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Deciphering Adult Autism: Exploring Polygenic Risk, Brain Structure, Well-being, Migraine, and Mental Health Disorders
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.ORCID iD: 0000-0002-6050-4708
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. , p. 38
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2074
Keywords [en]
Genetic risk score, mental health disorder, autism, migraine, well-being, MRI, brain
National Category
Neurosciences
Research subject
Molecular Life Sciences; Bioinformatics; Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-537917ISBN: 978-91-513-2225-4 (print)OAI: oai:DiVA.org:uu-537917DiVA, id: diva2:1895778
Public defence
2024-10-25, room A1:111a, Uppsala biomedicinska centrum (BMC), Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2024-10-02 Created: 2024-09-06 Last updated: 2024-10-02
List of papers
1. Job satisfaction and job tenure of people with mental health disorders: a UK Biobank cohort study
Open this publication in new window or tab >>Job satisfaction and job tenure of people with mental health disorders: a UK Biobank cohort study
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2023 (English)In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 51, no 8, p. 1248-1257Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Sage Publications, 2023
National Category
Health Care Service and Management, Health Policy and Services and Health Economy Occupational Health and Environmental Health Other Health Sciences Public Health, Global Health and Social Medicine Occupational Therapy Sociology (Excluding Social Work, Social Anthropology, Demography and Criminology)
Identifiers
urn:nbn:se:uu:diva-486628 (URN)10.1177/14034948221119639 (DOI)000844827500001 ()36016477 (PubMedID)
Funder
Swedish Research CouncilSwedish Society for Medical Research (SSMF)Swedish Society of Medicine
Available from: 2022-10-13 Created: 2022-10-13 Last updated: 2025-02-20Bibliographically approved
2. Well-being spectrum traits are associated with polygenic scores for autism
Open this publication in new window or tab >>Well-being spectrum traits are associated with polygenic scores for autism
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2023 (English)In: Autism Research, ISSN 1939-3792, E-ISSN 1939-3806, Vol. 16, no 10, p. 1891-1902Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
Autism spectrum disorder, well-being spectrum, polygenic risk score, genetic risk score, neuroticism, depression, loneliness, life satisfaction, positive affect
National Category
Psychiatry
Research subject
Neuroscience; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-496547 (URN)10.1002/aur.3011 (DOI)001051519800001 ()
Funder
Swedish Society for Medical Research (SSMF)
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2023-02-15 Created: 2023-02-15 Last updated: 2024-09-06Bibliographically approved
3. Migraine and its major subtypes: with and without aura are associated with polygenic scores for autism
Open this publication in new window or tab >>Migraine and its major subtypes: with and without aura are associated with polygenic scores for autism
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2025 (English)In: Cephalalgia, ISSN 0333-1024, E-ISSN 1468-2982, Vol. 45, no 1, p. 1-12Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Sage Publications, 2025
Keywords
aura, autism, headache, migraine, polygenic risk score
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-537908 (URN)10.1177/03331024241312666 (DOI)001411832200005 ()2-s2.0-85215995515 (Scopus ID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2024-09-06 Created: 2024-09-06 Last updated: 2025-02-20Bibliographically approved
4. Association of polygenic scores for autism with volumetric MRI phenotypes in cerebellum and brainstem in adults
Open this publication in new window or tab >>Association of polygenic scores for autism with volumetric MRI phenotypes in cerebellum and brainstem in adults
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2024 (English)In: Molecular Autism, ISSN 2040-2392, Vol. 15, no 1, article id 34Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Autism, Polygenic risk score, Brain MRI, Cerebellum, Brainstem
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-536604 (URN)10.1186/s13229-024-00611-7 (DOI)001286354200001 ()39113134 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2024-08-20 Created: 2024-08-20 Last updated: 2024-09-06Bibliographically approved

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