Shared genetics and bidirectional causal relationships between type 2 diabetes and attention-deficit/hyperactivity disorder

Background Type 2 diabetes(T2D)is a chronic metabolic disorder with high comorbidity with mental disorders.The genetic links between attention-deficit/hyperactivity disorder(ADHD)and T2D have yet to be elucidated.Aims We aim to assess shared genetics and potential associations between ADHD and T2D.Methods We performed genetic correlation,two-sample Mendelian randomisation and polygenic overlap analyses between ADHD and T2D.The genome-wide association study(GWAS)summary results of T2D(80154 cases and 853816 controls),ADHD2019(20183 cases and 35191 controls from the 2019 GWAS ADHD dataset)and ADHD2022(38691 cases and 275986 controls from the 2022 GWAS ADHD dataset)were used for the analyses.The T2D dataset was obtained from the DIAGRAM Consortium.The ADHD datasets were obtained from the Psychiatric Genomics Consortium.We compared genome-wide association signals to reveal shared genetic variation between T2D and ADHD using the larger ADHD2022 dataset.Moreover,molecular pathways were constructed based on large-scale literature data to understand the connection between ADHD and T2D.Results T2D has positive genetic correlations with ADHD2019(rg=0.33)and ADHD2022(rg=0.31).Genetic liability to ADHD2019 was associated with an increased risk for T2D(odds ratio(OR):1.30,p<0.001),while genetic liability to ADHD2022 had a suggestive causal effect on T2D(OR:1.30,p=0.086).Genetic liability to T2D was associated with a higher risk for ADHD2019(OR:1.05,p=0.001)and ADHD2022(OR:1.03,p<0.001).The polygenic overlap analysis showed that most causal variants of T2D are shared with ADHD2022.T2D and ADHD2022 have three overlapping loci.Molecular pathway analysis suggests that ADHD and T2D could promote the risk of each other through inflammatory pathways.Conclusions Our study demonstrates substantial shared genetics and bidirectional causal associations between ADHD and T2D.

Exploring the influences of education,intelligence and income on mental disorders

Background Previous studies have shown that educational attainment(EA),intelligence and income are key factors associated with mental disorders.However,the direct effects of each factor on major mental disorders are unclear.Aims We aimed to evaluate the overall and independent causal effects of the three psychosocial factors on common mental disorders.Methods Using genome-wide association study summary datasets,we performed Mendelian randomisation(MR)and multivariable MR(MVMR)analyses to assess potential associations between the 3 factors(EA,N=766345;household income,N=392422;intelligence,N=146808)and 13 common mental disorders,with sample sizes ranging from 9907 to 807553.Inverse-variance weighting was employed as the main method in the MR analysis.Results Our MR analysis showed that(1)higher EA was a protective factor for eight mental disorders but contributed to anorexia nervosa,obsessive-compulsive disorder(OCD),bipolar disorder(BD)and autism spectrum disorder(ASD);(2)higher intelligence was a protective factor for five mental disorders but a risk factor for OCD and ASD;(3)higher household income protected against 10 mental disorders but confers risk for anorexia nervosa.Our MVMR analysis showed that(1)higher EA was a direct protective factor for attention-deficit/hyperactivity disorder(ADHD)and insomnia but a direct risk factor for schizophrenia,BD and ASD;(2)higher intelligence was a direct protective factor for schizophrenia but a direct risk factor for major depressive disorder(MDD)and ASD;(3)higher income was a direct protective factor for seven mental disorders,including schizophrenia,BD,MDD,ASD,post-traumatic stress disorder,ADHD and anxiety disorder.Conclusions Our study reveals that education,intelligence and income intertwine with each other.For each factor,its independent effects on mental disorders present a more complex picture than its overall effects.

Causal associations between major depressive disorder and COVID-19

Background We aimed to evaluate whether major depressive disorder(MDD)could aggravate the outcomes of coronavirus disease 2019(COVID-19)or whether the genetic liability to COVID-19 could trigger MDD.Aims We aimed to assess bidirectional causal associations between MDD and COVID-19.Methods We performed genetic correlation and Mendelian randomisation(MR)analyses to assess potential associations between MDD and three COVID-19 outcomes.Literature-based network analysis was conducted to construct molecular pathways connecting MDD and COVID-19.Results We found that MDD has positive genetic correlations with COVID-19 outcomes(rg:0.10–0.15).Our MR analysis indicated that genetic liability to MDD is associated with increased risks of COVID-19 infection(odds ratio(OR)=1.05,95%confidence interval(CI):1.00 to 1.10,p=0.039).However,genetic liability to the three COVID-19 outcomes did not confer any causal effects on MDD.Pathway analysis identified a panel of immunity-related genes that may mediate the links between MDD and COVID-19.Conclusions Our study suggests that MDD may increase the susceptibility to COVID-19.Our findings emphasise the need to increase social support and improve mental health intervention networks for people with mood disorders during the pandemic.

Detection and evaluation of different morphological forms of Mycoplasma hominis in human semen

Recently discovered microcolonial forms of Mycoplasma hominis(M.hominis)and their impact on human spermatogenesis are studied.The spermatozoa of 125 fertile men(sperm donors;from Reprobank[Reproductive Tissue Bank,Moscow,Russial)and of 93 patients with fertility problems(from the Federal State Budgetary Institution"Research Centre for Medical Genetics[RCMG]",Moscow,Russia)were used.Classical colonies of M.hominis and microcolonies were detected by molecular biological methods,culture of bacteria,and transmission electron microscopy.The unique structure of microcolonial cells,in which the cytoplasmic cylinder is surrounded by concentric electron-dense and electron-light layers with a periodicity of 12-14 nm,and the ability of microcolonial cells to attach to spermatozoa are shown.In patients with lower sperm quality,microcolonies of M.hominis were detected 2.5 times more frequently than classical colonies.The detection of microcolonies in the ejaculate and the frequent isolation of microcolonies from sperm samples of patients with fertility problems suggest that microcolonial cells may be one cause of infertility.

Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency

The objective of this study was to analyze the current evidence for the use of pancreatic enzyme replacement therapy (PERT) in affecting survival and quality of life in patients with pancreatic exocrine insufficiency (PEI). Systematic searches of the literature were performed using the PubMed database. Articles were selected for inclusion if they reported findings from trials assessing the effects of PERT on quality of life, survival, malabsorption, growth parameters (such as height, body weight and body mass index), or gastrointestinal symptoms (such as abdominal pain, stool consistency and flatulence). PERT improved PEI-related malabsorption and weight maintenance in patients with cystic fibrosis, chronic pancreatitis, pancreatic cancer, and post-surgical states. In patients with chronic pancreatitis, PERT improved PEI-related symptoms and quality of life measures. Several small retrospective studies have also suggested that PERT may have a positive impact on survival, but long-term studies assessing this effect were not identified. PERT is effective for treating malnutrition and supporting weight maintenance, and it is associated with improved quality of life and possibly with enhanced survival in patients with PEI. However, there is evidence that not all patients with PEI receive adequate PERT. Future work should aim to assess the long-term effects of PERT on the survival of patients with PEI.

Association of rare SPINK1 gene mutation with another base substitution in chronic pancreatitis patients

AIM: To verify and expand the known spectrum of serine protease inhibitor Kazal type 1 (SPINK1) gene mutations in chronic pancreatitis. METHODS: DNA extracted from 172 chronic pancreatitis patients was assayed for SPINK1 gene mutations by PCR and DNA sequencing. A control cohort of 90 unrelated healthy individuals was analysed by the same methods for presence of common populational polymorphisms, and frequency of five-loci haplotypes was calculated. Linkages of gene aberrations in single SPINK1 gene copies were analysed by long-distance PCR followed by allele-specifi c PCR and DNA sequencing. RESULTS: The most frequent SPINK1 gene mutation N34S was found at a frequency of 6%. Furthermore, we detected the heterozygous intervening sequence (IVS) 3 + 2 T > C mutated gene in 2 German patients and 1 Macedonian chronic pancreatitis patient. In all three SPINK1 gene copies an additional rare base substitution was found: 5’untranslated region (UTR)-215 G > A. Poly-morphism analysis revealed that all three affected genes carried the same fi ve-loci haplotype. DNA sequencing of another chronic pancreatitis-related gene PRSS1 (cationic trypsinogen) did not reveal any mutations in these 3 pa-tients.CONCLUSION: We found in 3 (2%) of 172 chronic pancreatitis patients an IVS3 + 2 T > C SPINK1 gene mutation and a base substitution 5’UTR-215 G > A inthe same gene copy. Most probably the 5’UTR-215 G >A represents a rare polymorphism and not a mutationas previously concluded. Haplotype analysis suggests acommon origin of the IVS3 + 2 T > C mutation in thesepatients.

Clinical significance of molecular subtypes of gastrointestinal tract adenocarcinoma

Adenocarcinomas of the gastrointestinal tract(esophagus,stomach,and colon)represent a heterogeneous group of diseases with distinct etiology,clinical features,treatment approaches,and prognosis.Studies are ongoing to isolate molecular genetic subtypes,perform complete biological characterization of the tumor,determine prognostic groups,and find predictive markers to the effectiveness of therapy.Separate molecular genetic classifications were created for esophageal adenocarcinoma[The Cancer Genome Atlas(TCGA)],stomach cancer(TCGA,Asian Cancer Research Group),and colon cancer(Colorectal Cancer Subtyping Consortium).In 2018,isolation of TCGA molecular genetic subtypes for adenocarcinomas of the gastrointestinal tract(esophagus,stomach,and colon)highlighted the need for further studies and clinical validation of subtyping of gastrointestinal adenocarcinomas.However,this approach has limitations.The aim of our work was to critically analyze integration of molecular genetic subtyping of gastrointestinal adenocarcinomas in clinical practice.

Non-enzymatic antioxidant blood plasma profile in the period of high training loads of elite speed skaters in the altitude

At the altitude,hypoxia and training load are key factors in the development of oxidative stress.Altitude-induced oxidative stress is developed due to the depletion of antioxidant potential.In the current study,we examined the non-enzymatic antioxidant profile of blood plasma in 7 males and 5 females specializing in speed skating at a 21-day training camp at 1850m above sea level.Training included:cycling,roller skating,ice skating,strength training,and special training.At the start point and the endpoint,total hemoglobin mass(tHb-mass),hemoglobin concentration,and circulating blood volume were determined.Antioxidant profiles,hypoxic doses,hypoxic impulses,and training impulses were assessed at 3,6,10,14,and 18 days.Antioxidant profiles consisting of“urate”and“thiol”parts were registered with chemiluminometry.In the training dynamics,antioxidant parameters changed individually,but in total there was a decrease in the“urate”capacity by a factor of 1.6(p=0.001)and an increase in the“thiol”capacity by a factor of 1.8(p=0.013).The changes in“urate”capacity positively correlated(r_(S)=0.40)and the changes in“thiol”capacity negatively correlated(r_(S)=−0.45)with changes in tHb-mass.Both exercise and hypoxic factors affect the antioxidant parameters bidirectionally.They correlated with a decrease in thiol capacity and with an increase in urate capacity.The assessment of the non-enzymatic antioxidant profile can be a simple and useful addition to screening the reactive oxygen species homeostasis and can help choose the personalized training schedule,individualize recovery and ergogenic support.

Global methylation status of sperm DNA in carriers of chromosome structural aberrations

Male infertility might be clearly associated with aberrant DNA methylation patterns in human spermatozoa. An association between oxidative stress and the global methylation status of the sperm genome has also been suggested. The aim of the present study was to determine whether the global sperm DNA methylation status was affected in the spermatozoa of carriers of chromosome structural aberrations. The relationships between the 5-methylcytosine （msC） levels in spermatozoa and chromatin integrity status were evaluated. The study patients comprised male carriers of chromosome structural aberrations with reproductive failure （n = 24）, and the controls comprised normozoospermic sperm volunteers （n = 23）. The global msC level was measured using thin-layer chromatography （TLC） and immunofluorescence （IF） techniques. The sperm chromatin integrity was assessed using aniline blue （AB） staining and TUNEL assay. The mean msC levels were similar between the investigated chromosome structural aberrations carriers （P） and controls （K）. However, sperm chromatin integrity tests revealed significantly higher values in chromosomal rearrangement carriers than in controls （P 〈 0.05）. Although the potential relationship between sperm chromatin integrity status and sperm DNA fragmentation and the msC level juxtaposed in both analyzed groups （P vs K） was represented in a clearly opposite manner, the low chromatin integrity might be associated with the high hypomethylation status of the sperm DNA observed in carriers of chromosome structural aberrations.