203 research outputs found
Analysis of GWAS top hits in ADHD suggests association to two polymorphisms located in genes expressed in the cerebellum
No full textAttention deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder influenced by genetic factors. Several chromosomal regions with potential linkage and candidate genes associations have been reported, but findings are often inconsistent and non-replicated. The few genome-wide association studies (GWAS) carried out so far differ for study design and phenotypes analyzed, and did not detect any association significant at the genome-wide level. In the present study we examined the top SNPs reported in the GWAS by Neale et al. [2008] in an independent cohort. Although our sample size is smaller (415 trios vs. 909), the power was sufficient to confirm the role of candidate markers in ADHD if a true association exists. Two out of 36 top SNPs were significant at alpha = 0.05 in our sample, although none was still significant after correction for multiple tests. These two SNPs are both located in genes coding for as yet uncharacterized proteins expressed in the cerebellum, XKR4 in 8q12.1, and FAM190A in 4q22.1. Three other FAM190A SNPs have TDT P-values of <10(-5) in our sample, a level of significance only reached by a total of five SNPs in our genome-wide data. While these findings could be due to chance, we cannot exclude that these markers are indeed associated to disease risk. Remarkably, brain imaging studies have shown reduction of the posterior inferior cerebellar lobules volume of ADHD boys and girls compared to controls, persistent with age and not present in unaffected siblings, suggesting that the cerebellum may be directly related to pathophysiology of ADHD. (C) 2010 Wiley-Liss, Inc
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
No full textMultiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis
Fast identification of biological pathways associated with a quantitative trait using group lasso with overlaps.
No full textWhere causal SNPs (single nucleotide polymorphisms) tend to accumulate within biological pathways, the incorporation of prior pathways information into a statistical model is expected to increase the power to detect true associations in a genetic association study. Most existing pathways-based methods rely on marginal SNP statistics and do not fully exploit the dependence patterns among SNPs within pathways.We use a sparse regression model, with SNPs grouped into pathways, to identify causal pathways associated with a quantitative trait. Notable features of our "pathways group lasso with adaptive weights" (P-GLAW) algorithm include the incorporation of all pathways in a single regression model, an adaptive pathway weighting procedure that accounts for factors biasing pathway selection, and the use of a bootstrap sampling procedure for the ranking of important pathways. P-GLAW takes account of the presence of overlapping pathways and uses a novel combination of techniques to optimise model estimation, making it fast to run, even on whole genome datasets.In a comparison study with an alternative pathways method based on univariate SNP statistics, our method demonstrates high sensitivity and specificity for the detection of important pathways, showing the greatest relative gains in performance where marginal SNP effect sizes are small
Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes
No full textComparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects
No full textInflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk. Additionally, we show that T1D risk alleles residing at the PTPN22, IL27, IL18RAP and IL10 loci protect against CD. Furthermore, the strongest risk alleles for T1D within the major histocompatibility complex (MHC) confer strong protection against CD and UC; however, given the multi-allelic nature of the MHC haplotypes, sequencing of the MHC locus will be required to interpret this observation. These results extend our current knowledge on genetic variants that predispose to autoimmunity, and suggest that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effect. Our analysis implies that variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations, making autoimmune diseases especially amenable to genetic dissection by genome-wide association studies. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn's disease
No full textLoci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease
No full textInflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 × 10-8 and 6.95 × 10-8, respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 × 10-8; OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively. © 2008 Nature Publishing Group
Quorum sensing is not required for twitching motility in Pseudomonas aeruginosa
No full textIt has been reported that mutations in the quorum-sensing genes lasI and rhlI in Pseudomonas aeruginosa result in, among many other things, loss of twitching motility (A. Glessner, R. S. Smith, B. H. Iglewski, and J. B. Robinson, J. Bacteriol. 181:1623-1629, 1999). We constructed knockouts of lasI and rhlI and the corresponding regulatory genes lasR and rhlR and found no effect on twitching motility. However, twitching-defective variants accumulated during culturing of lasI and rhlI mutants. Further analysis showed that the stable twitching-defective variants of lasI and rhlI mutants had arisen as a consequence of secondary mutations in vfr and algR, respectively, both of which encode key regulators affecting a variety of phenotypes, including twitching motility. In addition, when grown in shaking broth culture, lasI and rhlI mutants, but not the wild-type parent, also accumulated unstable variants that lacked both twitching motility and swimming motility and appeared to be identical in phenotype to the S1 and S2 variants that were recently reported to occur at high frequencies in P. aeruginosa strains grown as a biofilm or in static broth culture (E. Deziel, Y. Comeau, and R. Villemur, J. Bacteriol. 183:1195-1204, 2001). These results indicate that mutations in one regulatory system may create distortions that select during subsequent culturing for compensatory mutations in other regulatory genes within the cellular network. This problem may have compromised some past studies of regulatory hierarchies controlled by quorum sensing and of bacterial regulatory systems in general
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