Differences in the gut microbiome of young adults with schizophrenia spectrum disorder: using machine learning to distinguish cases from controls.

While an association between the gut microbiome and schizophrenia spectrum disorders (SSD) has been suggested, the existing evidence is still inconclusive. To this end, we analyzed bacteria and bacterial genes in feces from 52 young adult SSD patients and 52 controls using fecal shotgun metagenomic sequencing. Compared to controls, young SSD patients were found to have significantly lower α-diversity and different ß-diversity both regarding bacterial species (i.e., taxonomic diversity) and bacterial genes (i.e., functional diversity). Furthermore, the α-diversity measures 'Pielou's evenness' and 'Shannon' were significantly higher for both bacterial species, bacterial genes encoding enzymes and gut brain modules in young SSD patients on antipsychotic treatment (young SSD not on antipsychotics=9 patients, young SSD on antipsychotics=43 patients). We also applied machine learning classifiers to distinguish between young SSD patients and healthy controls based on their gut microbiome. Results showed that taxonomic and functional data classified young SSD individuals with an accuracy of ≥ 70% and with an area under the receiver operating characteristic curve (AUROC) of ≥ 0.75. Differential abundance analysis on the most important features in the classifier models revealed that most of the species with higher abundance in young SSD patients had their natural habitat in the oral cavity. In addition, many of the modules with higher abundance in young SSD patients were amino acid biosynthesis modules. Moreover, the abundances of gut-brain modules of butyrate synthesis and acetate degradation were lower in the SSD patients compared to controls. Collectively, our findings continue to support the presence of gut microbiome alterations in SSD and provide support for the use of machine learning algorithms to distinguish patients from controls based on gut microbiome profiles.

Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome.

The association between Attention Deficit Hyperactivity Disorder (ADHD) and low-grade inflammation has been explored in children but rarely in adults. Inflammation is characteristic of some, but not all, patients with ADHD and might be influenced by ADHD medication but also lifestyle factors including nutrition, smoking, and stress. It is also still unclear if any specific symptoms are related to inflammation. Therefore, we assessed 96 inflammatory proteins in a deeply phenotyped cohort of 126 adult ADHD participants with a stable medication status using OLINK technology. A data-based, unsupervised hierarchical clustering method could identify two distinct biotypes within the 126 ADHD participants based on their inflammatory profile: a higher inflammatory potential (HIP) and a lower inflammatory protein potential (LIP) group. Biological processes that differed strongest between groups were related to the NF-κB pathway, chemokine signaling, IL-17 signaling, metabolic alterations, and chemokine attraction. A comparison of sample characteristics revealed that the HIP group was more likely to have higher levels of chronic stress (p < 0.001), a higher clinical global impression scale score (p = 0.030), and a higher risk for suicide (p = 0.032). Medication status did not influence protein levels significantly (p ≥ 0.074), but psychotropic co-medication (p ≤ 0.009) did. In conclusion, our data suggest the presence of two distinct biotypes in adults with ADHD. Higher levels of inflammatory proteins in ADHD are linked to higher levels of chronic perceived stress in a linear fashion. Further research on inflammation in adults with ADHD should take stress levels into account.

Functional Variation in the FAAH Gene Is Directly Associated with Subjective Well-Being and Indirectly Associated with Problematic Alcohol Use.

Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored. Since well-being is a dynamic trait that can fluctuate over time, we hypothesized that we could provide deeper insights into the link between FAAH and well-being using longitudinal data. To this end, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in the FAAH gene (rs324420, Pro129Thr) in a sample of 2822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points (Wave I, B: -0.52, p = 0.007; Wave II, B: -0.41, p = 0.03, adjusted for age and sex). A subsequent phenome-wide association study (PheWAS) affirmed our well-being findings in the UK Biobank (N = 126,132, alternative C-allele associated with elevated happiness, p = 0.008) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being (indirect effect Boot: 0.015, 95% CI [0.003, 0.030], adjusted for AUDIT in Wave I). We propose that chronically elevated anandamide levels might influence disruptions in the endocannabinoid system-a biological contributor to well-being-which could, in turn, contribute to increased alcohol intake, though multiple factors may be at play. Further genetic studies and mediation analyses are needed to validate and extend these findings.

Exposures during pregnancy and at birth are associated with the risk of offspring eating disorders.

BACKGROUND: Eating disorders (ED) are severe psychiatric disorders, commonly debuting early. Aberrances in the intrauterine environment and at birth have been associated with risk of ED. Here, we explore if, and at what effect size, a variety of such exposures associate with offspring ED, that is, anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS). METHODS: This population-based cohort study, conducted from September 2021 to August 2023, used Finnish national registries of all live births in 1996-2014 (N = 1,097,753). Cox proportional hazards modeling was used to compare ED risk in exposed versus unexposed offspring, adjusting for potential confounders and performing sex-stratified analyses. RESULTS: A total of 6614 offspring were diagnosed with an ED; 3668 AN, 666 BN, and 4248 EDNOS. Lower risk of offspring AN was seen with young mothers, continued smoking, and instrumental delivery, while higher risk was seen with older mothers, inflammatory disorders, prematurity, small for gestational age, and low Apgar. Offspring risk of BN was higher with continued smoking and prematurity, while lower with postmature birth. Offspring risk of EDNOS was lower with instrumental delivery, higher for older mothers, polycystic ovary syndrome, insulin-treated pregestational diabetes, antibacterial treatment, prematurity, and small for gestational age. Sex-specific associations were found. CONCLUSIONS: Several prenatal and at birth exposures are associated with offspring ED; however, we cannot exclude confounding by maternal BMI. Nevertheless, several exposures selectively associate with risk of either AN, BN, or EDNOS, and some are sex-specific, emphasizing the importance of subtype- and sex-stratified analyses of ED. PUBLIC SIGNIFICANCE: We define environmental factors involved in the development of different ED, of importance as preventive measure, but also in order to aid in defining the molecular pathways involved and thus in the longer perspective contribute to the development of pharmacological treatment of ED.

Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD-A Randomized Controlled Trial.

Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota-gut-brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1ß-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels.

Bacterial gut microbiome differences in adults with ADHD and in children with ADHD on psychostimulant medication.

Recent evidence suggests that there is a link between neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD), and the gut microbiome. However, most studies to date have had low sample sizes, have not investigated the impact of psychostimulant medication, and have not adjusted for potential confounders, including body mass index, stool consistency and diet. To this end, we conducted the largest, to our knowledge, fecal shotgun metagenomic sequencing study in ADHD, with 147 well-characterized adult and child patients. For a subset of individuals, plasma levels of inflammatory markers and short-chain fatty acids were also measured. In adult ADHD patients (n = 84), compared to controls (n = 52), we found a significant difference in beta diversity both regarding bacterial strains (taxonomic) and bacterial genes (functional). In children with ADHD (n = 63), we found that those on psychostimulant medication (n = 33 on medication vs. n = 30 not on medication) had (i) significantly different taxonomic beta diversity, (ii) lower functional and taxonomic evenness, (iii) lower abundance of the strain Bacteroides stercoris CL09T03C01 and bacterial genes encoding an enzyme in vitamin B12 synthesis, and (iv) higher plasma levels of vascular inflammatory markers sICAM-1 and sVCAM-1. Our study continues to support a role for the gut microbiome in neurodevelopmental disorders and provides additional insights into the effects of psychostimulant medication. However, additional studies are needed to replicate these findings and examine causal relationships with the disorder.

Lithium and risk of cardiovascular disease, dementia and venous thromboembolism.

OBJECTIVE: To determine if long-term lithium treatment is associated with protective effects or increased risk of vascular, neurological, and renal disorders. METHODS: Using nationwide registers, we included all citizens of Finland with dispensations of lithium for three or more consecutive years between 1995 and 2016. We identified 9698 cases and matched 96,507 controls without lithium treatment. Studied outcomes were vascular, neurological, renal disorders, and suicide. Analyses were performed applying Cox proportional hazards modeling in full cohort and in further subcohort analysis of individuals with a comparable diagnosis of mood or psychotic disorder. RESULTS: Lithium users had a significantly higher overall disease burden compared to matched population controls, including a higher risk of cardiovascular and cerebrovascular disorders and dementia. However, compared to individuals with a diagnosis of mood or psychotic disorders without lithium treatment, we observed a lower risk of cardiovascular and cerebrovascular disorders (HR = 0.80, 99% CI = 0.73-0.89), and no significant difference for dementia (HR = 1.15, 99% CI = 0.99-1.33), in lithium users. Pulmonary embolism was more common in the lithium-treated cases both in comparison to the general population (HR = 2.86, 99% CI = 2.42-3.37) and in comparison to the psychiatric subcohort (HR = 1.68, 99% CI = 1.31-2.17). Similarly, the risks of Parkinson's disease and kidney disease were higher in both comparisons. CONCLUSIONS: We conclude that individuals prescribed lithium have a lower risk of cardiovascular and cerebrovascular disease, but no marked effect on dementia, compared to individuals with a mood or psychotic disorder not prescribed lithium. Venous thromboembolism, Parkinson's disease, and kidney disease were significantly more prevalent in individuals prescribed lithium.

Plasma circulating cell-free mitochondrial DNA in social anxiety disorder.

OBJECTIVE: To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). METHODS: In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9-11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. RESULTS: SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. Plasma ccf-mtDNA did not significantly correlate with PBMC mtDNA-cn in patients. CONCLUSION: This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

Heritability of nervous system tumors: a sibling-based design.

Background: The contribution of genetic and environmental factors to susceptibility to nervous system tumors remains unclear. We performed a quantitative genetic study using a sibling design to estimate the heritability of nervous system tumors, as well as the proportion of the risk of these tumors, which is attributable to environmental factors. Methods: We conducted a population-based cohort study using Swedish National Register data. All individuals born in Sweden during 1950-2010 with available information on both biological parents were included. A Multi-Generation Register was used to identify family clusters, including both full- and half-siblings. Initially, one index person was randomly selected from each cluster containing only full siblings and one sibling was randomly assigned to this index person. Subsequently, within each of the remaining clusters of full- and half-siblings, an index person was randomly selected, and a half-sibling was randomly assigned to this index person. Among the randomly selected siblings, cases of nervous system tumors were identified using the cancer registry. Quantitative genetic models were used to estimate the proportion of the variance in nervous system tumors attributable to additive genetic factors, shared environment, and individual-specific environment. Results: The heritability of nervous system tumors was estimated to be 29% (95% confidence interval (CI) = 19%-39%), while the contribution of the non-shared environment to the variance of nervous system tumors was estimated to be 71% (95% CI = 61%-81%). The shared environmental parameter was estimated as zero in the full model. Conclusion: The variation in susceptibility to nervous system tumors is predominantly attributable to non-shared environmental factors, followed by genetic factors.

Birth outcomes in mothers with hypertensive disorders and polycystic ovary syndrome: a population-based cohort study.

STUDY QUESTION: Is polycystic ovary syndrome (PCOS) associated with higher risks of extreme birth size and/or preterm birth in mothers with different hypertension types? SUMMARY ANSWER: PCOS was associated with additional risks of preterm birth in mothers with chronic hypertension and in singleton pregnancies of mothers with pre-eclampsia, and with higher risks of offspring born large for gestational age (LGA) in mothers with gestational hypertension. WHAT IS KNOWN ALREADY: Women with PCOS are more likely to develop gestational hypertension, pre-eclampsia, and chronic hypertension. Although adverse birth outcomes have been frequently reported in mothers with PCOS, such associations in the setting of a hypertensive disorder remain unknown. STUDY DESIGN SIZE DURATION: This is a population-based cohort study including all live births 2004-2014 in Finland (n = 652 732). To ensure diagnosis specificity, mothers with diagnoses that could cause signs and symptoms resembling PCOS were excluded. PARTICIPANTS/MATERIALS SETTING METHODS: Maternal diagnoses of PCOS, gestational hypertension, chronic hypertension, and pre-eclampsia were identified from the Finnish national registries. Generalized estimating equation and multivariable logistic regression were used to assess the adjusted odds ratio (aOR) and 95% CIs of preterm birth, very preterm birth, and offspring being small for gestational age (SGA) or LGA in hypertensive mothers with or without PCOS, using normotensive mothers without PCOS as reference. MAIN RESULTS AND THE ROLE OF CHANCE: Of 43 902 (6.7%) mothers with hypertensive disorders, 1709 (3.9%) had PCOS. Significant interactions were detected for PCOS with hypertension on preterm birth, very preterm birth, offspring born SGA and LGA (Fpreterm = 504.1, Pinteraction < 0.001; Fvery preterm = 124.2, Pinteraction < 0.001; FSGA = 99.5, Pinteraction < 0.001; FLGA = 2.7, Pinteraction = 0.012, respectively). Using mothers with no hypertensive disorder and no PCOS as reference, the risks of preterm and very preterm birth were overrepresented in non-PCOS mothers with chronic hypertension or pre-eclampsia. PCOS was associated with higher risks of preterm birth (aORPCOS 4.02, 3.14-5.15 vs aORnon-PCOS 2.51, 2.32-2.71) in mothers with chronic hypertension, with significant interaction between the exposures (F = 32.7, Pinteraction < 0.001). PCOS was also associated with a higher risk of preterm birth in singleton pregnancies of mothers with pre-eclampsia (aORPCOS 7.33, 5.92-9.06 vs aORnon-PCOS 5.72, 5.43-6.03; F = 50.0, Pinteraction < 0.001). Furthermore, the associations of PCOS comorbid with chronic hypertension or pre-eclampsia was detected also for spontaneous births. Moreover, the risk of offspring LGA was higher in mothers with PCOS and gestational hypertension although lower in those with gestational hypertension alone (aORPCOS 2.04, 1.48-2.80 vs aORnon-PCOS 0.80, 0.72-0.89; F = 9.7, Pinteraction = 0.002), whereas for offspring SGA, the risks were comparable between hypertensive mothers with and those without PCOS. LIMITATIONS REASONS FOR CAUTION: Information on medication treatment, gestational weeks of onset for pre-eclampsia and gestational hypertension, weight gain during pregnancy, and PCOS phenotypes were not available. All diagnoses were retrieved from registries, representing only those seeking medical care for their symptoms. The ICD-9 codes used to identify PCOS before year 1996 are known to underestimate the prevalence of PCOS, while the inclusion of anovulatory infertility as PCOS might introduce an overrepresentation bias, although PCOS constitutes 80% of anovulatory infertility. The risk of very preterm birth in relation to maternal PCOS and hypertensive disorders should be interpreted with caution owing to limited sample sizes. Multifetal pregnancies among maternal PCOS were too few for a subgroup analysis. Moreover, ART included IVF/ICSI only. Potential effects of other treatments, such as ovulation induction, were not examined. WIDER IMPLICATIONS OF THE FINDINGS: PCOS was associated with additional risks of preterm birth or offspring being LGA in hypertensive mothers, which varied between hypertension types. The exacerbated risks highlight consideration of PCOS in pregnancy counseling and management for women with hypertensive disorders. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Shandong Provincial Natural Science Foundation, China [ZR2020MH064 to X.C.], the joint research funding of Shandong University and Karolinska Institute [SDU-KI-2019-08 to X.C. and C.L.], the Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2022-01188 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [RS2021-0855 to C.L.], the Swedish Brain Foundation [FO2021-0412 to C.L.]. The funders had no role in study design, data collection, analysis, and interpretation, writing of the report or decision to submit for publication. The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Plasma Concentrations of Short-Chain Fatty Acids in Active and Recovered Anorexia Nervosa.

Anorexia nervosa (AN) is one of the most lethal psychiatric disorders. To date, we lack adequate knowledge about the (neuro)biological mechanisms of this disorder to inform evidence-based pharmacological treatment. Gut dysbiosis is a trending topic in mental health, including AN. Communication between the gut microbiota and the brain is partly mediated by metabolites produced by the gut microbiota such as short-chain fatty acids (SCFA). Previous research has suggested a role of SCFA in weight regulation (e.g., correlations between specific SCFA-producing bacteria and BMI have been demonstrated). Moreover, fecal SCFA concentrations are reported to be altered in active AN. However, data concerning SCFA concentrations in individuals who have recovered from AN are limited. In the present study, we analyzed and compared the plasma concentrations of seven SCFA (acetic-, butyric-, formic-, isobutyric-, isovaleric-, propionic-, and succinic acid) in females with active AN (n = 109), recovered from AN (AN-REC, n = 108), and healthy-weight age-matched controls (CTRL, n = 110), and explored correlations between SCFA concentrations and BMI. Significantly lower plasma concentrations of butyric, isobutyric-, and isovaleric acid were detected in AN as well as AN-REC compared with CTRL. We also show significant correlations between plasma concentrations of SCFA and BMI. These results encourage studies evaluating whether interventions directed toward altering gut microbiota and SCFA could support weight restoration in AN.

Shorter telomere length and suicidal ideation in familial bipolar disorder.

Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.

Lower plasma concentrations of short-chain fatty acids (SCFAs) in patients with ADHD.

Short-chain fatty acids (SCFAs), produced during bacterial fermentation, have been shown to be mediators in the microbiota-gut-brain axis. This axis has been proposed to influence psychiatric symptoms seen in attention deficit hyperactivity disorder (ADHD). However, there is no report of plasma SCFA concentrations in ADHD. The aim of this study was to explore the plasma concentrations of SCFAs in children and adults with ADHD and the possible factors that could influence those levels. We collected data on age group, sex, serum vitamin D levels, delivery mode, body mass index, diet, medication and blood samples from 233 ADHD patients and 36 family-related healthy controls. The concentrations of SCFAs and the intermediary metabolite succinic acid, were measured using liquid chromatography-mass spectrometry. Adults with ADHD had lower plasma concentrations of formic, acetic, propionic and succinic acid than their healthy family members. When adjusting for SCFA-influential factors among those with ADHD, children had lower concentrations of formic, propionic and isovaleric acid than adults, and those who had more antibiotic medications during the last 2 years had lower concentrations of formic, propionic and succinic acid. When adjusting for antibiotic medication, we found that among children, those currently on stimulant medication had lower acetic and propionic acid levels, and adults with ADHD had lower formic and propionic acid concentrations than adult healthy family members. In all, our findings show lower-than-normal plasma concentrations of SCFAs in ADHD explained in-part by antibiotic medication, age and stimulant medication. Whether or not this is of clinical significance is yet to be explored.

Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden.

BACKGROUND: Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. METHODS: We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipoläR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipoläR, and the Swedish prescription registry. The median time between timepoints was 1·07 years for cohort 1 and 1·09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. FINDINGS: 2357 patients who were administered lithium (1423 women [60·4%] and 934 men [39·6%]; mean age 53·6 years [range 17-89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R2]: R2cohort1=0·41 and R2cohort2=0·31; both p<0·0001), sex (R2cohort1=0·0063 [p=0·045] and R2cohort2=0·026 [p<0·0001]), eGFR (R2cohort1=0·38 and R2cohort2=0·20; both p<0·0001), comedication with diuretics (R2cohort1=0·0058 [p=0·014] and R2cohort2=0·0026 [p<0·0001]), and agents acting on the renin-aldosterone-angiotensin system (R2cohort1=0·028 and R2cohort2=0·015; both p<0·0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R2cohort1=0·13 and R2cohort2=0·15; both p<0·0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; ß=-0·053 [95% CI -0·071 to -0·034]; p<0·00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0·0014, corrected FDR=0·04) and cortex of the kidney (p=0·0015, corrected FDR=0·04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0·05, p=0·01), body-mass index (p value threshold: 0·05, p=0·00025), and blood urea nitrogen (p value threshold: 0·001, p=0·00043). The model based on six clinical predictors explained 61·4% of the variance in CLLi in cohort 1 and 49·8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59·32% to 59·36% in cohort 1 and from 49·21% to 50·03% in cohort 2 when including rs583503 and the four first principal components. INTERPRETATION: Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. FUNDING: Stanley Medical Research Institute, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Swedish Research Council, Söderström-Königska Foundation, Bror Gadelius Minnesfond, Swedish Mental Health Fund, Karolinska Institutet and Hospital.

Investigating the Long-Term Effect of an Interdisciplinary Multimodal Rehabilitation Program on Levels of Bioactive Lipids and Telomerase Activity in Blood from Patients with Chronic Pain.

Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP.

The cannabinoid receptor-1 gene interacts with stressful life events to increase the risk for problematic alcohol use.

Problematic alcohol use is a major contributor to the global burden of death and disabilities, and it represents a public health concern that has grown substantially following the COVID-19 pandemic. The available treatment options remain limited and to develop better pharmacotherapies for alcohol misuse we need to identify suitable biological targets. Previous research has implicated the brain's endocannabinoid system (ECS) in psychiatric and stress-related outcomes, including substance use and habituation to repeated stress. Moreover, genetic variants in the cannabinoid-1 receptor gene (CNR1; CB1R) have been associated with personality traits, which are in turn predictors of substance use disorders. To date, however, no human genome-wide association study has provided evidence for an involvement of the ECS in substance use outcomes. One reason for this ECS-related "missing heritability" may be unexamined gene-environment interactions. To explore this possibility, we conducted cross-sectional analyses using DNA samples and stress-exposure data from a longitudinal Swedish population-based study (N = 2,915). Specifically, we genotyped rs2023239, a functional C/T single nucleotide polymorphism in CNR1, previously reported to be associated with CNR1 binding in the brain, subjective reward following alcohol intake, and alcohol cue-elicited brain activation. Our two outcomes of interest were (i) problematic alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), and (ii) personality trait scores based on the Five Factor Model. We found no baseline association between rs2023239 and problematic alcohol use or personality traits. However, there was a clear trend for interaction between rs2023239's risk allele (C) and stressful life events (SLEs) in both childhood and adulthood, which predicted problematic alcohol use. Although not significant, there was also some indication that the risk allele interacted with child SLEs to increase scores on neuroticism. Our study supports the notion that the ECS can affect alcohol intake behaviors by interacting with life adversities and is-to the best of our knowledge-the first to focus on the interaction between CNR1 and stressors in both childhood and adulthood in humans. Further studies are warranted to confirm these findings.

Association of maternal polycystic ovary syndrome and diabetes with preterm birth and offspring birth size: a population-based cohort study.

STUDY QUESTION: Is the presence of polycystic ovary syndrome (PCOS) associated with more adverse infant outcomes in mothers with different types of diabetes? SUMMARY ANSWER: The presence of PCOS implies higher risks of total (medically indicated and spontaneously combined) and spontaneous preterm birth in mothers with non-insulin-treated type 2 diabetes and gestational diabetes mellitus (GDM), and lower risk of offspring being large for gestational age (LGA) in mothers with insulin-treated diabetes. WHAT IS KNOWN ALREADY: PCOS is suggested to be an independent risk factor for adverse infant outcomes, and it is highly prevalent in mothers with diabetes. However, the impact of PCOS on the associations of different types of maternal diabetes with preterm birth and offspring birth sizes has not been reported. STUDY DESIGN, SIZE, DURATION: This is a population-based cohort study including all live births between 1996 and 2014 in Finland. Children with concurrent maternal diagnoses that could cause signs and symptoms similar to PCOS were excluded. A total of 1 097 753 children were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: National registries were linked to identify births with maternal PCOS (n = 24 682), stratified by diabetes types. Logistic regression was used to examine the association of maternal PCOS and comorbid insulin-treated diabetes, non-insulin-treated type 2 diabetes or GDM with offspring LGA and small for gestational age (SGA). Generalized estimating equation was used to assess the risk of preterm birth in relation to maternal PCOS and diabetes. Potential interaction between PCOS and diabetes was evaluated on both additive and multiplicative scales. MAIN RESULTS AND THE ROLE OF CHANCE: Using mothers with no PCOS and no diabetes as the reference and adjusting for maternal and birth factors, there were higher risks of total (odds ratio (OR) 2.84, 95% CI 2.21 - 3.66 vs. OR 1.91, 95% CI 1.77 - 2.07, P = 0.01) and spontaneous (OR 4.02, 95% CI 2.94 - 5.50 vs. OR 2.35, 95% CI 2.13 - 2.59, P = 0.001) preterm birth for those with PCOS in mothers with non-insulin-treated type 2 diabetes and higher risks of total (OR 1.42, 95% CI 1.27-1.58 vs. OR 0.89, 95% CI 0.86-0.91, P = 0.0001) and spontaneous (OR 1.80, 95% CI 1.59-2.05 vs. OR 1.01, 95% CI 0.98-1.05, P = 0.0001) preterm birth for those with PCOS in mothers with GDM. Among mothers with type 2 diabetes, further adjusting for maternal BMI eliminated the difference in preterm birth risks between those with and those without PCOS, and adjustment for infertility treatment and pre-eclampsia also reduced the preterm risks associated with PCOS significantly. For mothers with GDM, however, the risks of total and spontaneous preterm birth remained higher for those with PCOS following these aforementioned adjustments or stratified analysis. The risk of offspring being LGA was lower for those with PCOS than those without PCOS among mothers with insulin-treated diabetes (OR 18.90, 95% CI 14.21-25.14 vs. OR 32.04, 95% CI 29.79-34.46, P = 0.0001), showing departure from additivity (relative excess risk due to interaction -11.74, 95% CI -16.17 to -7.31, P < 0.001) and multiplicativity (P < 0.001). PCOS did not alter the risk estimate of preterm birth in mothers with insulin-treated diabetes or offspring LGA and SGA in mothers with type 2 diabetes or GDM. LIMITATIONS, REASONS FOR CAUTION: The register-based diagnoses used in this study captured only women with PCOS seeking medical care and having live births. Including female infertility associated with anovulation as PCOS exposure was a risk for misclassification. Sample sizes for pregestational diabetes were small. Insulin purchase during pregnancy in those without a diabetes diagnosis was not accounted for in the analysis. For patients treated with insulin or other medications, we were unable to assess how they complied with such prescriptions. Also, maternal BMI was recorded only once in early pregnancy, thus the potential influence of gestational weight gain on birth outcomes could not be examined. Data on the causes for preterm birth were not available from the registers. WIDER IMPLICATIONS OF THE FINDINGS: The presence of PCOS implied higher risks of total and spontaneous preterm birth in mothers with type 2 diabetes or GDM, and lower risk of offspring being LGA in mothers with insulin-treated diabetes. The higher risks of preterm birth added by PCOS could be explained by prepregnancy BMI or in part by infertility treatment and pre-eclampsia in maternal non-insulin-treated type 2 diabetes, but not in maternal GDM. The differential effects of PCOS on the associations of different types of maternal diabetes with infant outcomes have implications for preventative strategies and clinical counseling for affected pregnancies. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Shandong Provincial Natural Science Foundation, China (ZR2020MH064 to X.C.), Shandong Province Medical and Health Technology Development Plan (2018WS338 to X.C.), the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C. and C.L.), the Finnish National Institute for Health and Welfare: Drug and pregnancy project (M.G.), the Swedish Research Council (2014-10171 to C.L.), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council (SLL20170292 and SLL20190589 to C.L.), the Swedish Brain Foundation (FO2019-0201 and FO2020-0305 to C.L.). X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Physical exercise is associated with a reduction in plasma levels of fractalkine, TGF-ß1, eotaxin-1 and IL-6 in younger adults with mobility disability.

Mobility disability (MD) refers to substantial limitations in life activities that arise because of movement impairments. Although MD is most prevalent in older individuals, it can also affect younger adults. Increasing evidence suggests that inflammation can drive the development of MD and may need to be targeted for MD prevention. Physical exercise has anti-inflammatory properties and has been associated with MD prevention. However, no studies to date have examined whether exercise interventions affect the peripheral inflammatory status in younger adults with MD. To this end, we used blood samples from young and middle-aged adults with MD (N = 38; median age = 34 years) who participated in a 12-week intervention that included aerobic and resistance exercise training. A pre-post assessment of inflammatory biomarkers was conducted in plasma from two timepoints, i.e., before the exercise trial and at follow-up (3-7 days after the last exercise session). We successfully measured 15 inflammatory biomarkers and found that exercise was associated with a significant reduction in levels of soluble fractalkine, transforming growth factor beta 1 (TGF-ß1), eotaxin-1 and interleukin (IL) 6 (corrected α = 0.004). We also found significant male-specific effects of exercise on (i) increasing IL-16 and (ii) decreasing vascular endothelial growth factor-A (VEGF-A). In line with our results, previous studies have also found that exercise can reduce levels of TGF-ß1, eotaxin-1 and IL-6. However, our finding that exercise reduces plasma levels of fractalkine in younger adults with MD, as well as the sex-dependent findings, have not been previously reported and warrant replication in larger cohorts. Given the suggested role of inflammation in promoting MD development, our study provides additional support for the use of physical exercise as a treatment modality for MD.

Association of Preeclampsia and Perinatal Complications With Offspring Neurodevelopmental and Psychiatric Disorders.

Importance: Maternal preeclampsia has been reported to increase the risk of autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability in offspring. However, the association between maternal preeclampsia combined with perinatal complications and neurodevelopmental and psychiatric disorders in offspring is less well documented. Objective: To examine the association of maternal preeclampsia, separately and together with perinatal complications, with neurodevelopmental and psychiatric disorders in offspring. Design, Setting, and Participants: This population-based cohort study used data from nationwide registries in Finland to assess all singleton live births (N = 1 012 723) between January 1, 1996, and December 31, 2014. Offspring were followed up until December 31, 2018 (when the oldest reached age 22 years). Exclusion criteria were maternal inpatient psychiatric diagnoses and pregestational diabetes. The study and data analysis were conducted from May 1, 2020, to June 1, 2021. Exposures: Preeclampsia and perinatal complications (delivery earlier than 34 weeks' gestation and/or small for gestational age). Main Outcomes and Measures: The primary outcomes were neurodevelopmental and psychiatric diagnoses and dispensation of psychotropic drugs among offspring until December 31, 2018. Cox proportional hazards regression analyses were performed to assess the associations. Results: Of 1 012 723 singleton live births (51.1% boys; mean [SD] maternal age at birth, 30.0 [5.4] years; specific data on race and ethnicity were not available in the data set), 21 010 children (2.1%) were exposed to preeclampsia alone, 33 625 children (3.3%) were exposed to perinatal complications alone, and 4891 children (0.5%) were exposed to both preeclampsia and perinatal complications. A total of 93 281 children (9.2%) were diagnosed with a neurodevelopmental or psychiatric disorder. Offspring exposed to both preeclampsia and perinatal complications had an increased risk of any neurodevelopmental or psychiatric disorder after adjusting for potential confounding (adjusted hazard ratio [aHR], 2.11; 95% CI, 1.96-2.26) compared with those not exposed to either preeclampsia or perinatal complications; this risk was higher than exposure to either preeclampsia alone (aHR, 1.18; 95% CI, 1.12-1.23) or perinatal complications alone (aHR, 1.77; 95% CI, 1.72-1.82). Sibling pair analyses did not detect any increase in the risk of neurodevelopmental or psychiatric disorders after exposure to preeclampsia alone, but offspring exposed to both preeclampsia and perinatal complications had increased risks of intellectual disabilities (aHR, 3.24; 95% CI, 1.05-10.06), specific developmental disorders (aHR, 3.56; 95% CI, 2.35-5.41), ADHD and conduct disorders (aHR, 2.42; 95% CI, 1.09-5.39), and other behavioral and emotional disorders (aHR, 2.45; 95% CI, 1.17-5.13). The risk estimates for specific developmental disorders (aHR, 2.82; 95% CI, 2.60-3.05) and ADHD and conduct disorders (aHR, 1.88; 95% CI, 1.65-2.14) were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications alone (aHR, 2.26 [95% CI, 2.18-2.33] and 1.60 [95% CI, 1.52-1.68], respectively). Conclusions and Relevance: In this study, exposure to both maternal preeclampsia and perinatal complications was associated with intellectual disabilities, specific developmental disorders, ADHD and conduct disorders, and other behavioral and emotional disorders in offspring. For specific developmental disorders and ADHD and conduct disorders, the risk estimates were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications only.

Sirtuins and neuropeptide y downregulation in Flinders Sensitive Line rat model of depression.

Since the NAD+-dependent histone deacetylases sirtuin-1 (SIRT1) and sirtuin-2 (SIRT2) are critically involved in epigenetics, endocrinology and immunology and affect the longevity in model organisms, we investigated their expression in brains of 3-month-old and 14-15 months old rat model of depression Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats. In view of the dysregulated NPY system in depression, we also studied NPY in young and old FSL to explore the temporal trajectory of depressive-like-ageing interaction. Sirt1, Sirt2 and Npy mRNA were determined using qRT-PCR in prefrontal cortex (PFC) from young and old FSL and FRL, and in hippocampi from young FSL and FRL. PFC: Sirt1 expression was decreased in FSL (p = 0.001). An interaction between age and genotype was found (p = 0.032); young FSL had lower Sirt1 with respect to both age (p = 0.026) and genotype (p = 0.001). Sirt2 was lower in FSL (p = 0.003). Npy mRNA was downregulated in FSL (p = 0.001) but did not differ between the young and old rat groups. Hippocampus: Sirt1 was reduced in young FSL compared to young FRL (p = 0.005). There was no difference in Sirt2 between FSL and FRL. Npy levels were decreased in hippocampus of young FSL compared to young FRL (p = 0.003). Effects of ageing could not be investigated due to loss of samples. To conclude, i this is the first demonstration that SIRT1 and SIRT2 are changed in brain of FSL, a rat model of depression; ii the changes are age-dependent; iii sirtuins are potential targets for treatment of age-related neurodegenerative diseases.