Blood soluble E-selectin (sE-selectin) levels have been related to various conditions such as type 2 diabetes. We performed a genome-wide association study among women of European ancestry from the ...Nurses' Health Study, and identified genome-wide significant associations between a cluster of markers at the ABO locus (9q34) and plasma sE-selectin concentration. The strongest association was with rs651007, which explained ∼9.71% of the variation in sE-selectin concentrations. SNP rs651007 was also nominally associated with soluble intracellular cell adhesion molecule-1 (sICAM-1) (P = 0.026) and TNF-R2 levels (P = 0.018), independent of sE-selectin. In addition, the genetic-inferred ABO blood group genotypes were associated with sE-selectin concentrations (P = 3.55 × 10−47). Moreover, we found that the genetic-inferred blood group B was associated with a decreased risk (OR = 0.44, 0.27–0.70) of type 2 diabetes compared with blood group O, adjusting for sE-selectin, sICAM-1, TNF-R2 and other covariates. Our findings indicate that the genetic variants at ABO locus affect plasma sE-selectin levels and diabetes risk. The genetic associations with diabetes risk were independent of sE-selectin levels.
Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and ...identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10−4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10−10, OR 0.87, confidence interval 0.83–0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.
Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy ...number variants in some cases, 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.
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
; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.
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 . . .
Primary open-angle glaucoma (POAG) is a genetically complex common disease characterized by progressive optic nerve degeneration that results in irreversible blindness. Recently, a genome-wide ...association study (GWAS) for POAG in an Icelandic population identified significant associations with single nucleotide polymorphisms (SNPs) between the CAV1 and CAV2 genes on chromosome 7q31. In this study, we confirm that the identified SNPs are associated with POAG in our Caucasian US population and that specific haplotypes located in the CAV1/CAV2 intergenic region are associated with the disease. We also present data suggesting that associations with several CAV1/CAV2 SNPs are significant mostly in women.
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.
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