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Association of polygenic scores for autism with volumetric MRI phenotypes in cerebellum and brainstem in adults
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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.ORCID iD: 0000-0002-4070-1229
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Neuropsychopharmacology.ORCID iD: 0000-0001-8637-3390
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.ORCID iD: 0000-0003-0000-7694
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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. Vol. 15, no 1, article id 34
Keywords [en]
Autism, Polygenic risk score, Brain MRI, Cerebellum, Brainstem
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-536604DOI: 10.1186/s13229-024-00611-7ISI: 001286354200001PubMedID: 39113134OAI: oai:DiVA.org:uu-536604DiVA, id: diva2:1890648
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
In thesis
1. Deciphering Adult Autism: Exploring Polygenic Risk, Brain Structure, Well-being, Migraine, and Mental Health Disorders
Open this publication in new window or tab >>Deciphering Adult Autism: Exploring Polygenic Risk, Brain Structure, Well-being, Migraine, and Mental Health Disorders
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
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
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:nbn:se:uu:diva-537917 (URN)978-91-513-2225-4 (ISBN)
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

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Mohammad, SalahuddinGentreau, MélissaDubol, ManonRukh, GullMwinyi, JessicaSchiöth, Helgi B.

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Mohammad, SalahuddinGentreau, MélissaDubol, ManonRukh, GullMwinyi, JessicaSchiöth, Helgi B.
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Functional Pharmacology and NeuroscienceScience for Life Laboratory, SciLifeLabNeuropsychopharmacology
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