Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study

Introduction

Behçet's disease is a chronic systemic inflammatory disease that remains incompletely understood. Herein, we perform the first genome-wide association study in Behçet's disease.

Methods

Using DNA pooling technology and the Affymetrix 500K arrays, we identified possible candidate gene associations with Behçet's disease in a cohort of 152 Behçet's disease patients and 172 healthy ethnically matched controls. Genetic loci that were identified in the pooling study were genotyped in patients and controls using TaqMan genotyping technology.

Results

We identified genetic associations between Behçet's disease and single-nucleotide polymorphisms (SNPs) in KIAA1529, CPVL, LOC100129342, UBASH3B, and UBAC2 (odds ratio = 2.04, 2.26, 1.84, 1.71, and 1.61, respectively; P value = 4.2 × 10^-5, 1.0 × 10^-4, 3.0 × 10^-4, 1.5 × 10^-3, and 5.8 × 10^-3, respectively). Among the associated SNPs, the Behçet's disease-risk allele in rs2061634 leads to substitution of serine to cysteine at amino acid position 995 (S995C) in the KIAA1529 protein.

Conclusions

Using an unbiased whole-genome genetic association approach, we identified novel candidate genetic loci that are associated with increased susceptibility for Behçet's disease. These findings will help to better understand the pathogenesis of Behçet's disease and identify novel targets for therapeutic intervention.     

Genome-wide association mapping in bacteria?

Bacteria display many interesting phenotypes such as virulence, tissue specificity and host range, for which it would be useful to know the genetic basis. Association mapping involves identifying causal variants by showing that particular genotypes are statistically associated with a phenotypic trait in a sample of strains taken from a natural population. With the advent of high-throughput genotyping, association mapping is becoming an increasingly powerful approach. However, until recently, association studies had not been used in bacteria because of their strong population structure, which can produce false positives and/or loss of statistical power unless elucidated and taken into account in analyses. Here, we describe how association mapping could be successfully applied to bacteria and outline the necessary sampling and genotyping strategies.     

Does genetic diversity limit disease spread in natural host populations?

It is a commonly held view that genetically homogenous host populations are more vulnerable to infection than genetically diverse populations. The underlying idea, known as the 'monoculture effect,' is well documented in agricultural studies. Low genetic diversity in the wild can result from bottlenecks (that is, founder effects), biparental inbreeding or self-fertilization, any of which might increase the risk of epidemics. Host genetic diversity could buffer populations against epidemics in nature, but it is not clear how much diversity is required to prevent disease spread. Recent theoretical and empirical studies, particularly in Daphnia populations, have helped to establish that genetic diversity can reduce parasite transmission. Here, we review the present theoretical work and empirical evidence, and we suggest a new focus on finding 'diversity thresholds.'     

Does diversity beget diversity? A case study of crops and weeds

Abstract. The ecological literature is ambiguous as to whether the initial diversity of a plant community facilitates or deters the diversity of colonizing species. We experimentally planted annual crop species in monoculture and polyculture, and examined the resulting weed communities. The species composition of weeds was similar among treatments, but the species richness of weeds was significantly higher in the polycultures than in the monocultures. This supports the ‘diversity begets diversity’ hypothesis. Environmental microheterogeneity, diversity promoters, and ecological equivalency do not seem able to explain the observed patterns.     

Does natural selection organize ecosystems for the maintenance of high productivity and diversity?

Three types of evidence suggest that natural ecosystems are organized for high productivity and diversity: (i) changes not previously experienced by a natural ecosystem, such as novel human disturbances, tend to diminish its productivity and/or diversity, just as 'random' changes in a machine designed for a function usually impair its execution of that function; (ii) humans strive to recreate properties of natural ecosystems to enhance productivity of artificial ones, as farmers try to recreate properties of natural soils in their fields; and (iii) productivity and diversity have increased during the Earth's history as a whole, and after every major biotic crisis. Natural selection results in ecosystems organized to maintain high productivity of organic matter and diversity of species, just as competition among individuals in Adam Smith's ideal economy favours high production of wealth and diversity of occupations. In nature, poorly exploited energy attracts more efficient users. This circumstance favours the opening of new ways of life and more efficient recycling of resources, and eliminates most productivity-reducing 'ecological monopolies'. Ecological dominants tend to be replaced by successors with higher metabolism, which respond to more stimuli and engage in more varied interactions. Finally, increasingly efficient predators and herbivores favour faster turnover of resources.     

Does herbivore diversity depend on plant diversity? The case of California butterflies

It is widely believed that the diversity of plants influences the diversity of animals, and this should be particularly true of herbivores. We examine this supposition at a moderate spatial extent by comparing the richness patterns of the 217 butterfly species resident in California to those of plants, including all 5,902 vascular plant species and the 552 species known to be fed on by caterpillars. We also examine the relationships between plant/butterfly richness and 20 environmental variables. We found that although plant and butterfly diversities are positively correlated, multiple regression, path models, and spatial analysis indicate that once primary productivity (estimated by a water-energy variable, actual evapotranspiration) and topographical variability are incorporated into models, neither measure of plant richness has any relationship with butterfly richness. To examine whether butterflies with the most specialized diets follow the pattern found across all butterflies, we repeated the analyses for 37 species of strict monophages and their food plants and found that plant and butterfly richness were similarly weakly associated after incorporating the environmental variables. We condude that plant diversity does not directly influence butterfly diversity but that both are probably responding to similar environmental factors.     

Pathway analysis of genome-wide association studies for Parkinson’s disease

The study was done to identify the candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms that contribute to Parkinson’s disease (PD) susceptibility and to generate a SNP to ene to pathway hypothesis using an analytical pathway-based approach. We used a PD genome-wide association study (GWAS) meta-analysis data of the genotypes of 2,525,705 SNPs in 4,238 PD cases and 4,239 controls. Identify candidate Causal SNPs and Pathways (ICSNPathway) analysis was applied to the PD GWAS dataset. The first stage involved the pre-selection of candidate causal SNPs by linkage disequilibrium analysis and the functional SNP annotation of the most significant SNPs found. The second stage involved the annotation of biological mechanisms for the pre-selected candidate causal SNPs using improved-gene set enrichment analysis. ICSNPathway analysis identified three candidate SNPs, two genes, twenty-one pathways, and three hypothetical biological mechanisms: (1) rs17651549 to microtubule-associated protein tau (MAPT) to protein domain specific binding (nominal p < 0.001, false discovery rate (FDR) < 0.001), neurogenesis (nominal p < 0.001, FDR < 0.001), regulation of neurogenesis (nominal p < 0.001, FDR = 0.001), positive regulation of axonogenesis (nominal p < 0.001, FDR = 0.001), regulation of protein polymerization (nominal p < 0.001, FDR = 0.004), negative regulation of organelle organization (nominal p < 0.001, FDR = 0.004), hsa01510 (nominal p < 0.001, FDR = 0.005), neuron differentiation (nominal p < 0.001, FDR = 0.009), and axonogenesis (nominal p < 0.001, FDR = 0.009); (2) rs10445337 to MAPT to protein domain specific binding (nominal p < 0.001, FDR < 0.001), neurogenesis (nominal p < 0.001, FDR < 0.001), regulation of neurogenesis (nominal p < 0.001, FDR = 0.001), and positive regulation of axonogenesis (nominal p < 0.001, FDR = 0.001); (3) rs9938550 to HSD3B7 to hsa00363 (nominal p < 0.001, FDR = 0.004), bile acid metabolic process (nominal p = 0.005, FDR = 0.019), and steroid metabolic process (nominal p = 0.010, FDR = 0.039). By applying the ICSNPathway analysis to PD GWAS meta-analysis data, three candidate SNPs, two genes (MAPT and HSD3B7), and 21 pathways involving protein domain specific binding and neurogenesis were identified, which may contribute to PD susceptibility.     

Does predation contribute to tree diversity?

Seed and seedling predation may differentially affect competitively superior tree species to increase the relative recruitment success of poor competitors and contribute to the coexistence of tree species. We examined the effect of seed and seedling predation on the seedling recruitment of three tree species, Acer rubrum (red maple), Liriodendron tulipifera (yellow poplar), and Quercus rubra (northern red oak), over three years by manipulating seed and seedling exposure to predators under contrasting microsite conditions of shrub cover, leaf litter, and overstory canopy. Species rankings of seedling emergence were constant across microsites, regardless of exposure to seed predators, but varied across years. A. rubrum had the highest emergence probabilities across microsites in 1997, but Q. rubra had the highest emergence probabilities in 1999. Predators decreased seedling survival uniformly across species, but did not affect relative growth rates (RGRs). Q. rubra had the highest seedling survivorship across microsites, while L. tulipifera had the highest RGRs. Our results suggest that annual variability in recruitment success contributes more to seedling diversity than differential predation across microsites. We synthesized our results from separate seedling emergence and survival experiments to project seedling bank composition. With equal fecundity assumed across species, Q. rubra dominated the seedling bank, capturing 90% of the regeneration sites on average, followed by A. rubrum (8% of sites) and L. tulipifera (2% of sites). When seed abundance was weighted by species-specific fecundity, seedling bank composition was more diverse; L. tulipifera captured 62% of the regeneration sites, followed by A. rubrum (21% of sites) and Q. rubra (17% of sites). Tradeoffs between seedling performance and fecundity may promote the diversity of seedling regeneration by increasing the probability of inferior competitors capturing regeneration sites.     

Does predation maintain tit community diversity?

European tits of the genus Parus constitute a complex group of coexisting boreal birds. Here we present a survey of the distribution of three coniferous-living Parus species and one of their main predators, the pygmy owl ( Glaucidium passerinum ), on nine isolated islands in Scandinavia. On all islands the coal tit ( Parus ater ) is the sole tit species when the pygmy owl is absent. The two larger species, the willow tit ( P. montanus ) and the crested tit ( P. cristatus ), only coexist with the coal tit when pygmy owls are present. We suggest that the coexistence of willow tits, crested tits and coal tits is the result of a combination of competition for food and predator-safe foraging sites. The smaller coal tit is superior in exploitation competition for food, while the two larger species have an advantage in interference competition for predator-safe foraging sites. The association between the distribution of the pygmy owl and the two larger tit species on isolated islands in Scandinavia is consistent with the idea that the pygmy owl is a keystone predator.     

Does habitat disturbance increase infectious disease risk for primates?

Many studies have suggested that ecosystem conservation protects human and wildlife populations against infectious disease. We tested this hypothesis using data on primates and their parasites. First, we tested for relationships between species' resilience to human disturbance and their parasite richness, prevalence and immune defences, but found no associations. We then conducted a meta‐analysis of the effects of disturbance on parasite prevalence, which revealed no overall effect, but a positive effect for one of four types of parasites (indirectly transmitted parasites). Finally, we conducted intraspecific analyses of malaria prevalence as a function of mammalian species richness in chimpanzees and gorillas, and an interspecific analysis of geographic overlap and parasite species richness, finding that higher levels of host richness favoured greater parasite risk. These results suggest that anthropogenic effects on disease transmission are complex, and highlight the need to define the conditions under which environmental change will increase or decrease disease transmission.     

Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?

The PTPN22 locus is one of the strongest risk factors outside of the major histocompatability complex that associates with autoimmune diseases. PTPN22 encodes lymphoid protein tyrosine phosphatase (Lyp) which is expressed exclusively in immune cells. A single base change in the coding region of this gene resulting in an arginine to tryptophan amino acid substitution within a polyproline binding motif associates with type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosis, Hashimotos thyroiditis, Graves disease, Addison's disease, Myasthenia Gravis, vitiligo, systemic sclerosis juvenile idiopathic arthritis and psoriatic arthritis. Here, we review the current understanding of the PTPN22 locus from a genetic, geographical, biochemical and functional perspective.     

Does animal behavior underlie covariation between hosts' exposure to infectious agents and susceptibility to infection? Implications for disease dynamics

Animal behavior is unique in influencing both components of the process of transmission of disease: exposure to infectious agents, and susceptibility to infection once exposed. To date, the influence of behavior on exposure versus susceptibility has largely been considered separately. Here, we ask whether these two key mechanisms act in concert in natural populations, whereby individuals who are most exposed to infectious agents or have the most contact with conspecifics are also the most susceptible or infectious. We propose three mechanisms that can generate covariation between these two key elements of the transmission of disease within and among hosts, and we provide empirical examples of each. We then use a mathematical model to examine the effect of this covariation on the dynamics of disease at the population level. First, we show that the empirical mechanisms generating covariation between behavioral and physiological components of disease transmission are widespread and include endocrine mediators of behavior, mate choice, group size, sickness behaviors, and behavioral avoidance of infectious conspecifics. The diversity of these empirical mechanisms underscores the potential importance and breadth of covariation in the disease process. Second, we show mathematically that the variability in hosts' exposure to infectious agents and susceptibility or infectiousness, and how tightly they are coupled, strongly influences the ability of a disease to invade a host population. Overall, we propose that covariation between behavioral and physiological components of transmission is likely widespread in natural populations, and can have important consequences for the dynamics of disease at the population level as well as for our understanding of sexual selection, social behavior, and animal communication.     

Does allelopathy involve in the association pattern of Trifolium resupinatum?

Indoor experiments demonstrated that allelopathic potential of rosette and flowering plants of qort is an important factor explaining the growth reduction of its associated species. Aqueous tissue extracts of flowering plants exhibited strong inhibitory effects on the germination percentage and radicle growth rate of the tested species as compared with those of vegetative plants. Under laboratory conditions, this inhibition was in agreement with toxicity assessments of soil samples collected from the rhizosphere of T. resupinatum L., where shoot and root dry mass of the tested species were significantly reduced. Detoxification of allelochemicals by presence of activated carbon can eliminate the inhibitory effects of the different extracts. This technique clarifies the occurrence of allelopathic interference by qort on seed germination and seedling growth, and hence suspects the allelopathic potential of qort in the growth reduction of associate species under field conditions along with competition. This revised version was published online in August 2006 with corrections to the Cover Date.     

Does intragenomic conflict predict intrapersonal conflict?

Parts of the genome of a single individual can have conflicting interests, depending on which parent they were inherited from. One mechanism by which these conflicts are expressed in some taxa, including mammals, is genomic imprinting, which modulates the level of expression of some genes depending on their parent of origin. Imprinted gene expression is known to affect body size, brain size, and the relative development of various tissues in mammals. A high fraction of imprinted gene expression occurs in the brain. Biologists including Hamilton, Trivers and Haig have proposed that this may explain some intrapersonal conflict in humans. This speculation amounts to an inference from conflict within the genome (which is well-established) to conflict within the brain or mind. This is a provocative proposal, which deserves serious attention. In this paper I assess aspects of Haig’s version of the proposal. I argue, first, that the notion that intragenomic conflict predicts personal inconsistency should be rejected. Second, while it is unlikely that it credibly predicts sub-personal agents representing conflicting genetic interests, it is plausible that it predicts that the division of cognitive labour could be exploited to turn sub-systems into proxies for conflicting interests.     

Does stand structure influence susceptibility of eucalypt floodplain forests to dieback?

Forest dieback is a worldwide problem that is likely to increase with climate change and increasing human demands for resources. Eucalyptus camaldulensis forests are an acute example of forest dieback, with 70% of the Victorian Murray River floodplain in some state of dieback. If we are to halt dieback in these floodplain forests, we need to understand what makes stands susceptible to dieback. Forest diebacks are often related to stand structure, with dieback more severe in senescent or high‐density stands. We determined whether certain stand structures make these forests more susceptible to dieback. We undertook an extensive survey of 176 stands across 100 000 ha of forest, covering the range of stand condition on this floodplain. Large and small trees (20‐, 40‐, 80‐ and 120‐cm diameter) showed a similar reduction in the probability of being alive with decreasing stand condition. A slight improvement in stand condition was found at higher densities and basal areas, which may reflect the higher productivity or younger age of these stands. Stand condition was moderately, positively correlated with longitude, with stand condition being higher in the east of the Murray River floodplain where flooding frequencies are currently higher. This suggests that dieback of these floodplain forests would be more effectively mitigated by increased water availability through flooding than by altering stand structure.     

Does serotonin deficit mediate susceptibility to ADHD?

The onset of attention-deficit-hyperactivity-disorder (ADHD) in childhood is characterized by developmentally inappropriate levels of hyperactivity, impulsivity and inattention. A chronic deficit of serotonin (5-HT) at the synapse may trigger symptoms of ADHD. This review focuses on neuro-anatomical, experimental and clinical pharmacological evidence, as well as the genetic underpinnings of serotoninergic involvement in the etiology of ADHD. Neuro-anatomical investigations suggest that serotonin through the orbitofrontal–striatal circuitry may regulate behavioral domains of hyperactivity and impulsivity in ADHD. Studies from animal models of ADHD indicate intimate interplay between 5-HT and dopaminergic neurotransmission. Selective serotonin re-uptake inhibitors, as also non-stimulant drugs acting on the 5-HT system are, however, clinically effective. They impart less severe side effects in patients with no risk of addiction. Oral administration of l-tryptophan, the amino acid precursor of 5-HT, significantly alleviates ADHD symptoms. Given the multifactorial nature of ADHD, candidate gene and genome-wide association studies have suggested that serotoninergic gene variants are associated with increased risk of ADHD with each locus individually exerting a modest effect on overall risk.