Jordan S. Orange, MD, PhD, Joseph T

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Presentation transcript:

Genome-wide association identifies diverse causes of common variable immunodeficiency Jordan S. Orange, MD, PhD, Joseph T. Glessner, MS, Elena Resnick, MD, Kathleen E. Sullivan, MD, Mary Lucas, MD, Berne Ferry, MD, Cecilia E. Kim, BS, Cuiping Hou, BS, Fengxiang Wang, BS, Rosetta Chiavacci, BSN, Subra Kugathasan, MD, John W. Sleasman, MD, Robert Baldassano, MD, Elena E. Perez, MD, Helen Chapel, MD, Charlotte Cunningham-Rundles, MD, Hakon Hakonarson, MD, PhD Journal of Allergy and Clinical Immunology Volume 127, Issue 6, Pages 1360-1367.e6 (June 2011) DOI: 10.1016/j.jaci.2011.02.039 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Case-control allele frequency significance. SNP-based case-control significance is shown in negative log base 10 genome-wide analysis for (A) discovery- and (B) replication-inclusive CVID cohorts. (C) Subsequently, CVID cases with specific disease subphenotypes were compared with CVID cases without the subphenotype. The single-SNP tests are shown as single points. Multiple neighboring SNPs of similar significance boost confidence in the association, as shown in the strong peak on 6p22.1-p21.32 of the discovery case-control cohort. Conversely, the median significance P value is kept low by minimizing population stratification, which minimizes the genomic inflation factor. Journal of Allergy and Clinical Immunology 2011 127, 1360-1367.e6DOI: (10.1016/j.jaci.2011.02.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 SVM prediction of CVID status. Plotted are log base 2 SVM scaling values of cost C (the penalty parameter of SVMs) and γ (1/number of variables) from LIMSVM software. Data were coded as +1 for affected and −1 for unaffected subjects. Genotype was scaled as follows: AA, 0; AB, 0.5; and BB, 1. Lines represent modeling with increasing resolution, with the green line representing the final model solution. The model was generated by using the discovery cohort and control subjects, whereas the subjects represented (blue, CVID cases; red, control subjects) were from the separate replication cohort. Journal of Allergy and Clinical Immunology 2011 127, 1360-1367.e6DOI: (10.1016/j.jaci.2011.02.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

CVID clinical subphenotypes CVID clinical subphenotypes. The core diagnosis of CVID has many clinical progressions with varying frequencies. The height and size of subphenotypes signify the frequency of the specific progression. Given significant SNP genotype associations for each CVID subphenotype progression versus patients with CVID without the progression, predictions can be made that might improve clinical outcomes. GI, Gastrointestinal; OSAI, organ-specific autoimmunity. Journal of Allergy and Clinical Immunology 2011 127, 1360-1367.e6DOI: (10.1016/j.jaci.2011.02.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Frequency of deletion and duplication CNVs in cases and control subjects. CNVs are called on a single sample basis, with deletions and duplications in specific genomic regions based on the genotype and intensity signal of contiguous SNPs. These single-sample CNV profiles are plotted as an SNP-based statistic to allow for SNP-based association testing. Lastly, neighboring SNPs with similar significance define a CNV. Red, Case deletion; blue, case duplication; black, control deletion; purple, control duplication. Journal of Allergy and Clinical Immunology 2011 127, 1360-1367.e6DOI: (10.1016/j.jaci.2011.02.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Duplication of ORC4L found exclusive to 15 CVID cases Duplication of ORC4L found exclusive to 15 CVID cases. Vertical blue lines indicate the SNP probe coverage. Green rectangles delineate regions of CNVs in individual cases. Three exons of ORC4L are shown duplicated in 15 cases and 0 control subjects. It is likely that the duplications could extend to a larger region of ORC4L based on coverage. Journal of Allergy and Clinical Immunology 2011 127, 1360-1367.e6DOI: (10.1016/j.jaci.2011.02.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

CNV validation with Illumina intensity data review and independent array technology with Affymetrix 2.7M. A, Visual validation of all reported CNV loci by using Illumina Quad 610 intensity data. Results from visual inspections are provided. The gray rectangle represents normal diploid 2-copy state. B, Representative experimental validation of 2 of the most significant deletions and 2 duplications by using Affymetrix 2.7M intensity data at a high resolution. Intensity values are plotted for each region listed on the basis of samples with CNV calls. C, Experimental validation of all Table II loci using Affymetrix 2.7M intensity data. Intensity values are plotted for each region listed based on samples with CNV calls. Table II loci are labeled with corresponding intensity values for contiguous probes in the genomic region. Journal of Allergy and Clinical Immunology 2011 127, 1360-1367.e6DOI: (10.1016/j.jaci.2011.02.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

CNV validation with Illumina intensity data review and independent array technology with Affymetrix 2.7M. A, Visual validation of all reported CNV loci by using Illumina Quad 610 intensity data. Results from visual inspections are provided. The gray rectangle represents normal diploid 2-copy state. B, Representative experimental validation of 2 of the most significant deletions and 2 duplications by using Affymetrix 2.7M intensity data at a high resolution. Intensity values are plotted for each region listed on the basis of samples with CNV calls. C, Experimental validation of all Table II loci using Affymetrix 2.7M intensity data. Intensity values are plotted for each region listed based on samples with CNV calls. Table II loci are labeled with corresponding intensity values for contiguous probes in the genomic region. Journal of Allergy and Clinical Immunology 2011 127, 1360-1367.e6DOI: (10.1016/j.jaci.2011.02.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions