Genetic architecture of brain age and its causal relations with brain and mental disorders.

The difference between chronological age and the apparent age of the brain estimated from brain imaging data-the brain age gap (BAG)-is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and nongenetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3-95 years). A genome-wide association analysis across 28,104 individuals (40-84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG (p < 5 × 10-8) implicating neurological, metabolic, and immunological pathways - among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson's disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD (p = 7.9 × 10-4) and bipolar disorder (p = 1.35 × 10-2) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG.

Machine-learning-derived heart and brain age are independently associated with cognition.

BACKGROUND AND PURPOSE: A heart age biomarker has been developed using deep neural networks applied to electrocardiograms. Whether this biomarker is associated with cognitive function was investigated. METHODS: Using 12-lead electrocardiograms, heart age was estimated for a population-based sample (N = 7779, age 40-85 years, 45.3% men). Associations between heart delta age (HDA) and cognitive test scores were studied adjusted for cardiovascular risk factors. In addition, the relationship between HDA, brain delta age (BDA) and cognitive test scores was investigated in mediation analysis. RESULTS: Significant associations between HDA and the Word test, Digit Symbol Coding Test and tapping test scores were found. HDA was correlated with BDA (Pearson's r = 0.12, p = 0.0001). Moreover, 13% (95% confidence interval 3-36) of the HDA effect on the tapping test score was mediated through BDA. DISCUSSION: Heart delta age, representing the cumulative effects of life-long exposures, was associated with brain age. HDA was associated with cognitive function that was minimally explained through BDA.

Comparing prevalence of chronic kidney disease and its risk factors between population-based surveys in Russia and Norway.

BACKGROUND: Little data exists on the prevalence of chronic kidney disease (CKD) in the Russian population. We aimed to estimate the prevalence of CKD in a population-based study in Russia, compare with a similar study in Norway, and investigate whether differences in risk factors explained between-study differences in CKD. METHODS: We compared age- and sex-standardised prevalence of reduced eGFR (< 60 ml/min/1.73m2 CKD-EPI creatinine equation), albuminuria and or a composite indicator of CKD (one measure of either reduced eGFR or albuminuria) between participants aged 40-69 in the population-based Know Your Heart (KYH) study, Russia (2015-2018 N = 4607) and the seventh Tromsø Study (Tromsø7), Norway (2015-2016 N = 17,646). We assessed the contribution of established CKD risk factors (low education, diabetes, hypertension, antihypertensive use, smoking, obesity) to between-study differences using logistic regression. RESULTS: Prevalence of reduced eGFR or albuminuria was 6.5% (95% Confidence Interval (CI) 5.4, 7.7) in KYH and 4.6% (95% CI 4.0, 5.2) in Tromsø7 standardised for sex and age. Odds of both clinical outcomes were higher in KYH than Tromsø7 (reduced eGFR OR 2.06 95% CI 1.67, 2.54; albuminuria OR 1.54 95% CI 1.16, 2.03) adjusted for sex and age. Risk factor adjustment explained the observed between-study difference in albuminuria (OR 0.92 95% CI 0.68, 1.25) but only partially reduced eGFR (OR 1.42 95% CI 1.11, 1.82). The strongest explanatory factors for the between-study difference was higher use of antihypertensives (Russian sample) for reduced eGFR and mean diastolic blood pressure for albuminuria. CONCLUSIONS: We found evidence of a higher burden of CKD within the sample from the population in Arkhangelsk and Novosibirsk compared to Tromsø, partly explained by between-study population differences in established risk factors. In particular hypertension defined by medication use was an important factor associated with the higher CKD prevalence in the Russian sample.

Pharmacological management of modifiable cardiovascular risk factors (blood pressure and lipids) following diagnosis of myocardial infarction, stroke and diabetes: comparison between population-based studies in Russia and Norway.

BACKGROUND: Cardiovascular disease (CVD) mortality is substantially higher in Russia than in neighbouring Norway. We aimed to compare blood pressure- and lipid-lowering medication use and proportion meeting treatment targets between general population samples in the two countries in those with CVD and diabetes. METHODS: The study population was adults aged 40-69 years reporting a diagnosis of myocardial infarction (MI), stroke and/or diabetes participating in cross-sectional population-based studies in Russia (Know Your Heart (KYH) 2015-18 N = 626) and Norway (The Tromsø Study 2015-16 (Tromsø 7) N = 1353). Reported medications were coded according to the 2016 WHO Anatomical Therapeutic Chemical Classification system. Treatment targets were defined using the Joint European Societies guidelines for CVD prevention in clinical practice (2016). RESULTS: Age- and sex-standardized prevalence of use of lipid-lowering medications was higher in Tromsø 7 for all three conditions with a disproportionately large difference in those reporting MI (+ 48% (95% CI 39, 57%)). Proportion meeting treatment targets for LDL cholesterol was poor in both studies (age- and sex-standardized prevalence of control KYH vs Tromsø 7: MI 5.1% vs 10.1%; stroke 11.6% vs 5.8%; diabetes 24.9% vs 23.3%). Use of antihypertensive medication was higher in KYH for stroke (+ 40% (95% CI 30, 50%)) and diabetes (+ 27% (95% CI 19, 34%)) groups but approximately equal for the MI group (- 1% (95% CI -1, 1%)). Proportion meeting blood pressure targets was lower in KYH vs Tromsø 7 (MI 51.8% vs 76.3%; stroke 49.5% vs 69.6%; diabetes 51.9% vs 63.9%). CONCLUSIONS: We identified different patterns of medication use in people with CVD and diabetes. However despite higher use of lipid-lowering medication in the Norwegian study treatment to target for total cholesterol was poor in both Russian and Norwegian studies. In contrast we found higher levels of use of antihypertensive medications in the Russian study but also that less participants met treatment targets for blood pressure. Further work should investigate what factors are responsible for this seeming paradox and how management of modifiable risk factors for secondary prevention could be improved.

Correlates of Serosorting and Knowledge of Sexual Partner's HIV Status Among Men Who have Sex with Men in Ukraine.

Ukraine has among the highest rates of newly diagnosed HIV infections in the WHO European region. Men who have sex with men (MSM) is the least studied group in the context of the HIV epidemics in Ukraine. The present paper aims to estimate the prevalence and correlates of knowledge of sexual partner's HIV status and potentially discordant anal intercourse (failure to serosort) among MSM. Data of the cross-sectional study among 8100 MSM in Ukraine in 2013 were used for this analysis. Less than half of the participants (42.5%) reported that they knew the HIV serostatus of their most recent male sexual partner, and about 13% of participants reported failure to serosort during their most recent anal sexual intercourse with a male partner. Targeted interventions can be implemented to increase knowledge about sexual partner's HIV status, both among HIV-negative and HIV-positive MSM, to reduce the risk of HIV acquisition and transmission.

Correlates of HIV and Inconsistent Condom Use Among Female Sex Workers in Ukraine.

While female sex workers (FSWs) carry one of the highest risks of HIV transmission, little is known about predictors of HIV and risky behavior of FSWs in Ukraine. In this study of 4806 Ukrainian FSWs, the prevalence of HIV was 5.6 %. FSWs had higher odds to be HIV infected if they had lower income, were older, injected drugs, experienced violence, and solicited clients on highways. Inconsistent condom use with clients was reported by 34.5 % of FSWs. FSWs who solicited clients at railway stations, via media, through previous clients and other FSWs, and on highways reported lower consistency of condom use. Furthermore, inconsistent condom use was related to younger age, alcohol use, having fewer clients, not being covered with HIV prevention, and experiences of violence. The present study expands on the rather limited knowledge of correlates of the HIV and inconsistent condom use among FSWs in Ukraine.

Genetic evidence for causal effects of immune dysfunction in psychiatric disorders: where are we?

The question of whether immune dysfunction contributes to risk of psychiatric disorders has long been a subject of interest. To assert this hypothesis a plethora of correlative evidence has been accumulated from the past decades; however, a variety of technical and practical obstacles impeded on a cause-effect interpretation of these data. With the advent of large-scale omics technology and advanced statistical models, particularly Mendelian randomization, new studies testing this old hypothesis are accruing. Here we synthesize these new findings from genomics and genetic causal inference studies on the role of immune dysfunction in major psychiatric disorders and reconcile these new data with pre-omics findings. By reconciling these evidences, we aim to identify key gaps and propose directions for future studies in the field.

Genetic evidence for the causal effects of C-reactive protein on self-reported habitual sleep duration.

Inflammatory responses to acute stimuli are proposed to regulate sleep, but the relationship between chronic inflammation and habitual sleep duration is elusive. Here, we study this relation using genetically predicted level of chronic inflammation, indexed by CRP and IL6 signaling, and self-reported sleep duration. By Mendelian randomization analysis, we show that elevated CRP level within <10 mg/L has a homeostatic effect that facilitates maintaining 7-8 h sleep duration per day - making short-sleepers sleep longer (p = 2.42 × 10-2) and long-sleepers sleep shorter (1.87 × 10-7); but it is not associated with the overall sleep duration (p = 0.17). This homeostatic effect replicated in an independent CRP dataset. We observed causal effects of the soluble interleukin 6 receptor and gp130 on overall sleep duration (p = 1.62 × 10-8, p = 2.61 × 10-58, respectively), but these effects disappeared when CRP effects were accounted for in the model. Using polygenic score analysis, we found that the homeostatic effect of CRP on sleep duration stems primarily from the genetic variants within the CRP gene region: when genetic variants outside of this region were used to predict CRP levels, the opposite direction of effect was observed. In conclusion, we show that elevated CRP level may causally facilitate maintaining an optimal sleep duration that is beneficial to health, thus updating our current knowledge of immune regulation on sleep.

Circulating S100B levels at birth and risk of six major neuropsychiatric or neurological disorders: a two-sample Mendelian Randomization Study.

Circulating levels of the astrocytic marker S100B have been associated with risk of neuropsychiatric or neurological disorders. However, reported effects have been inconsistent, and no causal relations have yet been established. We applied two-sample Mendelian Randomization (MR) on the association statistics from genome-wide association studies (GWAS) for circulating S100B levels measured 5-7 days after birth (the iPSYCH sample) and in an older adult sample (mean age, 72.5 years; the Lothian sample), upon those derived from major depression disorder (MDD), schizophrenia (SCZ), bipolar disorder (BIP), autism spectral disorder (ASD), Alzheimer's disease (AD), and Parkinson's disease (PD). We studied the causal relations in the two S100B datasets for risk of these six neuropsychiatric disorders. MR suggested increased S100B levels 5-7 days after birth to causally increase the risk of MDD (OR = 1.014; 95%CI = 1.007-1.022; FDR-corrected p = 6.43×10-4). In older adults, MR suggested increased S100B levels to have a causal relation to the risk of BIP (OR = 1.075; 95%CI = 1.026-1.127; FDR-corrected p = 1.35×10-2). No significant causal relations were found for the other five disorders. We did not observe any evidence for reverse causality of these neuropsychiatric or neurological disorders on altered S100B levels. Sensitivity analyses using more stringent SNP-selection criteria and three alternative MR models suggested the results are robust. Altogether, our findings imply a small cause-effect relation for the previously reported associations of S100B and mood disorders. Such findings may provide a novel avenue for the diagnosis and management of disorders.

Heavy alcohol drinking and subclinical echocardiographic abnormalities of structure and function.

OBJECTIVE: The aim of the study is to assess changes in heart structure and function associated with heavy alcohol use by comparing echocardiographic indices in a population-based sample to those in patients admitted to an inpatient facility with severe alcohol problems. METHODS AND RESULTS: We used data from the Know Your Heart study (2015-2017) which is a cross-sectional study that recruited 2479 participants aged 35-69 years from the general population of the city of Arkhangelsk in Northwest Russia and 278 patients from the Arkhangelsk Regional Psychiatric Hospital with a primary diagnosis related to chronic alcohol use (narcology clinic subsample). The drinking patterns of the population-based sample were characterised in detail. We used regression models controlling for age, sex, smoking, education and waist to hip ratio to evaluate the differences in echocardiographic indices in participants with different drinking patterns. The means of left ventricular end-diastolic diameter and indexed left atrial systolic diameter were increased among heavy drinkers (narcology clinic subsample), while mean left ventricular ejection fraction was decreased in this group compared with the population-based sample. In contrast, the harmful and hazardous drinkers in the population-based sample did not differ from non-problem drinkers with respect to echocardiographic indices of systolic and diastolic function. CONCLUSIONS: Extremely heavy drinking is associated with a specific set of structural and functional abnormalities of the heart that may be regarded as precursors of alcohol-related dilated cardiomyopathy.

What factors explain the much higher diabetes prevalence in Russia compared with Norway? Major sex differences in the contribution of adiposity.

INTRODUCTION: Compared with many other countries Russia has a high prevalence of diabetes in men and women. However, contrary to what is found in most other populations, the risk is greater among women than men. The reasons for this are unclear. RESEARCH DESIGN AND METHODS: Prevalence and risk factors for diabetes at ages 40-69 years were compared in two population-based studies: Know Your Heart (KYH) (Russia, 2015-2018, n=4121) and the seventh wave of the Tromsø Study (Tromsø 7) (Norway, 2015-2016, n=17 649). Diabetes was defined by the level of glycated hemoglobin and/or self-reported diabetes and/or diabetes medication use. Marginal structural models were used to estimate the role of key risk factors for diabetes in differences between the studies. RESULTS: Age-standardized prevalence of diabetes was higher in KYH compared with Tromsø 7 in men (11.6% vs 6.2%) and in women (13.2% vs 4.3%). Age-adjusted ORs for diabetes in KYH compared with Tromsø 7 were 2.01 (95% CI 1.68 to 2.40) for men and 3.66 (95% CI 3.13 to 4.26) for women. Adiposity (body mass index and waist circumference) explained none of this effect for men but explained 46.0% (39.6, 53.8) for women. Addition of smoking and C reactive protein, as further mediators, slightly increased the percentage explained of the difference between studies to 55.5% (46.5, 66.0) for women but only to 9.9% (-0.6, 20.8) for men. CONCLUSIONS: Adiposity is a key modifiable risk factor that appears to explain half of the almost threefold higher female prevalence of diabetes in Russia compared with Norway, but none of the twofold male difference.

Evidence for a Direct Harmful Effect of Alcohol on Myocardial Health: A Large Cross-Sectional Study of Consumption Patterns and Cardiovascular Disease Risk Biomarkers From Northwest Russia, 2015 to 2017.

Background Alcohol drinking is an increasingly recognized risk factor for cardiovascular disease. However, there are few studies of the impact of harmful and hazardous drinking on biomarkers of myocardial health. We conducted a study in Russia to investigate the impact of heavy drinking on biomarkers of cardiac damage and inflammation. Methods and Results The Know Your Heart study recruited a random sample of 2479 participants from the population of northwest Russia (general population) plus 278 patients (narcology clinic subsample) with alcohol problems. The general population sample was categorized into harmful drinkers, hazardous drinkers, nonproblem drinkers, and nondrinkers, according to self-reported level of alcohol consumption, whereas the narcology clinic sample was treated as the separate group in the analysis. Measurements were made of the following: (1) high-sensitivity cardiac troponin T, (2) NT-proBNP (N-terminal pro-B-type natriuretic peptide), and (3) hsCRP (high-sensitivity C-reactive protein). The narcology clinic subsample had the most extreme drinking pattern and the highest levels of all 3 biomarkers relative to nonproblem drinkers in the general population: high-sensitivity cardiac troponin T was elevated by 10.3% (95% CI, 3.7%-17.4%), NT-proBNP by 46.7% (95% CI, 26.8%-69.8%), and hsCRP by 69.2% (95% CI, 43%-100%). In the general population sample, NT-proBNP was 31.5% (95% CI, 3.4%-67.2%) higher among harmful drinkers compared with nonproblem drinkers. Overall, NT-proBNP and hsCRP increased with increasing intensity of alcohol exposure (test of trend P<0.001). Conclusions These results support the hypothesis that heavy alcohol drinking has an adverse effect on cardiac structure and function that may not be driven by atherosclerosis.

Quantifying the contribution of established risk factors to cardiovascular mortality differences between Russia and Norway.

Surprisingly few attempts have been made to quantify the simultaneous contribution of well-established risk factors to CVD mortality differences between countries. We aimed to develop and critically appraise an approach to doing so, applying it to the substantial CVD mortality gap between Russia and Norway using survey data in three cities and mortality risks from the Emerging Risk Factor Collaboration. We estimated the absolute and relative differences in CVD mortality at ages 40-69 years between countries attributable to the risk factors, under the counterfactual that the age- and sex-specific risk factor profile in Russia was as in Norway, and vice-versa. Under the counterfactual that Russia had the Norwegian risk factor profile, the absolute age-standardized CVD mortality gap would decline by 33.3% (95% CI 25.1-40.1) among men and 22.1% (10.4-31.3) among women. In relative terms, the mortality rate ratio (Russia/Norway) would decline from 9-10 to 7-8. Under the counterfactual that Norway had the Russian risk factor profile, the mortality gap reduced less. Well-established CVD risk factors account for a third of the male and around a quarter of the female CVD mortality gap between Russia and Norway. However, these estimates are based on widely held epidemiological assumptions that deserve further scrutiny.

Hepatitis C virus status awareness and test results confirmation among people who inject drugs in Ukraine.

BACKGROUND: Among the estimated 340,000 people who inject drugs (PWID) in Ukraine, HCV prevalence is approximately 70%. As HCV treatment availability increases, an assessment of the HCV treatment cascade is needed to guide HCV prevention and treatment strategies. METHODS: Opioid dependent PWID were interviewed and tested for HIV and HCV in five Ukrainian cities from January 2014 to March 2015. Logistic regression was used to examine the independent correlates of two cascade steps: a) anti-HCV positive status awareness; b) chronic HCV confirmation; and of c) annual HCV testing for PWID. RESULTS: Among 1613 PWID, 1002 (62.1%) had anti-HCV positive test result, of which 568 (56.7%) were aware of it before the study and 346 (34.5%) reported previous confirmatory testing for chronic HCV. Independent correlates of being aware they had anti-HCV positivity included: current [AOR: 3.08; 95%CI: 2.16-4.40] or prior [AOR: 1.85; 95%CI: 1.27-2.68] opioid agonistic treatment (OAT) experience, relative to no prior OAT, living in Lviv [AOR: 0.50; 95%CI: 0.31-0.81] or Odesa [AOR: 2.73; 95%CI: 1.51-4.93] relative to Kyiv and being aware of having HIV [AOR: 4.10; 95%CI: 2.99-5.62]. Independent correlates of confirming HCV infection among those who were aware of their anti-HCV positive status included: current OAT [AOR: 2.00; 95%CI: 1.24-3.23], relative to prior OAT, the middle income category [AOR: 1.74, 95%CI: 1.15-2.63], relative to the lowest, and receiving ART [AOR: 4.54; 95%CI: 2.85-7.23]. Among 1613 PWID, 918 (56.9%) were either HCV negative or not aware of their HCV positive status, of which 198 (21.6%) reported recent anti-HCV test (during last 12 month). Recent anti-HCV test in this group was associated with current [AOR: 7.17; 95%CI: 4.63-11.13] or prior [AOR: 2.24; 95%CI: 1.32-3.81] OAT experience, relative to no prior OAT. CONCLUSION: Encouraging PWID to participate in OAT may be an effective strategy to diagnose and link PWID who are HCV positive to care. Among HIV negative participants, regular HCV testing may be ensured by participation in OAT. More studies are needed to assess HCV treatment utilization among PWID in Ukraine and OAT as a possible way to retain them in treatment.

The impact of early life stress on risk of tobacco smoking initiation by adolescents.

AIMS: Our study aimed to examine the association between early life stress and early initiation of alcohol and tobacco use. DESIGN: This prospective cohort study of women and children belongs to the Ukrainian component of the European Longitudinal Study of Pregnancy and Childhood. SETTING: Dniprodzerzhynsk, a city of some 250,000 inhabitants in south central Ukraine. PARTICIPANTS: All 4398 women who visited antenatal clinics between December 25, 1992 and July 23, 1994, planned to continue their pregnancy, and were permanent residents of the city were invited to participate. Of the 4398 invitees, 2148 agreed and 1020 of the mother-child pairs were available for complete follow-up until the children were 16 years old. MEASUREMENTS: When study children reached ages 3 and 7, their mothers completed questionnaires about their children's exposure to and impact from a standard list of recent stressful life events. From the data on event prevalence and severity, we assigned each child to low, medium, or high early life stress. When the children became age 16, they completed questionnaires about their history of smoking and drinking. FINDINGS: In multivariate analysis that controlled for current level of family income, current family type, current school type, year of child's birth, lifetime smoking and current drinking by mother, and education of mother and father, girls with high stress at age 3 had 2.2 times (95% confidence interval: 1.23-4.08) higher odds than girls with low stress to start smoking early. CONCLUSIONS: Our study may be the first to use a longitudinal study design to examine early life stress as a risk factor for early smoking initiation in adolescence.