The tonoplast-localized OsTIP2;1 is involved in aluminum detoxification in rice.

Aluminum (Al) stress is a significant issue in acidic soils, severely affecting crop growth and yield. Rice is notably resilient to Al toxicity, yet the internal tolerance mechanisms remain inadequately addressed. Here, we examined the role of OsTIP2;1, a tonoplast-bound intrinsic protein (TIP), in rice's internal Al detoxification. Our findings reveal that OsTIP2;1 expression was quickly and explicitly activated by Al ions in roots but not in shoots. The OsTIP2;1-GFP protein localizes to the tonoplast in plant and yeast cells. Non-functional ostip2;1 rice mutants were more vulnerable to Al toxicity. In the roots, the ostip2;1 mutants exhibited considerably lower levels of Al in the cell sap, primarily the vacuolar contents, than in the wild-type plant. Moreover, the ostip2;1 mutants showed reduced Al accumulation in the roots but increased translocation to the shoots. Heterologous expression of tonoplast-localized OsTIP2;1 in yeast led to enhanced Al tolerance, suggesting that OsTIP2;1 facilitates Al sequestration to the vacuole. These findings indicate that OsTIP2;1 mediates internal detoxification by transporting Al into the vacuole in the root and restricting its transport to above-ground tissues, thus contributing to Al resistance in rice.

A multidimensional social risk atlas of depression and anxiety: An observational and genome-wide environmental interaction study.

Background: Mental disorders are largely socially determined, yet the combined impact of multidimensional social factors on the two most common mental disorders, depression and anxiety, remains unclear. Methods: We constructed a polysocial risk score (PsRS), a multidimensional social risk indicator including components from three domains: socioeconomic status, neighborhood and living environment and psychosocial factors. Supported by the UK Biobank cohort, we randomly divided 110 332 participants into the discovery cohort (60%; n = 66 200) and the replication cohort (40%; n = 44 134). We tested the associations between 13 single social factors with Patient Health Questionnaire (PHQ) score, Generalized Anxiety Disorder Scale (GAD) score and self-reported depression and anxiety. The significant social factors were used to calculate PsRS for each mental disorder by considering weights from the multivariable linear model. Generalized linear models were applied to explore the association between PsRS and depression and anxiety. Genome-wide environmental interaction study (GWEIS) was further performed to test the effect of interactions between PsRS and SNPs on the risk of mental phenotypes. Results: In the discovery cohort, PsRS was positively associated with PHQ score (ß = 0.37; 95% CI = 0.35-0.38), GAD score (ß = 0.27; 95% CI = 0.25-0.28), risk of self-reported depression (OR = 1.29; 95% CI = 1.28-1.31) and anxiety (OR = 1.19; 95% CI = 1.19-1.23). Similar results were observed in the replication cohort. Emotional stress, lack of social support and low household income were significantly associated with the development of depression and anxiety. GWEIS identified multiple candidate loci for PHQ score, such as rs149137169 (ST18) (Pdiscovery = 1.08 × 10-8, Preplication = 3.25 × 10-6) and rs3759812 (MYO9A) (Pdiscovery = 3.87 × 10-9, Preplication = 6.21 × 10-5). Additionally, seven loci were detected for GAD score, such as rs114006170 (TMPRSS11D) (Pdiscovery = 1.14 × 10-9, Preplication = 7.36 × 10-5) and rs77927903 (PIP4K2A) (Pdiscovery = 2.40 × 10-9, Preplication = 0.002). Conclusions: Our findings reveal the positive effects of multidimensional social factors on the risk of depression and anxiety. It is important to address key social disadvantage in mental health promotion and treatment.

A systematical association analysis of 25 common virus infection and genetic susceptibility of COVID-19 infection.

OBJECTIVES: Previous studies identified a number of diseases were associated with 2019 coronavirus disease (COVID-19). However, the associations between these diseases related viral infections and COVID-19 remains unknown now. METHODS: In this study, we utilized single nucleotide polymorphisms (SNPs) related to COVID-19 from genome-wide association study (GWAS) and individual-level genotype data from the UK biobank to calculate polygenic risk scores (PRS) of 487,409 subjects for eight COVID-19 clinical phenotypes. Then, multiple logistic regression models were established to assess the correlation between serological measurements (positive/negative) of 25 viruses and the PRS of eight COVID-19 clinical phenotypes. And we performed stratified analyses by age and gender. RESULTS: In whole population, we identified 12 viruses associated with the PRS of COVID-19 clinical phenotypes, such as VZV seropositivity for Varicella Zoster Virus (Unscreened/Exposed_Negative: ß = 0.1361, P = 0.0142; Hospitalized/Unscreened: ß = 0.1167, P = 0.0385) and MCV seropositivity for Merkel Cell Polyomavirus (Unscreened/Exposed_Negative: ß = -0.0614, P = 0.0478). After age stratification, we identified seven viruses associated with the PRS of eight COVID-19 clinical phenotypes in the age < 65 years group. After gender stratification, we identified five viruses associated with the PRS of eight COVID-19 clinical phenotypes in the women group. CONCLUSION: Our study findings suggest that the genetic susceptibility to different COVID-19 clinical phenotypes is associated with the infection status of various common viruses.

Evaluating the interaction between 3'aQTL and alcohol consumption/smoking on anxiety and depression: 3'aQTL-by-environment interaction study in UK Biobank cohort.

BACKGROUND: Smoking and alcohol consumption were associated with the development of depression and anxiety. 3'UTR APA quantitative trait loci (3'aQTLs) have been associated with multiple health states and conditions. Our aim is to evaluate the interactive effects of 3'aQTLs-alcohol consumption/tobacco smoking on the risk of anxiety and depression. METHODS: The 3'aQTL data of 13 brain regions were extracted from the large-scale 3'aQTL atlas. The phenotype data (frequency of cigarette smoking and alcohol drinking, anxiety score, self-reported anxiety, depression score and self-reported depression) of 90,399-103,011 adults aged 40-69 years living in the UK and contributing to the UK Biobank during 2006-2010, were obtained from the UK Biobank cohort. The frequency of cigarette smoking and alcohol drinking of each subject were defined by the amount of smoking and alcohol drinking of self-reported, respectively. The continuous alcohol consumption/smoking terms were further categorized in tertiles. 3'aQTL-by-environmental interaction analysis was then performed to evaluate the associations of gene-smoking/alcohol consumption interactions with anxiety and depression using generalized linear model (GLM) of PLINK 2.0 with an additive mode of inheritance. Furthermore, GLM was also used to explore the relationship between alcohol consumption/smoking with hazard of anxiety/depression stratified by allele for the significant genotyped SNPs that modified the alcohol consumption/smoking-anxiety/depression association. RESULTS: The interaction analysis identified several candidate 3'aQTLs-alcohol consumption interactions, such as rs7602638 located in PPP3R1 (ß = 0.08, P = 6.50 × 10-6) for anxiety score; rs10925518 located in RYR2 (OR = 0.95, P = 3.06 × 10-5) for self-reported depression. Interestingly, we also observed that the interactions between TMOD1 (ß = 0.18, P = 3.30 × 10-8 for anxiety score; ß = 0.17, P = 1.42 × 10-6 for depression score), ZNF407 (ß = 0.17, P = 2.11 × 10-6 for anxiety score; ß = 0.15, P = 4.26 × 10-5 for depression score) and alcohol consumption was not only associated with anxiety, but related to depression. Besides, we found that relationship between alcohol consumption and hazard of anxiety/depression was significantly different for different SNPs genotypes, such as rs34505550 in TMOD1 (AA: OR = 1.03, P = 1.79 × 10-6; AG: OR = 1.00, P = 0.94; GG: OR = 1.00, P = 0.21) for self-reported anxiety. LIMITATIONS: The identified 3'aQTLs-alcohol consumption/smoking interactions were associated with depression and anxiety, and its potential biological mechanisms need to be further revealed. CONCLUSIONS: Our study identified important interactions between candidate 3'aQTL and alcohol consumption/smoking on depression and anxiety, and found that the 3'aQTL may modify the associations between consumption/smoking with depression and anxiety. These findings may help to further explore the pathogenesis of depression and anxiety.

Mitochondria-wide association study observed significant interactions of mitochondrial respiratory and the inflammatory in the development of anxiety and depression.

The aim of this study was to investigate the possible interaction of mitochondrial dysfunction and inflammatory cytokines in the risk of anxiety and depression. We utilized the UK Biobank for the sample of this study. A mitochondria-wide association(MiWAS) and interaction analysis was performed to investigate the interaction effects of mitochondrial DNA (mtDNA)×C-reactive protein (CRP) on the risks of self-reported anxiety (N = 72,476), general anxiety disorder (GAD-7) scores (N = 80,853), self-reported depression (N = 80,778), Patient Health Questionnaire (PHQ-9) scores (N = 80,520) in total samples, females and males, respectively, adjusting for sex, age, Townsend deprivation index (TDI), education score, alcohol intake, smoking and 10 principal components. In all, 25 mtSNPs and 10 mtSNPs showed significant level of association with self-reported anxiety and GAD-7 score respectively. A total of seven significant mtDNA × CRP interactions were found for anxiety, such as m.3915G>A(MT-ND1) for self-reported anxiety in total subjects (P = 6.59 × 10-3), m.4561T>C(MT-ND2) (P = 3.04 × 10-3) for GAD-7 score in total subjects. For depression, MiWAS identified 17 significant mtSNPs for self-reported depression and 14 significant mtSNPs for PHQ-9 scores. 17 significant mtDNA associations (2 for self-reported depression and 15 for PHQ-9 score) was identified, such as m.14869G>A(MT-CYB; P = 2.22 × 10-3) associated with self-reported depression and m.4561T>C (MT-ND2; P value = 3.02 × 10-8) associated with PHQ-9 score in all subjects. In addition, 5 common mtDNA shared with anxiety and depression were found in MiWAS, and 4 common mtDNA variants were detected to interact with CRP for anxiety and depression, such as m.9899T>C(MT-CO3). Our study suggests the important interaction effects of mitochondrial function and CRP on the risks of anxiety and depression.

Assessing the joint effects of mitochondrial function and human behavior on the risks of anxiety and depression.

BACKGROUND: Psychiatric disorders have great health hazards and the exact pathogeny remains elusive now. We aim to explore the potential interaction effects of mitochondrial function and human behavior on the risks of anxiety and depression. METHODS: The genome-wide association study (GWAS) data of mitochondrial function (N = 383,476-982,072) were obtained from published studies. Individual level genotype and phenotype data of anxiety, depression and behavioral factors (including drinking, smoking and physical activity) were all from the UK Biobank (N = 84,805-85,164). We first calculated the polygenic risk scores (PRS) of mitochondrial function as the instrumental variables, and then constructed linear regression analyses to systematically explore the potential interaction effects of mitochondrial function and human behavior on anxiety and depression. RESULTS: In total samples, we observed mitochondrial heteroplasmy (MtHz) vs. Drinking (PGAD-7 = 6.49 × 10-3; PPHQ-9 = 1.89 × 10-3) was positively associated with both anxiety and depression. In males, MtHz vs. Drinking (PMale = 3.46 × 10-5) was positively correlated with depression. In females, blood mitochondrial DNA copy number (mtDNA-CN) vs. Drinking (PFemale = 8.63 × 10-3) was negatively related to anxiety. Furthermore, we identified additional 6 suggestive interaction effects (P < 0.05) for anxiety and depression. LIMITATIONS: Considering all subjects were from UK Biobank, it should be careful to extrapolate our findings to other populations with different genetic background. CONCLUSIONS: Our results suggest the significant impacts of mitochondrial function and human behavior interactions on the development of anxiety and depression, providing new clues for clarifying the pathogenesis of anxiety and depression.

Assessing the interaction effects of brain structure longitudinal changes and life environmental factors on depression and anxiety.

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = -.003, p = .018 for depression; beta = -003, p = .008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta = .088, p = .002 for depression; beta = .070, p = .008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = -.004, p = .020 for depression; beta = -.005, p = .002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety.

Maternal smoking around birth may lower the protective effects of breastfeeding on anxiety, depression and neuroticism in adult offspring: a UK biobank study.

We aim to explore the combined effects of the smoking and breastfeeding on offspring mental health outcomes. We used data from UK biobank (N = 342,846) to evaluate joint effect of breastfeeding and maternal smoke during pregnancy (MSDP) on seven adult offspring mental health outcomes (self-reported depression, depression score, self-reported anxiety, anxiety score, neuroticism score, self-harm, suicide). We stratified individuals to MSDP group and non-MSDP group as well as breastfeeding group and non-breastfeeding group. Multiple linear regression and logistic regressions analysis were performed between independent variables (MSDP or breastfeeding) and dependent variables separately (seven mental health outcomes) in each stratum. Effect estimates were expressed as ß values and OR values. Sex, age, 10 principle components of population structure, smoking, alcohol use, and Townsend deprivation index were examined as covariates. At MSDP grouping level, coefficients (odds ratio [OR]) for association of breastfed as a baby with self-reported anxiety (category variable) were 0.87 (95%CI, (0.82-0.93), P = 1.74 × 10-5) in the MSDP group and 0.83 (95%CI, (0.79-0.87), P = 2.76 × 10-17) in the non-MSDP group. At breastfeeding grouping level, OR for association of MSDP and self-reported anxiety were 1.15 (95%CI, (1.10-1.20), P = 5.36 × 10-11) in breastfeeding group and 1.12(95%CI, (1.06-1.20), P = 2.02 × 10-4) in non-breastfeeding group. At MSDP grouping level, negatively associations were found for breastfeeding and anxiety score (continuable variable) in MSDP group (-0.04 SD change per SD change in MSDP, 95% CI, (- 0.06, - 0.02), P = 2.42 × 10-3) and non-MSDP group (-0.06 SD change per SD change in MSDP, 95%CI, (- 0.07, - 0.04), P = 1.70 × 10-11). At breastfeeding grouping level, positive association was found for MSDP and anxiety score in the breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.06-0.09), P = 1.49 × 10-20) and non-breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.05-0.09), P = 7.19 × 10-8). Compared with non-MSDP group, the protective effect (reflected by coefficients) of breastfeeding on anxiety in the MSDP decreased. Our preliminary study found MSDP may lower the protective effect of breastfeeding on the adult offspring anxiety, depression and neuroticism, providing useful recommendations for health care service via quitting smoking during pregnancy and encouraging prolonged breastfeeding.

The plasma membrane-localized OsNIP1;2 mediates internal aluminum detoxification in rice.

Aluminum (Al) toxicity significantly restricts crop production on acidic soils. Although rice is highly resistant to Al stress, the underlying resistant mechanisms are not fully understood. Here, we characterized the function of OsNIP1;2, a plasma membrane-localized nodulin 26-like intrinsic protein (NIP) in rice. Aluminum stress specifically and quickly induced OsNIP1;2 expression in the root. Functional mutations of OsNIP1;2 in two independent rice lines led to significantly enhanced sensitivity to Al but not other metals. Moreover, the Osnip1;2 mutants had considerably more Al accumulated in the root cell wall but less in the cytosol than the wild-type rice. In addition, compared with the wild-type rice plants, the Osnip1;2 mutants contained more Al in the root but less in the shoot. When expressed in yeast, OsNIP1;2 led to enhanced Al accumulation in the cells and enhanced sensitivity to Al stress, suggesting that OsNIP1;2 facilitated Al uptake in yeast. These results suggest that OsNIP1;2 confers internal Al detoxification via taking out the root cell wall's Al, sequestering it to the root cell's vacuole, and re-distributing it to the above-ground tissues.

The interaction of early life factors and depression-associated loci affecting the age at onset of the depression.

Multiple previous studies explored the associations between early life factors and the age at onset of the depression. However, they only focused on the influence of environmental or genetic factors, without considering the interactions between them. Based on previous genome-wide association study (GWAS) data, we first calculated polygenic risk score (PRS) for depression. Regression analyses were conducted to assess the interacting effects of depression PRS and 5 early life factors, including felt hated by family member (N = 40,112), physically abused by family (N = 40,464), felt loved (N = 35633), and sexually molested (N = 41,595) in childhood and maternal smoking during pregnancy (N = 38,309), on the age at onset of the depression. Genome-wide environment interaction studies (GWEIS) were then performed to identify the genes interacting with early life factors for the age at onset of the depression. In regression analyses, we observed significant interacting effects of felt loved as a child and depression PRS on the age at onset of depression in total sample (ß = 0.708, P = 5.03 × 10-3) and males (ß = 1.421, P = 7.64 × 10-4). GWEIS identified a novel candidate loci interacting with felt loved as a child at GSAP (rs2068031, P = 4.24 × 10-8) and detected several genes with suggestive significance association, such as CMYA5 (rs7343, P = 2.03 × 10-6) and KIRREL3 (rs535603, P = 4.84 × 10-6) in males. Our results indicate emotional care in childhood may affect the age at onset of depression, especially in males, and GSAP plays an important role in their interaction.

The roles of selectivity filters in determining aluminum transport by AtNIP1;2.

Aquaporins (AQPs) are channel proteins involved in transporting a variety of substrates. It has been proposed that the constriction regions in the central pores of the AQP channels play a crucial role in determining transport substrates and activities of AQPs. Our previous results suggest that AtNIP1;2, a member of the AQP superfamily in Arabidopsis, facilitates aluminum transport across the plasma membrane. However, the functions of the constriction regions in AtNIP1;2-mediated transport activities are unclear. This study reports that residue substitutions of the constriction regions affect AtNIP1;2-mediated aluminum uptake, demonstrating the critical roles of the constriction regions for transport activities. Furthermore, a constriction region that partially or wholly mimics AtNIP5;1, a demonstrated boric-acid transporter, could not render the boric-acid transport activity to AtNIP1;2. Therefore, besides the constriction regions, other structural features are also involved in determining the nature of AtNIP1;2's transport activities.Abbreviations: AIAR: alanine-isoleucine-alanine-arginine; AIGR: alanine-isoleucine-glycine- arginine; AQP: aquaporin; Al-Mal: aluminum-malate; ar/R: aromatic/arginine; AVAR: alanine-valine-alanine-arginine; CK: control; H: helical domain; ICP-MS: inductively coupled plasma mass spectrometry; LA - LE: inter-helical loops A to E; NIP: nodulin 26-like intrinsic protein; NPA: asparagine-proline-alanine; NPG: asparagine-proline- glycine; NPS: asparagine-proline-Serine; NPV: asparagine-proline-valine; ORF: open reading frame; PIP: plasma membrane intrinsic proteins; SIP: small basic intrinsic proteins; TM: transmembrane helices; WIAR: tryptophan-isoleucine-alanine-arginine; WVAR: tryptophan-valine-alanine-arginine; WVGR: tryptophan-valine-glycine- arginine.