A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program

BackgroundHeight has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.Methods and findingsAnalyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.ConclusionsWe conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.     

Detection of two loci involved in (1-->3)-beta-glucan (curdlan) biosynthesis by Agrobacterium sp. ATCC31749, and comparative sequence analysis of the putative curdlan synthase gene

Genes essential for the production of a linear, bacterial (1-->3)-beta- glucan, curdlan, have been cloned for the first time from Agrobacterium sp. ATCC31749. The genes occurred in two, nonoverlapping, genomic fragments that complemented different sets of curdlan( crd )-deficient transposon-insertion mutations. These were detected as colonies that failed to stain with aniline blue, a (1-->3)-beta-glucan specific dye. One fragment carried a biosynthetic gene cluster (locus I) containing the putative curdlan synthase gene, crdS, and at least two other crd genes. The second fragment may contain only a single crd gene (locus II). Determination of the DNA sequence adjacent to several locus I mutations revealed homology to known sequences only in the cases of crdS mutations. Complete sequencing of the 1623 bp crdS gene revealed highest similarities between the predicted CrdS protein (540 amino acids) and glycosyl transferases with repetitive action patterns. These include bacterial cellulose synthases (and their homologs), which form (1-->4)-beta-glucans. No similarity was detected with putative (1-->3)- beta-glucan synthases from yeasts and filamentous fungi. Whatever the determinants of the linkage specificity of these beta-glucan synthases might be, these results raise the possibility that (1-->3)-beta-glucans and (1-->4)-beta-glucans are formed by related catalytic polypeptides.      

A state and transition model for the eastern Monte Phytogeographycal Province in Rio Negro

We developed a functional model for a shrub steppe vegetation of the eastern Monte Phytogeographical Province in Río Negro (Argentina) with six stable states and 12 transitions, based on the woody encroachment degree, characteristics of the herbaceous layer and the soil surface, and biological crust cover. Information was obtained from letters of naturalists and travelers along the region since the late eighteenth century, reports of old settlers, and our own research work. On the Monte, different functional groups can be distinguished. Our work focused on the three most conspicuous to analyze the dynamics of the system: shrubs, grasses and biological crust. The shrub layer is only affected by large-scale disturbances (fire, mechanical clearing) which maintain the balance between grasses and shrubs in the system. Mechanical clearing with soil removal also causes a decrease in grass cover and vegetation diversity. This layer, however, is most frequently affected by intensive and continuous grazing, which reduces the occurrence of fires and shifts the equilibrium toward the shrubs. All disturbances in general deteriorate the biological crust that covers the soil, which offers situations of facilitation for the regeneration of the herbaceous layer. Grazing and mechanical clearing reduce soil cover and promote the development of soil compaction, which reduce water infiltration and germination and/or seedling establishment, and this creates deteriorated states difficult to reverse. Those states can also be produced by tillage for agriculture and stubble grazing. Some of the transitions that we describe can be favored through grassland management strategies, in order to reach higher states of pastoral value and reverse deteriorating situations.     

Genome of Herbaspirillum seropedicae strain SmR1, a specialized diazotrophic endophyte of tropical grasses

The molecular mechanisms of plant recognition, colonization, and nutrient exchange between diazotrophic endophytes and plants are scarcely known. Herbaspirillum seropedicae is an endophytic bacterium capable of colonizing intercellular spaces of grasses such as rice and sugar cane. The genome of H. seropedicae strain SmR1 was sequenced and annotated by The Paraná State Genome Programme--GENOPAR. The genome is composed of a circular chromosome of 5,513,887 bp and contains a total of 4,804 genes. The genome sequence revealed that H. seropedicae is a highly versatile microorganism with capacity to metabolize a wide range of carbon and nitrogen sources and with possession of four distinct terminal oxidases. The genome contains a multitude of protein secretion systems, including type I, type II, type III, type V, and type VI secretion systems, and type IV pili, suggesting a high potential to interact with host plants. H. seropedicae is able to synthesize indole acetic acid as reflected by the four IAA biosynthetic pathways present. A gene coding for ACC deaminase, which may be involved in modulating the associated plant ethylene-signaling pathway, is also present. Genes for hemagglutinins/hemolysins/adhesins were found and may play a role in plant cell surface adhesion. These features may endow H. seropedicae with the ability to establish an endophytic life-style in a large number of plant species.     

Exopolysaccharide Biosynthesis Enables Mature Biofilm Formation on Abiotic Surfaces by Herbaspirillum seropedicae

H. seropedicae associates endophytically and epiphytically with important poaceous crops and is capable of promoting their growth. The molecular mechanisms involved in plant colonization by this microrganism are not fully understood. Exopolysaccharides (EPS) are usually necessary for bacterial attachment to solid surfaces, to other bacteria, and to form biofilms. The role of H. seropedicae SmR1 exopolysaccharide in biofilm formation on both inert and plant substrates was assessed by characterization of a mutant in the espB gene which codes for a glucosyltransferase. The mutant strain was severely affected in EPS production and biofilm formation on glass wool. In contrast, the plant colonization capacity of the mutant strain was not altered when compared to the parental strain. The requirement of EPS for biofilm formation on inert surface was reinforced by the induction of eps genes in biofilms grown on glass and polypropylene. On the other hand, a strong repression of eps genes was observed in H. seropedicae cells adhered to maize roots. Our data suggest that H. seropedicae EPS is a structural component of mature biofilms, but this development stage of biofilm is not achieved during plant colonization.     

Individual optimization: Mechanisms shaping the optimal reaction norm

In general, optimal reaction norms in heterogeneous populations can be obtained only by iterative numerical procedures (McNamara, 1991; Kawecki and Stearns, 1993). We consider two particular, but biologically plausible and analytically tractable cases of individual optimization to gain insight into the mechanisms which shape the optimal reaction norm of fecundity in relation to an environmental variable or an individual trait. In the first case, we assume that the quality of the environment (e.g. food abundance) or the quality of the individual (e.g. body size) is fixed during its entire life; it may also be a heritable individual trait. In the second case, individual quality is assumed to change randomly such that the probability distribution of quality in the next year is the same for the parent and for her offspring. For these two cases, we obtain analytical expressions for the shape of the optimal reaction norm, which are heuristically interpretable in terms of underlying selective mechanisms. It is shown that better quality may reduce the optimal fecundity. This outcome is particularly likely if better quality increases a fecundity-independent factor of parental survival in a long-lived species with fixed quality. This revised version was published online in July 2006 with corrections to the Cover Date.