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Linkage analysis of anti-CCP levels as dichotomized and quantitative traits using GAW15 single-nucleotide polymorphism scan of NARAC families.

Yang XR, Kerstann KF, Bergen AW, Goldstein AM, Goldin LR - BMC Proc (2007)

Bottom Line: We also wanted to compare linkage signals when analyzing anti-CCP levels as dichotomized (CCP_binary), categorical (CCP_cat), and continuous traits, with and without transformation (log_CCP and CCP_cont).The only exception was that we observed improved linkage signals and a narrower region for CCP_binary as compared to a clinical diagnosis of rheumatoid arthritis alone on chromosome 7, a region which previously showed variation in linkage results with rheumatoid arthritis according to anti-CCP levels.Our study also highlighted that quantitative trait linkage results are highly sensitive to phenotype transformation and analytic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, MSC 7236, Bethesda, Maryland 20892, USA. royang@mail.nih.gov

ABSTRACT
Rheumatoid arthritis is a clinically and genetically heterogeneous disease. Anti-cyclic citrullinated (anti-CCP) antibodies have a high specificity for rheumatoid arthritis and levels correlate with disease severity. The focus of this study was to examine whether analyzing anti-CCP levels could increase the power of linkage analysis by identifying a more homogeneous subset of rheumatoid arthritis patients. We also wanted to compare linkage signals when analyzing anti-CCP levels as dichotomized (CCP_binary), categorical (CCP_cat), and continuous traits, with and without transformation (log_CCP and CCP_cont). Illumina single-nucleotide polymorphism scans of the North American Rheumatoid Arthritis Consortium families were analyzed for four chromosomes (6, 7, 11, 22) using nonparametric linkage (NPL) (rheumatoid arthritis and CCP_binary), regress (CCP_cat and Log_CCP), and deviates (CCP_cont) analysis options as implemented in Merlin. Similar linkage results were obtained from analyses of rheumatoid arthritis, CCP_binary, and CCP_cont. The only exception was that we observed improved linkage signals and a narrower region for CCP_binary as compared to a clinical diagnosis of rheumatoid arthritis alone on chromosome 7, a region which previously showed variation in linkage results with rheumatoid arthritis according to anti-CCP levels. Analyses of CCP_cat and Log_CCP had little power to detect linkage. Our data suggested that linkage analyses of anti-CCP levels may facilitate identification of rheumatoid arthritis genes but quantitative analyses did not further improve power. Our study also highlighted that quantitative trait linkage results are highly sensitive to phenotype transformation and analytic approaches.

No MeSH data available.


Related in: MedlinePlus

Linkage analyses of 4 chromosomes for RA and anti-CCP levels using SNPs. LOD scores for binary outcomes (RA, CCP_binary), transformed quantitative traits (CCP_cat, Log_CCP), and untransformed quantitative trait (CCP_cont) were calculated using Merlin NPL, Merlin Regress, Merlin --deviates, respectively. The scale of the Y-axis for chromosome 6 is different.
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Figure 1: Linkage analyses of 4 chromosomes for RA and anti-CCP levels using SNPs. LOD scores for binary outcomes (RA, CCP_binary), transformed quantitative traits (CCP_cat, Log_CCP), and untransformed quantitative trait (CCP_cont) were calculated using Merlin NPL, Merlin Regress, Merlin --deviates, respectively. The scale of the Y-axis for chromosome 6 is different.

Mentions: Results obtained from NPL analysis of RA are consistent with those shown previously by Amos et al. [6]. Overall, similar linkage signals were obtained from analyses with RA and CCP_binary, with weaker evidence for linkage with CCP_binary on chromosomes 6 and 11 (Table 3, Figure 1). On the other hand, higher LOD scores and improved definition of a linkage peak for CCP_binary were observed on chromosome 7 (Figure 1), which has been suggested to be more closely linked to anti-CCP compared to RA. Among quantitative anti-CCP levels, only analysis of untransformed anti-CCP levels showed comparable results with that of RA. Analyses of either categorical or log-transformed anti-CCP levels resulted in significantly reduced linkage signals for both positive control (chromosome 6) and test regions (chromosomes 7 and 11). Adjustment of gender and ever smoking in the regression-based linkage analyses did not significantly change the results (data not shown). As expected, chromosome 22 did not show evidence for linkage to any of the phenotypes.


Linkage analysis of anti-CCP levels as dichotomized and quantitative traits using GAW15 single-nucleotide polymorphism scan of NARAC families.

Yang XR, Kerstann KF, Bergen AW, Goldstein AM, Goldin LR - BMC Proc (2007)

Linkage analyses of 4 chromosomes for RA and anti-CCP levels using SNPs. LOD scores for binary outcomes (RA, CCP_binary), transformed quantitative traits (CCP_cat, Log_CCP), and untransformed quantitative trait (CCP_cont) were calculated using Merlin NPL, Merlin Regress, Merlin --deviates, respectively. The scale of the Y-axis for chromosome 6 is different.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2367471&req=5

Figure 1: Linkage analyses of 4 chromosomes for RA and anti-CCP levels using SNPs. LOD scores for binary outcomes (RA, CCP_binary), transformed quantitative traits (CCP_cat, Log_CCP), and untransformed quantitative trait (CCP_cont) were calculated using Merlin NPL, Merlin Regress, Merlin --deviates, respectively. The scale of the Y-axis for chromosome 6 is different.
Mentions: Results obtained from NPL analysis of RA are consistent with those shown previously by Amos et al. [6]. Overall, similar linkage signals were obtained from analyses with RA and CCP_binary, with weaker evidence for linkage with CCP_binary on chromosomes 6 and 11 (Table 3, Figure 1). On the other hand, higher LOD scores and improved definition of a linkage peak for CCP_binary were observed on chromosome 7 (Figure 1), which has been suggested to be more closely linked to anti-CCP compared to RA. Among quantitative anti-CCP levels, only analysis of untransformed anti-CCP levels showed comparable results with that of RA. Analyses of either categorical or log-transformed anti-CCP levels resulted in significantly reduced linkage signals for both positive control (chromosome 6) and test regions (chromosomes 7 and 11). Adjustment of gender and ever smoking in the regression-based linkage analyses did not significantly change the results (data not shown). As expected, chromosome 22 did not show evidence for linkage to any of the phenotypes.

Bottom Line: We also wanted to compare linkage signals when analyzing anti-CCP levels as dichotomized (CCP_binary), categorical (CCP_cat), and continuous traits, with and without transformation (log_CCP and CCP_cont).The only exception was that we observed improved linkage signals and a narrower region for CCP_binary as compared to a clinical diagnosis of rheumatoid arthritis alone on chromosome 7, a region which previously showed variation in linkage results with rheumatoid arthritis according to anti-CCP levels.Our study also highlighted that quantitative trait linkage results are highly sensitive to phenotype transformation and analytic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, MSC 7236, Bethesda, Maryland 20892, USA. royang@mail.nih.gov

ABSTRACT
Rheumatoid arthritis is a clinically and genetically heterogeneous disease. Anti-cyclic citrullinated (anti-CCP) antibodies have a high specificity for rheumatoid arthritis and levels correlate with disease severity. The focus of this study was to examine whether analyzing anti-CCP levels could increase the power of linkage analysis by identifying a more homogeneous subset of rheumatoid arthritis patients. We also wanted to compare linkage signals when analyzing anti-CCP levels as dichotomized (CCP_binary), categorical (CCP_cat), and continuous traits, with and without transformation (log_CCP and CCP_cont). Illumina single-nucleotide polymorphism scans of the North American Rheumatoid Arthritis Consortium families were analyzed for four chromosomes (6, 7, 11, 22) using nonparametric linkage (NPL) (rheumatoid arthritis and CCP_binary), regress (CCP_cat and Log_CCP), and deviates (CCP_cont) analysis options as implemented in Merlin. Similar linkage results were obtained from analyses of rheumatoid arthritis, CCP_binary, and CCP_cont. The only exception was that we observed improved linkage signals and a narrower region for CCP_binary as compared to a clinical diagnosis of rheumatoid arthritis alone on chromosome 7, a region which previously showed variation in linkage results with rheumatoid arthritis according to anti-CCP levels. Analyses of CCP_cat and Log_CCP had little power to detect linkage. Our data suggested that linkage analyses of anti-CCP levels may facilitate identification of rheumatoid arthritis genes but quantitative analyses did not further improve power. Our study also highlighted that quantitative trait linkage results are highly sensitive to phenotype transformation and analytic approaches.

No MeSH data available.


Related in: MedlinePlus