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Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32.

Conde L, Halperin E, Akers NK, Brown KM, Smedby KE, Rothman N, Nieters A, Slager SL, Brooks-Wilson A, Agana L, Riby J, Liu J, Adami HO, Darabi H, Hjalgrim H, Low HQ, Humphreys K, Melbye M, Chang ET, Glimelius B, Cozen W, Davis S, Hartge P, Morton LM, Schenk M, Wang SS, Armstrong B, Kricker A, Milliken S, Purdue MP, Vajdic CM, Boyle P, Lan Q, Zahm SH, Zhang Y, Zheng T, Becker N, Benavente Y, Boffetta P, Brennan P, Butterbach K, Cocco P, Foretova L, Maynadié M, de Sanjosé S, Staines A, Spinelli JJ, Achenbach SJ, Call TG, Camp NJ, Glenn M, Caporaso NE, Cerhan JR, Cunningham JM, Goldin LR, Hanson CA, Kay NE, Lanasa MC, Leis JF, Marti GE, Rabe KG, Rassenti LZ, Spector LG, Strom SS, Vachon CM, Weinberg JB, Holly EA, Chanock S, Smith MT, Bracci PM, Skibola CF - Nat. Genet. (2010)

Bottom Line: To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study.We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility.We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

View Article: PubMed Central - PubMed

Affiliation: School of Public Health, University of California, Berkeley, Berkeley, California, USA.

ABSTRACT
To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

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LD and association results for the FL-associated regions in the major histocompatibility complex (MHC)In the main panel, trend p-values (as -log10) are shown for SNPs genotyped in the MHC region between positions 30,000Mb and 35,000Mb, where two independent FL-associated peaks were found. The first peak, represented by rs6457327 (in yellow), is located at 6p21.33 in the MHC Class I region. The second independent peak, represented by rs10484561 (in green), is located at 6p21.32 in the MHC Class II region. The secondary panel shows the SNPs genotyped (in black) and imputed (in red) in Stage 1 in a 500kb region centered on rs10484561 at 6p21.32. Imputations were based on data from HapMap Phase II release #22 in CEU population. Figure constructed using the snp.plotter R package (http://cbdb.nimh.nih.gov/∼kristin/snp.plotter.html).
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Figure 1: LD and association results for the FL-associated regions in the major histocompatibility complex (MHC)In the main panel, trend p-values (as -log10) are shown for SNPs genotyped in the MHC region between positions 30,000Mb and 35,000Mb, where two independent FL-associated peaks were found. The first peak, represented by rs6457327 (in yellow), is located at 6p21.33 in the MHC Class I region. The second independent peak, represented by rs10484561 (in green), is located at 6p21.32 in the MHC Class II region. The secondary panel shows the SNPs genotyped (in black) and imputed (in red) in Stage 1 in a 500kb region centered on rs10484561 at 6p21.32. Imputations were based on data from HapMap Phase II release #22 in CEU population. Figure constructed using the snp.plotter R package (http://cbdb.nimh.nih.gov/∼kristin/snp.plotter.html).

Mentions: In Stage 1, we conducted a GWAS using a subset of samples (SF1 study) chosen from a larger population-based case-control study of NHL based in the San Francisco Bay Area3. After applying quality control metrics (Supplementary Methods), 213 FL, 211 CLL/SLL and 257 DLBCL cases and 750 controls were included in the final statistical analysis of Stage 1. The genome-wide results for FL, CLL/SLL and DLBCL are represented in Supplementary Fig. 2a-c, where overall, 18 SNPs showed unadjusted trend p-values below a 10-5 threshold (Supplementary Table 2). The most notable findings were for SNPs associated with FL in the major histocompatibility complex (MHC) region on chromosome 6, concentrated around two independent peaks at 6p21.33 and 6p21.32 (r2<0.01; Figure 1). The strongest signal in 6p21.33 is located at the psoriasis susceptibility region 1 (PSORS1) (rs1265086, trend p-value=3.34×10-6, Supplementary Table 3), where we have previously detected a FL susceptibility locus2. The 6p21.32 association peak is located in a region encompassing the HLA-DR and HLA-DQ genes. Here, eight SNPs exhibited trend p-values ≤10-4 (Supplementary Table 3).


Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32.

Conde L, Halperin E, Akers NK, Brown KM, Smedby KE, Rothman N, Nieters A, Slager SL, Brooks-Wilson A, Agana L, Riby J, Liu J, Adami HO, Darabi H, Hjalgrim H, Low HQ, Humphreys K, Melbye M, Chang ET, Glimelius B, Cozen W, Davis S, Hartge P, Morton LM, Schenk M, Wang SS, Armstrong B, Kricker A, Milliken S, Purdue MP, Vajdic CM, Boyle P, Lan Q, Zahm SH, Zhang Y, Zheng T, Becker N, Benavente Y, Boffetta P, Brennan P, Butterbach K, Cocco P, Foretova L, Maynadié M, de Sanjosé S, Staines A, Spinelli JJ, Achenbach SJ, Call TG, Camp NJ, Glenn M, Caporaso NE, Cerhan JR, Cunningham JM, Goldin LR, Hanson CA, Kay NE, Lanasa MC, Leis JF, Marti GE, Rabe KG, Rassenti LZ, Spector LG, Strom SS, Vachon CM, Weinberg JB, Holly EA, Chanock S, Smith MT, Bracci PM, Skibola CF - Nat. Genet. (2010)

LD and association results for the FL-associated regions in the major histocompatibility complex (MHC)In the main panel, trend p-values (as -log10) are shown for SNPs genotyped in the MHC region between positions 30,000Mb and 35,000Mb, where two independent FL-associated peaks were found. The first peak, represented by rs6457327 (in yellow), is located at 6p21.33 in the MHC Class I region. The second independent peak, represented by rs10484561 (in green), is located at 6p21.32 in the MHC Class II region. The secondary panel shows the SNPs genotyped (in black) and imputed (in red) in Stage 1 in a 500kb region centered on rs10484561 at 6p21.32. Imputations were based on data from HapMap Phase II release #22 in CEU population. Figure constructed using the snp.plotter R package (http://cbdb.nimh.nih.gov/∼kristin/snp.plotter.html).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913472&req=5

Figure 1: LD and association results for the FL-associated regions in the major histocompatibility complex (MHC)In the main panel, trend p-values (as -log10) are shown for SNPs genotyped in the MHC region between positions 30,000Mb and 35,000Mb, where two independent FL-associated peaks were found. The first peak, represented by rs6457327 (in yellow), is located at 6p21.33 in the MHC Class I region. The second independent peak, represented by rs10484561 (in green), is located at 6p21.32 in the MHC Class II region. The secondary panel shows the SNPs genotyped (in black) and imputed (in red) in Stage 1 in a 500kb region centered on rs10484561 at 6p21.32. Imputations were based on data from HapMap Phase II release #22 in CEU population. Figure constructed using the snp.plotter R package (http://cbdb.nimh.nih.gov/∼kristin/snp.plotter.html).
Mentions: In Stage 1, we conducted a GWAS using a subset of samples (SF1 study) chosen from a larger population-based case-control study of NHL based in the San Francisco Bay Area3. After applying quality control metrics (Supplementary Methods), 213 FL, 211 CLL/SLL and 257 DLBCL cases and 750 controls were included in the final statistical analysis of Stage 1. The genome-wide results for FL, CLL/SLL and DLBCL are represented in Supplementary Fig. 2a-c, where overall, 18 SNPs showed unadjusted trend p-values below a 10-5 threshold (Supplementary Table 2). The most notable findings were for SNPs associated with FL in the major histocompatibility complex (MHC) region on chromosome 6, concentrated around two independent peaks at 6p21.33 and 6p21.32 (r2<0.01; Figure 1). The strongest signal in 6p21.33 is located at the psoriasis susceptibility region 1 (PSORS1) (rs1265086, trend p-value=3.34×10-6, Supplementary Table 3), where we have previously detected a FL susceptibility locus2. The 6p21.32 association peak is located in a region encompassing the HLA-DR and HLA-DQ genes. Here, eight SNPs exhibited trend p-values ≤10-4 (Supplementary Table 3).

Bottom Line: To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study.We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility.We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

View Article: PubMed Central - PubMed

Affiliation: School of Public Health, University of California, Berkeley, Berkeley, California, USA.

ABSTRACT
To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

Show MeSH
Related in: MedlinePlus