Genetic variants of LEAP2 are associated with anthropometric traits and circulating insulin-like growth factor-1 concentration: A UK Biobank study.

AIM: To test the hypothesis that liver-expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity. METHODS: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin-like growth factor-1 (IGF-1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRSLEAP2) using linear and logistic regression models. Sex-stratified analyses were also conducted. RESULTS: Five SNPs showed positive associations with obesity-related traits. rs57880964 was associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI), in the total population and among women. Four independent SNPs were positively associated with higher serum IGF-1 concentrations in both men and women. GRSLEAP2 was associated with BMI and WHRadjBMI only in women and with serum IGF-1 concentration in both sexes. CONCLUSIONS: These findings reveal sex-specific associations between key LEAP2 gene variants and several obesity traits, while also indicating a strong independent association of LEAP2 variants with serum IGF-1 concentration.

LEAP2 is associated with impulsivity and reward sensitivity depending on the nutritional status and decreases with protein intake in humans.

AIM: Liver-expressed antimicrobial peptide 2 (LEAP2) dynamics in human plasma and its association with feeding behaviour remain poorly understood. Therefore, this study aims: (a) to investigate fasting LEAP2 in participants with normal weight or with overweight or mild obesity (OW/OB); (b) to study the association between fasting LEAP2 and anthropometric and metabolic traits, feeding behaviour, LEAP2 genetic variants and blood cell DNA methylation status; and (c) to ascertain postprandial changes in LEAP2 after high protein intake and the association with feeding behaviour and food intake. METHODS: Anthropometric and behavioural measures, genotyping, methylation profiling, plasma glucose and LEAP2 concentrations were assessed in 327 females and males. A subgroup of 123 participants received an ad libitum high-protein meal, and postprandial LEAP2 concentration and behavioural measures were assessed. RESULTS: LEAP2 concentration was higher in participants with OW/OB (p < 0.001) and in females (p < 0.001), and was associated with LEAP2 single nucleotide polymorphisms rs765760 (p = 0.012) and rs803223 (p = 0.019), but not with LEAP2 methylation status. LEAP2 concentration was directly related to glycaemia (p = 0.001) and fullness (p = 0.003) in participants with normal weight, whereas it was associated with body mass index (p = 0.018), waist circumference (p = 0.014) and motor impulsivity in participants with OW/OB (p = 0.005). A negative association with reward responsiveness was observed in participants with OW/OB (p = 0.023). LEAP2 concentration was inversely associated with food intake (p = 0.034) and decreased after a high-protein meal (p < 0.001), particularly in women (p = 0.002). CONCLUSION: Increased LEAP2 in participants with OW/OB is associated with behavioural characteristics of obesity. Our results show sexual dimorphism in LEAP2 concentration before and after food intake and highlight the role of LEAP2 in feeding regulation.

Higher fresh fruit intake relates to larger grey matter volumes in areas involved in dementia and depression: A UK Biobank study.

The benefits of consuming fruits and vegetables are widely accepted. While previous studies suggest a protective role of fruits and vegetables against a variety of diseases such as dementia and depression, the biological mechanisms/effects remain unclear. Here we investigated the effect of fruit and vegetable consumption on brain structure. Particularly on grey matter (GM) and white matter (WM) volumes, regional GM volumes and subcortical volumes. Cross-sectional imaging data from UK Biobank cohort was used. A total of 9925 participants (Mean age 62.4 ± 7.5 years, 51.1 % men) were included in the present analysis. Measures included fruit and vegetable intake, other dietary patterns and a number of selected lifestyle factors and clinical data. Brain volumes were derived from structural brain magnetic resonance imaging. General linear model was used to study the associations between brain volumes and fruit/vegetable intakes. After adjusting for selected confounding factors, salad/raw vegetable intake showed a positive association with total white matter volume, fresh fruit intake showed a negative association with total grey matter (GM) volume. Regional GM analyses showed that higher fresh fruit intake was associated with larger GM volume in the left hippocampus, right temporal occipital fusiform cortex, left postcentral gyrus, right precentral gyrus, and right juxtapositional lobule cortex. We conclude that fruit and vegetable consumption seems to specifically modulate brain volumes. In particular, fresh fruit intake may have a protective role in specific cortical areas such as the hippocampus, areas robustly involved in the pathophysiology of dementia and depression.

Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study.

BACKGROUND: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls. METHODS: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume. RESULTS: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm3, 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm3, 95% CI [-7, 100]) and gray matter (mean difference: 49 mm3, 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm3, 95% CI [-7, 40]). CONCLUSION: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study.

OBJECTIVE: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. BACKGROUND: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. METHODS: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. RESULTS: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction. CONCLUSIONS: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.

Job satisfaction and job tenure of people with mental health disorders: a UK Biobank cohort study.

AIMS: Job satisfaction plays an important role for the life quality and health of working individuals. While studies have shown that self-reported mental health conditions such as stress, anxiety and depression are associated with job satisfaction, a large population-based study exploring and comparing self-reported physician posed diagnosed conditions and their association with job satisfaction and job tenure is missing. This study addresses the gap along with exploring the impact of the neurotic personality trait and other possible contributing factors. METHODS: Sixteen mental health disorders diagnosed by physicians, categorised into four major groups were investigated in relation to employment status (108,711 participants) and in relation to job satisfaction and job tenure (34,808 participants). Analyses were performed using linear regression adjusted for age, sex, townsend deprivation index, body mass index, education, physical activity, work hours and neuroticism. RESULTS: Neurotic and stress disorders, eating disorders and other mental health disorders were strongly associated with lower job satisfaction and shorter job tenure in both unadjusted and adjusted analyses. Neuroticism was strongly linked to job satisfaction but was not associated with job tenure. CONCLUSIONS: Study findings clarify the complex relationship of mental health with job satisfaction and job tenure, which is very important to understand in designing measures to improve working life participation of individuals with mental health issues.

Effect of worry, depression, and sensitivity to environmental stress owing to neurotic personality on risk of cardiovascular disease: A Mendelian randomization study.

OBJECTIVE: This study investigated the putative causal link between neuroticism (using three genetically distinct subclusters namely depressed affect, worry, and sensitivity to environmental stress and adversity [SESA]) and cardiovascular disease (CVD). METHOD: A two-sample bi-directional Mendelian randomization (MR) approach was used. Genetic instruments were extracted from publically available GWAS summary statistics. RESULTS: In forward MR analyses with neuroticism subclusters as exposures, no causal associations between worry or SESA cluster and any of the CVD traits were observed (p > .05 for all). However, a higher risk of having heart failure (odds ratio (95% confidence interval):1.32(1.12 to 1.56); p = .0011) and myocardial infarction (1.47[1.18 to 1.83]; p = 6.3 × 10-4) associated with depressed affect cluster was observed. In reverse MR analyses with CVD traits as exposures, no significant associations were observed (p > .05 for all). CONCLUSIONS: Individuals with high neuroticism who are more susceptible to depressive symptoms are at higher risk for developing heart failure and myocardial infarction and should be more carefully evaluated for CVD risk in clinical settings. These individuals can potentially benefit from interventions aimed at reducing depressive symptoms to decrease CVD risk. There is no evidence to suggest that being sensitive to environmental stressors or being more worried can increase the risk for CVD.

Time spent outdoors and risk of myocardial infarction and stroke in middle and old aged adults: Results from the UK Biobank prospective cohort.

BACKGROUND: Time spent outdoors has been previously related to several cardiovascular risk factors, implying that it may confer either beneficial or harmful effects on cardiovascular health. However, no large population-based studies have examined the relation between time spent outdoors and myocardial infarction and stroke. OBJECTIVES: We aimed to investigate the longitudinal relation between time spent outdoors and myocardial infarction and stroke in large UK population-based cohort. METHODS: A total of 446,648 participants from UK Biobank were included in the study of which 431,146 participants (56% females and 44% males with a mean age of 56.4 ± 8.1 years) were followed for a median time of 7 years. Time spent outdoors was self-reported and participants were stratified into quantiles (less than 1.5 [reference group]; 1.5 to 2.4; 2.5 to 3.5 and more than 3.5 h per day outdoors). Myocardial infarction and stroke events were either collected from hospital records and death registries or were self-reported by the participants. Cox proportional hazard regression was used for the analysis. In addition to age and sex, analyses were adjusted for potential demographic (TDI, ethnic background, current employment status), lifestyle (alcohol intake frequency, current tobacco use, sedentary time and moderate-to-vigorous physical activity), health related factors (BMI, systolic and diastolic blood pressure) and environmental indicators (NO2, NOx, PM10, PM2.5-10, PM2,5, noise pollution, % greenspace, % natural environment and % water). RESULTS: A 20% increased risk for myocardial infarction incidence was observed among participants who reported spending more than 3.5 h/day outdoors (HR: 1.20, 95% CI: 1.06-1.36) compared to the reference group. A trend was also observed for stroke (HR: 1.14, 95% CI: 0.97-1.34). CONCLUSION: Findings from the present study indicate that spending more than 3.5 h/day outdoors is a risk factor for myocardial infarction and stroke. Future research is needed to further understand the relation between time spent outdoors and cardiovascular disease.

Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry.

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction  = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction  = 0.014 vs. n = 71,611, Pinteraction  = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction  = 0.003) and the SEC16B rs10913469 (Pinteraction  = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.

IMPORTANCE: Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE: To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS: Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461). MAIN OUTCOMES AND MEASURES: Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS: The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02). CONCLUSIONS AND RELEVANCE: Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.

Association of polygenic scores for autism with volumetric MRI phenotypes in cerebellum and brainstem in adults.

Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level. We utilized the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and constructed the ASD PRS in an independent cohort, the UK Biobank. Regression analyses controlled for multiple comparisons with the false-discovery rate (FDR) at 5% were performed to investigate the association between ASD PRS and forty-four brain magnetic resonance imaging (MRI) phenotypes among ~ 31,000 participants. Primary analyses included sixteen MRI phenotypes: total volumes of the brain, cerebrospinal fluid (CSF), grey matter (GM), white matter (WM), GM of whole cerebellum, brainstem, and ten regions of the cerebellum (I_IV, V, VI, VIIb, VIIIa, VIIIb, IX, X, CrusI and CrusII). Secondary analyses included twenty-eight MRI phenotypes: the sub-regional volumes of cerebellum including the GM of the vermis and both left and right lobules of each cerebellar region. ASD PRS were significantly associated with the volumes of seven brain areas, whereby higher PRS were associated to reduced volumes of the whole brain, WM, brainstem, and cerebellar regions I-IV, IX, and X, and an increased volume of the CSF. Three sub-regional volumes including the left cerebellar lobule I-IV, cerebellar vermes VIIIb, and X were significantly and negatively associated with ASD PRS. The study highlights a substantial connection between susceptibility to ASD, its underlying genetic etiology, and neuroanatomical alterations of the adult brain.

Oxytocin pathway gene variation and corticostriatal resting-state functional connectivity.

Genetic variations in single nucleotide polymorphisms (SNPs) within oxytocin pathway genes have been linked to social behavior and neurodevelopmental conditions. However, the neurobiological mechanisms underlying these associations remain elusive. In this study, we investigated the relationship between variations of 10 SNPs in oxytocin pathway genes and resting-state functional connectivity among 55 independent components using a large sample from the UK Biobank (N ≈ 30,000). Our findings revealed that individuals with the GG genotype at rs4813627 within the oxytocin structural gene (OXT) exhibited weaker resting-state functional connectivity in the corticostriatal circuit compared to those with the GA/AA genotypes. Empirical evidence has linked the GG genotype at OXT rs4813627 with a behavioral tendency of insensitivity to others. These results inform the neural mechanisms by which oxytocin-related genetic factors can influence social behavior.

Exploring sex differences: insights into gene expression, neuroanatomy, neurochemistry, cognition, and pathology.

Increased knowledge about sex differences is important for development of individualized treatments against many diseases as well as understanding behavioral and pathological differences. This review summarizes sex chromosome effects on gene expression, epigenetics, and hormones in relation to the brain. We explore neuroanatomy, neurochemistry, cognition, and brain pathology aiming to explain the current state of the art. While some domains exhibit strong differences, others reveal subtle differences whose overall significance warrants clarification. We hope that the current review increases awareness and serves as a basis for the planning of future studies that consider both sexes equally regarding similarities and differences.

Differential change in alcohol consumption during the COVID-19 pandemic: the role of loneliness, socialization, and mental well-being.

Introduction: The COVID-19 pandemic led to a surge in mental health issues and psychological distress, disruption to work/studying conditions, and social isolation particularly among young adults. Changes in these factors are differentially associated with alcohol use. Moreover, the relationship between these factors are bidirectional and may have fluctuated throughout the different phases of the pandemic. However, studies focusing on young adults had conflicting results, short follow-up periods, and lacked comprehensive data to describe underlying mechanisms. Methods: 1067 young adults participated in repetitive measures termed wave 4 (2021) of the Survey of Adolescent Life in Västmanland Cohort "SALVe" Cohort. Of these, 889 also completed pre-pandemic measurements termed wave 3 (2018). Participants completed the Alcohol Use Disorders Identification Test (AUDIT) to evaluate alcohol consumption and harmful use. Cross-sectional associations between perceived changes in alcohol use and shift in individual, mental health, and work environment factors were examined using Chi-square tests. Logistic regression was utilized to identify pre-pandemic predictors of harmful consumption during the pandemic. Results: Harmful consumption decreased only in females following the COVID-19 pandemic. Participants who reported increased feelings of depression, anxiety, and loneliness were more likely to increase their alcohol use. Interestingly, the subgroup who felt less lonely and met their friends more often, as well as those who continued working/studying from their regular workplace also had an increased likelihood of higher consumption. Only pre-pandemic ADHD and delinquency symptoms predicted harmful alcohol consumption following the pandemic. Conclusion: Females reduced harmful alcohol consumption during the COVID-19 pandemic. While those who suffered the burden of social isolation and distress were more likely to increase their alcohol use, young adults who felt less lonely and met their friends more often also had a similar outcome. The relationship between loneliness and alcohol consumption among young adults is influenced by the social factors that may be facilitated by drinking.

Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study.

Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas. Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions. Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]). Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

Job satisfaction has differential associations with delay discounting and risk-taking.

Low job satisfaction has been associated with both negative health and negative organizational outcomes. Knowledge on which factors influence job satisfaction remains limited. This study assesses the associations between job satisfaction and three personality traits related to cognitive- and inhibitory control: delay discounting, risk-taking and sensation seeking (DRS-traits). Delay discounting and sensation seeking were inferred using self-reported behavioral data and health measurements for 80,676 participants in the UK Biobank. Multiple linear regression analysis produced beta coefficients and confidence intervals for each DRS-trait and job satisfaction. Analyses were adjusted for age, socioeconomic status and sleep quality. A combination of the three DRS-traits (CDRS) was assessed as well. Delay discounting and risk-taking were associated with, respectively, lower and higher job satisfaction in both sexes. Sensation seeking had no significant association with job satisfaction for either sex. The combined score, CDRS, was only negatively associated with job satisfaction in females but not in males. We discuss that the negative association between delay discounting and job satisfaction may be due to career related delay discounting effects, but also highlight that low job satisfaction itself may also lead to increased delay discounting. Additionally, we discuss why increased risk-taking behavior may have a positive effect on job satisfaction.

Well-being spectrum traits are associated with polygenic scores for autism.

Individuals with autism spectrum disorder (ASD) tend to experience lower well-being as demonstrated mostly for children and adolescents in epidemiological studies. A further investigation of inclusive well-being, in terms of five well-being spectrum (5-WBS) traits including neuroticism, depression, loneliness, life satisfaction, and positive affect, among adults with ASD may deepen our understanding of their well-being, and lead to the possibility to further modify societal supportive mechanisms for individuals with ASD. This study aims to investigate if a genetic predisposition for ASD is associated with 5-WBS traits using polygenic risk score (PRS) analysis. PRS for ASD were calculated based on the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and were created in the independent cohort UK Biobank. Regression analyses were performed to investigate the association between ASD PRS and 5-WBS traits in the UK Biobank population including 337,423 individuals. ASD PRS were significantly associated with all 5-WBS traits, showing a positive association with the negative WBS traits, neuroticism (max R2 = 0.04%, p < 1 × 10-4 ), depression (max R2 = 0.06%, p < 1 × 10-4 ), loneliness (max R2 = 0.04%, p < 1 × 10-4 ), and a negative association with the positive WBS traits, life satisfaction (max R2 = 0.08%, p < 1 × 10-4 ), positive affect (max R2 = 0.10%, p < 1 × 10-4 ). The findings suggest that adults carrying a high load of risk single nucleotide peptides (SNPs) for ASD are more likely to report decreased well-being. The study demonstrates a considerable connection between susceptibility to ASD, its underlying genetic etiology and well-being.

The Effects of Statins on Cognitive Performance Are Mediated by Low-Density Lipoprotein, C-Reactive Protein, and Blood Glucose Concentrations.

Statins are widely used for cardiovascular disease prevention but their effects on cognition remain unclear. Statins reduce cholesterol concentration and have been suggested to provide both beneficial and detrimental effects. Our aim was to investigate the cross-sectional and longitudinal association between statin use and cognitive performance, and whether blood low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, C-reactive protein, and vitamin D biomarkers mediated this association. We used participants from the UK biobank aged 40-69 without neurological and psychiatric disorders (n = 147 502 and n = 24 355, respectively). We performed linear regression to evaluate the association between statin use and cognitive performance and, mediation analysis to quantify the total, direct, indirect effects and the proportion meditated by blood biomarkers. Statin use was associated with lower cognitive performance at baseline (ß = -0.40 [-0.53, -0.28], p = <.0001), and this association was mediated by low-density lipoprotein (proportion mediated = 51.4%, p = .002), C-reactive protein (proportion mediated = -11%, p = .006) and blood glucose (proportion mediated = 2.6%, p = .018) concentrations. However, statin use was not associated with cognitive performance, measured 8 years later (ß = -0.003 [-0.11, 0.10], p = .96). Our findings suggest that statins are associated with lower short-term cognitive performance by lowering low-density lipoprotein and raising blood glucose concentrations, and better performance by lowering C-reactive protein concentrations. In contrast, statins have no effect on long-term cognition and remain beneficial in reducing cardiovascular risk factors.

A deep learning model for brain age prediction using minimally preprocessed T1w images as input.

Introduction: In the last few years, several models trying to calculate the biological brain age have been proposed based on structural magnetic resonance imaging scans (T1-weighted MRIs, T1w) using multivariate methods and machine learning. We developed and validated a convolutional neural network (CNN)-based biological brain age prediction model that uses one T1w MRI preprocessing step when applying the model to external datasets to simplify implementation and increase accessibility in research settings. Our model only requires rigid image registration to the MNI space, which is an advantage compared to previous methods that require more preprocessing steps, such as feature extraction. Methods: We used a multicohort dataset of cognitively healthy individuals (age range = 32.0-95.7 years) comprising 17,296 MRIs for training and evaluation. We compared our model using hold-out (CNN1) and cross-validation (CNN2-4) approaches. To verify generalisability, we used two external datasets with different populations and MRI scan characteristics to evaluate the model. To demonstrate its usability, we included the external dataset's images in the cross-validation training (CNN3). To ensure that our model used only the brain signal on the image, we also predicted brain age using skull-stripped images (CNN4). Results: The trained models achieved a mean absolute error of 2.99, 2.67, 2.67, and 3.08 years for CNN1-4, respectively. The model's performance in the external dataset was in the typical range of mean absolute error (MAE) found in the literature for testing sets. Adding the external dataset to the training set (CNN3), overall, MAE is unaffected, but individual cohort MAE improves (5.63-2.25 years). Salience maps of predictions reveal that periventricular, temporal, and insular regions are the most important for age prediction. Discussion: We provide indicators for using biological (predicted) brain age as a metric for age correction in neuroimaging studies as an alternative to the traditional chronological age. In conclusion, using different approaches, our CNN-based model showed good performance using one T1w brain MRI preprocessing step. The proposed CNN model is made publicly available for the research community to be easily implemented and used to study ageing and age-related disorders.