-title":"The New England journal of medicine"},{"issue":"5903","key":"1000_CR4","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1126\/science.1156409","volume":"322","author":"D Altshuler","year":"2008","unstructured":"Altshuler D, Daly MJ, Lander ES: Genetic mapping in human disease. Science. 2008, 322 (5903): 881-888. 10.1126\/science.1156409.","journal-title":"Science"},{"issue":"23","key":"1000_CR5","doi-asserted-by":"publisher","first-page":"9362","DOI":"10.1073\/pnas.0903103106","volume":"106","author":"LA Hindorff","year":"2009","unstructured":"Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA: Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the USA. 2009, 106 (23): 9362-9367. 10.1073\/pnas.0903103106.","journal-title":"Proceedings of the National Academy of Sciences of the USA"},{"issue":"6","key":"1000_CR6","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nrg2809","volume":"11","author":"EE Eichler","year":"2010","unstructured":"Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH: Missing heritability and strategies for finding the underlying causes of complex disease. Nature reviews Genetics. 2010, 11 (6): 446-450. 10.1038\/nrg2809.","journal-title":"Nature reviews Genetics"},{"issue":"4","key":"1000_CR7","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1073\/pnas.1119675109","volume":"109","author":"O Zuk","year":"2012","unstructured":"Zuk O, Hechter E, Sunyaev SR, Lander ES: The mystery of missing heritability: Genetic interactions create phantom heritability. Proceedings of the National Academy of Sciences of the USA. 2012, 109 (4): 1193-1198. 10.1073\/pnas.1119675109.","journal-title":"Proceedings of the National Academy of Sciences of the USA"},{"issue":"1","key":"1000_CR8","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1086\/321276","volume":"69","author":"MD Ritchie","year":"2001","unstructured":"Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH: Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. American journal of human genetics. 2001, 69 (1): 138-147. 10.1086\/321276.","journal-title":"American journal of human genetics"},{"issue":"11","key":"1000_CR9","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1038\/nrg2452","volume":"9","author":"PC Phillips","year":"2008","unstructured":"Phillips PC: Epistasis--the essential role of gene interactions in the structure and evolution of genetic systems. Nature reviews Genetics. 2008, 9 (11): 855-867. 10.1038\/nrg2452.","journal-title":"Nature reviews Genetics"},{"issue":"6","key":"1000_CR10","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nrg2579","volume":"10","author":"HJ Cordell","year":"2009","unstructured":"Cordell HJ: Detecting gene-gene interactions that underlie human diseases. Nature reviews Genetics. 2009, 10 (6): 392-404.","journal-title":"Nature reviews Genetics"},{"issue":"4","key":"1000_CR11","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1159\/000321967","volume":"70","author":"X Wang","year":"2010","unstructured":"Wang X, Elston RC, Zhu X: The meaning of interaction. Human heredity. 2010, 70 (4): 269-277. 10.1159\/000321967.","journal-title":"Human heredity"},{"issue":"1","key":"1000_CR12","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.atherosclerosis.2006.09.014","volume":"195","author":"CT Tsai","year":"2007","unstructured":"Tsai CT, Hwang JJ, Ritchie MD, Moore JH, Chiang FT, Lai LP, Hsu KL, Tseng CD, Lin JL, Tseng YZ: Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction. Atherosclerosis. 2007, 195 (1): 172-180. 10.1016\/j.atherosclerosis.2006.09.014.","journal-title":"Atherosclerosis"},{"key":"1000_CR13","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1186\/1471-2105-12-475","volume":"12","author":"J Shang","year":"2011","unstructured":"Shang J, Zhang J, Sun Y, Liu D, Ye D, Yin Y: Performance analysis of novel methods for detecting epistasis. BMC bioinformatics. 2011, 12: 475-10.1186\/1471-2105-12-475.","journal-title":"BMC bioinformatics"},{"issue":"3","key":"1000_CR14","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.ajhg.2010.07.021","volume":"87","author":"X Wan","year":"2010","unstructured":"Wan X, Yang C, Yang Q, Xue H, Fan X, Tang NL, Yu W: BOOST: A fast approach to detecting gene-gene interactions in genome-wide case-control studies. American journal of human genetics. 2010, 87 (3): 325-340. 10.1016\/j.ajhg.2010.07.021.","journal-title":"American journal of human genetics"},{"issue":"7","key":"1000_CR15","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1038\/cr.2010.68","volume":"20","author":"X Hu","year":"2010","unstructured":"Hu X, Liu Q, Zhang Z, Li Z, Wang S, He L, Shi Y: SHEsisEpi, a GPU-enhanced genome-wide SNP-SNP interaction scanning algorithm, efficiently reveals the risk genetic epistasis in bipolar disorder. Cell research. 2010, 20 (7): 854-857. 10.1038\/cr.2010.68.","journal-title":"Cell research"},{"issue":"23","key":"1000_CR16","doi-asserted-by":"publisher","first-page":"2784","DOI":"10.1093\/bioinformatics\/btn516","volume":"24","author":"M Holden","year":"2008","unstructured":"Holden M, Deng SW, Wojnowski L, Kulle B: GSEA-SNP: applying gene set enrichment analysis to SNP data from genome-wide association studies. Bioinformatics. 2008, 24 (23): 2784-2785. 10.1093\/bioinformatics\/btn516.","journal-title":"Bioinformatics"},{"issue":"12","key":"1000_CR17","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/nrg2884","volume":"11","author":"K Wang","year":"2010","unstructured":"Wang K, Li MY, Hakonarson H: Analysing biological pathways in genome-wide association studies. Nature Reviews Genetics. 2010, 11 (12): 843-854. 10.1038\/nrg2884.","journal-title":"Nature Reviews Genetics"},{"issue":"1","key":"1000_CR18","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1111\/j.1469-1809.2010.00630.x","volume":"75","author":"MD Ritchie","year":"2011","unstructured":"Ritchie MD: Using biological knowledge to uncover the mystery in the search for epistasis in genome-wide association studies. Annals of human genetics. 2011, 75 (1): 172-182. 10.1111\/j.1469-1809.2010.00630.x.","journal-title":"Annals of human genetics"},{"issue":"12","key":"1000_CR19","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/nrg2884","volume":"11","author":"K Wang","year":"2010","unstructured":"Wang K, Li M, Hakonarson H: Analysing biological pathways in genome-wide association studies. Nature reviews Genetics. 2010, 11 (12): 843-854. 10.1038\/nrg2884.","journal-title":"Nature reviews Genetics"},{"issue":"4","key":"1000_CR20","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/j.ajhg.2010.02.020","volume":"86","author":"H Zhong","year":"2010","unstructured":"Zhong H, Yang X, Kaplan LM, Molony C, Schadt EE: Integrating pathway analysis and genetics of gene expression for genome-wide association studies. American journal of human genetics. 2010, 86 (4): 581-591. 10.1016\/j.ajhg.2010.02.020.","journal-title":"American journal of human genetics"},{"issue":"9","key":"1000_CR21","doi-asserted-by":"publisher","first-page":"e24220","DOI":"10.1371\/journal.pone.0024220","volume":"6","author":"N Akula","year":"2011","unstructured":"Akula N, Baranova A, Seto D, Solka J, Nalls MA, Singleton A, Ferrucci L, Tanaka T, Bandinelli S, Cho YS: A network-based approach to prioritize results from genome-wide association studies. PloS one. 2011, 6 (9): e24220-10.1371\/journal.pone.0024220.","journal-title":"PloS one"},{"issue":"7","key":"1000_CR22","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1101\/gr.118992.110","volume":"21","author":"I Lee","year":"2011","unstructured":"Lee I, Blom UM, Wang PI, Shim JE, Marcotte EM: Prioritizing candidate disease genes by network-based boosting of genome-wide association data. Genome research. 2011, 21 (7): 1109-1121. 10.1101\/gr.118992.110.","journal-title":"Genome research"},{"issue":"6","key":"1000_CR23","doi-asserted-by":"publisher","first-page":"e1002101","DOI":"10.1371\/journal.pgen.1002101","volume":"7","author":"R Braun","year":"2011","unstructured":"Braun R, Buetow K: Pathways of distinction analysis: a new technique for multi-SNP analysis of GWAS data. PLoS genetics. 2011, 7 (6): e1002101-10.1371\/journal.pgen.1002101.","journal-title":"PLoS genetics"},{"issue":"6","key":"1000_CR24","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.burns.2010.02.001","volume":"36","author":"RM Huebinger","year":"2010","unstructured":"Huebinger RM, Garner HR, Barber RC: Pathway genetic load allows simultaneous evaluation of multiple genetic associations. Burns: journal of the International Society for Burn Injuries. 2010, 36 (6): 787-792. 10.1016\/j.burns.2010.02.001.","journal-title":"Burns: journal of the International Society for Burn Injuries"},{"issue":"10","key":"1000_CR25","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1038\/ejhg.2009.15","volume":"17","author":"M Emily","year":"2009","unstructured":"Emily M, Mailund T, Hein J, Schauser L, Schierup MH: Using biological networks to search for interacting loci in genome-wide association studies. Eur J Hum Genet. 2009, 17 (10): 1231-1240. 10.1038\/ejhg.2009.15.","journal-title":"Eur J Hum Genet"},{"issue":"22","key":"1000_CR26","doi-asserted-by":"publisher","first-page":"4345","DOI":"10.1093\/hmg\/ddq356","volume":"19","author":"YV Sun","year":"2010","unstructured":"Sun YV, Kardia SLR: Identification of epistatic effects using a protein-protein interaction database. Hum Mol Genet. 2010, 19 (22): 4345-4352. 10.1093\/hmg\/ddq356.","journal-title":"Hum Mol Genet"},{"issue":"6","key":"1000_CR27","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1007\/s00439-011-1009-6","volume":"130","author":"TP Slavin","year":"2011","unstructured":"Slavin TP, Feng T, Schnell A, Zhu XF, Elston RC: Two-marker association tests yield new disease associations for coronary artery disease and hypertension. Hum Genet. 2011, 130 (6): 725-733. 10.1007\/s00439-011-1009-6.","journal-title":"Hum Genet"},{"issue":"7","key":"1000_CR28","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S0168-9525(01)02310-1","volume":"17","author":"RC Jansen","year":"2001","unstructured":"Jansen RC, Nap JP: Genetical genomics: the added value from segregation. Trends in genetics: TIG. 2001, 17 (7): 388-391. 10.1016\/S0168-9525(01)02310-1.","journal-title":"Trends in genetics: TIG"},{"issue":"6929","key":"1000_CR29","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/nature01434","volume":"422","author":"EE Schadt","year":"2003","unstructured":"Schadt EE, Monks SA, Drake TA, Lusis AJ, Che N, Colinayo V, Ruff TG, Milligan SB, Lamb JR, Cavet G: Genetics of gene expression surveyed in maize, mouse and man. Nature. 2003, 422 (6929): 297-302. 10.1038\/nature01434.","journal-title":"Nature"},{"issue":"5","key":"1000_CR30","doi-asserted-by":"publisher","first-page":"e107","DOI":"10.1371\/journal.pbio.0060107","volume":"6","author":"EE Schadt","year":"2008","unstructured":"Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C: Mapping the genetic architecture of gene expression in human liver. PLoS biology. 2008, 6 (5): e107-10.1371\/journal.pbio.0060107.","journal-title":"PLoS biology"},{"issue":"10","key":"1000_CR31","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1038\/ng2109","volume":"39","author":"AL Dixon","year":"2007","unstructured":"Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KC, Taylor J, Burnett E, Gut I, Farrall M: A genome-wide association study of global gene expression. Nature genetics. 2007, 39 (10): 1202-1207. 10.1038\/ng2109.","journal-title":"Nature genetics"},{"issue":"7186","key":"1000_CR32","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/nature06757","volume":"452","author":"YQ Chen","year":"2008","unstructured":"Chen YQ, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang CS, Lamb J, Edwards S, Sieberts SK: Variations in DNA elucidate molecular networks that cause disease. Nature. 2008, 452 (7186): 429-435. 10.1038\/nature06757.","journal-title":"Nature"},{"key":"1000_CR33","doi-asserted-by":"crossref","unstructured":"Nicolae DL, Gamazon E, Zhang W, Duan SW, Dolan ME, Cox NJ: Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS genetics. 2010, 6 (4):","DOI":"10.1371\/journal.pgen.1000888"},{"issue":"3","key":"1000_CR34","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ: PLINK: A tool set for whole-genome association and population-based linkage analyses. American journal of human genetics. 2007, 81 (3): 559-575. 10.1086\/519795.","journal-title":"American journal of human genetics"},{"issue":"Database","key":"1000_CR35","doi-asserted-by":"publisher","first-page":"D561","DOI":"10.1093\/nar\/gkq973","volume":"39","author":"D Szklarczyk","year":"2011","unstructured":"Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Doerks T, Stark M, Muller J, Bork P: The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic acids research. 2011, 39 (Database): D561-568. 10.1093\/nar\/gkq973.","journal-title":"Nucleic acids research"},{"key":"1000_CR36","volume-title":"Bmc Med Inform Decis","author":"JE Lim","year":"2010","unstructured":"Lim JE, Hong KW, Jin HS, Kim YS, Park HK, Oh B: Type 2 diabetes genetic association database manually curated for the study design and odds ratio. Bmc Med Inform Decis. 2010, 10:"},{"issue":"1","key":"1000_CR37","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1006\/jagm.1995.1029","volume":"19","author":"P Klein","year":"1995","unstructured":"Klein P, Ravi R: A nearly best-possible approximation algorithm for node-weighted Steiner trees. J Algorithm. 1995, 19 (1): 104-115. 10.1006\/jagm.1995.1029.","journal-title":"J Algorithm"},{"key":"1000_CR38","volume-title":"AMIA Summit on Translational Bioinformatics","author":"Y Liu","year":"2012","unstructured":"Liu Y, Koyuturk M, Maxwell S, Zhao Z, Chance M: Integrative analysis of common neurodegenerative diseases using gene association, interaction network, and mRNA expression data. AMIA Summit on Translational Bioinformatics. 2012,"},{"issue":"3","key":"1000_CR39","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.ygeno.2011.12.005","volume":"99","author":"S Zheng","year":"2012","unstructured":"Zheng S, Zhao Z: GenRev: exploring functional relevance of genes in molecular networks. Genomics. 2012, 99 (3): 183-188. 10.1016\/j.ygeno.2011.12.005.","journal-title":"Genomics"},{"issue":"2","key":"1000_CR40","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1093\/bioinformatics\/btp644","volume":"26","author":"ER Gamazon","year":"2010","unstructured":"Gamazon ER, Zhang W, Konkashbaev A, Duan SW, Kistner EO, Nicolae DL, Dolan ME, Cox NJ: Scan: Snp and Copy Number Annotation. Bioinformatics. 2010, 26 (2): 259-262. 10.1093\/bioinformatics\/btp644.","journal-title":"Bioinformatics"},{"issue":"32","key":"1000_CR41","doi-asserted-by":"publisher","first-page":"14199","DOI":"10.1073\/pnas.1002494107","volume":"107","author":"T Tsunoda","year":"2010","unstructured":"Tsunoda T, Takashima Y, Tanaka Y, Fujimoto T, Doi K, Hirose Y, Koyanagi M, Yoshida Y, Okamura T, Kuroki M: Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands. Proceedings of the National Academy of Sciences of the USA. 2010, 107 (32): 14199-14204. 10.1073\/pnas.1002494107.","journal-title":"Proceedings of the National Academy of Sciences of the USA"},{"issue":"1","key":"1000_CR42","doi-asserted-by":"publisher","first-page":"89","DOI":"10.2478\/s11658-010-0041-1","volume":"16","author":"K Doi","year":"2011","unstructured":"Doi K, Fujimoto T, Koyanagi M, Tsunoda T, Tanaka Y, Yoshida Y, Takashima Y, Kuroki M, Sasazuki T, Shirasawa S: Zfat Is a Critical Molecule for Cell Survival in Mouse Embryonic Fibroblasts. Cell Mol Biol Lett. 2011, 16 (1): 89-100. 10.2478\/s11658-010-0041-1.","journal-title":"Cell Mol Biol Lett"},{"issue":"5","key":"1000_CR43","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.cell.2006.03.044","volume":"125","author":"X Lin","year":"2006","unstructured":"Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC: PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell. 2006, 125 (5): 915-928. 10.1016\/j.cell.2006.03.044.","journal-title":"Cell"},{"issue":"3","key":"1000_CR44","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1172\/JCI7535","volume":"105","author":"K Cusi","year":"2000","unstructured":"Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ: Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. The Journal of clinical investigation. 2000, 105 (3): 311-320. 10.1172\/JCI7535.","journal-title":"The Journal of clinical investigation"},{"issue":"16","key":"1000_CR45","doi-asserted-by":"publisher","first-page":"4744","DOI":"10.1093\/emboj\/17.16.4744","volume":"17","author":"M Takekawa","year":"1998","unstructured":"Takekawa M, Maeda T, Saito H: Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways. The EMBO journal. 1998, 17 (16): 4744-4752. 10.1093\/emboj\/17.16.4744.","journal-title":"The EMBO journal"},{"issue":"16","key":"1000_CR46","doi-asserted-by":"publisher","first-page":"14299","DOI":"10.1074\/jbc.M211699200","volume":"278","author":"P Ofek","year":"2003","unstructured":"Ofek P, Ben-Meir D, Kariv-Inbal Z, Oren M, Lavi S: Cell cycle regulation and p53 activation by protein phosphatase 2C alpha. The Journal of biological chemistry. 2003, 278 (16): 14299-14305. 10.1074\/jbc.M211699200.","journal-title":"The Journal of biological chemistry"},{"issue":"8","key":"1000_CR47","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/nrendo.2010.89","volume":"6","author":"A Hiukka","year":"2010","unstructured":"Hiukka A, Maranghi M, Matikainen N, Taskinen MR: PPARalpha: an emerging therapeutic target in diabetic microvascular damage. Nature reviews Endocrinology. 2010, 6 (8): 454-463. 10.1038\/nrendo.2010.89.","journal-title":"Nature reviews Endocrinology"},{"issue":"7","key":"1000_CR48","doi-asserted-by":"publisher","first-page":"2720","DOI":"10.1210\/jc.2006-2280","volume":"92","author":"SJ Meex","year":"2007","unstructured":"Meex SJ, van Greevenbroek MM, Ayoubi TA, Vlietinck R, van Vliet-Ostaptchouk JV, Hofker MH, Vermeulen VM, Schalkwijk CG, Feskens EJ, Boer JM: Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians. The Journal of clinical endocrinology and metabolism. 2007, 92 (7): 2720-2725. 10.1210\/jc.2006-2280.","journal-title":"The Journal of clinical endocrinology and metabolism"},{"issue":"3","key":"1000_CR49","doi-asserted-by":"publisher","first-page":"839","DOI":"10.2337\/diabetes.55.03.06.db05-1002","volume":"55","author":"F Thameem","year":"2006","unstructured":"Thameem F, Farook VS, Bogardus C, Prochazka M: Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes. 2006, 55 (3): 839-842. 10.2337\/diabetes.55.03.06.db05-1002.","journal-title":"Diabetes"},{"key":"1000_CR50","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1471-2156-10-39","volume":"10","author":"R Nassir","year":"2009","unstructured":"Nassir R, Kosoy R, Tian C, White PA, Butler LM, Silva G, Kittles R, Alarcon-Riquelme ME, Gregersen PK, Belmont JW: An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels. BMC genetics. 2009, 10: 39-","journal-title":"BMC genetics"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-6-S3-S15.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T20:54:53Z","timestamp":1630529693000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-6-S3-S15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,12]]},"references-count":50,"journal-issue":{"issue":"S3","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["1000"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-6-s3-s15","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,12]]},"assertion":[{"value":"17 December 2012","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"S15"}}