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Article ; Online: Genetic relationship between the immune system and autism.

Arenella, Martina / Fanelli, Giuseppe / Kiemeney, Lambertus A / McAlonan, Grainne / Murphy, Declan G / Bralten, Janita

Brain, behavior, & immunity - health

2023 Volume 34, Page(s) 100698

Abstract: Autism spectrum disorder (ASD) is a common and complex neurodevelopmental condition. The pathophysiology of ASD is poorly defined; however, it includes a strong genetic component and there is increasing evidence to support a role of immune dysregulation. ...

Abstract	Autism spectrum disorder (ASD) is a common and complex neurodevelopmental condition. The pathophysiology of ASD is poorly defined; however, it includes a strong genetic component and there is increasing evidence to support a role of immune dysregulation. Nonetheless, it is unclear which immune phenotypes link to ASD through genetics. Hence, we investigated the genetic correlation between ASD and diverse classes of immune conditions and markers; and if these immune-related genetic factors link to specific autistic-like traits in the population. We estimated global and local genetic correlations between ASD (n = 55,420) and 11 immune phenotypes (n = 14,256-755,406) using genome-wide association study summary statistics. Subsequently, polygenic scores (PGS) for these immune phenotypes were calculated in a population-based sample (n = 2487) and associated to five autistic-like traits (i.e., attention to detail, childhood behaviour, imagination, rigidity, social skills), and a total autistic-like traits score. Sex-stratified PGS analyses were also performed. At the genome-wide level, ASD was positively correlated with allergic diseases (ALG), and negatively correlated with lymphocyte count, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) (FDR-p = 0.01-0.02). At the local genetic level, ASD was correlated with RA, C-reactive protein, and granulocytes and lymphocyte counts (p = 5.8 × 10
Language	English
Publishing date	2023-11-03
Publishing country	United States
Document type	Journal Article
ISSN	2666-3546
ISSN (online)	2666-3546
DOI	10.1016/j.bbih.2023.100698
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Article ; Online: The ethics of polygenic scores in psychiatry: minefield or opportunity for patient-centered psychiatry?

Wouters, Roel H P / van der Horst, Marte Z / Aalfs, Cora M / Bralten, Janita / Luykx, Jurjen J / Zinkstok, Janneke R

Psychiatric genetics

2024 Volume 34, Issue 2, Page(s) 31–36

Abstract: Recent advancements in psychiatric genetics have sparked a lively debate on the opportunities and pitfalls of incorporating polygenic scores into clinical practice. Yet, several ethical concerns have been raised, casting doubt on whether further ... ...

Abstract	Recent advancements in psychiatric genetics have sparked a lively debate on the opportunities and pitfalls of incorporating polygenic scores into clinical practice. Yet, several ethical concerns have been raised, casting doubt on whether further development and implementation of polygenic scores would be compatible with providing ethically responsible care. While these ethical issues warrant thoughtful consideration, it is equally important to recognize the unresolved need for guidance on heritability among patients and their families. Increasing the availability of genetic counseling services in psychiatry should be regarded as a first step toward meeting these needs. As a next step, future integration of novel genetic tools such as polygenic scores into genetic counseling may be a promising way to improve psychiatric counseling practice. By embedding the exploration of polygenic psychiatry into the supporting environment of genetic counseling, some of the previously identified ethical pitfalls may be prevented, and opportunities to bolster patient empowerment can be seized upon. To ensure an ethically responsible approach to psychiatric genetics, active collaboration with patients and their relatives is essential, accompanied by educational efforts to facilitate informed discussions between psychiatrists and patients.
MeSH term(s)	Humans ; Mental Disorders/genetics ; Psychiatry ; Psychiatrists ; Multifactorial Inheritance/genetics ; Patient-Centered Care
Language	English
Publishing date	2024-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1067837-2
ISSN	1473-5873 ; 0955-8829
ISSN (online)	1473-5873
ISSN	0955-8829
DOI	10.1097/YPG.0000000000000363
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Article ; Online: Autism spectrum disorder and brain volume link through a set of mTOR-related genes.

Arenella, Martina / Mota, Nina R / Teunissen, Mariel W A / Brunner, Han G / Bralten, Janita

Journal of child psychology and psychiatry, and allied disciplines

2023 Volume 64, Issue 7, Page(s) 1007–1014

Abstract: Background: Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD ...

Abstract	Background: Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. Methods: We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. Results: Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81). Conclusions: This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD.
MeSH term(s)	Humans ; Autism Spectrum Disorder/genetics ; Brain ; Intellectual Disability ; TOR Serine-Threonine Kinases/genetics ; Genetic Predisposition to Disease
Chemical Substances	TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218136-8
ISSN	1469-7610 ; 0021-9630 ; 0373-8086
ISSN (online)	1469-7610
ISSN	0021-9630 ; 0373-8086
DOI	10.1111/jcpp.13783
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Article ; Online: Immunogenetics of autism spectrum disorder: A systematic literature review.

Arenella, Martina / Matuleviciute, Rugile / Tamouza, Ryad / Leboyer, Marion / McAlonan, Grainne / Bralten, Janita / Murphy, Declan

Brain, behavior, and immunity

2023 Volume 114, Page(s) 488–499

Abstract: The aetiology of autism spectrum disorder (ASD) is complex and, partly, accounted by genetic factors. Nonetheless, the genetic underpinnings of ASD are poorly defined. The presence of immune dysregulations in autistic individuals, and their families, ... ...

Abstract	The aetiology of autism spectrum disorder (ASD) is complex and, partly, accounted by genetic factors. Nonetheless, the genetic underpinnings of ASD are poorly defined. The presence of immune dysregulations in autistic individuals, and their families, supports a role of the immune system and its genetic regulators. Albeit immune responses belong either to the innate or adaptive arms, the overall immune system genetics is broad, and encompasses a multitude of functionally heterogenous pathways which may have different influences on ASD. Hence, to gain insights on the immunogenetic underpinnings of ASD, we conducted a systematic literature review of previous immune genetic and transcription studies in ASD. We defined a list of immune genes relevant to ASD and explored their neuro-immune function. Our review confirms the presence of immunogenetic variability in ASD, accounted by inherited variations of innate and adaptive immune system genes and genetic expression changes in the blood and post-mortem brain of autistic individuals. Besides their immune function, the identified genes control neurodevelopment processes (neuronal and synaptic plasticity) and are highly expressed in pre/peri-natal periods. Hence, our synthesis bolsters the hypothesis that perturbation in immune genes may contribute to ASD by derailing the typical trajectory of neurodevelopment. Our review also helped identifying some of the limitations of prior immunogenetic research in ASD. Thus, alongside clarifying the neurodevelopment role of immune genes, we outline key considerations for future work into the aetiology of ASD and possible novel intervention targets.
Language	English
Publishing date	2023-09-16
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2023.09.010
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Zs.A 2276: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 327: Show issues

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Article: De bouw van de hersenen bij adolescenten en jongvolwassenen met ADHD.

Greven, Corina / Bralten, Janita

Tijdschrift voor psychiatrie

2015 Volume 57, Issue 8, Page(s) 615

MeSH term(s)	Adolescent Development ; Attention Deficit Disorder with Hyperactivity/pathology ; Brain/pathology ; Caudate Nucleus/pathology ; Child Development ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Putamen/pathology ; Siblings
Language	Dutch
Publishing date	2015
Publishing country	Netherlands
Document type	Comment ; Journal Article
ZDB-ID	604662-9
ISSN	0303-7339
ISSN	0303-7339
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Zs.B 2520: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 29: Show issues

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Article ; Online: Multi-polygenic scores in psychiatry: From disorder specific to transdiagnostic perspectives.

Shi, Yingjie / Sprooten, Emma / Mulders, Peter / Vrijsen, Janna / Bralten, Janita / Demontis, Ditte / Børglum, Anders D / Walters, G Bragi / Stefansson, Kari / van Eijndhoven, Philip / Tendolkar, Indira / Franke, Barbara / Mota, Nina Roth

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

2023 Volume 195, Issue 1, Page(s) e32951

Abstract: The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we ... ...

Abstract	The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R
MeSH term(s)	Humans ; Attention Deficit Disorder with Hyperactivity/diagnosis ; Attention Deficit Disorder with Hyperactivity/genetics ; Psychopathology ; Substance-Related Disorders ; Anxiety Disorders ; Psychiatry ; Multifactorial Inheritance/genetics
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2108616-3
ISSN	1552-485X ; 1552-4841 ; 0148-7299
ISSN (online)	1552-485X
ISSN	1552-4841 ; 0148-7299
DOI	10.1002/ajmg.b.32951
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Article ; Online: Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders.

Fanelli, Giuseppe / Franke, Barbara / De Witte, Ward / Ruisch, I Hyun / Haavik, Jan / van Gils, Veerle / Jansen, Willemijn J / Vos, Stephanie J B / Lind, Lars / Buitelaar, Jan K / Banaschewski, Tobias / Dalsgaard, Søren / Serretti, Alessandro / Mota, Nina Roth / Poelmans, Geert / Bralten, Janita

Translational psychiatry

2022 Volume 12, Issue 1, Page(s) 59

Abstract: The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of ... ...

Abstract	The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain "insulinopathies" were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (r
MeSH term(s)	Attention Deficit Disorder with Hyperactivity/psychology ; Autism Spectrum Disorder/psychology ; Brain ; Depressive Disorder, Major/genetics ; Diabetes Mellitus, Type 2/genetics ; Genome-Wide Association Study ; Humans ; Insulin
Chemical Substances	Insulin
Language	English
Publishing date	2022-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-022-01817-0
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Article: Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions.

Fanelli, Giuseppe / Franke, Barbara / Fabbri, Chiara / Werme, Josefin / Erdogan, Izel / De Witte, Ward / Poelmans, Geert / Ruisch, I Hyun / Reus, Lianne Maria / van Gils, Veerle / Jansen, Willemijn J / Vos, Stephanie J B / Alam, Kazi Asraful / Martinez, Aurora / Haavik, Jan / Wimberley, Theresa / Dalsgaard, Søren / Fóthi, Ábel / Barta, Csaba /

Fernandez-Aranda, Fernando / Jimenez-Murcia, Susana / Berkel, Simone / Matura, Silke / Salas-Salvadó, Jordi / Arenella, Martina / Serretti, Alessandro / Mota, Nina Roth / Bralten, Janita

medRxiv : the preprint server for health sciences

2024

Abstract: The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the ... ...

Abstract	The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (\|r
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.07.24303921
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Article ; Online: ADHD symptoms in the adult general population are associated with factors linked to ADHD in adult patients.

Li, Ting / Mota, Nina R / Galesloot, Tessel E / Bralten, Janita / Buitelaar, Jan K / IntHout, Joanna / AriasVasquez, Alejandro / Franke, Barbara

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

2019 Volume 29, Issue 10, Page(s) 1117–1126

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children and adults. It is characterized by inappropriate levels of inattention (IA) and/or hyperactivity and impulsivity (HI). The ADHD diagnosis is hypothesized to ... ...

Abstract	Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children and adults. It is characterized by inappropriate levels of inattention (IA) and/or hyperactivity and impulsivity (HI). The ADHD diagnosis is hypothesized to represent the extreme of a continuous distribution of ADHD symptoms in the general population. In this study, we investigated whether factors linked to adult ADHD as a disorder are associated with adult ADHD symptoms in the general population. Our population-based sample included 4987 adults (mean age 56.1 years; 53.8% female) recruited by the Nijmegen Biomedical Study (NBS). Participants completed the Dutch ADHD DSM-IV Rating Scale for current and childhood ADHD symptoms, the Symptom Check List-90-R (SCL-90-R) anxiety subscale, and the Eysenk Personality Questionnaire (EPQR-S). Partial Spearman correlation and Hurdle negative binomial regression analysis were used to assess how age, sex, childhood ADHD symptoms, anxiety symptoms, and personality traits (neuroticism, extraversion, and psychoticism) are associated with current IA and HI symptoms. Increasing age was associated with a lower proportion of participants reporting HI symptoms and with reduced levels of HI; IA levels remained fairly stable over the age-range, but the probability of reporting IA symptoms increased throughout middle/late adulthood. Females were more likely to report IA symptoms than males. Childhood ADHD symptoms, neuroticism, and psychoticism were positively associated with current IA and HI symptoms, while extraversion had an opposite association with these symptom domains. Anxiety symptoms affected HI symptoms in females. Our results indicate that factors associated with categorical ADHD are also correlated with ADHD symptoms in the adult population.
MeSH term(s)	Age Factors ; Attention ; Attention Deficit Disorder with Hyperactivity/complications ; Attention Deficit Disorder with Hyperactivity/diagnosis ; Attention Deficit Disorder with Hyperactivity/psychology ; Female ; Healthy Volunteers/psychology ; Humans ; Hyperkinesis/complications ; Impulsive Behavior ; Male ; Middle Aged ; Personality ; Psychiatric Status Rating Scales ; Self Report ; Sex Factors
Language	English
Publishing date	2019-08-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1082947-7
ISSN	1873-7862 ; 0924-977X
ISSN (online)	1873-7862
ISSN	0924-977X
DOI	10.1016/j.euroneuro.2019.07.136
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Zs.A 3288: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Pleiotropic Contribution of

van Donkelaar, Marjolein M J / Hoogman, Martine / Pappa, Irene / Tiemeier, Henning / Buitelaar, Jan K / Franke, Barbara / Bralten, Janita

Frontiers in behavioral neuroscience

2018 Volume 12, Page(s) 61

Abstract: Reactive and proactive subtypes of aggression have been recognized to help parse etiological heterogeneity of this complex phenotype. With a heritability of about 50%, genetic factors play a role in the development of aggressive behavior. Imaging studies ...

Abstract	Reactive and proactive subtypes of aggression have been recognized to help parse etiological heterogeneity of this complex phenotype. With a heritability of about 50%, genetic factors play a role in the development of aggressive behavior. Imaging studies implicate brain structures related to social behavior in aggression etiology, most notably the amygdala and striatum. This study aimed to gain more insight into the pathways from genetic risk factors for aggression to aggression phenotypes. To this end, we conducted genome-wide gene-based cross-trait meta-analyses of aggression with the volumes of amygdala, nucleus accumbens and caudate nucleus to identify genes influencing both aggression and aggression-related brain volumes. We used data of large-scale genome-wide association studies (GWAS) of: (a) aggressive behavior in children and adolescents (EAGLE,
Language	English
Publishing date	2018-04-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2018.00061
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