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to most complex diseases is controlled by many genes, each having a small effect on the disease. One example is rheumatoid arthritis (RA), a common complex multifactorial autoimmune disease. Several studies have been carried out to detect the genetic basis of RA, and more than 30 genomic regions have shown evidence of linkage to the disease. Most of these genomic regions did not reach a genome-wide significant threshold value of linkage, with P values between 0.05 and 0.001 [1-5]. Thus, these loci only have a small effect on RA. Small genetic contributions could also be seen from the susceptibility genes of RA identified so far, including HLA-DR4, PADI4, PTPN22 and FCRL3 [6-9]. Except for HLA-DR4, which is strongly associated with RA, all the other susceptibility genes have only a small effect on the disease. In the mouse model of RA, small genetic contributions are also often observed. For example, in a previous study, we carried out a genome screen to identify the quantitative trait loci (QTL) in collagen-induced arthritis (CIA), which is a widely used animal model of RA. Only one QTL, Cia2, was identified for the phenotype of CIA severity, but this QTL contributes to only 16% of the phenotype variations for CIA susceptibility in F2 progeny [10]. This suggests that there must be other susceptibility genes whose contributions were not big enough to reach the stringent significance threshold value of linkage analysis.\nOne aim of using animal models for complex diseases is to detect the genetic basis of these diseases. With controllable environmental factors as well as the known genetic background, animal models are powerful tools to search for susceptibility genes for complex diseases, and have been intensively employed for that purpose. More than 27,000 QTL have been identified in the mouse genome since the first QTL was identified at the beginning of the 1990s [11]. By 2005, approximately 20 quantitative trait genes (QTGs) in the mouse genome had been identified [12,13]. Interestingly, most QTGs identified in animal models have the causal polymorphisms in the protein-coding region [14], which provoke protein structure changes or protein deficiency. This suggests, on the one hand, that small-effect QTL are difficult to identify with traditional strategies and, on the other hand, that the polymorphisms regulating gene expression might only slightly affect the quantitative traits, and thus are more difficult to identify.\nMicroarray-based global gene expression is a powerful technique for investigating complex diseases. During disease development, genes involved in the disease are likely to be differentially regulated. Therefore, signature genes of the diseases could be identified by detecting the expression patterns of the disease-related cells/tissues and their ideal controls. In the past decade, many studies applied this technique to study both RA and its animal models [15-22]. Indeed, genes involved in arthritis show distinct expression patterns in certain tissues and pathological stages of the disease. Genes involved in immunoinflammatory responses were differentially expressed in the blood cells in RA patients [18]. Chemokines and adhesion molecules were upregulated in the joint at the initiation phase of arthritis in animal models [21,22], while genes involved in cartilage destruction and bone erosion were differentially expressed at the late phase of arthritis in animal models of RA [15,16]. Besides detecting genes involved in complex diseases, microarrays could also be used to detect the genetic polymorphisms regulating gene expression because differential expressions between two strains might be the result of a polymorphism located in regulatory elements.\nTo identify the small-effect QTL of CIA as well as the potential candidate genes inside them, we investigated CIA genetically susceptible and resistant strains at both the genome and transcriptome levels. At the genome level, F2 progeny of the CIA susceptible (DBA/1) and resistant (FVB/N) strains were generated and a genome-wide linkage analysis was performed to identify small-effect QTL. At the transcriptome level, we detected the gene expression patterns of both the DBA/1 and FVB/N strains at four different phases of CIA. The potential candidate genes were identified based on three criteria: they are located within the genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed between the two parental strains during CIA."}
craft-ca-core-ex-dev
{"project":"craft-ca-core-ex-dev","denotations":[{"id":"T2321","span":{"begin":56,"end":66},"obj":"GO:0065007"},{"id":"T2322","span":{"begin":75,"end":80},"obj":"SO_EXT:0000704"},{"id":"T2323","span":{"begin":203,"end":209},"obj":"UBERON:0002405"},{"id":"T2324","span":{"begin":271,"end":278},"obj":"SO_EXT:0000704"},{"id":"T2325","span":{"begin":309,"end":316},"obj":"SO_EXT:0001026"},{"id":"T2326","span":{"begin":386,"end":393},"obj":"SO_EXT:0001026"},{"id":"T2327","span":{"begin":418,"end":424},"obj":"SO_EXT:0001026"},{"id":"T2328","span":{"begin":569,"end":576},"obj":"SO_EXT:0000704"},{"id":"T2329","span":{"begin":634,"end":639},"obj":"SO_EXT:0000704"},{"id":"T2330","span":{"begin":675,"end":682},"obj":"PR_EXT:000002021"},{"id":"T2331","span":{"begin":684,"end":689},"obj":"PR_EXT:000012222"},{"id":"T2332","span":{"begin":691,"end":697},"obj":"PR_EXT:000013457"},{"id":"T2333","span":{"begin":702,"end":707},"obj":"PR_EXT:000007442"},{"id":"T2334","span":{"begin":726,"end":733},"obj":"PR_EXT:000002021"},{"id":"T2335","span":{"begin":802,"end":807},"obj":"SO_EXT:0000704"},{"id":"T2336","span":{"begin":856,"end":861},"obj":"NCBITaxon:10088"},{"id":"T2337","span":{"begin":881,"end":888},"obj":"SO_EXT:0000704"},{"id":"T2338","span":{"begin":979,"end":985},"obj":"SO_EXT:0001026"},{"id":"T2339","span":{"begin":1009,"end":1032},"obj":"SO_EXT:0000771"},{"id":"T2340","span":{"begin":1034,"end":1037},"obj":"SO_EXT:0000771"},{"id":"T2341","span":{"begin":1042,"end":1050},"obj":"CHEBI_PR_EXT:collagen"},{"id":"T2342","span":{"begin":1099,"end":1105},"obj":"NCBITaxon:33208"},{"id":"T2343","span":{"begin":1128,"end":1131},"obj":"SO_EXT:0000771"},{"id":"T2344","span":{"begin":1198,"end":1201},"obj":"SO_EXT:0000771"},{"id":"T2345","span":{"begin":1351,"end":1356},"obj":"SO_EXT:0000704"},{"id":"T2346","span":{"begin":1487,"end":1493},"obj":"NCBITaxon:33208"},{"id":"T2347","span":{"begin":1539,"end":1546},"obj":"SO_EXT:0000704"},{"id":"T2348","span":{"begin":1633,"end":1640},"obj":"SO_EXT:0000704"},{"id":"T2349","span":{"begin":1653,"end":1659},"obj":"NCBITaxon:33208"},{"id":"T2350","span":{"begin":1715,"end":1720},"obj":"SO_EXT:0000704"},{"id":"T2351","span":{"begin":1813,"end":1816},"obj":"SO_EXT:0000771"},{"id":"T2352","span":{"begin":1845,"end":1850},"obj":"NCBITaxon:10088"},{"id":"T2353","span":{"begin":1851,"end":1857},"obj":"SO_EXT:0001026"},{"id":"T2354","span":{"begin":1874,"end":1877},"obj":"SO_EXT:0000771"},{"id":"T2355","span":{"begin":1974,"end":1979},"obj":"SO_EXT:0000704"},{"id":"T2356","span":{"begin":1994,"end":1999},"obj":"NCBITaxon:10088"},{"id":"T2357","span":{"begin":2000,"end":2006},"obj":"SO_EXT:0001026"},{"id":"T2358","span":{"begin":2075,"end":2081},"obj":"NCBITaxon:33208"},{"id":"T2359","span":{"begin":2105,"end":2118},"obj":"SO_EXT:polymorphism"},{"id":"T2360","span":{"begin":2126,"end":2133},"obj":"CHEBI_PR_EXT:protein"},{"id":"T2361","span":{"begin":2126,"end":2140},"obj":"SO:0000010"},{"id":"T2362","span":{"begin":2134,"end":2147},"obj":"SO_EXT:coding_sequence"},{"id":"T2363","span":{"begin":2168,"end":2175},"obj":"CHEBI_PR_EXT:protein"},{"id":"T2364","span":{"begin":2197,"end":2204},"obj":"CHEBI_PR_EXT:protein"},{"id":"T2365","span":{"begin":2267,"end":2270},"obj":"SO_EXT:0000771"},{"id":"T2366","span":{"begin":2358,"end":2371},"obj":"SO_EXT:polymorphism"},{"id":"T2367","span":{"begin":2372,"end":2382},"obj":"GO:0065007"},{"id":"T2368","span":{"begin":2383,"end":2387},"obj":"SO_EXT:0000704"},{"id":"T2369","span":{"begin":2383,"end":2398},"obj":"GO:0010467"},{"id":"T2370","span":{"begin":2516,"end":2520},"obj":"SO_EXT:0000704"},{"id":"T2371","span":{"begin":2516,"end":2531},"obj":"GO:0010467"},{"id":"T2372","span":{"begin":2620,"end":2625},"obj":"SO_EXT:0000704"},{"id":"T2373","span":{"begin":2682,"end":2691},"obj":"GO:0065007"},{"id":"T2374","span":{"begin":2714,"end":2719},"obj":"SO_EXT:0000704"},{"id":"T2375","span":{"begin":2773,"end":2783},"obj":"GO:0010467"},{"id":"T2376","span":{"begin":2816,"end":2821},"obj":"CL_GO_EXT:cell"},{"id":"T2377","span":{"begin":2822,"end":2829},"obj":"UBERON:0000479"},{"id":"T2378","span":{"begin":2937,"end":2943},"obj":"NCBITaxon:33208"},{"id":"T2379","span":{"begin":2968,"end":2973},"obj":"SO_EXT:0000704"},{"id":"T2380","span":{"begin":3010,"end":3020},"obj":"GO:0010467"},{"id":"T2381","span":{"begin":3041,"end":3048},"obj":"UBERON:0000479"},{"id":"T2382","span":{"begin":3089,"end":3094},"obj":"SO_EXT:0000704"},{"id":"T2383","span":{"begin":3107,"end":3135},"obj":"GO:0002437"},{"id":"T2384","span":{"begin":3156,"end":3165},"obj":"GO:0010467"},{"id":"T2385","span":{"begin":3173,"end":3178},"obj":"UBERON:0000178"},{"id":"T2386","span":{"begin":3173,"end":3184},"obj":"CL:0000081"},{"id":"T2387","span":{"begin":3179,"end":3184},"obj":"CL_GO_EXT:cell"},{"id":"T2388","span":{"begin":3206,"end":3216},"obj":"GO_EXT:0008009"},{"id":"T2389","span":{"begin":3221,"end":3229},"obj":"GO_PATO_EXT:biological_adhesion_entity_or_process"},{"id":"T2390","span":{"begin":3230,"end":3239},"obj":"CHEBI:36357"},{"id":"T2391","span":{"begin":3245,"end":3256},"obj":"GO_EXT:positive_regulation"},{"id":"T2392","span":{"begin":3264,"end":3269},"obj":"UBERON:0004905"},{"id":"T2393","span":{"begin":3310,"end":3316},"obj":"NCBITaxon:33208"},{"id":"T2394","span":{"begin":3339,"end":3344},"obj":"SO_EXT:0000704"},{"id":"T2395","span":{"begin":3357,"end":3366},"obj":"UBERON_EXT:cartilage_element_or_tissue"},{"id":"T2396","span":{"begin":3383,"end":3387},"obj":"UBERON_EXT:bone_element_or_tissue"},{"id":"T2397","span":{"begin":3416,"end":3425},"obj":"GO:0010467"},{"id":"T2398","span":{"begin":3460,"end":3466},"obj":"NCBITaxon:33208"},{"id":"T2399","span":{"begin":3507,"end":3512},"obj":"SO_EXT:0000704"},{"id":"T2400","span":{"begin":3588,"end":3595},"obj":"SO_EXT:0000704"},{"id":"T2401","span":{"begin":3596,"end":3609},"obj":"SO_EXT:polymorphism"},{"id":"T2402","span":{"begin":3610,"end":3620},"obj":"GO:0065007"},{"id":"T2403","span":{"begin":3621,"end":3625},"obj":"SO_EXT:0000704"},{"id":"T2404","span":{"begin":3621,"end":3636},"obj":"GO:0010467"},{"id":"T2405","span":{"begin":3658,"end":3669},"obj":"GO:0010467"},{"id":"T2406","span":{"begin":3715,"end":3727},"obj":"SO_EXT:polymorphism"},{"id":"T2407","span":{"begin":3739,"end":3749},"obj":"GO:0065007"},{"id":"T2408","span":{"begin":3739,"end":3758},"obj":"SO_EXT:0005836"},{"id":"T2409","span":{"begin":3789,"end":3792},"obj":"SO_EXT:0000771"},{"id":"T2410","span":{"begin":3835,"end":3840},"obj":"SO_EXT:0000704"},{"id":"T2411","span":{"begin":3874,"end":3885},"obj":"SO_EXT:0000704"},{"id":"T2412","span":{"begin":3932,"end":3938},"obj":"SO_EXT:0001026"},{"id":"T2413","span":{"begin":3972,"end":3978},"obj":"SO_EXT:0001026"},{"id":"T2414","span":{"begin":4079,"end":4085},"obj":"SO_EXT:0001026"},{"id":"T2415","span":{"begin":4147,"end":4150},"obj":"SO_EXT:0000771"},{"id":"T2416","span":{"begin":4196,"end":4200},"obj":"SO_EXT:0000704"},{"id":"T2417","span":{"begin":4196,"end":4211},"obj":"GO:0010467"},{"id":"T2418","span":{"begin":4314,"end":4319},"obj":"SO_EXT:0000704"},{"id":"T2419","span":{"begin":4389,"end":4396},"obj":"SO_EXT:0001026"},{"id":"T2420","span":{"begin":4460,"end":4469},"obj":"GO:0010467"},{"id":"T2421","span":{"begin":4526,"end":4535},"obj":"GO:0010467"}],"text":"Introduction\nSusceptibility to most complex diseases is controlled by many genes, each having a small effect on the disease. One example is rheumatoid arthritis (RA), a common complex multifactorial autoimmune disease. Several studies have been carried out to detect the genetic basis of RA, and more than 30 genomic regions have shown evidence of linkage to the disease. Most of these genomic regions did not reach a genome-wide significant threshold value of linkage, with P values between 0.05 and 0.001 [1-5]. Thus, these loci only have a small effect on RA. Small genetic contributions could also be seen from the susceptibility genes of RA identified so far, including HLA-DR4, PADI4, PTPN22 and FCRL3 [6-9]. Except for HLA-DR4, which is strongly associated with RA, all the other susceptibility genes have only a small effect on the disease. In the mouse model of RA, small genetic contributions are also often observed. For example, in a previous study, we carried out a genome screen to identify the quantitative trait loci (QTL) in collagen-induced arthritis (CIA), which is a widely used animal model of RA. Only one QTL, Cia2, was identified for the phenotype of CIA severity, but this QTL contributes to only 16% of the phenotype variations for CIA susceptibility in F2 progeny [10]. This suggests that there must be other susceptibility genes whose contributions were not big enough to reach the stringent significance threshold value of linkage analysis.\nOne aim of using animal models for complex diseases is to detect the genetic basis of these diseases. With controllable environmental factors as well as the known genetic background, animal models are powerful tools to search for susceptibility genes for complex diseases, and have been intensively employed for that purpose. More than 27,000 QTL have been identified in the mouse genome since the first QTL was identified at the beginning of the 1990s [11]. By 2005, approximately 20 quantitative trait genes (QTGs) in the mouse genome had been identified [12,13]. Interestingly, most QTGs identified in animal models have the causal polymorphisms in the protein-coding region [14], which provoke protein structure changes or protein deficiency. This suggests, on the one hand, that small-effect QTL are difficult to identify with traditional strategies and, on the other hand, that the polymorphisms regulating gene expression might only slightly affect the quantitative traits, and thus are more difficult to identify.\nMicroarray-based global gene expression is a powerful technique for investigating complex diseases. During disease development, genes involved in the disease are likely to be differentially regulated. Therefore, signature genes of the diseases could be identified by detecting the expression patterns of the disease-related cells/tissues and their ideal controls. In the past decade, many studies applied this technique to study both RA and its animal models [15-22]. Indeed, genes involved in arthritis show distinct expression patterns in certain tissues and pathological stages of the disease. Genes involved in immunoinflammatory responses were differentially expressed in the blood cells in RA patients [18]. Chemokines and adhesion molecules were upregulated in the joint at the initiation phase of arthritis in animal models [21,22], while genes involved in cartilage destruction and bone erosion were differentially expressed at the late phase of arthritis in animal models of RA [15,16]. Besides detecting genes involved in complex diseases, microarrays could also be used to detect the genetic polymorphisms regulating gene expression because differential expressions between two strains might be the result of a polymorphism located in regulatory elements.\nTo identify the small-effect QTL of CIA as well as the potential candidate genes inside them, we investigated CIA genetically susceptible and resistant strains at both the genome and transcriptome levels. At the genome level, F2 progeny of the CIA susceptible (DBA/1) and resistant (FVB/N) strains were generated and a genome-wide linkage analysis was performed to identify small-effect QTL. At the transcriptome level, we detected the gene expression patterns of both the DBA/1 and FVB/N strains at four different phases of CIA. The potential candidate genes were identified based on three criteria: they are located within the genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed between the two parental strains during CIA."}
2_test
{"project":"2_test","denotations":[{"id":"17244351-16691188-4361111","span":{"begin":508,"end":509},"obj":"16691188"},{"id":"17244351-9724775-4361111","span":{"begin":508,"end":509},"obj":"9724775"},{"id":"17244351-11254450-4361111","span":{"begin":508,"end":509},"obj":"11254450"},{"id":"17244351-12687532-4361111","span":{"begin":508,"end":509},"obj":"12687532"},{"id":"17244351-16278286-4361111","span":{"begin":508,"end":509},"obj":"16278286"},{"id":"17244351-3059797-4361112","span":{"begin":709,"end":710},"obj":"3059797"},{"id":"17244351-12833157-4361112","span":{"begin":709,"end":710},"obj":"12833157"},{"id":"17244351-15838509-4361112","span":{"begin":709,"end":710},"obj":"15838509"},{"id":"17244351-15208781-4361112","span":{"begin":709,"end":710},"obj":"15208781"},{"id":"17244351-15529344-4361113","span":{"begin":1292,"end":1294},"obj":"15529344"},{"id":"17244351-1675432-4361114","span":{"begin":1924,"end":1926},"obj":"1675432"},{"id":"17244351-12089518-4361115","span":{"begin":2028,"end":2030},"obj":"12089518"},{"id":"17244351-15803197-4361116","span":{"begin":2031,"end":2033},"obj":"15803197"},{"id":"17244351-12493905-4361117","span":{"begin":2149,"end":2151},"obj":"12493905"},{"id":"17244351-12482389-4361118","span":{"begin":2952,"end":2954},"obj":"12482389"},{"id":"17244351-11908948-4361118","span":{"begin":2952,"end":2954},"obj":"11908948"},{"id":"17244351-9122163-4361118","span":{"begin":2952,"end":2954},"obj":"9122163"},{"id":"17244351-15158620-4361118","span":{"begin":2952,"end":2954},"obj":"15158620"},{"id":"17244351-15496955-4361118","span":{"begin":2952,"end":2954},"obj":"15496955"},{"id":"17244351-15973463-4361118","span":{"begin":2952,"end":2954},"obj":"15973463"},{"id":"17244351-15987489-4361118","span":{"begin":2952,"end":2954},"obj":"15987489"},{"id":"17244351-15743466-4361118","span":{"begin":2952,"end":2954},"obj":"15743466"},{"id":"17244351-15158620-4361119","span":{"begin":3201,"end":3203},"obj":"15158620"},{"id":"17244351-15987489-4361120","span":{"begin":3325,"end":3327},"obj":"15987489"},{"id":"17244351-15743466-4361121","span":{"begin":3328,"end":3330},"obj":"15743466"},{"id":"17244351-12482389-4361122","span":{"begin":3481,"end":3483},"obj":"12482389"},{"id":"17244351-11908948-4361123","span":{"begin":3484,"end":3486},"obj":"11908948"}],"text":"Introduction\nSusceptibility to most complex diseases is controlled by many genes, each having a small effect on the disease. One example is rheumatoid arthritis (RA), a common complex multifactorial autoimmune disease. Several studies have been carried out to detect the genetic basis of RA, and more than 30 genomic regions have shown evidence of linkage to the disease. Most of these genomic regions did not reach a genome-wide significant threshold value of linkage, with P values between 0.05 and 0.001 [1-5]. Thus, these loci only have a small effect on RA. Small genetic contributions could also be seen from the susceptibility genes of RA identified so far, including HLA-DR4, PADI4, PTPN22 and FCRL3 [6-9]. Except for HLA-DR4, which is strongly associated with RA, all the other susceptibility genes have only a small effect on the disease. In the mouse model of RA, small genetic contributions are also often observed. For example, in a previous study, we carried out a genome screen to identify the quantitative trait loci (QTL) in collagen-induced arthritis (CIA), which is a widely used animal model of RA. Only one QTL, Cia2, was identified for the phenotype of CIA severity, but this QTL contributes to only 16% of the phenotype variations for CIA susceptibility in F2 progeny [10]. This suggests that there must be other susceptibility genes whose contributions were not big enough to reach the stringent significance threshold value of linkage analysis.\nOne aim of using animal models for complex diseases is to detect the genetic basis of these diseases. With controllable environmental factors as well as the known genetic background, animal models are powerful tools to search for susceptibility genes for complex diseases, and have been intensively employed for that purpose. More than 27,000 QTL have been identified in the mouse genome since the first QTL was identified at the beginning of the 1990s [11]. By 2005, approximately 20 quantitative trait genes (QTGs) in the mouse genome had been identified [12,13]. Interestingly, most QTGs identified in animal models have the causal polymorphisms in the protein-coding region [14], which provoke protein structure changes or protein deficiency. This suggests, on the one hand, that small-effect QTL are difficult to identify with traditional strategies and, on the other hand, that the polymorphisms regulating gene expression might only slightly affect the quantitative traits, and thus are more difficult to identify.\nMicroarray-based global gene expression is a powerful technique for investigating complex diseases. During disease development, genes involved in the disease are likely to be differentially regulated. Therefore, signature genes of the diseases could be identified by detecting the expression patterns of the disease-related cells/tissues and their ideal controls. In the past decade, many studies applied this technique to study both RA and its animal models [15-22]. Indeed, genes involved in arthritis show distinct expression patterns in certain tissues and pathological stages of the disease. Genes involved in immunoinflammatory responses were differentially expressed in the blood cells in RA patients [18]. Chemokines and adhesion molecules were upregulated in the joint at the initiation phase of arthritis in animal models [21,22], while genes involved in cartilage destruction and bone erosion were differentially expressed at the late phase of arthritis in animal models of RA [15,16]. Besides detecting genes involved in complex diseases, microarrays could also be used to detect the genetic polymorphisms regulating gene expression because differential expressions between two strains might be the result of a polymorphism located in regulatory elements.\nTo identify the small-effect QTL of CIA as well as the potential candidate genes inside them, we investigated CIA genetically susceptible and resistant strains at both the genome and transcriptome levels. At the genome level, F2 progeny of the CIA susceptible (DBA/1) and resistant (FVB/N) strains were generated and a genome-wide linkage analysis was performed to identify small-effect QTL. At the transcriptome level, we detected the gene expression patterns of both the DBA/1 and FVB/N strains at four different phases of CIA. The potential candidate genes were identified based on three criteria: they are located within the genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed between the two parental strains during CIA."}
craft-ca-core-dev
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"begin":3835,"end":3840},"obj":"SO:0000704"},{"id":"T2310","span":{"begin":3874,"end":3885},"obj":"SO:0000704"},{"id":"T2311","span":{"begin":3932,"end":3938},"obj":"SO:0001026"},{"id":"T2312","span":{"begin":3972,"end":3978},"obj":"SO:0001026"},{"id":"T2313","span":{"begin":4079,"end":4085},"obj":"SO:0001026"},{"id":"T2314","span":{"begin":4147,"end":4150},"obj":"SO:0000771"},{"id":"T2315","span":{"begin":4196,"end":4200},"obj":"SO:0000704"},{"id":"T2316","span":{"begin":4196,"end":4211},"obj":"GO:0010467"},{"id":"T2317","span":{"begin":4314,"end":4319},"obj":"SO:0000704"},{"id":"T2318","span":{"begin":4389,"end":4396},"obj":"SO:0001026"},{"id":"T2319","span":{"begin":4460,"end":4469},"obj":"GO:0010467"},{"id":"T2320","span":{"begin":4526,"end":4535},"obj":"GO:0010467"}],"text":"Introduction\nSusceptibility to most complex diseases is controlled by many genes, each having a small effect on the disease. One example is rheumatoid arthritis (RA), a common complex multifactorial autoimmune disease. Several studies have been carried out to detect the genetic basis of RA, and more than 30 genomic regions have shown evidence of linkage to the disease. Most of these genomic regions did not reach a genome-wide significant threshold value of linkage, with P values between 0.05 and 0.001 [1-5]. Thus, these loci only have a small effect on RA. Small genetic contributions could also be seen from the susceptibility genes of RA identified so far, including HLA-DR4, PADI4, PTPN22 and FCRL3 [6-9]. Except for HLA-DR4, which is strongly associated with RA, all the other susceptibility genes have only a small effect on the disease. In the mouse model of RA, small genetic contributions are also often observed. For example, in a previous study, we carried out a genome screen to identify the quantitative trait loci (QTL) in collagen-induced arthritis (CIA), which is a widely used animal model of RA. Only one QTL, Cia2, was identified for the phenotype of CIA severity, but this QTL contributes to only 16% of the phenotype variations for CIA susceptibility in F2 progeny [10]. This suggests that there must be other susceptibility genes whose contributions were not big enough to reach the stringent significance threshold value of linkage analysis.\nOne aim of using animal models for complex diseases is to detect the genetic basis of these diseases. With controllable environmental factors as well as the known genetic background, animal models are powerful tools to search for susceptibility genes for complex diseases, and have been intensively employed for that purpose. More than 27,000 QTL have been identified in the mouse genome since the first QTL was identified at the beginning of the 1990s [11]. By 2005, approximately 20 quantitative trait genes (QTGs) in the mouse genome had been identified [12,13]. Interestingly, most QTGs identified in animal models have the causal polymorphisms in the protein-coding region [14], which provoke protein structure changes or protein deficiency. This suggests, on the one hand, that small-effect QTL are difficult to identify with traditional strategies and, on the other hand, that the polymorphisms regulating gene expression might only slightly affect the quantitative traits, and thus are more difficult to identify.\nMicroarray-based global gene expression is a powerful technique for investigating complex diseases. During disease development, genes involved in the disease are likely to be differentially regulated. Therefore, signature genes of the diseases could be identified by detecting the expression patterns of the disease-related cells/tissues and their ideal controls. In the past decade, many studies applied this technique to study both RA and its animal models [15-22]. Indeed, genes involved in arthritis show distinct expression patterns in certain tissues and pathological stages of the disease. Genes involved in immunoinflammatory responses were differentially expressed in the blood cells in RA patients [18]. Chemokines and adhesion molecules were upregulated in the joint at the initiation phase of arthritis in animal models [21,22], while genes involved in cartilage destruction and bone erosion were differentially expressed at the late phase of arthritis in animal models of RA [15,16]. Besides detecting genes involved in complex diseases, microarrays could also be used to detect the genetic polymorphisms regulating gene expression because differential expressions between two strains might be the result of a polymorphism located in regulatory elements.\nTo identify the small-effect QTL of CIA as well as the potential candidate genes inside them, we investigated CIA genetically susceptible and resistant strains at both the genome and transcriptome levels. At the genome level, F2 progeny of the CIA susceptible (DBA/1) and resistant (FVB/N) strains were generated and a genome-wide linkage analysis was performed to identify small-effect QTL. At the transcriptome level, we detected the gene expression patterns of both the DBA/1 and FVB/N strains at four different phases of CIA. The potential candidate genes were identified based on three criteria: they are located within the genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed between the two parental strains during CIA."}