DOCSLIB.ORG

Autism Diagnosis Differentiates Neurophysiological Responses To

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Autism Diagnosis Differentiates Neurophysiological Responses To Tye et al. Journal of Neurodevelopmental Disorders (2015) 7:33 DOI 10.1186/s11689-015-9129-2 RESEARCH Open Access Autism diagnosis differentiates neurophysiological responses to faces in adults with tuberous sclerosis complex Charlotte Tye1,2*, Teresa Farroni3,4, Ágnes Volein4, Evelyne Mercure5, Leslie Tucker4, Mark H. Johnson4 and Patrick F. Bolton1,2 Abstract Background: Autism spectrum disorder (ASD) is a common and highly heritable neurodevelopmental disorder that is likely to be the outcome of complex aetiological mechanisms. One strategy to provide insight is to study ASD within tuberous sclerosis complex (TSC), a rare disorder with a high incidence of ASD, but for which the genetic cause is determined. Individuals with ASD consistently demonstrate face processing impairments, but these have not been examined in adults with TSC using event-related potentials (ERPs) that are able to capture distinct temporal stages of processing. Methods: For adults with TSC (n = 14), 6 of which had a diagnosis of ASD, and control adults (n = 13) passively viewed upright and inverted human faces with direct or averted gaze, with concurrent EEG recording. Amplitude and latency of the P1 and N170 ERPs were measured. Results: Individuals with TSC + ASD exhibited longer N170 latencies to faces compared to typical adults. Typical adults and adults with TSC-only exhibited longer N170 latency to inverted versus upright faces, whereas individuals with TSC + ASD did not show latency differences according to face orientation. In addition, individuals with TSC + ASD showed increased N170 latency to averted compared to direct gaze, which was not demonstrated in typical adults. A reduced lateralization was shown for the TSC + ASD groups on P1 and N170 amplitude. Conclusions: The findings suggest that individuals with TSC + ASD may have similar electrophysiological abnormalities to idiopathic ASD and are suggestive of developmental delay. Identifying brain-based markers of ASD that are similar in TSC and idiopathic cases is likely to help elucidate the risk pathways to ASD. Keywords: Autism spectrum disorder, ERP, Face, Gaze, Tuberous sclerosis complex Background genetic risk in a substantial minority of cases [4, 5]. Autism spectrum disorder (ASD) is a common childhood- Genome-wide association studies indicate that other more onset disorder characterized by social and communication common variants likely play a role, but the studies re- impairments and restricted/repetitive behaviours and in- ported to date are underpowered to confidently identify terests. Family and twin studies indicate that genetic fac- the major variants involved [6, 7]. Nevertheless, the find- tors play an important role in the aetiology of ASD, but ings to date are helping to identify putative neurobio- non-genetic factors are also likely to be relevant in caus- logical processes involved in aetiology, with a major focus ation [1–3]. Molecular genetic studies have identified a on the genes involved in synaptic development and func- number of copy numbers and rare variants that underlie tion [8]. Neuroimaging studies have also begun to chart the structural and functional correlates of ASD, * Correspondence: [email protected] but findings have been rather inconsistent, possibly 1 MRC Social, Genetic and Developmental Psychiatry Centre, Institute of reflecting clinical and underlying genetic heterogen- Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF, UK 2Child and Adolescent Psychiatry, Institute of Psychiatry, King’s College eity. One strategy to address the problem of genetic het- London, London, UK erogeneity is to study syndromic model systems of ASD Full list of author information is available at the end of the article © 2015 Tye et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tye et al. Journal of Neurodevelopmental Disorders (2015) 7:33 Page 2 of 9 where the genetic cause is constrained. Tuberous sclerosis the disorder such as impaired eye contact, joint attention complex (TSC) is a multi-systemic disorder caused by a and theory of mind, which suggests it is a key brain-based mutation in TSC1 on chromosome 9q34 or TSC2 on biomarker of risk for ASD. chromosome 16p13.3. Individuals with mutations in the Given that previous findings suggest an association TSC genes develop a variable and diverse array of physical, between the presence of tubers in the temporal regions cognitive and behavioural manifestations [9]. Remarkable associated with face processing and risk of ASD in TSC progress has been made with regard to clarifying the mo- [40], there is relatively little work examining whether the lecular biology of TSC, and this has led to extremely same neurophysiological correlates of impaired face pro- promising new treatment approaches [10–12]. cessing operate in syndromic ASD. A study of young Several studies have shown that autistic behaviours children with TSC reported delayed N290 (the develop- are frequently observed [13, 14], and between 30 and mental ‘precursor’ to the N170) and reduced lateralization, 60 % of individuals with TSC meet diagnostic criteria effects that were particularly pronounced in children with for ASD [9, 15–17]. It is likely, therefore, that there a diagnosis of ASD [41]. There has not, however, been an are specific risk mechanisms that determine which in- investigation of electrophysiological responses to changes dividuals develop ASD [18]. To shed light on the gene- in face orientation and gaze direction in adults with TSC. brain-behaviour risk pathways, an important approach is The current study aimed to examine neurophysio- to examine brain-based candidate biomarkers. In particu- logical responses to faces and eye gaze in adults with lar, event-related potentials (ERPs) are able to capture fast- TSC with and without a diagnosis of ASD, compared to occurring altered cognitive processes in individuals of typical adult controls, using a paradigm that has been different ages and abilities and thus are suitable for identi- used in several previous studies of ASD [21, 35, 42, 43]. fying biomarkers of complex neurodevelopmental disor- On the basis of previous work, it was hypothesized that ders [19–23]. In order to identify these risk factors, it is neurophysiological responses to faces would differ in important to demonstrate that syndromic ASD (occurring TSC + ASD compared to controls. Specifically, we pre- within a syndrome such as TSC) is the same as idiopathic dicted that adults with TSC + ASD would show (1) slo- ASD, by examining a domain that is known to be altered wed processing of faces, (2) a reduced effect of face in the latter. A strong candidate biomarker of ASD is im- orientation and (3) altered processing of gaze direction. pairment in the ability to process information from the face, associated with activity in temporal brain regions. Methods Findings from ERP studies indicate abnormal responses to Participants face stimuli in ASD, notably a delayed ‘face-sensitive’ N170 Typical control adults (n =13,male n = 11) and adults [24], a reduction or absence of the face inversion effect on with TSC (n = 14, male n = 9) were recruited for the the visual P1 and N170 amplitude [24–34] and altered pro- study. Participants with TSC underwent a multidiscip- cessing of gaze direction on the N170 [21, 35, 36]. Abnor- linary clinical assessment, and six participants (male mal ERP responses to gaze direction are also observed in n = 5) were given a clinical diagnosis of ASD accord- infant siblings of children with ASD [37, 38] and are pre- ing to DSM-IV criteria. Participants were aged 16– dictive of subsequent ASD diagnosis [37]. In addition, 46 years (mean age = 26.85, SD = 7.29); there were no while the N170 is larger in the right hemiscalp compared significant differences in age or gender proportions to the left hemiscalp in typically developing individuals, in- between groups (Table 1). Intellectual ability was dividuals with autism show an atypical bilateral scalp distri- measured using different tools depending on the abil- bution [24, 29, 36, 39] suggestive of abnormal cortical ity level of the participant (Vineland Adaptive Behav- specialization for faces [27]. Altered processing of faces iour Scales, Wechsler Intelligence Scale for Children, may contribute to the social impairments characterizing Wechsler Adult Intelligence Scale, Raven’s matrices, Table 1 Demographic and clinical characteristics Controls TSC TSC + ASD Age (SD) 29.77 (5.67) 25.50 (8.52) 22.33 (6.92) n.s.d. Gender (male, %) 85 50 83 n.s.d. IQ (SD) All >70 88.29 (13.64) 53.33 (30.82) F = 7.40, p = .02 Current epilepsy n/a 25 % 50 % n.s.d Epilepsy severity (SD) n/a 1.43 (3.77) 3.75 (2.87) n.s.d. Epilepsy medication n/a 25 % 100 % x2 = 7.88, p = .01 Abbreviations: n/a not applicable, n.s.d. non-significant difference Tye et al. Journal of Neurodevelopmental Disorders (2015) 7:33 Page 3 of 9 British Picture Vocabulary Scale), and a proxy IQ com- recording. This paradigm has been used previously in bining these measures was created for 13 of the TSC ASD and infant samples [21, 35, 42]. participants (data missing on one participant), similar to previous work in TSC [44]. There was a significant dif- EEG recording and processing ference between TSC-only and ASD groups in intellec- Electroencephalography was recorded using a Hydrocel tual ability measured using this parameter, driven by in control adults and the Geodesic Sensor Net in adults two ASD participants with severe intellectual disability with TSC, each with 128 electrodes (Electrical Geode- (ID) (IQ 20–26).
Load more

Recommended publications
  • Phenotyping, Etiological Factors, and Biomarkers: Toward Precision Medicine in Autism Spectrum Disorders David Q
    Special Article Phenotyping, Etiological Factors, and Biomarkers: Toward Precision Medicine in Autism Spectrum Disorders David Q. Beversdorf, MD; MISSOURI AUTISM SUMMIT CONSORTIUM* ABSTRACT: Despite the progress made in understanding the biology of autism spectrum disorder (ASD), effective biological interventions for the core symptoms remain elusive. Because of the etiological hetero- geneity of ASD, identification of a “one-size-fits-all” treatment approach will likely continue to be chal- lenging. A meeting was convened at the University of Missouri and the Thompson Center to discuss strategies for stratifying patients with ASD for the purpose of moving toward precision medicine. The “white paper” presented here articulates the challenges involved and provides suggestions for future solutions. (J Dev Behav Pediatr 37:659–673, 2016) Index terms: autism, biomarkers, precision medicine. Significant progress has been made in understanding Phase II clinical trials.5 This perceived “failure” is likely the biology of autism spectrum disorder (ASD) over the due to the etiological heterogeneity of the subjects with past decade. However, effective biological interventions ASD who received the specific treatment. A review of the for the core symptoms remain elusive. Instead of a single data for the arbaclofen study suggests a strong positive or even a small set of causes, a consensus has emerged response for at least a subset of fragile X and patients with that genetic and environmental causes of ASD are likely ASD. Positive responses in some individuals, but other- multifactorial. The genetic architecture of ASD has be- wise statistically nonsignificant beneficial group effects, come increasingly clear and increasingly complex with are characteristic of most of these early pharmacological estimates of at least 1000 genetic alterations associated treatment trials of ASD.
    [Show full text]
  • Sleep As a Translationally-Relevant Endpoint in Studies of Autism Spectrum Disorder (ASD)
    www.nature.com/npp NEUROPSYCHOPHARMACOLOGY REVIEWS Sleep as a translationally-relevant endpoint in studies of autism spectrum disorder (ASD) Galen Missig 1, Christopher J. McDougle2,3 and William A. Carlezon Jr.1 Sleep has numerous advantages for aligning clinical and preclinical (basic neuroscience) studies of neuropsychiatric illness. Sleep has high translational relevance, because the same endpoints can be studied in humans and laboratory animals. In addition, sleep experiments are conducive to continuous data collection over long periods (hours/days/weeks) and can be based on highly objective neurophysiological measures. Here, we provide a translationally-oriented review on what is currently known about sleep in the context of autism spectrum disorder (ASD), including ASD-related conditions, thought to have genetic, environmental, or mixed etiologies. In humans, ASD is frequently associated with comorbid medical conditions including sleep disorders. Animal models used in the study of ASD frequently recapitulate dysregulation of sleep and biological (diurnal, circadian) rhythms, suggesting common pathophysiologies across species. As our understanding of the neurobiology of ASD and sleep each become more refined, it is conceivable that sleep-derived metrics may offer more powerful biomarkers of altered neurophysiology in ASD than the behavioral tests currently used in humans or lab animals. As such, the study of sleep in animal models for ASD may enable fundamentally new insights on the condition and represent a basis for strategies that enable the development of more effective therapeutics. Neuropsychopharmacology (2020) 45:90–103; https://doi.org/10.1038/s41386-019-0409-5 INTRODUCTION dysregulation are frequently comorbid and thus also represent A recent estimate suggests that as many as 2.5% of children have important aspects of these conditions [10].
    [Show full text]
  • Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings
    G C A T T A C G G C A T genes Article Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings Jasleen Dhaliwal 1 , Ying Qiao 1,2, Kristina Calli 1,2, Sally Martell 1,2, Simone Race 3,4,5, Chieko Chijiwa 1,5, Armansa Glodjo 3,5, Steven Jones 1,6 , Evica Rajcan-Separovic 2,7, Stephen W. Scherer 4 and Suzanne Lewis 1,2,5,* 1 Department of Medical Genetics, University of British Columbia (UBC), Vancouver, BC V6H 3N1, Canada; [email protected] (J.D.); [email protected] (Y.Q.); [email protected] (K.C.); [email protected] (S.M.); [email protected] (C.C.); [email protected] (S.J.) 2 BC Children’s Hospital, Vancouver, BC V5Z 4H4, Canada; [email protected] 3 Department of Pediatrics, University of British Columbia (UBC), Vancouver, BC V6T 1Z7, Canada; [email protected] (S.R.); [email protected] (A.G.) 4 The Centre for Applied Genomics and McLaughlin Centre, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada; [email protected] 5 BC Children’s and Women’s Health Center, Vancouver, BC V6H 3N1, Canada 6 Michael Smith Genome Sciences Centre, Vancouver, BC V5Z 4S6, Canada 7 Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC V6T 1Z7, Canada * Correspondence: [email protected] Abstract: Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in Citation: Dhaliwal, J.; Qiao, Y.; Calli, children and shows high heritability.
    [Show full text]
  • Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample
    Research Original Investigation Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample Emma Colvert, PhD; Beata Tick, MSc; Fiona McEwen, PhD; Catherine Stewart, PhD; Sarah R. Curran, MD; Emma Woodhouse, BSc; Nicola Gillan, BSc; Victoria Hallett, PhD; Stephanie Lietz, PhD; Tracy Garnett, DClinPsych; Angelica Ronald, PhD; Robert Plomin, PhD; Frühling Rijsdijk, PhD; Francesca Happé, PhD; Patrick Bolton, MD Supplemental content at IMPORTANCE Most evidence to date highlights the importance of genetic influences on the jamapsychiatry.com liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population. OBJECTIVES To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD. DESIGN, SETTING, AND PARTICIPANTS We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview–Revised (ADI-R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs).
    [Show full text]
  • Autism Diagnosis As Social Process
    Drawing a line in the sand: Autism diagnosis as social process Submitted by Jennie Hayes to the University of Exeter as a thesis for the degree of Doctor of Philosophy in Medical Studies December 2019 Submitted by Jennie Hayes, this thesis is available for Library use on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. I certify that all material in this thesis which is not my own work has been identified and that no material has previously been submitted and approved for the award of a degree by this or any other University. Signature……………………………………………………………………………… 1 2 This PhD project was funded by a Wellcome Trust Investigator Award ‘Exploring Diagnosis’ 3 4 Abstract This PhD explored how clinicians make diagnostic decisions about autism in secondary care. Symptoms of autism are considered to be widely heterogeneous, meaning that decisions about where the diagnostic threshold lies can be challenging. Diagnosis in the UK is usually undertaken by multi- disciplinary teams (MDTs) and can involve numerous stages of decision-making in different contexts across an extended time period. The process of diagnosis is complex and multi-faceted, and can be particularly challenging when cases are considered ‘borderline’ or where there are coexisting conditions. A qualitative approach was used in four studies. A narrative review of twenty- one clinical guidelines was conducted (study one); observation of eighteen assessment team meetings on four sites was undertaken (studies two and three); and sixteen interviews were conducted with clinicians engaged in autism diagnosis (study four).
    [Show full text]
  • Diagnostic Change and the Genetic Makeup of the Autism Population1
    Looping Genomes: Diagnostic Change and the Genetic Makeup of the Autism Population1 Daniel Navon University of California, San Diego Gil Eyal Columbia University This article builds on Hacking’s framework of “dynamic nominal- ism” to show how knowledge about biological etiology can interact with the “kinds of people” delineated by diagnostic categories in ways that “loop” or modify both over time. The authors use historical ma- terials to show how “geneticization” played a crucial role in binding together autism as a biosocial community and how evidence from ge- netics research later made an important contribution to the diagnostic expansion of autism. In the second part of the article, the authors draw on quantitative and qualitative analyses of autism rates over time in several rare conditions that are delineated strictly according to geno- mic mutations in order to demonstrate that these changes in diagnos- tic practice helped to both increase autism’s prevalence and create its enormous genetic heterogeneity. Thus, a looping process that began with geneticization and involved the social effects of genetics research itself transformed the autism population and its genetic makeup. It is by now well recognized that most traits and disease categories do not line up in a straightforward way with characteristics of the human genome ðLock 2005; Wade 2009Þ. Nevertheless, the project of explaining, tracing, 1 This study was conducted with the generous support of the USA-Israel Binational Sci- ence Foundation ðgrant 2010175Þ and a seed grant from the Institute for Social and Economic Research and Policy at Columbia University. We would like to thank the AJS reviewers as well as Peter Bearman, Alberto Cambrosio, James Evans, Uri Shwed, Claire Edington, Daniel Wojtkiewicz, Ayelet Evrony, and audiences at Northwestern © 2016 by The University of Chicago.
    [Show full text]
  • The Heritability of Autism Spectrum Disorder R01CA203809 from the National Cancer Institute (NCI; Dr Mccabe) of the National Institutes of Health (NIH)
    Letters Conflict of Interest Disclosures: All authors have completed and submitted the 6. Centers for Disease Control and Prevention. TBI data and statistics: ICMJE Form for Disclosure of Potential Conflicts of Interest and none were emergency department visits, hospitalizations and deaths, 2001–2010. reported. https://www.cdc.gov/traumaticbraininjury/data/index.html. Accessed Funding/Support: This work was supported by research grants L40DA042452 December 15, 2016. (Dr Veliz), R01DA031160, and R01DA036541 (both Dr McCabe) from the National Institute on Drug Abuse (NIDA), K23HD078502 from the National Institute of Child Health and Human Development (Dr Eckner), and The Heritability of Autism Spectrum Disorder R01CA203809 from the National Cancer Institute (NCI; Dr McCabe) of the National Institutes of Health (NIH). The Monitoring the Future data were Studies have found that autism spectrum disorder (ASD) ag- collected under grant R01DA001411 from NIDA (Dr Schulenberg). gregates in families, and twin studies estimate the propor- Role of the Funder/Sponsor: The NIH had no involvement in the design and tion of the phenotype variance due to genetic factors (herita- conduct of the study; collection, management, analysis, and interpretation of bility) to be about 90%.1 the data; preparation, review, or approval of the manuscript; and decision to In a previous study,2 ASD heritability was estimated to be submit the manuscript for publication. 0.50, and shared familial environmental influences to be 0.04. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of NIDA, NCI, or the NIH. To define presence or absence of ASD, the study used a data 1.
    [Show full text]
  • The Interplay of Common, Rare Variation in Autism
    Spectrum | Autism Research News https://www.spectrumnews.org VIEWPOINT The interplay of common, rare variation in autism BY MARK DALY 27 JUNE 2017 Two seemingly different genetic influences contribute to autism: inherited factors and spontaneous mutations. We are racing to discover more about each of these paths, and yet this should not be viewed as a race. Indeed, an ‘either-or’ framing may well shortchange what we can learn about how these two influences may interact to govern an individual’s risk of developing autism spectrum disorder. Genetic variation, like autism itself, occurs along a spectrum. First, the basics: Autism is common in the population, affecting at least 1 in 100 people. And it runs in families, which suggests that most risk factors for the condition are inherited. But people with autism have fewer children on average than their neurotypical peers. These general features are nearly identical to those of another heritable condition: schizophrenia. The pattern is so distinctive and so precisely matched that coincidence is unlikely. Also, the two conditions share genetic risk factors. Autism and schizophrenia are serious conditions that, by the rules of genetics and natural selection, permit scientists to predict how frequently inherited, associated genetic variants should appear. For example, a mutation that arises and confers a small, two-fold increase in risk for autism is expected to be found only at a frequency of 0.01 percent. Variants with such a low frequency and impact cannot be detected in case-control studies until the study includes hundreds of thousands of people. However, variants that increase risk by only 10 to 20 percent — a tiny effect on the individual — can be quite common and relatively easy to detect.
    [Show full text]
  • An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity
    International Journal of Molecular Sciences Review An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity 1, 1, 1 2 Elena Masini y, Eleonora Loi y, Ana Florencia Vega-Benedetti , Marinella Carta , Giuseppe Doneddu 3, Roberta Fadda 4 and Patrizia Zavattari 1,* 1 Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, 09042 Cagliari, Italy; [email protected] (E.M.); [email protected] (E.L.); [email protected] (A.F.V.-B.) 2 Center for Pervasive Developmental Disorders, Azienda Ospedaliera Brotzu, 09121 Cagliari, Italy; [email protected] 3 Centro per l’Autismo e Disturbi correlati (CADc), Nuovo Centro Fisioterapico Sardo, 09131 Cagliari, Italy; [email protected] 4 Department of Pedagogy, Psychology, Philosophy, University of Cagliari, 09123 Cagliari, Italy; [email protected] * Correspondence: [email protected] The authors contributed equally to this work. y Received: 30 September 2020; Accepted: 30 October 2020; Published: 5 November 2020 Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects social interaction and communication, with restricted interests, activity and behaviors. ASD is highly familial, indicating that genetic background strongly contributes to the development of this condition. However, only a fraction of the total number of genes thought to be associated with the condition have been discovered. Moreover, other factors may play an important role in ASD onset. In fact, it has been shown that parental conditions and in utero and perinatal factors may contribute to ASD etiology. More recently, epigenetic changes, including DNA methylation and micro RNA alterations, have been associated with ASD and proposed as potential biomarkers.
    [Show full text]
  • The Role of RFX-Target Genes in Neurodevelopmental and Psychiatric Disorders
    The role of RFX-target genes in neurodevelopmental and psychiatric disorders Abhishekapriya Ganesan Degree project in bioinformatics, 2021 Examensarbete i bioinformatik 45 hp till masterexamen, 2021 Biology Education Centre, Uppsala University, and Department of Women’s and Children’s Health, Karolinska Institutet Supervisors: Kristiina Tammimies and Michelle Watts ABSTRACT Neurodevelopmental disorders such as autism spectrum disorder (ASD) and psychiatric disorders, for example, schizophrenia (SCZ) represent a large spectrum of disorders that manifest through cognitive and behavioural problems. ASD and SCZ are both highly heritable, and some phenotypic similarities between ASD and SCZ have sparked an interest in understanding their genetic commonalities. The genetics of both disorders exhibit significant heterogeneity. Developments in genomics and systems biology, continually increases people’s understanding of these disorders. Recently, pathogenic genetic variants in the regulatory factor X (RFX) family of transcription factors have been identified in a number of ASD cases. In this thesis, common genetic variants and expression patterns of genes identified to have a conserved promotor X-Box motif region, a binding site of RFX factors, are studied. Significant common variants identified through expression quantitative trait loci (eQTLs) and genome wide association studies (GWAS) are mapped to the regulatory regions of these genes and analysed for putative enrichment. In addition, single-cell RNA sequencing data is utilised to examine enrichment of cell types having high X-Box gene expression in the developing human cortex. Through the study, genes that have eQTLs or SNPs in the genomic regulatory regions of the X-Box genes have been identified. While there were no eQTLs or GWAS SNPs in the X-Box motifs, in the X-Box promoter regions there were 247 eQTLs, 359 ASD GWAS SNPs, 16 eQTL-ASD GWAS SNP overlaps, 745 SCZ GWAS SNPs and 27 eQTL-SCZ GWAS SNP overlaps.
    [Show full text]
  • Common Genetic Risk Variants Identified in the SPARK Cohort
    medRxiv preprint doi: https://doi.org/10.1101/2020.01.13.20017319; this version posted January 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 1 Common genetic risk variants identified in the SPARK cohort implicate 2 DDHD2 as a novel autism risk gene 3 4 Nana Matoba1,2, Dan Liang1,2, Huaigu Sun1,2, Nil Aygün1,2, Jessica C. McAfee1,2, Jessica E. 5 Davis3-8, Laura M. RaffielD1, Huijun Qian9, JosepH Piven10, Yun Li1,11,12, Sriam Kosuri3-8, Hyejung 6 Won1,2,*, Jason L. Stein1,2,* 7 8 1. Department of Genetics, University of NortH Carolina at CHapel Hill, NortH Carolina, USA 9 2. UNC Neuroscience Center, University of NortH Carolina at CHapel Hill, NortH Carolina, USA 10 3. Department of CHemistry anD Biochemistry, University of California, Los Angeles, Los 11 Angeles, California, USA 12 4. UCLA-DOE Institute for Genomics anD Proteomics, University of California, Los Angeles, 13 Los Angeles, California, USA 14 5. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, 15 USA 16 6. Quantitative anD Computational Biology Institute, University of California, Los Angeles, Los 17 Angeles, California, USA 18 7. Eli anD EDytHe BroaD Center of Regenerative MeDicine anD Stem Cell Research, University 19 of California, Los Angeles, Los Angeles, California, USA 20 8. Jonsson CompreHensive Cancer Center, University of California, Los Angeles, Los Angeles, 21 California, USA 22 9.
    [Show full text]
  • "Genetics of Mathematical Aptitude" In
    Genetics of Mathematical Advanced article Article Contents Aptitude • Introduction • Quantifying Mathematical Aptitude Varun Warrier, Autism Research Centre, Department of Psychiatry, University of • Mathematical Aptitude, Disability and Talent Cambridge, Cambridge, UK • Individual and Group Differences in MA Simon Baron-Cohen, Autism Research Centre, Department of Psychiatry, Uni- • Molecular Genetic Studies • versity of Cambridge, Cambridge, UK and CLASS Clinic, Cambridgeshire and Peterborough Conclusions NHS Foundation Trust (CPFT), Cambridgeshire, UK Online posting date: 16th August 2016 Normative variation in mathematical aptitude and arithmetic, suggesting evolutionary conservation of brain (MA) is relevant to many aspects of societal regions for numerosity (Hubbard et al., 2008). Several studies functioning, in particular for occupations in sci- have established numerosity in infants, suggesting that certain ence, technology, engineering and mathematics aspects of MA may be innate, and these are supported by studies that have identified a heritable component to MA. More recent (STEM). Though elements of numerosity have studies have focused on other aspects of MA, including sub- been identified in some animals, complex MA is domains of MA, and genetic correlation with other traits such uniquely human. Several studies, using a variety as reading and general intelligence (g). These studies have also of designs, have investigated the heritability of investigated changes in heritability of MA with time. A few MA, and the extreme ends of the dimension of this studies have also investigated the heritability of mathematical tal- trait – mathematics learning disability (MLD) and ent (MT) and mathematical learning disability (MLD). Over the mathematical talent (MT). Initial estimates of the last decade, molecular genetic investigations have provided novel heritability of MA ranged from 0.2 to 0.9, while insights into the genetic architecture of MA, suggesting that MA later studies identify more modest heritabilities is polygenic.
    [Show full text]