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1.
Transl Psychiatry ; 11(1): 431, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417442

RESUMO

We aimed to explore the underlying genetic mechanisms of traumatic events during childhood affecting the risks of adult substance use in present study. Using UK Biobank cohort, linear regression model was first applied to assess the relationships between cigarette smoking and alcohol drinking in adults with traumatic events during childhood, including felt hated by family member (41,648-111,465), felt loved (46,394-124,481) and sexually molested (47,598-127,766). Using traumatic events as exposure variables, genome-wide by environment interaction study was then performed by PLINK 2.0 to identify cigarette smoking and alcohol drinking associated genes interacting with traumatic events during childhood. We found that the frequency of cigarette smoking was significantly associated with felt hated by family member (coefficient = 0.42, P < 1.0 × 10-9), felt loved (coefficient = -0.31, P < 1.0 × 10-9) and sexually molested (coefficient = 0.46, P < 1.0 × 10-9). We also observed weaker associations of alcohol drinking with felt hated by family member (coefficient = 0.08, P = 3.10 × 10-6) and felt loved (coefficient = -0.06, P = 3.15 × 10-7). GWEIS identified multiple candidate loci interacting with traumatic events, such as CTNNA3 (rs189142060, P = 4.23 × 10-8) between felt hated by family member and the frequency of cigarette smoking, GABRG3 (rs117020886, P = 2.77 × 10-8) between felt hated by family member and the frequency of alcohol drinking. Our results suggested the significant impact of traumatic events during childhood on the risk of cigarette smoking and alcohol drinking.


Assuntos
Interação Gene-Ambiente , Transtornos Relacionados ao Uso de Substâncias , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Humanos , Reino Unido/epidemiologia
2.
Sleep Med ; 85: 184-190, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34343768

RESUMO

STUDY OBJECTIVES: We aim to explore the mechanism of relationship between insomnia and liver metabolism by examining the gene × insomnia interactions. METHODS: Individual level genotypic and phenotypic data were obtained from the UK Biobank cohort. Regression analysis was first conducted to test the association of insomnia with plasma total bilirubin (TBil; n = 186,793), direct bilirubin (DBil; n = 159,854) and total protein (TP; n = 171,574) in UK Biobank cohort. Second, genome-wide gene-environment interaction study (GWGEIS) was conducted by PLINK 2.0, and FUMA platform was used to identify enriched pathway terms. RESULTS: In UK Biobank cohort, we found that TP (P < 2.00 × 10-16), DBil (P = 1.72 × 10-3) and TBil (P = 3.38 × 10-5) were significantly associated with insomnia. GWGEIS of both DBil and TBil observed significant G × INSOMNIA effects between insomnia and UDP Glucuronosyltransferase Family 1 (rs6431558, P = 6.26 × 10-11) gene. GWGEIS of TP also detected several significant genes interacting with insomnia, such as KLF15, (rs70940816, P = 6.77 × 10-10) and DOK7, (rs2344205, P = 1.37 × 10-9). Multiple gene ontology (GO) terms were identified for bilirubin, such as GO_URONIC_ACID_METABOLIC_PROCESS (adjusted P = 4.15 × 10-26). CONCLUSION: Our study results suggested negative associations between insomnia and DBil and TBil; and a positive association between insomnia and TP.

3.
J Psychiatr Res ; 140: 149-158, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118634

RESUMO

BACKGROUND: Maternal smoking during pregnancy (MSDP) has been reported to be associated with increased anxiety and depression behaviors in offspring. However, there is still scant evidence to support the link between MSDP and anxiety/depression. METHODS: Using the subjects from the UK Biobank cohort (n = 371,903-432,881). Logistic regression analyses were first conducted to test the correlation between MSDP and anxiety/depression in offspring. Second, genome-wide gene-environment interaction study (GWGEIS) analyses were conducted by PLINK, using MSDP as environmental factor. Genetic correlation analysis of anxiety/depression and smoking was conducted by the LDSC software using the published genome-wide association study (GWAS) summary data of four smoking traits (n = 337,334-1,232,091), anxiety (n = 31,880) and depression (n = 490,359). Finally, pathway enrichment analysis was carried out to detect the pathway involved in the development of offspring anxiety caused by the interaction of MSDP × SNPs. RESULTS: Observational analyses showed that anxiety and depression status in offspring were significantly associated with MSDP (all p < 0.0001). Further GWEGI analyses observed significant MSDP-gene interaction effects at UNC80 gene for anxiety (p = 9.09 × 10-9). LDSC did not detect significant genetic correlation between anxiety and smoking traits. Pathway analysis identified 19 significant pathways for anxiety, such as MANALO_HYPOXIA_UP (FDR = 5.50 × 10-4), REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS (FDR = 0.0304) and ONDER_CDH1_TARGETS_2_UP (FDR = 0.0371). CONCLUSION: Our study results suggested the important impact of MDSP on the risk of anxiety in offspring, partly attributing to environment-gene interactions effects.


Assuntos
Interação Gene-Ambiente , Efeitos Tardios da Exposição Pré-Natal , Ansiedade/epidemiologia , Ansiedade/genética , Bancos de Espécimes Biológicos , Proteínas de Transporte , Depressão/epidemiologia , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar , Reino Unido/epidemiologia
4.
Endocrine ; 73(3): 702-711, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34046847

RESUMO

INTRODUCTION: Serum urate is associated with BMD and may be a protective factor. However, the exact association and mechanism are still unclear. We performed a genome-wide gene-environmental interaction study (GWGEIS) to explore the interaction effects between gene and urate on BMD, using data from the UK Biobank cohort. METHODS: A total of 4575 participants for femur total BMD, 4561 participants for L1-L4 BMD, and 237799 participants for heel BMD were included in the present study. Linear regression models were used to test for associations between urate and BMD (femur total BMD, L1-L4 BMD, heel BMD) by R software. GWGEIS was conducted by PLINK 2.0 using a generalize linear model, adjusted for age, sex, weight, smoking behavior, drinking behavior, physical activity and 10 principle components for population structure. RESULTS: Results showed that urate was positively associated with femur total BMD, L1-L4 BMD and heel BMD and similar findings were observed in both the male and female subgroups. GWGEIS identified 261 genome-wide significant (P < 5.00 × 10-8) SNP × urate interaction effects for femur total BMD (rs8192585 in NOTCH4, rs116080577 in PBX1, rs9409991 in COL5A1), 17 genome-wide significant SNP × urate interaction effects for heel BMD (rs145344540 in PDE11A and rs78485379 in DKK2), 17 suggestive genome-wide SNP × urate interaction effects (P < 1.00 × 10-5) for L1-L4 BMD (rs10977015 in PTPRD). We also detected genome-wide significant and suggestive SNP × urate interaction effects for BMD in both the male and female subgroups. CONCLUSIONS: This study reported several novel candidate genes, and strengthen the evidence of the interactive effects between gene and urate on the variations of BMD.


Assuntos
Densidade Óssea , Ácido Úrico , Bancos de Espécimes Biológicos , Densidade Óssea/genética , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Reino Unido
5.
Bone ; 150: 115997, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33964467

RESUMO

BACKGROUND: Kashin-Beck disease (KBD) is an endemic chronic osteochondropathy. The clinical manifestations and radiographic features of adult KBD were similar to those of osteoarthritis (OA). METHODS: We first performed a genetic association scan of 32 OA susceptibility genes with KBD in 898 Han Chinese subjects. The MassARRAY genotyping system (Agena) was used for SNP genotyping. PLINK 1.9 was used for quality control and association testing. Using articular cartilage specimens from 7 adult KBD patients and 4 control subjects, lentivirus-mediated RNA interference (RNAi), qRT-PCR, Western blot and immunohistochemistry were employed to explore the functional relevance of TP63 to KBD chondrocyte. RESULTS: SNP genotyping and association analysis identified TP63 (rs12107036, P = 0.005, OR = 0.71) and OARD1 (rs11280, P = 0.004, OR = 1.51) were significantly associated with KBD. It was also found that TP63 was significantly up-regulated in KBD articular cartilage in both mRNA and protein level compared with the controls (P < 0.05). TP63 suppression by lentivirus-mediated RNAi notably decreased the abundance of Caspase3 and SOX9 in chondrocytes. Most importantly, compared with the scrambled sequence (shControl) group, the protein level of ACAN was increased in the shTP63 group. The mRNA expression of chondrocyte marker genes (COL2A1 and ACAN) was not significantly changed after TP63 knockdown relative to shControl group. CONCLUSION: Our study identifies TP63 as a novel susceptibility gene for KBD, and demonstrates that the inhibition of TP63 suppresses chondrocyte apoptosis and partly facilitates chondrogenesis. The combination of SNP genotyping and molecular biology techniques provides a useful tool for understanding the biological mechanism and differential diagnosis studies of KBD and OA.


Assuntos
Cartilagem Articular , Doença de Kashin-Bek , Osteoartrite , Adulto , Apoptose , Cartilagem Articular/diagnóstico por imagem , Condrócitos , Humanos , Doença de Kashin-Bek/genética , Osteoartrite/genética , Fatores de Transcrição , Proteínas Supressoras de Tumor
6.
World J Biol Psychiatry ; 22(7): 495-504, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33834943

RESUMO

OBJECTIVE: The relationships between gut microbiota and brain-related diseases/traits remains not fully understood. METHOD: A two-stage study was performed to investigate the relationships between gut microbiota and brain-related diseases/traits, and evaluate the potential sex specific effects of gut microbiota. In discovery stage, we systematically scanned the relationships between 515 brain-related diseases/traits and gut microbiota through two-sample Mendelian randomisation analysis. Using ∼500,000 individuals derived from the UK Biobank, polygenetic risk scoring (PRS) analysis was performed to validate the associations detected in discovery stage. To evaluate the potential sex-specific effect of gut microbiota on brain-related disorders, PRS analysis was conducted in female and male, respectively. RESULTS: After systematically scanning diseases or traits, 41 of the 515 brain-related diseases/traits were identified to be associated with gut microbiota, such as Neuroticism score (P2-MR = 0.0018), worrier/anxious feelings (P2-MR = 0.0013), Suffer from 'nerves' (P2-MR = 0.0062) and Nervous feelings (P2-MR = 0.0158). 5 of 41 brain-related diseases or traits were successfully validated in UK Biobank, such as Neuroticism score (PUK = 0.0024, PUK-female = 0.0063, PUK-male = 0.1142), Nervous feelings (PUK = 0.0043, PUK-female = 0.0115, PUK-male = 0.1670) and Worrier/anxious feelings (PUK = 0.0166, PUK-female = 0.0196, PUK-male = 0.2930). CONCLUSION: Our results suggest that gut microbiota contributed more to brain-related diseases or traits in females than in males.Key pointsA two-stage study was performed to investigate the relationships between gut microbiota and brain-related diseases/traits.Using the individuals derived from the UK Biobank, polygenetic risk scoring analysis was performed to validate the associations detected in the discovery stage.Our results suggest that gut microbiota contributed more to brain-related diseases or traits in females than in males.


Assuntos
Microbioma Gastrointestinal , Transtornos Mentais , Bancos de Espécimes Biológicos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Reino Unido
7.
Nutrients ; 13(4)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807197

RESUMO

Dietary habits have considerable impact on brain development and mental health. Despite long-standing interest in the association of dietary habits with mental health, few population-based studies of dietary habits have assessed depression and fluid intelligence. Our aim is to investigate the association of dietary habits with depression and fluid intelligence. In total, 814 independent loci were utilized to calculate the individual polygenic risk score (PRS) for 143 dietary habit-related traits. The individual genotype data were obtained from the UK Biobank cohort. Regression analyses were then conducted to evaluate the association of dietary habits with depression and fluid intelligence, respectively. PLINK 2.0 was utilized to detect the single nucleotide polymorphism (SNP) × dietary habit interaction effect on the risks of depression and fluid intelligence. We detected 22 common dietary habit-related traits shared by depression and fluid intelligence, such as red wine glasses per month, and overall alcohol intake. For interaction analysis, we detected that OLFM1 interacted with champagne/white wine in depression, while SYNPO2 interacted with coffee type in fluid intelligence. Our study results provide novel useful information for understanding how eating habits affect the fluid intelligence and depression.


Assuntos
Depressão/genética , Epigênese Genética , Comportamento Alimentar/fisiologia , Estudo de Associação Genômica Ampla , Inteligência/genética , Estudos de Coortes , Bases de Dados Genéticas , Depressão/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reino Unido
8.
Cartilage ; : 1947603521990859, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33522290

RESUMO

OBJECTIVE: Our aim is to explore the candidate pathogenesis genes and pathways of developmental dysplasia of hip (DDH). DESIGN: Proliferating primary chondrocytes from hip cartilage were used for total RNA extraction including 5 DDH patients and 5 neck of femur fracture (NOF) subjects. Genome-wide mRNA and microRNA (miRNA) were then sequenced on the Illumina platform (HiSeq2500). Limma package was used for difference analysis of mRNA expression profiles. edgeR was used for difference analysis of miRNA expression profiles. miRanda was used to predict miRNA-target genes. The overlapped DDH associated genes identified by mRNA and miRNA integrative analysis were further compared with the differently expressed genes in hip osteoarthritis (OA) cartilage. RESULTS: Differential expression analysis identified 1,833 differently expressed mRNA and 186 differently expressed miRNA for DDH. Integrative analysis of mRNA and miRNA expression profiles identified 175 overlapped candidate genes (differentially expressed genes, DEGs) for DDH, such as VWA1, TMEM119, and SCUBE3. Further gene ontology enrichment analysis detected 111 candidate terms for DDH, such as skeletal system morphogenesis (P = 4.92 × 10-5) and skeletal system development (P = 8.85 × 10-5). Pathway enrichment analysis identified 14 candidate pathways for DDH, such as Hedgehog signaling pathway (P = 4.29 × 10-5) and Wnt signaling pathway (P = 4.42 × 10-2). Among the identified DDH associated candidate genes, we also found some genes were detected in hip OA including EFNA1 and VWA1. CONCLUSIONS: We identified multiple novel candidate genes and pathways for DDH, providing novel clues for understanding the molecular mechanism of DDH.

9.
Mol Brain ; 14(1): 3, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407712

RESUMO

OBJECTIVE: To evaluate the genetic effects of sex hormone traits on the development of mental traits in middle-aged adults. METHODS: The SNPs associated with sex hormone traits were derived from a two-stage genome-wide association study (GWAS). Four sex hormone traits were selected in the current study, including sex hormone-binding globulin (SHBG), testosterone, bioavailable testosterone and estradiol. The polygenic risk score (PRS) of sex hormone traits were calculated from individual-level genotype data of the United Kingdom (UK) Biobank cohort. We then used logistic and linear regression models to assess the associations between individual PRS of sex hormone traits and the frequency of alcohol consumption, anxiety, intelligence and so on. Finally, gene-environment-wide interaction study (GEWIS) was performed to detect novel candidate genes interacting with the sex hormone traits on the development of fluid intelligence and the frequency of smoking and alcohol consumption by PLINK2.0. RESULTS: We observed positive association between SHBG and the frequency of alcohol consumption (b = 0.0101, p = 3.84 × 10-11) in middle-aged males and females. In addition, estradiol was positively associated with the frequency of alcohol consumption (b = 0.0128, p = 1.96 × 10-8) in middle-aged males. Moreover, bioavailable testosterone was associated with the fluid intelligence (b = - 0.0136, p = 5.74 × 10-5) in middle-aged females. Finally, GEWIS identified one significant loci, Tenascin R (TNR) (rs34633780, p = 3.45 × 10-8) interacting with total testosterone for fluid intelligence. CONCLUSION: Our study results support the genetic effects of sex hormone traits on the development of intelligence and the frequency of alcohol consumption in middle-aged adults in UK.


Assuntos
Bancos de Espécimes Biológicos , Interação Gene-Ambiente , Hormônios Esteroides Gonadais/genética , Saúde Mental , Herança Multifatorial/genética , Estudos de Coortes , Feminino , Genoma Humano , Humanos , Inteligência , Masculino , Pessoa de Meia-Idade , Tenascina/metabolismo , Testosterona/metabolismo , Reino Unido
10.
Biol Psychiatry ; 89(9): 888-895, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33500177

RESUMO

BACKGROUND: Psychiatric disorders are among the largest and fastest-growing categories of the global disease burden. However, limited effort has been made to further elucidate associations between socioeconomic factors and psychiatric disorders from a genetic perspective. METHODS: We randomly divided 501,882 participants in the UK Biobank cohort with socioeconomic Townsend deprivation index (TDI) data into a discovery cohort and a replication cohort. For both cohorts, we first conducted regression analyses to evaluate the associations between the TDI and common psychiatric disorders or traits, including anxiety, bipolar disorder, self-harm, and depression (based on self-reported depression and Patient Health Questionnaire scores). We then performed a genome-wide gene-by-environment interaction study using PLINK 2.0 with the TDI as an environmental factor to explore interaction effects. RESULTS: In the discovery cohort, significant associations were observed between the TDI and psychiatric disorders (p < 4.00 × 10-16), including anxiety (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.07-1.10), bipolar disorder (OR = 1.42, 95% CI = 1.36-1.48), self-harm (OR = 1.21, 95% CI = 1.19-1.23), self-reported depression (OR = 1.22, 95% CI = 1.20-1.24), and Patient Health Questionnaire scores (ß = .07, SE = 0.004). We observed similar significant associations in the replication cohort. In addition, multiple candidate loci were identified by the genome-wide gene-by-environment interaction study, including rs10886438 at 10q26.11 (GRK5) (p = 5.72 × 10-11) for Patient Health Questionnaire scores and rs162553 at 2p22.2 (CYP1B1) (p = 2.25 × 10-9) for self-harm. CONCLUSIONS: Our findings suggest the relevance of the TDI to psychiatric disorders. The genome-wide gene-by-environment interaction study identified several candidate genes interacting with the TDI, providing novel clues for understanding the biological mechanism of associations between the TDI and psychiatric disorders.


Assuntos
Bancos de Espécimes Biológicos , Esquizofrenia , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Fatores Socioeconômicos , Reino Unido/epidemiologia
11.
Neuropsychopharmacology ; 46(6): 1086-1092, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32801349

RESUMO

The relationships between long-term antibiotic use during early life and mental traits remain elusive now. A total of 158,444 subjects from UK Biobank were used in this study. Linear regression analyses were first conducted to assess the correlations between long-term antibiotic use during early life and mental traits. Gene-environment-wide interaction study (GEWIS) was then performed by PLINK2.0 to detect the interaction effects between long-term antibiotic use during early life and genes on the risks of mental traits. Finally, DAVID tool was used to conduct gene ontology (GO) analysis of the identified genes interacting with long-term antibiotic use during early life. We found negative associations of long-term antibiotic use during early life with remembrance (p value=1.74 × 10-6, b = -0.10) and intelligence (p value=2.64 × 10-26, b = -0.13), and positive associations of long-term antibiotic use during early life with anxiety (p value = 2.75 × 10-47, b = 0.12) and depression (p value=2.01 × 10-195, b = 0.25). GEWIS identified multiple significant genes-long-term antibiotic use during early life interaction effects, such as ANK3 (rs773585997, p value = 1.78 × 10-8) for anxiety and STRN (rs140049205, p value = 1.88 × 10-8) for depression. GO enrichment analysis detected six GO terms enriched in the identified genes interacting with long-term antibiotic use during early life for anxiety, such as GO:0030425~dendrite (p value = 3.41 × 10-2) and GO:0005886~plasma membrane (p value = 3.64 × 10-3). Our study results suggest the impact of long-term antibiotic use during early life on the development of mental traits.


Assuntos
Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Antibacterianos/efeitos adversos , Interação Gene-Ambiente , Humanos , Reino Unido
12.
Cereb Cortex ; 30(12): 6481-6489, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-32770201

RESUMO

Our aim is to explore the spatial and temporal features of anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) considering different brain regions and development stages. The gene sets related to 16 brain regions and nine development stages were obtained from a brain spatial and temporal transcriptomic dataset. Using the genome-wide association study data, transcriptome-wide association study (TWAS) was conducted to identify the genes whose imputed expressions were associated with AN and OCD, respectively. The mRNA expression profiles were analyzed by GEO2R to obtain differentially expressed genes. Gene set enrichment analysis was conducted to detect the spatial and temporal features related to AN and OCD using the TWAS and mRNA expression analysis results. We observed multiple common association signals shared by TWAS and mRNA expression analysis of AN, such as the primary auditory cortex vs. cerebellar cortex in fetal development and earlier vs. later fetal development in the somatosensory cortex. For OCD, we also detected multiple common association signals, such as medial prefrontal cortex vs. amygdala in adulthood and fetal development vs. infancy in mediodorsal nucleus of thalamus. Our study provides novel clues for describing the spatial and temporal features of brain development in the pathogenesis of AN and OCD.

13.
Eur Psychiatry ; 63(1): e73, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32706328

RESUMO

BACKGROUND: Birth weight influences not only brain development, but also mental health outcomes, including depression, but the underlying mechanism is unclear. METHODS: The phenotypic data of 12,872-91,009 participants (59.18-63.38% women) from UK Biobank were included to test the associations between the birth weight, depression, and brain volumes through the linear and logistic regression models. As birth weight is highly heritable, the polygenic risk scores (PRSs) of birth weight were calculated from the UK Biobank cohort (154,539 participants, 56.90% women) to estimate the effect of birth weight-related genetic variation on the development of depression and brain volumes. Finally, the mediation analyses of step approach and mediation analysis were used to estimate the role of brain volumes in the association between birth weight and depression. All analyses were conducted sex stratified to assess sex-specific role in the associations. RESULT: We observed associations between birth weight and depression (odds ratio [OR] = 0.968, 95% confidence interval [CI] = 0.957-0.979, p = 2.29 × 10-6). Positive associations were observed between birth weight and brain volumes, such as gray matter (B = 0.131, p = 3.51 × 10-74) and white matter (B = 0.129, p = 1.67 × 10-74). Depression was also associated with brain volume, such as left thalamus (OR = 0.891, 95% CI = 0.850-0.933, p = 4.46 × 10-5) and right thalamus (OR = 0.884, 95% CI = 0.841-0.928, p = 2.67 × 10-5). Additionally, significant mediation effects of brain volume were found for the associations between birth weight and depression through steps approach and mediation analysis, such as gray matter (B = -0.220, p = 0.020) and right thalamus (B = -0.207, p = 0.014). CONCLUSIONS: Our results showed the associations among birth weight, depression, and brain volumes, and the mediation effect of brain volumes also provide evidence for the sex-specific of associations.


Assuntos
Bancos de Espécimes Biológicos , Peso ao Nascer/fisiologia , Encéfalo/anatomia & histologia , Encéfalo/fisiopatologia , Depressão/genética , Depressão/fisiopatologia , Tamanho do Órgão/fisiologia , Adulto , Idoso , Estudos de Coortes , Depressão/etiologia , Feminino , Substância Cinzenta/anatomia & histologia , Substância Cinzenta/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Regressão , Fatores de Risco , Tálamo/anatomia & histologia , Tálamo/fisiopatologia , Reino Unido/epidemiologia , Substância Branca/anatomia & histologia , Substância Branca/fisiopatologia
14.
Clin Transl Med ; 10(2): e108, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32564518

RESUMO

BACKGROUND: Herpes simplex virus-1 (HSV-1) infection is reported to be associated with depression. But limited efforts were made to investigate the relationship between HSV-1 infection and the risk of depression, especially from the genetic perspective. METHODS: In UK Biobank cohort, linear and logistic regression analyses were first performed to test the association of HSV-1 seropositivity/antibody with depression, including depression status (N = 2951) and Patient Health Questionnaire (PHQ) score (N = 2839). Using individual genotypic and phenotypic data from the UK Biobank, genome-wide environmental interaction study (GWEIS) was then conducted by PLINK2.0 to evaluate gene × HSV-1 interacting effect on the risk of depression. Finally, gene set enrichment analysis was conducted to identify the biological pathways involved in the observed gene × HSV-1 interaction for depression. RESULT: In UK Biobank cohort, significant associations were observed between depression status and HSV-1 (odds ratio [OR] = 1.09; 95% confidence interval [CI], 1.02-1.16; P = 2.40 × 10-2 for HSV-1 antibody and OR = 1.28; 95% CI, 1.12-1.47, P = 2.59 × 10-3 for HSV-1 seropositivity). GWEIS revealed four significant gene × HSV-1 interaction signals for PHQ score (all P < 5.0 × 10-8 ) and the leading loci was SULF2 (rs6094791, P = 8.60 × 10-9 ). Pathway analyses identified 21 pathways for PHQ score and 19 for depression status, including multiple neural development- and immune-related ones, such as KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION (false discovery rate [FDR] = 3.18 × 10-2 ) for depression and LU_AGING_BRAIN_UP (FDR = 4.21 × 10-2 ) for PHQ score. CONCLUSION: Our results suggested that HSV-1 was associated with the risk of depression, which was modulated by the several genes that were related to the nerve development or immune function.

15.
J Psychiatr Res ; 124: 22-28, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109668

RESUMO

Subjective well-being (SWB), depressive symptoms, and neuroticism are common and vital traits of mental disorders. Genetic mechanisms of SWB, depressive symptoms and neuroticism remain elusive now. The large-scale GWAS summary datasets of SWB (n = 229,883), depressive symptoms (n = 180,866), and neuroticism (n = 170,911) were obtained from published studies. MASH tool was applied to the GWAS datasets for identifying candidate SNPs shared by SWB, depressive symptoms and neuroticism. SNPs detected by MASH, were then mapped to target genes considering regulatory SNP (rSNP), methylated quantitative trait locus (MeQTL) and the SNPs near to known genes. Gene set enrichment analysis (GSEA) was conducted by the FUMA platform. A total of 122 candidate SNPs were detected by MASH analysis, mapping to 29 target genes, such as CLDN23, MSRA and XKR6. GO enrichment analysis identified multiple immune related gene sets for SWB, depressive symptoms and neuroticism, such as GSE2770_UNTREATED_VS_IL4_TREATED_ACT_CD4_TCELL_48H_DN (P = 7.32 × 10-3), GSE6259_FLT3L_INDUCED_DEC205_POS_DC_VS_CD4_TCELL_DN (P = 2.52 × 10-2). We also found some mental disorders related gene sets were associated with three phenotypes, such as mood instability (P = 1.15 × 10-6) and neuroticism (P = 1.72 × 10-6). We identified multiple candidate genes and GO terms shared by SWB, depressive symptoms and neuroticism. Our results support the overlapping genetic mechanisms, and suggest a functional correlation between immunity and SWB, depressive symptoms and neuroticism.


Assuntos
Depressão , Estudo de Associação Genômica Ampla , Depressão/genética , Predisposição Genética para Doença/genética , Humanos , Neuroticismo , Polimorfismo de Nucleotídeo Único/genética
16.
Aging (Albany NY) ; 12(4): 3287-3297, 2020 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-32090979

RESUMO

BACKGROUND: Risky behaviors can lead to huge economic and health losses. However, limited efforts are paid to explore the genetic mechanisms of risky behaviors. RESULT: MASH analysis identified a group of target genes for risky behaviors, such as APBB2, MAPT and DCC. For GO enrichment analysis, FUMA detected multiple risky behaviors related GO terms and brain related diseases, such as regulation of neuron differentiation (adjusted P value = 2.84×10-5), autism spectrum disorder (adjusted P value =1.81×10-27) and intelligence (adjusted P value =5.89×10-15). CONCLUSION: We reported multiple candidate genes and GO terms shared by the four risky behaviors, providing novel clues for understanding the genetic mechanism of risky behaviors. METHODS: Multivariate Adaptive Shrinkage (MASH) analysis was first applied to the GWAS data of four specific risky behaviors (automobile speeding, drinks per week, ever-smoker, number of sexual partners) to detect the common genetic variants shared by the four risky behaviors. Utilizing genomic functional annotation data of SNPs, the SNPs detected by MASH were then mapped to target genes. Finally, gene set enrichment analysis of the identified candidate genes were conducted by the FUMA platform to obtain risky behaviors related gene ontology (GO) terms as well as diseases and traits, respectively.


Assuntos
Transtorno do Espectro Autista/genética , Ontologia Genética , Inteligência/genética , Neurogênese/genética , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Transcriptoma
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