hip-samples

The zipped file contains 587 .tsv files, one each for each of the 587 subjects included in the study. Each .tsv file (named with the unique identifier for that subject, for example HIPNNNN.tsv) contains a row for each unique nucleotide sequence identified in the analysis. Column titles are defined in the attached ReadMe

A Public Database of Memory and Naive B-Cell Receptor Sequences

<div><p>The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics.</p></div

V family and V gene usage patterns.

<p>The histograms show the relative percent of total sequences (by occupancy) for each of the IGHV families (as shown under the graphs), for the naive (left panel) and memory (right panel) samples, aggregated for the three donors. Within each family, discrete bands represent each of the individual genes. The most abundant genes within each family are indicated (e.g., 69 in IGHV01 refers to the gene IGHV01-69). Overall, memory samples contain fewer IGHV01 and more IGHV03 family sequences than naive samples, with some gene-level differences evident as well.</p

Comparison of CDR3 lengths in naive versus memory B-cell samples.

<p>(<b>a</b>) The graph shows the normalized percentage of total sequences for the naive (orange) and memory B cells (blue) from donor D2. (<b>b</b>) The graph shows the cumulative percentage of total sequences at a given CDR3 length for all naive and memory samples, as indicated in the inset. The technical replicates for donor D1 overlap closely and are not distinguishable in this figure. The memory repertoire is consistently 3 nucleotides (or 1 amino acid) shorter than the naive repertoire at the same cumulative frequency.</p

Experimental and informatic design.

<p><b>(a)</b> Peripheral blood samples from three healthy donors were sorted using flow cytometry to isolate naive (CD19⁺ CD27^- IgD⁺ IgM⁺) and memory (CD19⁺ CD27⁺) B cells. For each sample, approximately 10⁷ cells were distributed into two 96-well plates (i.e., into 188 wells, resulting in ~50,000 cells per well), and processed by immunosequencing. <b>(b)</b> Schematic of the ‘urn sampling’ quantitation method. Cells are represented by colored balls, with each color indicating a different clone identity. Each ball (cell) is randomly allocated to a sample bin (well). Occupancy is calculated after censoring count information, and thus is expressed as presence or absence. The majority of clones are present in just one out of 188 wells, indicating that they were almost certainly represented by a single cell in the original sample.</p

Comparison of Somatic Hyper Mutation in paired naive and memory B-cell samples from the same donor.

<p>The figure shows data for the naive (<b>a</b>) and memory sample (<b>b</b>) from Donor 1, which is representative of all three donors. The x-axis corresponds to the number of substitutions differing from the germline V gene sequence, and the y-axis indicates the number of unique sequences that display that number of substitutions. The colors indicate different total well occupancies, with blue indicating singletons present in just one well, and the other colors showing progressively higher well occupancy, as indicated in the figure. The majority of the sequences in the naive B-cell sample have 0 substitutions and correspond to low abundance clones observed in a single well (blue). In contrast, the memory B cell sample from the same individual shows a much broader distribution of substitutions, as well as many more sequences with occupancy greater than 1.</p

Pleiotropy of Cancer Susceptibility Variants on the Risk of Non-Hodgkin Lymphoma: The PAGE Consortium

<div><p>Background</p><p>Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy).</p><p>Objective</p><p>We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer.</p><p>Methods</p><p>As part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies.</p><p>Results</p><p>The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR = 1.29, <i>p</i> = 0.013; DLBCL OR = 1.23, <i>p</i> = 0.013; NHL OR = 1.22, <i>p</i> = 5.9×E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in <i>TERT</i>: OR per C allele = 0.89, <i>p</i> = 3.7×E-03; rs4975616 in <i>TERT</i>: OR per A allele = 0.90, <i>p</i> = 0.01; rs3131379 in <i>MSH5</i>: OR per T allele = 1.16, <i>p</i> = 0.03), prostate (rs7679673 in <i>TET2</i>: OR per C allele = 0.89, <i>p</i> = 5.7×E-03; rs10993994 in <i>MSMB</i>: OR per T allele = 1.09, <i>p</i> = 0.04), and breast (rs3817198 in <i>LSP1</i>: OR per C allele = 1.12, <i>p</i> = 0.01) cancers, but none of these associations remained significant after multiple test correction.</p><p>Conclusion</p><p>This study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.</p></div

Confirmation of the Reported Association of Clonal Chromosomal Mosaicism with an Increased Risk of Incident Hematologic Cancer

<div><p>Chromosomal abnormalities provide clinical utility in the diagnosis and treatment of hematologic malignancies, and may be predictive of malignant transformation in individuals without apparent clinical presentation of a hematologic cancer. In an effort to confirm previous reports of an association between clonal mosaicism and incident hematologic cancer, we applied the anomDetectBAF algorithm to call chromosomal anomalies in genotype data from previously conducted Genome Wide Association Studies (GWAS). The genotypes were initially collected from DNA derived from peripheral blood of 12,176 participants in the Group Health electronic Medical Records and Genomics study (eMERGE) and the Women’s Health Initiative (WHI). We detected clonal mosaicism in 169 individuals (1.4%) and large clonal mosaic events (>2 mb) in 117 (1.0%) individuals. Though only 9.5% of clonal mosaic carriers had an incident diagnosis of hematologic cancer (multiple myeloma, myelodysplastic syndrome, lymphoma, or leukemia), the carriers had a 5.5-fold increased risk (95% CI: 3.3–9.3; p-value = 7.5×10⁻¹¹) of developing these cancers subsequently. Carriers of large mosaic anomalies showed particularly pronounced risk of subsequent leukemia (HR = 19.2, 95% CI: 8.9–41.6; p-value = 7.3×10⁻¹⁴). Thus we independently confirm the association between detectable clonal mosaicism and hematologic cancer found previously in two recent publications.</p> </div

Comparison of GWAS-identified ANM variants in African American women in PAGE Study.

<p>Comparison of previously reported SNPs associated with ANM in European and Chinese descent women to 1,860 African American women from the PAGE Study. Data presented are for the previously identified SNP. If the previously identified SNP was not directly genotyped in present study, data are shown for the best proxy SNP based on linkage disequilibrium calculated from the International HapMap Project CEU data.</p

Regional Association Plots for Age at Menarche in African American women in the PAGE Study.

<p>Locus Zoom plots for selected gene regions in age at menarche analysis. Vertical axis is –log₁₀ of the p-value, the horizontal axis is the chromosomal position. Each dot represents a SNP tested for association with age at natural menopause in 1,860 African American women from the PAGE Study. Approximate linkage disequilibrium between the most significant SNP, listed at the top of each plot, and the other SNPs in the plot is shown by the r² legend in each plot. (A) Locus Zoom plot for the <i>CYP19A1</i> region, with rs10519297 the most significant SNP in the region. (B) Locus Zoom plot for the <i>FTO</i> region; rs2689243 was the most significant SNP in the plot region. (C) <i>LIN28B</i> region Locus Zoom plot; rs408949 was the most significant SNP in the plot region. (D) Locus Zoom plot of the <i>CYP1B1</i> region; rs13391045 was the most significant SNP in the plot region.</p