Explore the vast range of titles available.

Clostridioides difficile ( C. diff. ) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10 –14 ; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.

The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12–2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the “missing heritability” for other complex genetic traits.

Schizophrenia risk: link to chromosome 6p22.1 A genome-wide association study using the Molecular Genetics of Schizophrenia case-control data set, followed by a meta-analysis that included over 8,000 cases and 19,000 controls, revealed that while common genetic variation that underlies risk to schizophrenia can be identified, there probably are few or no single common loci with large effects. The common variants identified here lie on chromosome 6p22.1 in a region that includes a histone gene cluster and several genes implicated in immunity. In the third of three papers looking at the genetics of schizophrenia, a genome-wide association study using the Molecular Genetics of Schizophrenia case-control data set followed by a meta-analysis further implicates the major histocompatibility complex. The study also reveals that although common schizophrenia susceptibility alleles can be detected, there are probably few or no single common loci with large effects. Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission 1 . Recent studies implicate rare, large, high-penetrance copy number variants in some cases 2 , but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 ( P = 9.54 × 10 -9 ). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

A large genomewide association study of multiple sclerosis uncovered a number of single-nucleotide polymorphisms that have a strong statistical association with the disease. Of these allelic variants, the three with the strongest association relate to immunologic elements: a gene in the HLA region and alleles of IL2RA and IL7RA . Both IL2RA and IL7RA have been implicated in other autoimmune diseases. A large genomewide association study of multiple sclerosis uncovered a number of single-nucleotide polymorphisms that have a strong statistical association with the disease. Multiple sclerosis, the most common neurologic disease affecting young adults, is an inflammatory, presumed autoimmune disorder in which lymphocytes and macrophages infiltrate the central nervous system, 1 – 3 sometimes together with antibodies and complement. 4 , 5 Axonal transection with neuronal loss can be an early event in the disease. 6 Systemically, there is subtle dysregulation of cellular and humoral immune responses with a loss of regulatory T-cell function. 7 Studies of twins and sibling pairs suggest that genetic factors influence susceptibility to multiple sclerosis; the evidence indicates that multiple genes, each exerting only modest effects, probably play a part. 3 , 8 Candidate-gene studies have validated . . .

The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.

White blood cell count (WBC) is unique among identified inflammatory predictors of chronic disease in that it is routinely measured in asymptomatic patients in the course of routine patient care. We led a genome-wide association analysis to identify variants associated with WBC levels in 13,923 subjects in the electronic Medical Records and Genomics (eMERGE) Network. We identified two regions of interest that were each unique to subjects of genetically determined ancestry to the African continent (AA) or to the European continent (EA). WBC varies among different ancestry groups. Despite being ancestry specific, these regions were identifiable in the combined analysis. In AA subjects, the region surrounding the Duffy antigen/chemokine receptor gene ( DARC ) on 1q21 exhibited significant association ( p value = 6.71e−55). These results validate the previously reported association between WBC and of the regulatory variant rs2814778 in the promoter region, which causes the Duffy negative phenotype (Fy−/−). A second missense variant (rs12075) is responsible for the two principal antigens, Fya and Fyb of the Duffy blood group system. The two variants, consisting of four alleles, act in concert to produce five antigens and subsequent phenotypes. We were able to identify the marginal and novel interaction effects of these two variants on WBC. In the EA subjects, we identified significantly associated SNPs tagging three separate genes in the 17q21 region: (1) GSDMA , (2) MED24 , and (3) PSMD3. Variants in this region have been reported to be associated with WBC, neutrophil count, and inflammatory diseases including asthma and Crohn’s disease.

Purpose: Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors. Methods: The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making. Results: Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site). Conclusion: The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts. Genet Med 2012:14(4):424–431

Association of IL4R Haplotypes With Type 1 Diabetes Daniel B. Mirel 1 , Ana Maria Valdes 1 , Laura C. Lazzeroni 2 , Rebecca L. Reynolds 1 , Henry A. Erlich 1 3 and Janelle A. Noble 3 1 Department of Human Genetics, Roche Molecular Systems, Alameda, California 2 Division of Biostatistics, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California 3 Children’s Hospital Oakland Research Institute, Oakland, California Abstract We have investigated, in 282 multiplex Caucasian families (the Human Biological Data Interchange Repository), the association of type 1 diabetes with polymorphisms in the IL4R gene. IL4R encodes a subunit of the interleukin-4 receptor, a molecule critical to T-helper cell development. By genotyping eight different IL4R single-nucleotide polymorphisms (SNPs) and identifying haplotypes (complex alleles) in the multiplex type 1 diabetic families who were stratified for HLA genotype, we have observed significant evidence of linkage and association of the IL4R gene to type 1 diabetes. In particular, we have identified a specific haplotype that appears to be protective and observed that this protective effect is strongest among individuals not carrying the HLA DR3/DR4 genotype (which confers the strongest genetic risk for type 1 diabetes). These findings suggest an important role for the IL4R gene in immune-related disease susceptibility and illustrate the value of using multi-SNP haplotype information in association studies. Footnotes Address correspondence and reprint requests to Henry A. Erlich, Roche Molecular Systems, 1145 Atlantic Ave., Alameda CA 94501. E-mail: henry.erlich{at}roche.com . Received for publication 8 February 2002 and accepted in revised form 26 July 2002. HBDI, Human Biological Data Interchange; IBD, identity by descent; IL4, interleukin-4; LD, linkage disequilibrium; LOD, logarithm of odds; OR, odds ratio; SNP, single-nucleotide polymorphism; TDT, transmission disequilibrium test. DIABETES

To use genome-wide fixed marker arrays and improved analytical tools to detect genetic associations with type 2 diabetes in a carefully phenotyped human sample. A total of 1,087 Framingham Heart Study (FHS) family members were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array and examined for association with incident diabetes and six diabetes-related quantitative traits. Quality control filters yielded 66,543 SNPs for association testing. We used two complementary SNP selection strategies (a \"lowest P value\" strategy and a \"multiple related trait\" strategy) to prioritize 763 SNPs for replication. We genotyped a subset of 150 SNPs in a nonoverlapping sample of 1,465 FHS unrelated subjects and examined all 763 SNPs for in silico replication in three other 100K and one 500K genome-wide association (GWA) datasets. We replicated associations of 13 SNPs with one or more traits in the FHS unrelated sample (16 expected under the null); none of them showed convincing in silico replication in 100K scans. Seventy-eight SNPs were nominally associated with diabetes in one other 100K GWA scan, and two (rs2863389 and rs7935082) in more than one. Twenty-five SNPs showed promising associations with diabetes-related traits in 500K GWA data; one of them (rs952635) replicated in FHS. Five previously reported associations were confirmed in our initial dataset. The FHS 100K GWA resource is useful for follow-up of genetic associations with diabetes-related quantitative traits. Discovery of new diabetes genes will require larger samples and a denser array combined with well-powered replication strategies.