Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.

The worldwide emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis threatens to make this disease incurable. Drug resistance mechanisms are only partially understood, and whether the current understanding of the genetic basis of drug resistance in M. tuberculosis is sufficiently comprehensive remains unclear. Here we sequenced and analyzed 161 isolates with a range of drug resistance profiles, discovering 72 new genes, 28 intergenic regions (IGRs), 11 nonsynonymous SNPs and 10 IGR SNPs with strong, consistent associations with drug resistance. On the basis of our examination of the dN/dS ratios of nonsynonymous to synonymous SNPs among the isolates, we suggest that the drug resistance-associated genes identified here likely contain essentially all the nonsynonymous SNPs that have arisen as a result of drug pressure in these isolates and should thus represent a near-complete set of drug resistance-associated genes for these isolates and antibiotics. Our work indicates that the genetic basis of drug resistance is more complex than previously anticipated and provides a strong foundation for elucidating unknown drug resistance mechanisms.

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.

Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.

p-Values from tests of significance can be combined using the Sidák correction (or the closely related Bonferroni correction) or Fisher's method, but both these methods require that the p-values combined be independent when all null hypotheses tested are true. In this paper adjustments to these methods are proposed, using a new eigenvalue-based measure of the effective number of independent tests to which the actual tests performed are equivalent, and are compared with adjustments proposed by previous authors. The adjusted methods are evaluated using a sample of 726 Alzheimer's disease (AD) cases and 707 group-matched controls, genotyped at 84,975 single-nucleotide polymorphism loci in 2,000 randomly chosen genes. The tests for genetic association with AD at loci within each gene are combined. The number of loci tested per gene varies from 2 to 994. The adjusted combined p-values agree well with the significance of the combined p-values determined empirically by random permutation of the data (Sidák correction: r=0.990; Fisher's method: r=0.994). This indicates that the combined p-values can be used to assess the relative strength of evidence for association of these genes with AD. The adjustment proposed here is a refinement of that of Nyholt ([2004] Am. J. Hum. Genet. 74:765-769), giving improved agreement with the results of random permutation. The improvement obtained is similar to that given by the refinement proposed by Li and Ji ([2005] Heredity 95:221-227). It is concluded that the concept of an effective number of tests is a valid approximation that allows p-values to be combined in a highly informative way.

Assessments of the anatomy, porosity and profiles of radial O 2 loss from adventitious roots of 10 species in the Poaceae (from four subfamilies) and two species in the Cyperaceae identified a combination of features characteristic of species that inhabit wetland environments. These include a strong barrier to radial O 2 loss in the basal regions of the adventitious roots and extensive aerenchyma formation when grown not only in stagnant but also in aerated nutrient solution. Adventitious root porosity was greater for plants grown in stagnant compared with aerated solution, for all 10 species in the Poaceae. The 'wetland root' archetype was best developed in Oryza sativa and the two species of the Cyperaceae, in which the stele contributed less than 5% of the root cross-sectional area, the cells of the inner cortex were packed in a cuboidal arrangement, and aerenchyma was up to 35-52%. Variations of this root structure, in which the proportional and absolute area of stele was greater, with hexagonal arrangements of cells in the inner cortex and varying in the extent of aerenchyma formation, were present in the other wetland species from the subfamilies Pooideae, Panicoideae and Arundinoideae. Of particular interest were Vetiveria zizanoides and V. filipes , wetland grass species from the tribe Andropogoneae (the same tribe as sorghum, maize and sugarcane), that had a variant of the root anatomy found in rice. The results are promising with regard to enhancing these traits in waterlogging intolerant crops.

Nine species from the tribe Triticeae -three crop, three pasture and three 'wild' wetland species -were evaluated for tolerance to growth in stagnant deoxygenated nutrient solution and also for traits that enhance longitudinal O 2 movement within the roots. Critesion marinum (syn. Hordeum marinum ) was the only species evaluated that had a strong barrier to radial O 2 loss (ROL) in the basal regions of its adventitious roots. Barriers to ROL have previously been documented in roots of several wetland species, although not in any close relatives of dryland crop species. Moreover, the porosity in adventitious roots of C. marinum was relatively high: 14% and 25% in plants grown in aerated and stagnant solutions, respectively. The porosity of C. marinum roots in the aerated solution was 1·8-5·4-fold greater, and in the stagnant solution 1·2-2·8-fold greater, than in the eight other species when grown under the same conditions. These traits presumably contributed to C. marinum having a 1·4-3 times greater adventitious root length than the other species when grown in deoxygenated stagnant nutrient solution or in waterlogged soil. The length of the adventitious roots and ROL profiles of C. marinum grown in waterlogged soil were comparable to those of the extremely waterlogging-tolerant species Echinochloa crus-galli L. (P. Beauv.). The superior tolerance of C. marinum , as compared to Hordeum vulgare (the closest cultivated relative), was confirmed in pots of soil waterlogged for 21 d; H. vulgare suffered severe reductions in shoot and adventitious root dry mass (81% and 67%, respectively), whereas C. marinum shoot mass was only reduced by 38% and adventitious root mass was not affected.

Background: Evidence of genetic association between the NRG1 (Neuregulin-1) gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and singlenucleotide polymorphisms (SNPs) in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia.