Publications by authors named "Joachim Hallmayer"

120 Publications

Effects of X Chromosome Monosomy and Genomic Imprinting on Observational Markers of Social Anxiety in Prepubertal Girls with Turner Syndrome.

J Autism Dev Disord 2021 Mar 9. Epub 2021 Mar 9.

Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA, 94305-5795, USA.

Previous studies have suggested that girls with Turner syndrome (TS) exhibit symptoms of social anxiety during interactions with others. However, few studies have quantified these behaviors during naturalistic face-to-face social encounters. In this study, we coded observational markers of social anxiety in prepubertal girls with TS and age-matched controls during a 10-min social encounter with an unfamiliar examiner. Results showed that girls with TS exhibited significantly higher levels of gaze avoidance compared to controls. Impairments in social gaze were particularly increased in girls with a maternally retained X chromosome (Xm), suggesting a genomic imprinting effect. These data indicate that social gaze avoidance may be a critical behavioral marker for identifying early social dysfunction in young girls with TS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10803-021-04896-yDOI Listing
March 2021

Brain health registry GenePool study: A novel approach to online genetics research.

Alzheimers Dement (N Y) 2021 14;7(1):e12118. Epub 2021 Feb 14.

VA Advanced Imaging Research Center San Francisco Veteran's Administration Medical Center San Francisco California USA.

Introduction: Remote data collection, including the establishment of online registries, is a novel approach to efficiently identify risk for cognitive decline and Alzheimer's disease (AD) in older adults, with growing evidence for feasibility and validity. Addition of genetic data to online registries has the potential to facilitate identification of older adults at risk and to advance the understanding of genetic contributions to AD.

Methods: 573 older adult participants with longitudinal online Brain Health Registry (BHR) data underwent apolipoprotein E (APOE) genotyping using remotely collected saliva samples and a novel, automated Biofluid Collection Management Portal. We evaluated acceptability of genetic sample collection and estimated associations between (1) sociodemographic variables and willingness to participate in genetics research and (2) APOE results and online cognitive and functional assessments. We also assessed acceptance of hypothetical genetics research participation by surveying a larger sample of 25,888 BHR participants.

Results: 51% of invited participants enrolled in the BHR genetics study, BHR-GenePool Study (BHR-GPS); 27% of participants had at least one APOE ε4 allele. Older participants and those with higher educational attainment were more likely to participate. In the remotely administered Cogstate Brief Battery, APOE ε4/ε4 homozygotes (HM) had worse online learning scores, and greater decline in processing speed and attention, compared to ε3/ε4 heterozygotes (HT) and ε4 non-carriers (NC).

Discussion: APOE genotyping of more than 500 older adults enrolled in BHR supports the feasibility and validity of a novel, remote biofluids collection approach from a large cohort of older adults, with data linkage to longitudinal online cognitive data. This approach can be expanded for efficient collection of genetic data and other information from biofluids in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/trc2.12118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882536PMC
February 2021

Glucocorticoid regulation and neuroanatomy in fragile x syndrome.

J Psychiatr Res 2021 02 11;134:81-88. Epub 2020 Dec 11.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94304, USA; Department of Radiology, Stanford University, Stanford, CA, 94304, USA; Department of Pediatrics, Stanford University, Stanford, CA, 94304, USA. Electronic address:

Fragile X syndrome (FXS) is the leading known inherited cause for intellectual disability. Due to mutations in the FMR1 gene, affected individuals are at risk for serious cognitive and behavioral symptoms and developmental disability. Clinical presentation varies considerably, and investigation of genetic factors not directly related to FMR1 may help better understand variability. The present study examined the BclI polymorphism of the glucocorticoid receptor gene NR3C1 in 43 individuals with FXS (28 females, age 16 to 25). Females with FXS who presented with one or more G alleles demonstrated attenuated symptoms of anxiety/depression (p = 0.038) and externalizing behaviors (p = 0.042) relative to individuals with the C/C allele. In the combined sample (males and females) structural neuroimaging data differentiated individuals with a G allele from those with the C/C genotype (p < 0.001). Key components of anxiety/fear neurocircuitry (amygdala, insula) contributed more (relative to other regions) to the model differentiating groups. These results indicate that GR polymorphisms are associated with an altered pattern of behavioral and brain development in FXS. This information is important for understanding and treating mood disorders and altered brain development among individuals with FXS. With further research, these findings could be informative for understanding anxiety and mood disorders more broadly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2020.12.015DOI Listing
February 2021

Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.

Nat Med 2020 12 28;26(12):1888-1898. Epub 2020 Sep 28.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.

22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1043-9DOI Listing
December 2020

Network Effects of the 15q13.3 Microdeletion on the Transcriptome and Epigenome in Human-Induced Neurons.

Biol Psychiatry 2021 03 1;89(5):497-509. Epub 2020 Jul 1.

Department of Genetics, School of Humanities and Science, Stanford University, Stanford, California; Department of Psychiatry and Behavioral Sciences, School of Humanities and Science, Stanford University, Stanford, California. Electronic address:

Background: The 15q13.3 microdeletion is associated with several neuropsychiatric disorders, including autism and schizophrenia. Previous association and functional studies have investigated the potential role of several genes within the deletion in neuronal dysfunction, but the molecular effects of the deletion as a whole remain largely unknown.

Methods: Induced pluripotent stem cells, from 3 patients with the 15q13.3 microdeletion and 3 control subjects, were generated and converted into induced neurons. We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. Furthermore, we measured gene expression changes in induced neurons with CRISPR (clustered regularly interspaced short palindromic repeats) knockouts of individual 15q13.3 microdeletion genes.

Results: In both induced pluripotent stem cells and induced neurons, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Furthermore, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways and gene families, including Wnt signaling, ribosome function, DNA binding, and clustered protocadherins. Individual gene knockouts mirrored many of the observed changes in an overlapping fashion between knockouts.

Conclusions: Our multiomics analysis of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders and indications of interactions between genes within the deletion. This molecular systems analysis can be applied to other chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2020.06.021DOI Listing
March 2021

The 5-HTTLPR long allele predicts two-year longitudinal increases in cortisol and declines in verbal memory in older adults.

Int J Geriatr Psychiatry 2020 09 11;35(9):982-988. Epub 2020 Jun 11.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.

Objectives: The short form or s-allele variant of the serotonin transporter polymorphism (5-HTTLPR), as compared with the long-form or l-allele variant, has been associated with the presence of cognitive dysfunction, and particularly memory impairment in older adults. This body of cross-sectional work has culminated in the hypothesis that presence of the s-allele predicts greater memory decline in older adults. Yet, to date, there are no longitudinal studies that have investigated this issue.

Methods/design: Here, we examine 109 community-dwelling older adults (mean and SD of age = 70.7 ± 8.7 years) who underwent blood draw for genotyping, cognitive, and psychological testing at baseline, 12-, and 24-monthfollow-ups.

Results: Multilevel modeling found that s-allele carriers (ss or ls) performed worse than ll homozygotes at baseline on delayed verbal recall. Yet, s-allele carriers' memory performance was stable over the two-yearfollow-up period, while l-allele homozygotes experienced significant memory decline. l-allele homozygote status was associated with both increased cortisol and decreased memory over time, resulting in attenuated verbal memory performance differences compared to s-allele carriers with age.

Conclusions: Overall, our findings do not support the hypothesis that presence of the 5-HTTLPRs-allele is a marker for memory decline in older adults. J Am Geriatr Soc 68:-, 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gps.5319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755300PMC
September 2020

Integrated functional genomic analyses of Klinefelter and Turner syndromes reveal global network effects of altered X chromosome dosage.

Proc Natl Acad Sci U S A 2020 03 18;117(9):4864-4873. Epub 2020 Feb 18.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305;

In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are down-regulated but most differentially expressed inactive genes are up-regulated. In KS, differentially expressed escape genes are up-regulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (, , , , , and ) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1910003117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060706PMC
March 2020

Sleep-wake disorders in Alzheimer's disease: further genetic analyses in relation to objective sleep measures.

Int Psychogeriatr 2020 07;32(7):807-813

Department of Veterans Affairs, Sierra-Pacific MIRECC, Palo Alto, CA, USA.

This paper presents updated analyses on the genetic associations of sleep disruption in individuals with Alzheimer's disease (AD). We published previously a study of the association between single nucleotide polymorphisms (SNPs) found in eight genes related to circadian rhythms and objective measures of sleep-wake disturbances in 124 individuals with AD. Here, we present new relevant analyses using polygenic risk scores (PRS) and variable number tandem repeats (VNTRs) enumerations. PRS were calculated using the genetic data from the original participants and relevant genome wide association studies (GWAS). VNTRs for the same circadian rhythm genes studied with SNPs were obtained from a separate cohort of participants using whole genome sequencing (WGS). Objectively (wrist actigraphy) determined wake after sleep onset (WASO) was used as a measure of sleep disruption. None of the PRS were associated with sleep disturbance. Computer analyses using VNTRseek software generated a total of 30 VNTRs for the circadian-related genes but none appear relevant to our objective sleep measure. In addition, of 71 neurotransmitter function-related genes, 29 genes had VNTRs that differed from the reference VNTR, but it was not clear if any of these might affect circadian function in AD patients. Although we have not found in either the current analyses or in our previous published analyses of SNPs any direct linkages between identified genetic factors and WASO, research in this area remains in its infancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1041610219001777DOI Listing
July 2020

Genetic and Environmental Influences on Lobar Brain Structures in Twins With Autism.

Cereb Cortex 2020 03;30(3):1946-1956

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.

This investigation examined whether the variation of cerebral structure is associated with genetic or environmental factors in children with autism spectrum disorder (ASD) compared with typically developing (TD) controls. T1-weighted magnetic resonance imaging scans were obtained from twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or both were TD. Good quality data were available from 30 ASD, 18 discordant, and 34 TD pairs (n = 164). Structural measures (volume, cortical thickness, and surface area) were generated with FreeSurfer, and ACE modeling was completed. Lobar structures were primarily genetically mediated in TD twins (a2 = 0.60-0.89), except thickness of the temporal (a2 = 0.33 [0.04, 0.63]) and occipital lobes (c2 = 0.61 [0.45, 0.77]). Lobar structures were also predominantly genetically mediated in twins with ASD (a2 = 0.70-1.00); however, thickness of the frontal (c2 = 0.81 [0.71, 0.92]), temporal (c2 = 0.77 [0.60, 0.93]), and parietal lobes (c2 = 0.87 [0.77, 0.97]), and frontal gray matter (GM) volume (c2 = 0.79 [0.63, 0.95]), were associated with environmental factors. Conversely, occipital thickness (a2 = 0.93 [0.75, 1.11]) did not exhibit the environmental contributions that were found in controls. Differences in GM volume were associated with social communication impairments for the frontal (r = 0.52 [0.18, 0.75]), temporal (r = 0.61 [0.30, 0.80]), and parietal lobes (r = 0.53 [0.19, 0.76]). To our knowledge, this is the first investigation to suggest that environmental factors influence GM to a larger extent in children with ASD, especially in the frontal lobe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhz215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444733PMC
March 2020

Genetic and environmental influences on corticostriatal circuits in twins with autism

J Psychiatry Neurosci 2020 05;45(3):188-197

From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA (Hegarty, Lazzeroni, Raman, Hallmayer, Cleveland, Phillips, Reiss, Hardan); the Department of Biomedical Data Science, Stanford University, Stanford, CA (Lazzeroni); and the Department of Anesthesiology, Stanford University, Stanford, CA (Wolke).

Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs.

Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity.

Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated.

Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors.

Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1503/jpn.190030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828974PMC
May 2020

Brain Development in School-Age and Adolescent Girls: Effects of Turner Syndrome, Estrogen Therapy, and Genomic Imprinting.

Biol Psychiatry 2020 01 9;87(2):113-122. Epub 2019 Aug 9.

Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, Stanford, California; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Department of Pediatrics, Stanford University School of Medicine, Stanford, California; Department of Radiology, Stanford University School of Medicine, Stanford, California. Electronic address:

Background: The study of Turner syndrome (TS) offers a unique window of opportunity for advancing scientific knowledge of how X chromosome gene imprinting, epigenetic factors, hormonal milieu, and chronologic age affect brain development in females.

Methods: We described brain growth trajectories in 55 girls with TS and 53 typically developing girls (258 magnetic resonance imaging datasets) spanning 5 years. Using novel nonparametric and mixed effects analytic approaches, we evaluated influences of X chromosome genomic imprinting and hormone replacement therapy on brain development.

Results: Parieto-occipital gray and white matter regions showed slower growth during typical pubertal timing in girls with TS relative to typically developing girls. In contrast, some basal ganglia, cerebellar, and limited cortical areas showed enhanced volume growth with peaks around 10 years of age.

Conclusions: The parieto-occipital finding suggests that girls with TS may be particularly vulnerable to altered brain development during adolescence. Basal ganglia regions may be relatively preserved in TS owing to their maturational growth before or early in typical pubertal years. Taken together, our findings indicate that particular brain regions are more vulnerable to TS genetic and hormonal effects during puberty. These specific alterations in neurodevelopment may be more likely to affect long-term cognitive behavioral outcomes in young girls with this common genetic condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2019.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925344PMC
January 2020

Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder.

Sci Transl Med 2019 04;11(486)

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94304, USA.

A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aal3236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980337PMC
April 2019

Beyond a Binary Classification of Sex: An Examination of Brain Sex Differentiation, Psychopathology, and Genotype.

J Am Acad Child Adolesc Psychiatry 2019 08 9;58(8):787-798. Epub 2018 Oct 9.

Stanford University, CA.

Objective: Sex differences in the brain are traditionally treated as binary. We present new evidence that a continuous measure of sex differentiation of the brain can explain sex differences in psychopathology. The degree of sex-differentiated brain features (ie, features that are more common in one sex) may predispose individuals toward sex-biased psychopathology and may also be influenced by the genome. We hypothesized that individuals with a female-biased differentiation score would have greater female-biased psychopathology (internalizing symptoms, such as anxiety and depression), whereas individuals with a male-biased differentiation score would have greater male-biased psychopathology (externalizing symptoms, such as disruptive behaviors).

Method: Using the Philadelphia Neurodevelopmental Cohort database acquired from database of Genotypes and Phenotypes, we calculated the sex differentiation measure, a continuous data-driven calculation of each individual's degree of sex-differentiating features extracted from multimodal brain imaging data (magnetic resonance imaging [MRI] /diffusion MRI) from the imaged participants (n = 866, 407 female and 459 male).

Results: In male individuals, higher differentiation scores were correlated with higher levels of externalizing symptoms (r = 0.119, p = .016). The differentiation measure reached genome-wide association study significance (p < 5∗10) in male individuals with single nucleotide polymorphisms Chromsome5:rs111161632:RASGEF1C and Chromosome19:rs75918199:GEMIN7, and in female individuals with Chromosome2:rs78372132:PARD3B and Chromosome15:rs73442006:HCN4.

Conclusion: The sex differentiation measure provides an initial topography of quantifying male and female brain features. This demonstration that the sex of the human brain can be conceptualized on a continuum has implications for both the presentation of psychopathology and the relation of the brain with genetic variants that may be associated with brain differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaac.2018.09.425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456435PMC
August 2019

Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder.

Mol Psychiatry 2020 10 18;25(10):2556-2566. Epub 2019 Jan 18.

Department of Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Road, Stanford, CA, 94305, USA.

Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n = 164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639158PMC
October 2020

Integration of neural and epigenetic contributions to posttraumatic stress symptoms: The role of hippocampal volume and glucocorticoid receptor gene methylation.

PLoS One 2018 7;13(2):e0192222. Epub 2018 Feb 7.

Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford, California, United States of America.

Many Veterans exposed to physical and psychological trauma experience symptoms of posttraumatic stress disorder (PTSD). As the etiology of PTSD symptoms is complex, a better understanding of the underlying biological mechanisms may improve preventative care and treatment for PTSD. Recent findings from the fields of neuroimaging and epigenetics offer important insights into the potential brain structures and biochemical pathways of modified gene expression associated with PTSD. We combined neuroimaging and epigenetic measures to assess current PTSD symptoms by measuring overall hippocampal volume and methylation of the glucocorticoid receptor (GR) gene (promoter region). Multiple regression analyses indicated that the hippocampal volume/GR methylation interaction was a predictor of PTSD symptoms. Our findings suggest that neuroimaging and epigenetic measures contribute interactively to PTSD symptoms. Incorporation of these metrics may aid in the identification and treatment of PTSD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802910PMC
April 2018

Corticotropin-releasing factor 1 receptor haplotype and cognitive features of major depression.

Transl Psychiatry 2018 01 10;8(1). Epub 2018 Jan 10.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, USA.

Corticotropin-releasing factor signaling through CRF receptor type 1 (CRF) has been shown to contribute to learning and memory function. A haplotype of alleles T-A-T in a set of common polymorphisms in the gene encoding for CRF (CRHR1) has been associated with both depression vulnerability and alterations in cognitive functioning. The present study investigated the relations between the TAT haplotype and specific symptoms of depression, self-reported ruminative behaviors, and neuropsychological performance on a learning and memory task. Participants were adults with major depression with and without psychotic features (N = 406). Associations were examined between TAT haplotype and endorsement of depression symptoms from diagnostic interviews, scores on the rumination response scale (RRS), and verbal memory performance on the California Verbal Learning Test-II (CVLT-II). All analyses included depression subtype, age, and sex as covariates; CVLT-II analyses also included evening cortisol levels. Across the entire sample, carriers of more copies of the TAT haplotype reported greater endorsement of the symptom describing difficulty concentrating and making decisions. In separate subsamples, TAT homozygotes had higher rumination scores on the RRS, both brooding and reflection subscales, and more TAT copies were associated with poorer CVLT-II performance in both total learning and free recall trials. These data demonstrate that the CRHR1 TAT haplotype is associated with cognitive features of depression including difficulty with decision-making, higher rumination, and poorer learning and memory. It will be important in future research to identify the specific molecular mechanisms for CRF signaling that contribute to depression-related cognitive dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-017-0051-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802461PMC
January 2018

Serotonin transporter polymorphism, depressive symptoms, and emotional impulsivity among advanced breast cancer patients.

Support Care Cancer 2018 Apr 31;26(4):1181-1188. Epub 2017 Oct 31.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd., Stanford, CA, 94305, USA.

Purpose: This study tested a theory linking a marker of low serotonergic function to both depression and impulsivity in a sample of advanced breast cancer patients, among whom elevated depressive symptoms and difficulty regulating emotions are commonly reported.

Methods: A total of 95 patients provided blood samples for serotonin transporter polymorphic region of the gene (5-HTTLPR) and completed questionnaires that measured depressive symptoms and emotional impulsivity.

Results: Structural equation modeling revealed that the s allele of 5-HTTLPR was related to greater depressive symptoms (β = .20, p < .042) but only marginally to greater emotional impulsivity (β = .19, p < .068). Depressive symptoms and emotional impulsivity were positively related (β = .33, p < .003). Further tests explored possible mediation from genotype to one psychological variable via the other. Results suggest that depressive symptoms, particularly perceived interpersonal rejection, may be a pathway linking genotype to emotional impulsivity.

Conclusions: Findings provide the first evidence that low serotonergic function contributes to both depression and impulsivity within a clinically meaningful sample. Furthermore, the link of s allele of 5-HTTLPR to emotional impulsivity was mediated by depressive symptoms, particularly perceptions of social rejection. Findings have implications for advanced breast cancer patients' treatment decision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-017-3940-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322579PMC
April 2018

A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2018 Feb 21;81:153-160. Epub 2017 Sep 21.

Department of Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Road, Stanford, CA 94305, USA.

Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2017.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731458PMC
February 2018

Anomalous prefrontal-limbic activation and connectivity in youth at high-risk for bipolar disorder.

J Affect Disord 2017 11 23;222:7-13. Epub 2017 Jun 23.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States; Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, United States.

Objective: Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD.

Methods: We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene.

Results: While viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortex CONCLUSIONS: Similar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2017.05.051DOI Listing
November 2017

Assembly of functionally integrated human forebrain spheroids.

Nature 2017 05 26;545(7652):54-59. Epub 2017 Apr 26.

Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature22330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805137PMC
May 2017

Sleep Disturbances in Individuals With Phelan-McDermid Syndrome: Correlation With Caregivers' Sleep Quality and Daytime Functioning.

Sleep 2017 Feb;40(2)

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.

Study Objectives: The aims of this study were to document sleep disturbances in individuals with Phelan-McDermid syndrome (PMS), to assess whether these individuals had been evaluated for sleep disorders, and to examine relationships between the sleep behavior of these individuals and the sleep behavior and daytime functioning of their caregivers.

Methods: Participants were 193 caregivers of individuals with PMS recruited by the Phelan-McDermid Syndrome Foundation. Data were collected through a survey comprising 2 questionnaires: the Children's Sleep Habits Questionnaire (CSHQ) and the Parents' Sleep Habits Questionnaire. Data were analyzed using multiple linear regression analyses, Pearson correlation analyses, and independent-samples t-tests.

Results: Ninety percent of individuals with PMS showed evidence of marked sleep disturbance based on caregiver responses to the CSHQ. However, only 22% of individuals had undergone a formal sleep assessment. Reported increased sleep disturbance in individuals with PMS was a statistically significant predictor of reported increased sleep disturbance and daytime sleepiness in their caregivers.

Conclusions: Sleep disturbance may be present in a substantial proportion of individuals with PMS and is negatively associated with caregivers' well-being. However, most individuals with PMS have not been evaluated for sleep disorders. When properly diagnosed, many sleep disorders can be alleviated with intervention. Thus, routine screening for and evaluation of sleep disturbances in individuals with PMS may have long-term positive impacts on the well-being of these individuals and their caregivers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsw062DOI Listing
February 2017

Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome).

J Psychiatr Res 2017 08 16;91:139-144. Epub 2017 Mar 16.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Purpose: To describe the frequency and characteristics of developmental regression in a sample of 50 patients with Phelan McDermid Syndrome (PMS) and investigate the possibility of association between regression, epilepsy, and electroencephalogram (EEG) abnormalities and deletion size.

Methods: The Autism Diagnostic Interview-Revised (ADI-R) was used to evaluate regression in patients with a confirmed diagnosis of PMS. Information on seizure history and EEGs was obtained from medical record review. Deletion size was determined by DNA microarray.

Results: A history of regression at any age was present in 43% of all patients. Among those exhibiting regression, 67% had onset after the age of 30 months, affecting primarily motor and self-help skills. In 63% of all patients there was a history of seizures and a history of abnormal EEG was also present in 71%. No significant associations were found between regression and seizures or EEG abnormalities. Deletion size was significantly associated with EEG abnormalities, but not with regression or seizures.

Conclusion: This study found a high rate of regression in PMS. In contrast to regression in autism, that often occurs earlier in development and affects language and social skills, we found regression in PMS most frequently has an onset in mid-childhood, affecting motor and self-help skills. We also found high rates of seizures and abnormal EEGs in patients with PMS. However, a history of abnormal EEG and seizures was not associated with an increased risk of regression. Larger deletion sizes were found to be significantly associated with a history of abnormal EEG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2017.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469716PMC
August 2017

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.

Nat Neurosci 2017 Apr 6;20(4):602-611. Epub 2017 Mar 6.

The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nn.4524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501701PMC
April 2017

Autism genetics: opportunities and challenges for clinical translation.

Nat Rev Genet 2017 06 6;18(6):362-376. Epub 2017 Mar 6.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, California 94305, USA.

Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are highly variable, and they are frequently related to other conditions besides autism. However, many different variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics. Although this advancing insight should improve clinical care, at present there is a substantial discrepancy between research knowledge and its clinical application. In this Review, we discuss the current challenges and opportunities for the translation of autism genetics knowledge into clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrg.2017.4DOI Listing
June 2017

Incidental brain MRI findings in an autism twin study.

Autism Res 2017 Jan 22;10(1):113-120. Epub 2016 Nov 22.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.

Brain magnetic resonance imaging (MRI) studies suggest the prevalence of asymptomatic "incidental" findings (IF) in autism spectrum disorder (ASD) is similar to that of neurotypically developing (NT) controls. However, given the causes of IF may include both genetic and environmental factors, a twin study would facilitate comparing brain IF between ASD and NT subjects. MRI scans were examined to assess the prevalence of brain IF in twin "case pairs" (at least one twin with diagnosis of ASD) and twin "control pairs" (NT). Fifty case pairs and thirty-two control pairs were analyzed. IF were found in 68% of subjects with ASD, 71% of unaffected ASD siblings, and in 58% of control subjects (P = 0.4). IF requiring clinical follow-up occurred more frequently in subjects with ASD compared to NT controls (17% vs. 5%, respectively; P = 0.02). The concordance rate of IF in twins was 83%. A mixed effects model found younger age, male sex, and "family environment" to be significantly associated with IF. There was no difference in the prevalence rate of IF between ASD subjects and NT controls. More IF required clinical follow-up in ASD subjects compared to NT controls. The prevalence rate of IF observed in this twin study was higher than rates previously reported in singleton studies. Our results suggest the shared environment of twins - perhaps in utero - increases the risk of brain IF. Brain MRI in the initial work-up of ASD may be indicated in twins, especially in males. Autism Res 2017, 10: 113-120. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/aur.1720DOI Listing
January 2017

A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients.

Elife 2016 07 26;5. Epub 2016 Jul 26.

Novartis Institutes for BioMedical Research, Cambridge, United States.

Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.13073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961470PMC
July 2016

Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders.

Cell Syst 2015 Nov;1(5):361-374

Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA.

The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 causal for Fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cels.2015.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776331PMC
November 2015

Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography.

J Clin Sleep Med 2016 Mar;12(3):357-62

Stanford University Department of Psychiatry and Behavioral Sciences, Stanford, CA.

Study Objectives: Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.

Methods: One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.

Results: PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).

Conclusions: Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5664/jcsm.5584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773615PMC
March 2016

Association of Anxiety Symptoms in Offspring of Bipolar Parents with Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype.

J Child Adolesc Psychopharmacol 2015 Aug 28;25(6):458-66. Epub 2015 Jul 28.

2 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine , Stanford, California.

Objective: Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status.

Methods: A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC).

Results: Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group.

Conclusions: This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cap.2014.0115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545526PMC
August 2015

Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Mol Syst Biol 2014 Dec 30;10:774. Epub 2014 Dec 30.

Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA

Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300495PMC
http://dx.doi.org/10.15252/msb.20145487DOI Listing
December 2014