BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN... Show moreBackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.ResultsTwo loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism–h2) were 0.01–0.04 for age of onset, 0.16–0.25 for early-onset AN, and 0.17–0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN.ConclusionsOur results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction. Show less
Li, D.; Dorber, M.; Barbarossa, V.; Verones, F. 2022
Water temperature is an abiotic master variable for the survival of aquatic organisms. Global warming alters the thermal regimes of rivers and, thus, poses a threat to freshwater biodiversity. To... Show moreWater temperature is an abiotic master variable for the survival of aquatic organisms. Global warming alters the thermal regimes of rivers and, thus, poses a threat to freshwater biodiversity. To address the impacts of water temperature changes related to global warming on freshwater fish species in life cycle assessment (LCA), we developed spatially explicit characterization factors (CFs) for 207 greenhouse gases under four representative concentration pathways. We calculated fate factors by using the output of a global hydrological model fully coupled with a dynamic water temperature model. We developed six species sensitivity distribution curves for two thermal effects (i.e., lethal and sub-lethal) to derive effect factors, which take the differences in sensitivity between climate regions into account. The regional CFs for CO2 ranged from 2.91 x 10(-22) to 6.53 x 10(-18) PAF.yr/kg for sub-lethal effects and from 1.98 x 10(-22) to 4.58 x 10(-18) PDF.yr/kg for lethal effects, depending on the river watersheds and future climate scenarios. To identify the contribution of regional impacts on freshwater fish to their potential global extinction, the regional CFs were converted into global CFs. The largest CFs always occur in the tropical watersheds. The regional impacts in the Amazon watershed contribute the most to the global freshwater fish species extinction. This study contributes to assessing the potential impacts on freshwater biodiversity from global warming from a new cause-effect pathway in LCA. Show less
Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important... Show moreLoss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function. Show less
Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important... Show moreLoss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function. Show less
Limited and uneven distributed water resources have become one of the main obstacles to China's sustainable development, and the "virtual water hypothesis" (VWH) is expected to help mitigate water... Show moreLimited and uneven distributed water resources have become one of the main obstacles to China's sustainable development, and the "virtual water hypothesis" (VWH) is expected to help mitigate water stress. This study discusses the virtual water transfer pattern and water resources stress in China from the VWH perspective. Economic sectors in China are divided into land-dependent sectors and non-land-dependent sectors according to their dependence on specific local land types. Furthermore, the water resources withdrawal and utilization corresponding to these sectors are divided into land-dependent water resources (LDW) and non-land-dependent water resources (NLDW). Results show that the virtual LDW flows from economically poor to relatively developed regions, while the virtual NLDW flows in the opposite direction. LDW dominates Chinese water stress (78.2%) and virtual water flow (74.5%). Furthermore, the virtual water dominated by LDW ameliorates national water stress (the population under unsustainable water stress declined by 0.21 billion) but aggravates the imbalance of water resources between North and South. The transfer of virtual NLDW alleviates this imbalance slightly. Suitable land conditions play a decisive role in LDW withdrawal, which then cannot be replenished by virtual water. However, the withdrawal and transfer of NLDW are flexible, which should be a focus. The results point out that the possibility of water-rich regions as virtual water exporters is the key to alleviating the North-South water resource imbalance in China with VWH theory. Improvement of land productivity and water efficiency can be helpful to alleviate water stress. These findings may provide new insight into China's virtual water transfer pattern from the VWH perspective. Show less
Huang, Y.S.; Liu, S.J.; Shan, M.J.; Hagenaars, S.C.; Mesker, W.E.; Cohen, D.; ... ; Dijke, P. ten 2022
Transforming growth factor-beta (TGF-beta) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-beta signaling by binding to the inhibitory SMAD7... Show moreTransforming growth factor-beta (TGF-beta) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-beta signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-beta and AKT signaling pathways during breast cancer progression. Show less
Liu, Y.; Linz, H.; Fang, M.; Henning, T.; Wolf, S.; Flock, M.; ... ; Li, D. 2022
Understanding the spatiotemporal patterns of carbon footprints (CFs) of grains production is important to formulate regional heterogeneous greenhouse gas (GHG) mitigation strategies. This study... Show moreUnderstanding the spatiotemporal patterns of carbon footprints (CFs) of grains production is important to formulate regional heterogeneous greenhouse gas (GHG) mitigation strategies. This study evaluates the CFs, farm CFs (FCFs: CFs of per unit area), and production CFs (PCFs: CFs of per unit yield) of main grains production in China based on a new scale data set: agricultural statistics data of over 300 prefecture-level regions. A comparison of CFs of main grains production between main producing area (MPA) and non-main producing area (NMPA) are firstly discussed on a totally new scale. Results show that the CFs of main grains production of MPA accounts for 54-57% of country's total although the area of farmland of MPA only accounts for 42%. The PCF and FCF of rice production are higher in MPA, while those of wheat and maize production are lower in MPA. It implies that there are less GHG emission of rice (main paddy grain) productions in NMPA and less GHG emission of wheat and maize (main dryland grains) production in MPA. In additional, the PCF of rice shows growth, while that of wheat and maize shows decline from 2008 to 2017. The growth of PCF of rice is mainly driven by the rise of PCF in MPA. Findings are expected to improve the understanding patterns of China's CF of main grains production and subsequently contribute to GHG mitigation. Show less
CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous... Show moreCNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOTcomplex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development. Show less
Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest... Show moreEating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors. Show less
BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and... Show moreBACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function. Show less
Warfarin has been showed to increase vascular calcification. Apixaban, a direct factor Xa inhibitor, has no interaction with vitamin K and its effect on coronary plaques is unknown. We randomized... Show moreWarfarin has been showed to increase vascular calcification. Apixaban, a direct factor Xa inhibitor, has no interaction with vitamin K and its effect on coronary plaques is unknown. We randomized and compared warfarin and apixaban on progression of coronary atherosclerotic plaques measured by coronary computed tomographic angiography in 66 subjects with non-valvular atrial fibrillation over the period of one-year follow up. There was significant higher total, calcified and low attenuation plaque volume in the group randomized to warfarin as compared to apixaban (all P < .05). Greater volume of total (beta(2) = 28.54; P = .03), low attenuation plaque (beta(2) = 3.58; P = .02) and calcified (beta(2) = 14.10; P = .005) plaque progression was observed in the VKA_group. Show less
