Logo: to the web site of Uppsala University

Background

Individuals with autism spectrum disorder (ASD) experience a wide array of neurological, psychiatric and medical comorbidities, yet little attention has been given to the potential link between ASD and migraine, one of the most prevalent neurological disorders worldwide. This study aimed to investigate whether a genetic predisposition for ASD is linked to migraine and its major subtypes, with and without aura. Additionally, potential moderator and mediators of the association between ASD and migraine were explored.

Methods

Polygenic scores (PGS) for ASD were constructed based on the genome-wide association study by the Psychiatric Genomics Consortium, on the UK Biobank cohort dataset comprising 337,386 participants using PRSice-2. Regression analyses were performed to investigate the association of ASD PGS with migraine and its major subtypes, with and without aura. Sex was explored as a potential moderating factor. The mediation analyses took into consideration variables such as education, personality trait neuroticism, body mass index (BMI) and four categories of comorbidities (psychiatric, vascular, neurologic and others).

Results

ASD PGS were significantly and positively associated with migraine (odds ratio (OR) = 1.04, 95% confidence interval (CI) = 1.02–1.05, p < 0.002), migraine without aura (OR = 1.05, 95% CI = 1.02–1.07, p < 0.002) and migraine with aura (OR = 1.05, 95% CI = 1.02–1.07, p < 0.002). No moderating effect of sex on the association between ASD PGS and migraine was observed. As for potential mediators, only the personality trait neuroticism significantly mediated the association between ASD PGS and migraine, with the proportion of effect mediated 8.75% (95% CI = 4–18%).

Conclusions

Our study suggests that individuals genetically predisposed to autism are at higher risk of experiencing migraine, including the two major subtypes, with and without aura. While emphasizing the complex shared genetic and pathophysiological interactions of these conditions, the role of personality trait neuroticism as a mediator of this relationship is highlighted.

Background

Statins are cholesterol-lowering drugs widely prescribed for preventing cardiovascular diseases. They may cause adverse effects on skeletal muscle, but it remains unclear whether they affect muscle function and mass. We aimed to evaluate the association between statin use and muscle function and mass, and whether the pharmacogenomic score (PGS) of statin response modifies these associations.

Methods

We included 297 977 participants from the UK Biobank. Grip strength was measured using a Jamar J00105 hydraulic hand dynamometer, and the appendicular lean mass (ALM) was estimated using bioelectrical impedance analysis. We performed linear regression to evaluate the cross-sectional and longitudinal associations between statin use and (changes in) grip strength or ALM, adjusting for demographic, lifestyle and health factors. We tested the interaction with the PGS and stratified the analysis by PGS tertile.

 Results

Participants averaged 56.4 (± 8) years, and 46% were male. Statin use was associated with lower baseline grip strength (β = −0.68 kg [−0.89, −0.48]) and ALM (β = −0.19 kg [−0.22, −0.16]). Among 35 557 participants with follow-up data (10 ± 5 years), continuous statin use was associated with an accelerated decline in grip strength (β = −0.32 kg/year [−0.49, −0.14]) and ALM (β = −0.06 kg/year [−0.08, −0.03]) compared with never users. The PGS showed a potential modifying effect at baseline (p = 0.058 for grip strength and p = 0.068 for ALM) but did not significantly influence the rate of decline over time.

Conclusions

Continuous statin use is associated with a decline in muscle function and mass over time (25% decline in grip strength and 73% decline in ALM compared to never-users), irrespective of genetic susceptibility to statin response. This study emphasizes the importance of monitoring musculoskeletal health in statin users and supports further research into the potential role of a healthy diet and regular physical activity in preserving muscle function, which may also reinforce the cardiovascular benefits of statin therapy.

BackgroundGenetic risk variants for obesity and metabolic syndrome (MetS) have been identified, but their link to relevant metabolic health parameters warrants further attention. This study aimed to investigate the extent to which single-nucleotide polymorphisms (SNPs) associated with obesity are linked to changes in fatty acid (FA) profiles in serum cholesteryl esters, lipid metabolism, and MetS risk.MethodData from the Uppsala Longitudinal Study of Adult Men (ULSAM), conducted in men at age 50 (N = 1973) and age 70 (N = 982), were used to investigate SNPs associated with body mass index (BMI) in genome-wide association studies with metabolic parameters at age 50. The significant SNPs and associated lipid parameters were then used as predictors of MetS over a 20-year follow-up period, at age 70 in binary regression models.ResultsThe two genes, the brain-derived neurotrophic factor gene (BDNF) (rs7103411) and the fat mass and obesity-associated gene (FTO) (rs1558902), together with delta-5-desaturase (D5D) activity, 20:5n-3 in serum cholesteryl esters (CE), fasting blood glucose, abdominal skinfold thickness, apolipoprotein-B, and high-density lipoprotein cholesterol (HDL-C) at age 50, significantly predicted the risk of MetS at age 70.ConclusionThe findings suggest a considerable contribution of the SNPs BDNF rs7103411, FTO rs1558902, and ETV5 rs9816226, along with low D5D activities and serum levels of HDL-C in men at age 50, to the risk for MetS 20 years later.

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.

This research work comprises four studies investigating mental health disorders, with a particular focus on Autism Spectrum Disorder (ASD, hereafter referred to as autism). The research integrates epidemiological perspectives and genetic frameworks to explore connections with well-being, conditions such as migraine, and neuroanatomical brain structure changes in adulthood, utilizing data from the large European population cohort, UK Biobank, with over half a million participants.

Paper I examined the relationship between job satisfaction, job tenure, and 16 self-reported physician posed diagnosed mental health conditions. The findings show that Neurotic & Stress Disorders, Eating Disorders, and Other Mental Health Disorders are strongly associated with lower job satisfaction and shorter job tenure, highlighting the impact of mental health on workplace participation. Personality trait neuroticism significantly influences job satisfaction but not job tenure.

Paper II explored the relationship between genetic predispositions for autism and five well-being traits (neuroticism, depression, loneliness, life satisfaction, and positive affect). Polygenic risk scores (PRS) for autism were significantly associated with decreased well-being, particularly an increased risk of negative traits such as neuroticism and depression, and reduced positive traits such as life satisfaction, highlighting the genetic basis of well-being in individuals with autism.

Paper III examined the genetic link between autism and migraine, revealing that individuals with a genetic predisposition for autism have an increased risk of migraine, including both major types, migraine with and without aura. While no moderating effect of sex was found, personality trait neuroticism significantly mediated the relationship between autism and migraine, emphasizing the complex genetic and pathophysiological connections between autism and migraine, with neuroticism playing a key role in mediating this association.

Paper IV investigated the association between autism polygenic risk scores and brain volume alterations in the cerebellum, brainstem, and global brain structures in adults. The results demonstrated significant correlations, with higher autism PRS linked to reduced brain volumes, particularly in the cerebellum and brainstem, highlighting the genetic influence on neuroanatomical changes in autism adulthood.

These studies highlight the intricate connections between mental health, genetics, and brain structure, offering valuable insights for improving workplace participation and well-being in individuals with mental health issues including autism.

Job satisfaction plays an important role for 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. First study addresses the gap along with exploring the impact of the neurotic personality trait and other possible contributing factors.

Individuals with autism spectrum disorder (ASD) experience lower well-being as demonstrated epidemiologically mostly for children and adolescents. Further etiological investigation of inclusive wellbeing, in terms of five wellbeing spectrum (5-WBS) traits including neuroticism, depression, loneliness, life satisfaction and positive affect, among adults with ASD may deepen the understanding. Seond study aims to investigate if a genetic predisposition for ASD is associated with 5-WBS traits using polygenic risk score (PRS) analysis.

In the first study, sixteen mental health disorders diagnosed by physicians, categorized 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, TDI, BMI, education, physical activity, work hours and neuroticism. In the second study, PRS for ASD were constructed in the UK Biobank (N = 337,423), based on the GWAS conducted by Psychiatric Genetics Consortium (18,381 cases, 27,969 comparisons) using PRSice-2. 

First study showed Neurotic & 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. Second study showed, ASD PRS significantly predicted associations with all 5-WBS traits, showing a positive association with the negative WBS traits, neuroticism (max R2 = 0.04%, P < 1x10-4, AUC 0.51), depression (max R2 = 0.06%, P < 1x10-4, AUC 0.51), loneliness (max R2 = 0.04%, P < 1x10-4, AUC 0.51) and a negative association with the positive WBS traits, life satisfaction (max R2 = 0.08%, P < 1x10-4, AUC 0.56), positive affect (max R2 = 0.10%, P < 1x10-4, AUC 0.53).

Findings of first study 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. The findings of second study suggest that adults carrying a high load of susceptible SNPs for ASD are more likely to show a decreased well-being.

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.

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.

Migraine headache being considered 8th most burdensome disease of the world has complex pathophysiology, involving mechanisms mediated by mostly glutamate (Glu). The kynurenine pathway (KP) metabolites, accounting for more than 90 % of the tryptophan metabolism, interact with the glutamate receptors and therefore have been implicated in the migraine pathophysiology; still lacks the accurate and reliable method for absolute quantification in a single analytical run. In order to analyze thes metabolites in a single run, we have worked on developing a newer method better than the reported most selective and most sensitive method (LC-MS/MS). Synthetic tryptophan metabolites in a mixture were analyzed by ultra-performance chromatography hyphenated with tandem mass spectrometry using electrospray ionization (UPLC–ESI-MS/MS) at positive mode. The sample preparation included derivatization of the analytes. The analytes were chromatographically separated by gradient elution using a reverse phase column (Acquity UPLC® HSS T3, 1.8 μm, 2.1 × 100 mm column; Waters). This rapid and sensitive novel method was successful for analyzing tryptophan and its nine metabolites within 6 minutes. The results from the current study revealed that the method could be established as a reliable approach and demonstrate its biomedical applicability after validation.