Invertebrate dispersal by waterbird species in neotropical wetlands / A dispersão de invertebrados por aves aquáticas na região neotropical

Abstract Endozoochory by waterbirds is particularly relevant to the dispersal of non-flying aquatic invertebrates. This ecological function exercised by birds has been demonstrated in different biogeographical regions, but there are no studies for the neotropical region. In this work, we identified propagules of invertebrates in faeces of 14 syntopic South American waterbird species representing six families, and hatched additional invertebrates from cultured faeces. We tested whether propagule abundance, species richness and composition varied among bird species, and between the cold and warm seasons. We found 164 invertebrate propagules in faecal samples from seven different waterbirds species, including eggs of the Temnocephalida and Notonectidae, statoblasts of bryozoans (Plumatella sp.) and ephippia of Cladocera. Ciliates (including Paramecium sp. and Litostomatea), nematodes and rotifers (Adineta sp. and Nottomatidae) hatched from cultured samples. Potential for endozoochory was confirmed for 12 of 14 waterbird species. Our statistical models suggest that richness and abundance of propagules are associated with bird species and not affected by seasonality. Dispersal by endozoochory is potentially important to a broad variety of invertebrates, being promoted by waterbirds with different ecological and morphological traits, which are likely to drive the dispersal of invertebrates in neotropical wetlands.

Resumo A endozoocoria promovida por aves aquáticas é particularmente relevante para a dispersão de invertebrados aquáticos não-voadores. Essa função ecológica exercida pelas aves tem sido demonstrada para diferentes regiões biogeográficas, porém, não existem estudos para a região neotropical. Neste trabalho nós identificamos propágulos de invertebrados encontrados em fezes de 14 espécies sintópicas de aves aquáticas da América do Sul, representando seis famílias de aves, e também invertebrados emergidos de amostras fecais cultivadas em laboratório. Testamos se a abundância, riqueza de espécies e composição de propágulos de invertebrados variavam entre as espécies de aves e entre estações. Nós encontramos 164 propágulos de invertebrados em amostras fecais de sete espécies de aves, incluindo ovos de Temnocephalida e Notonectidae, estatoblastos de briozoários (Plumatella sp.) e efípios de Cladocera. Ciliados (incluindo Paramecium sp. e Litostomatea), nematóides e rotíferos (Adineta sp. e Nottomatidae) eclodiram de amostras cultivadas. O potencial para endozoocoria foi confirmado para 12 das 14 espécies de aves aquáticas investigadas. Nossos modelos estatísticos sugerem que a riqueza e abundância de propágulos estão associadas às espécies de aves e não são afetadas pela sazonalidade. A dispersão por endozoocoria é importante para uma ampla variedade de invertebrados, sendo promovida por aves aquáticas com diferentes características ecológicas e morfológicas as quais provavelmente regulam a dispersão de invertebrados entre áreas úmidas neotropicais.

Invertebrate dispersal by waterbird species in neotropical wetlands

Abstract Endozoochory by waterbirds is particularly relevant to the dispersal of non-flying aquatic invertebrates. This ecological function exercised by birds has been demonstrated in different biogeographical regions, but there are no studies for the neotropical region. In this work, we identified propagules of invertebrates in faeces of 14 syntopic South American waterbird species representing six families, and hatched additional invertebrates from cultured faeces. We tested whether propagule abundance, species richness and composition varied among bird species, and between the cold and warm seasons. We found 164 invertebrate propagules in faecal samples from seven different waterbirds species, including eggs of the Temnocephalida and Notonectidae, statoblasts of bryozoans (Plumatella sp.) and ephippia of Cladocera. Ciliates (including Paramecium sp. and Litostomatea), nematodes and rotifers (Adineta sp. and Nottomatidae) hatched from cultured samples. Potential for endozoochory was confirmed for 12 of 14 waterbird species. Our statistical models suggest that richness and abundance of propagules are associated with bird species and not affected by seasonality. Dispersal by endozoochory is potentially important to a broad variety of invertebrates, being promoted by waterbirds with different ecological and morphological traits, which are likely to drive the dispersal of invertebrates in neotropical wetlands.

Resumo A endozoocoria promovida por aves aquáticas é particularmente relevante para a dispersão de invertebrados aquáticos não-voadores. Essa função ecológica exercida pelas aves tem sido demonstrada para diferentes regiões biogeográficas, porém, não existem estudos para a região neotropical. Neste trabalho nós identificamos propágulos de invertebrados encontrados em fezes de 14 espécies sintópicas de aves aquáticas da América do Sul, representando seis famílias de aves, e também invertebrados emergidos de amostras fecais cultivadas em laboratório. Testamos se a abundância, riqueza de espécies e composição de propágulos de invertebrados variavam entre as espécies de aves e entre estações. Nós encontramos 164 propágulos de invertebrados em amostras fecais de sete espécies de aves, incluindo ovos de Temnocephalida e Notonectidae, estatoblastos de briozoários (Plumatella sp.) e efípios de Cladocera. Ciliados (incluindo Paramecium sp. e Litostomatea), nematóides e rotíferos (Adineta sp. e Nottomatidae) eclodiram de amostras cultivadas. O potencial para endozoocoria foi confirmado para 12 das 14 espécies de aves aquáticas investigadas. Nossos modelos estatísticos sugerem que a riqueza e abundância de propágulos estão associadas às espécies de aves e não são afetadas pela sazonalidade. A dispersão por endozoocoria é importante para uma ampla variedade de invertebrados, sendo promovida por aves aquáticas com diferentes características ecológicas e morfológicas as quais provavelmente regulam a dispersão de invertebrados entre áreas úmidas neotropicais.

Structural and electrochemical insights into novel Wadsley Roth Nb7Ti1.5Mo1.5O25 and Ta7Ti1.5Mo1.5O25 anodes for Li-ion battery application.

Niobium based anodes are gaining increasing popularity for application in high-power lithium-ion batteries, due to their high theoretical capacities, inherent safety at high current densities, and long-term stability. Here, we report the discovery and characterisation of a new Wadsley Roth niobate system, Nb7Ti1.5Mo1.5O25, showing that it is isostructural with known systems: Nb9PO25 and Nb9VO25. To evaluate the material's electrochemical performance, including performance at high current densities (for potential high power applications), and long-term stability, Li half-coin cells were prepared. The material showed an initial capacity of 268(9) mA h g-1 at 0.01 A g-1 (voltage range of 2.5-1.0 V). However, in subsequent cycles, some of this initial capacity is lost, which is attributed to Li trapping associated with the presence of reducible MoO4 units, similar to the situation observed for isostructural Nb9VO25. After this initial irreversible capacity loss, the material showed good performance at high current density rates, such that at 2 A g-1 and 4 A g-1 respective capacities of 132(10) mA h g-1 and 115(14) mA g-1 were delivered. Moreover, the material showed respectable capacity retention (97%) after being cycled for 100 cycles at 0.2 A g-1. In order to identify the different Nb, Ti, Mo redox couples involved in this system, a Ta analogue was also synthesized (Ta7Ti1.5Mo1.5O25) and the electrochemical performance for this phase is also reported. This phase shows a lower initial capacity at 0.01 A g-1 (140(3) mA h g-1) than the Nb analogue in the same voltage range, which can be increased (225 mA h g-1) if a lower cutoff voltage (0.5 V) is applied. The capacity retention for this Ta system after 100 cycles at 0.2 A g-1 is similar to the Nb analogue (97%). Further work has explored whether the Nb-Ti-Mo contents could be varied, and these results showed that single phase Nb10-2xTixMoxO25 samples could be prepared for 1.5 ≤ x ≤ 1.75, and electrochemical testing results for the x = 1.75 endmember are also reported. Overall, this research highlights the synthesis and electrochemical characterisation of two new Wadsley Roth phases, and further highlights the challenges associated with the presence of reducible cations in tetrahedral sites in such structures with respect to minimising initial irreversible capacity loss.

The utility of multiple genomic technologies for interpretation of modern next generation sequencing: A novel case of three FANCA gene variants resulting in autosomal recessive Fanconi anaemia.

Fanconi anaemia (FA) is a rare autosomal recessive condition resulting in changes in the FANC gene family. This report describes a case of Fanconi anaemia in a family with complex biallelic variants. The patient is a 32-year-old female diagnosed with FA on cascade testing during childhood with chromosome breakage studies. On examination she had a fixed deformity of the right thumb and the proximal interphalangeal joint was immobile. Her brother shared this radial abnormality and had FA, requiring a bone marrow transplant. She presented in adulthood seeking further BRCA advice and had next generation sequencing that showed three variants in the FANCA gene. One allele a known pathogenic change, the other had two sequence variants in tandem that have been reported as variants of uncertain significance. There is one other unrelated case of these two variants occurring together in cis, resulting in Fanconi anaemia. This case is an interesting example of three variants in the FANCA gene, one allele with a pathogenic deletion and the other with a single complex allele made up of two missense variants of uncertain significance, likely manifesting with FA. It highlights the utility of different genetic technologies in the interpretation of next generation sequencing.

Invertebrate dispersal by waterbird species in neotropical wetlands.

Endozoochory by waterbirds is particularly relevant to the dispersal of non-flying aquatic invertebrates. This ecological function exercised by birds has been demonstrated in different biogeographical regions, but there are no studies for the neotropical region. In this work, we identified propagules of invertebrates in faeces of 14 syntopic South American waterbird species representing six families, and hatched additional invertebrates from cultured faeces. We tested whether propagule abundance, species richness and composition varied among bird species, and between the cold and warm seasons. We found 164 invertebrate propagules in faecal samples from seven different waterbirds species, including eggs of the Temnocephalida and Notonectidae, statoblasts of bryozoans (Plumatella sp.) and ephippia of Cladocera. Ciliates (including Paramecium sp. and Litostomatea), nematodes and rotifers (Adineta sp. and Nottomatidae) hatched from cultured samples. Potential for endozoochory was confirmed for 12 of 14 waterbird species. Our statistical models suggest that richness and abundance of propagules are associated with bird species and not affected by seasonality. Dispersal by endozoochory is potentially important to a broad variety of invertebrates, being promoted by waterbirds with different ecological and morphological traits, which are likely to drive the dispersal of invertebrates in neotropical wetlands.

Urate-induced epigenetic modifications in myeloid cells.

OBJECTIVES: Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1ß. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. METHODS: Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. RESULTS: High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. CONCLUSION: Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS.

BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

Functional connectivity network between terrestrial and aquatic habitats by a generalist waterbird, and implications for biovectoring.

Birds are vectors of dispersal of propagules of plants and other organisms including pathogens, as well as nutrients and contaminants. Thus, through their movements they create functional connectivity between habitat patches. Most studies on connectivity provided by animals to date have focused on movements within similar habitat types. However, some waterbirds regularly switch between terrestrial, coastal and freshwater habitats throughout their daily routines. Lesser black-backed gulls that overwinter in Andalusia use different habitat types for roosting and foraging. In order to reveal their potential role in biovectoring among habitats, we created an inter-habitat connectivity network based on GPS tracking data. We applied connectivity measures by considering frequently visited sites as nodes, and flights as links, to determine the strength of connections in the network between habitats, and identify functional units where connections are more likely to happen. We acquired data for 42 tagged individuals (from five breeding colonies), and identified 5676 direct flights that connected 37 nodes. These 37 sites were classified into seven habitat types: reservoirs, natural lakes, ports, coastal marshes, fish ponds, rubbish dumps and ricefields. The Doñana ricefields acted as the central node in the network based on centrality measures. Furthermore, during the first half of winter when rice was harvested, ricefields were the most important habitat type in terms of total time spent. Overall, 90% of all direct flights between nodes were between rubbish dumps (for foraging) and roosts in other habitats, thereby connecting terrestrial and various wetland habitats. The strength of connections decreased between nodes as the distance between them increased, and was concentrated within ten independent spatial and functional units, especially between December and February. The pivotal role for ricefields and rubbish dumps in the network, and their high connectivity with aquatic habitats in general, have important implications for biovectoring into their surroundings.

Whole angiosperms Wolffia columbiana disperse by gut passage through wildfowl in South America.

For the first time to our knowledge, we demonstrate that whole angiosperm individuals can survive gut passage through birds, and that this occurs in the field. Floating plants of the genus Wolffia are the smallest of all flowering plants. Fresh droppings of white-faced whistling duck Dendrocygna viduata ( n = 49) and coscoroba swan Coscoroba coscoroba ( n = 22) were collected from Brazilian wetlands. Intact Wolffia columbiana were recovered from 16% of D. viduata and 32% of Coscoroba samples (total = 164 plantlets). The viability of plants was tested, and asexual reproduction was confirmed. Wolffia columbiana is an expanding alien in Europe. Avian endozoochory of asexual angiosperm propagules may be an important, overlooked dispersal means for aquatic plants, and may contribute to the invasive character of alien species.

ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl-1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl-1 on allopurinol ⩽300 mgd-1 and poor response as SU⩾6 mgdl-1 despite allopurinol >300 mgd-1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70-4.48), P=6.0 × 10-5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl-1 despite allopurinol >300 mgd-1.

Continuous daily assessment of multiple sclerosis disability using remote step count monitoring.

Disability measures in multiple sclerosis (MS) rely heavily on ambulatory function, and current metrics fail to capture potentially important variability in walking behavior. We sought to determine whether remote step count monitoring using a consumer-friendly accelerometer (Fitbit Flex) can enhance MS disability assessment. 99 adults with relapsing or progressive MS able to walk ≥2-min were prospectively recruited. At 4 weeks, study retention was 97% and median Fitbit use was 97% of days. Substudy validation resulted in high interclass correlations between Fitbit, ActiGraph and manual step count tally during a 2-minute walk test, and between Fitbit and ActiGraph (ICC = 0.76) during 7-day home monitoring. Over 4 weeks of continuous monitoring, daily steps were lower in progressive versus relapsing MS (mean difference 2546 steps, p < 0.01). Lower average daily step count was associated with greater disability on the Expanded Disability Status Scale (EDSS) (p < 0.001). Within each EDSS category, substantial variability in step count was apparent (i.e., EDSS = 6.0 range 1097-7152). Step count demonstrated moderate-strong correlations with other walking measures. Lower average daily step count is associated with greater MS disability and captures important variability in real-world walking activity otherwise masked by standard disability scales, including the EDSS. These results support remote step count monitoring as an exploratory outcome in MS trials.

MUTYH-Associated Polyposis: The Irish Experience>.

MUTYH is involved in DNA damage repair. Bi-allelic MUTYH mutations predispose to polyposis and gastrointestinal malignancies, distinct genetically from autosomal dominant familial adenomatous polyposis coli. Two common European MUTYH mutations account for 90% of MUTYH-associated polyposis (MAP). We aimed to examine the incidence of MAP in Ireland. A retrospective cohort study was undertaken. Patients undergoing MUTYH testing from 2003-2016 were identified by searching electronic databases using terms "MUTYH" and "MYH". Phenotypic and genotypic details were obtained by chart review. Bi-allelic mutations were confirmed in 26 individuals (17 families), of whom 16 (62%) developed colorectal malignancies, and 22(85%) polyposis. Eleven families had bi-allelic status for one/both common European mutations. Regional variation was noted, with over-representation of bi-allelic mutation carriers in the South-west of Ireland. MAP is under-diagnosed in Ireland. Increased awareness is required to facilitate appropriate identification and surveillance of bi-allelic mutation carriers for colorectal pathology.

Twenty-eight loci that influence serum urate levels: analysis of association with gout.

OBJECTIVES: Twenty-eight genetic loci are associated with serum urate levels in Europeans. Evidence for association with gout at most loci is absent, equivocal or not replicated. Our aim was to test the loci for association with gout meeting the American College of Rheumatology gout classification criteria in New Zealand European and Polynesian case-control sample sets. METHODS: 648 European cases and 1550 controls, and 888 Polynesian (Ma¯ori and Pacific) cases and 1095 controls were genotyped. Association with gout was tested by logistic regression adjusting for age and sex. Power was adequate (>0.7) to detect effects of OR>1.3. RESULTS: We focused on 24 loci without previous consistent evidence for association with gout. In Europeans, we detected association at seven loci, one of which was the first report of association with gout (IGF1R). In Polynesian, association was detected at three loci. Meta-analysis revealed association at eight loci-two had not previously been associated with gout (PDZK1 and MAF). In participants with higher Polynesian ancestry, there was association in an opposing direction to Europeans at PRKAG2 and HLF (HLF is the first report of association with gout). There was obvious inconsistency of gout association at four loci (GCKR, INHBC, SLC22A11, SLC16A9) that display very similar effects on urate levels. CONCLUSIONS: We provide the first evidence for association with gout at four loci (IGF1R, PDZK1, MAF, HLF). Understanding why there is lack of correlation between urate and gout effect sizes will be important in understanding the aetiology of gout.

Retinal axonal loss in very early stages of multiple sclerosis.

BACKGROUND AND PURPOSE: The lack of surrogates of clinical progression has limited the design of neuroprotection trials in multiple sclerosis (MS). Our aim was to study the association between time-domain optical coherence tomography measures and clinical and magnetic resonance imaging outcomes in early MS. METHODS: Forty-three relapsing-remitting MS patients within 1 year of onset were followed for up to 3 years. RESULTS: The peripapillary retinal nerve fiber layer (RNFL) decreased annually by 2 µm (95% confidence interval -3.89, -0.11; P = 0.038). The RNFL tended to be associated with normalized normal appearing white matter volume in cross-sectional (P = 0.08) and longitudinal analyses (P = 0.06). CONCLUSIONS: There is substantial RNFL loss even in very early MS. Our data suggest that retinal axonal atrophy is associated with atrophy in global white matter volume in early MS.

Phenotypic analysis of familial breast cancer: comparison of BRCAx tumors with BRCA1-, BRCA2-carriers and non-familial breast cancer.

AIMS: Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetime. However, only about 20% of familial breast cancer is attributed to mutations in BRCA1 and BRCA2, while a further 5-10% are attributed to mutations in other rare susceptibility genes such as TP53, STK11, PTEN, ATM and CHEK2. Despite extensive efforts to explain the missing heritability of this disease, the majority of familial clustering in breast cancer remains largely unexplained. We aim to analyze the pathology of familial cases of which no pathogenic mutation is yet identified. METHODS: We compared the pathological phenotype of BRCA1/BRCA2 negative familial breast cancer (BRCAx) to BRCA1-positive, BRCA2-positive and sporadic cases without a family history. Age-adjusted analysis is summarized in odd's ratios and confidence intervals for tumor type, grade, lymph node, ER and HER2 status. RESULTS: We found non-familial cases to be more likely to be ER positive (P = 0.041) as compared with BRCAx tumors. More cases of lobular carcinoma were found with BRCAx as compared to BRCA1 tumors (P = 0.05). After multivariate logistic regression analysis, BRCAx tumors are more likely ER positive (P = 0.001) and HER2 positive (P = 0.047) in comparison to BRCA1. Conversely, BRCAx cases are less likely to be ER positive (P = 0.02) but more likely to be HER2 positive (P = 0.021) as compared with BRCA2 tumors. CONCLUSION: Our findings suggest that BRCA1, BRCA2 and BRCAx tumors differ in phenotype from non-familial and familial BRCA1-positive and BRCA2-positive tumors. Further studies will need to be performed in this important population in order to develop strategies for early detection and prevention.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

A new genome scan for primary nonsyndromic vesicoureteric reflux emphasizes high genetic heterogeneity and shows linkage and association with various genes already implicated in urinary tract development.

Primary vesicoureteric reflux (VUR), the retrograde flow of urine from the bladder toward the kidneys, results from a developmental anomaly of the vesicoureteric valve mechanism, and is often associated with other urinary tract anomalies. It is the most common urological problem in children, with an estimated prevalence of 1-2%, and is a major cause of hypertension in childhood and of renal failure in childhood or adult life. We present the results of a genetic linkage and association scan using 900,000 markers. Our linkage results show a large number of suggestive linkage peaks, with different results in two groups of families, suggesting that VUR is even more genetically heterogeneous than previously imagined. The only marker achieving P < 0.02 for linkage in both groups of families is 270 kb from EMX2. In three sibships, we found recessive linkage to KHDRBS3, previously reported in a Somali family. In another family we discovered sex-reversal associated with VUR, implicating PRKX, for which there was weak support for dominant linkage in the overall data set. Several other candidate genes are suggested by our linkage or association results, and four of our linkage peaks are within copy-number variants recently found to be associated with renal hypodysplasia. Undoubtedly there are many genes related to VUR. Our study gives support to some loci suggested by earlier studies as well as suggesting new ones, and provides numerous indications for further investigations.