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Meta-Analysis
. 2016 Mar 9;7:10933.
doi: 10.1038/ncomms10933.

Meta-analysis of Genome-Wide Association Studies Discovers Multiple Loci for Chronic Lymphocytic Leukemia

Sonja I Berndt  1 Nicola J Camp  2 Christine F Skibola  3   4 Joseph Vijai  5 Zhaoming Wang  6 Jian Gu  7 Alexandra Nieters  8 Rachel S Kelly  9   10 Karin E Smedby  11 Alain Monnereau  12   13   14 Wendy Cozen  15   16 Angela Cox  17 Sophia S Wang  18 Qing Lan  1 Lauren R Teras  19 Moara Machado  1   20 Meredith Yeager  6 Angela R Brooks-Wilson  21   22 Patricia Hartge  1 Mark P Purdue  23 Brenda M Birmann  24 Claire M Vajdic  25 Pierluigi Cocco  26 Yawei Zhang  27 Graham G Giles  28   29 Anne Zeleniuch-Jacquotte  30   31   32 Charles Lawrence  33 Rebecca Montalvan  33 Laurie Burdett  6 Amy Hutchinson  6 Yuanqing Ye  7 Timothy G Call  34 Tait D Shanafelt  35 Anne J Novak  35 Neil E Kay  34 Mark Liebow  35 Julie M Cunningham  36 Cristine Allmer  37 Henrik Hjalgrim  38 Hans-Olov Adami  9   39 Mads Melbye  38   40 Bengt Glimelius  41 Ellen T Chang  42   43 Martha Glenn  44 Karen Curtin  45 Lisa A Cannon-Albright  45   46 W Ryan Diver  19 Brian K Link  47 George J Weiner  47 Lucia Conde  3   4 Paige M Bracci  48 Jacques Riby  3   4 Donna K Arnett  3 Degui Zhi  49 Justin M Leach  49 Elizabeth A Holly  48 Rebecca D Jackson  50 Lesley F Tinker  51 Yolanda Benavente  52   53 Núria Sala  54   55 Delphine Casabonne  56   57 Nikolaus Becker  58 Paolo Boffetta  59 Paul Brennan  60 Lenka Foretova  61 Marc Maynadie  62 James McKay  60 Anthony Staines  63 Kari G Chaffee  37 Sara J Achenbach  37 Celine M Vachon  37 Lynn R Goldin  1 Sara S Strom  7 Jose F Leis  64 J Brice Weinberg  65 Neil E Caporaso  1 Aaron D Norman  37 Anneclaire J De Roos  51   66 Lindsay M Morton  1 Richard K Severson  67 Elio Riboli  68 Paolo Vineis  10   69 Rudolph Kaaks  58 Giovanna Masala  70 Elisabete Weiderpass  39   71   72   73 María-Dolores Chirlaque  53   74 Roel C H Vermeulen  75   76 Ruth C Travis  77 Melissa C Southey  78 Roger L Milne  28   29 Demetrius Albanes  1 Jarmo Virtamo  79 Stephanie Weinstein  1 Jacqueline Clavel  12   13 Tongzhang Zheng  27 Theodore R Holford  80 Danylo J Villano  5 Ann Maria  5 John J Spinelli  81   82 Randy D Gascoyne  83   84 Joseph M Connors  83   85 Kimberly A Bertrand  9   24 Edward Giovannucci  9   24   86 Peter Kraft  9   87 Anne Kricker  88 Jenny Turner  89   90 Maria Grazia Ennas  91 Giovanni M Ferri  92 Lucia Miligi  93 Liming Liang  9   87 Baoshan Ma  9   94 Jinyan Huang  9 Simon Crouch  95 Ju-Hyun Park  96 Nilanjan Chatterjee  1 Kari E North  97   98 John A Snowden  17   99 Josh Wright  17   99 Joseph F Fraumeni  1 Kenneth Offit  5 Xifeng Wu  7 Silvia de Sanjose  52   53 James R Cerhan  37 Stephen J Chanock  1 Nathaniel Rothman  1 Susan L Slager  37
Affiliations
Free PMC article
Meta-Analysis

Meta-analysis of Genome-Wide Association Studies Discovers Multiple Loci for Chronic Lymphocytic Leukemia

Sonja I Berndt et al. Nat Commun. .
Free PMC article

Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Figures

Figure 1
Figure 1. Regional association plots of the three novel loci and new independent SNP at a known locus associated with the risk of CLL.
(a) Chromosome 3p24.1 (rs9880772), (b) chromosome 6p25.2 (rs73718779), (c) chromosome 3q28 (rs9815073) and (d) chromosome 2q13 (rs9308731). Shown are the −log10 association P values from the discovery fixed effects meta-analysis (dots) and combined discovery and replication fixed effects meta-analysis (diamonds). The lead SNPs are shown in purple. Estimated recombination rates (from 1000 Genomes) are plotted in blue. The SNPs surrounding the most significant SNP are colour-coded to reflect their correlation with this SNP. Pairwise r2 values are from 1000 Genomes European data (March 2012 release). Genes, position of exons and direction of transcription from UCSC genome browser (genome.ucsc.edu) are noted. Plots were generated using LocusZoom (http://csg.sph.umich.edu/locuszoom).
Figure 2
Figure 2. Relationships between loci associated with CLL risk.
(a) The GRAIL results are depicted in a circle plot with the connections between the SNPs and corresponding gene for the established CLL loci. The width of the line corresponds to the strength of the literature-based connectivity with thicker lines representing stronger connections. (b) Depiction of GeneMania results. Query genes are shown in large circles with hatch marks and tightly connected neighbouring genes were shown in small solid circles. The genes belonging to the top function, ‘regulation of apoptotic signalling pathway', are highlighted with red colour. The colour of the line indicates the network: co-expression (lavender), co-localization (purple), genetic interactions (grey), pathway (blue), physical interactions (pink), predicted (orange) and shared protein domains (beige). The figure was created with GeneMania Application version: 3.1.2.8.

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