High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications.

We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of Caucasians (65.2%) and African-Americans (34.2%), was analyzed for CNVs in a single study using a uniform array platform and computational process. We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These nonunique CNVs mapped to 3272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications, and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics.

Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn's disease.

BACKGROUND & AIMS: Recently an association was shown between the single nucleotide polymorphism (SNP), rs11209026, within the interleukin-23 receptor (IL23R) locus and Crohn's disease (CD) as a consequence of a genome-wide association study of this disease in adults. We examined the effects of this and other previously reported SNPs at this locus with respect to CD in children. METHODS: By using data from our ongoing genome-wide association study in our cohort of 142 pediatric CD patients and 281 matched controls, we investigated the association of the previously reported SNPs at the IL23R locus with the childhood form of this disease. RESULTS: By using the Fisher exact test, the minor allele frequency of rs11209026 in the patients was 1.75%, whereas it was 6.61% in the controls, yielding a protective odds ratio (OR) of 0.25 (95% confidence interval, 0.10-0.65; 1-sided P = 9.2 x 10(-4)). Furthermore, of all the SNPs previously reported, rs11209026 was associated the most strongly. A subsequent family based association test (which is more resistant to population stratification) with 65 sets of trios derived from our initial patient cohort yielded significant association with rs11209026 in a transmission disequilibrium test (1-sided P = .0017). In contrast, no association was detected to the caspase-recruitment domain 15 gene for the inflammatory bowel disease phenotype. CONCLUSIONS: The OR of the IL23R variant in our pediatric study is highly comparable with that reported previously in a non-Jewish adult inflammatory bowel disease case-control cohort (OR, 0.26). As such, variants in the IL23R gene confer a similar magnitude of risk of CD to children as for their adult counterparts.

A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study.

OBJECTIVE: In stage 1 of our genome-wide association (GWA) study for type 1 diabetes, one locus at 16p13 was detected (P = 1.03 x 10(-10)) and confirmed in two additional cohorts. Here we describe the results of testing, in these additional cohorts, 23 loci that were next in rank of statistical significance. RESEARCH DESIGN AND METHODS: Two independent cohorts were studied. The Type 1 Diabetes Genetics Consortium replication cohort consisted of 549 families with at least one child diagnosed with diabetes (946 total affected) and DNA from both parents. The Canadian replication cohort consisted of 364 nuclear family trios with one type 1 diabetes-affected offspring and two parents (1,092 individuals). RESULTS: One locus at 12q13, with the highest statistical significance among the 23, was confirmed. It involves type 1 diabetes association with the minor allele of rs1701704 (P = 9.13 x 10(-10), OR 1.25 [95% CI 1.12-1.40]). CONCLUSIONS: We have discovered a type 1 diabetes locus at 12q13 that is replicated in an independent cohort of type 1 diabetic patients and confers a type 1 diabetes risk comparable with that of the 16p13 locus we recently reported. These two loci are identical to two loci identified by the whole-genome association study of the Wellcome Trust Case-Control Consortium, a parallel independent discovery that adds further support to the validity of the GWA approach.