Document Detail


Whole-genome detection of disease-associated deletions or excess homozygosity in a case-control study of rheumatoid arthritis.
MedLine Citation:
PMID:  23223014     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Unlike genome-wide association studies, few comprehensive studies of copy number variation's contribution to complex human disease susceptibility have been performed. Copy number variations are abundant in humans and represent one of the least well-studied classes of genetic variants; in addition, known rheumatoid arthritis susceptibility loci explain only a portion of familial clustering. Therefore, we performed a genome-wide study of association between deletion or excess homozygosity and rheumatoid arthritis using high-density 550 K SNP genotype data from a genome-wide association study. We used a genome-wide statistical method that we recently developed to test each contiguous SNP locus between 868 cases and 1194 controls to detect excess homozygosity or deletion variants that influence susceptibility. Our method is designed to detect statistically significant evidence of deletions or homozygosity at individual SNPs for SNP-by-SNP analyses and to combine the information among neighboring SNPs for cluster analyses. In addition to successfully detecting the known deletion variants on major histocompatibility complex, we identified 4.3 and 28 kb clusters on chromosomes 10p and 13q, respectively, which were significant at a Bonferroni-type-corrected 0.05 nominal significant level. Independently, we performed analyses using PennCNV, an algorithm for identifying and cataloging copy numbers for individuals based on a hidden Markov model, and identified cases and controls that had chromosomal segments with copy number <2. Using Fisher's exact test for comparing the numbers of cases and controls with copy number <2 per SNP, we identified 26 significant SNPs (protective; more controls than cases) aggregating on chromosome 14 with P-values <10(-8).
Authors:
Chih-Chieh Wu; Sanjay Shete; Eun-Ji Jo; Yaji Xu; Emily Y Lu; Wei V Chen; Christopher I Amos
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-12-06
Journal Detail:
Title:  Human molecular genetics     Volume:  22     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-22     Completed Date:  2013-08-30     Revised Date:  2014-03-26    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  1249-61     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Arthritis, Rheumatoid / genetics*
Case-Control Studies
DNA Copy Number Variations
Female
Genome-Wide Association Study*
Homozygote
Humans
Male
Polymorphism, Single Nucleotide
Sequence Deletion*
Grant Support
ID/Acronym/Agency:
AR44422/AR/NIAMS NIH HHS; P30 CA016672/CA/NCI NIH HHS; P30 CA016772/CA/NCI NIH HHS; R01 AR044422/AR/NIAMS NIH HHS; R03 CA143979/CA/NCI NIH HHS; R03 CA143979/CA/NCI NIH HHS
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