Joachim Hallmayer

Stanford University, Palo Alto, California, United States

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Publications (207)1480.71 Total impact

  • No preview · Article · Nov 2015
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    ABSTRACT: Polysomnography (PSG) is the gold standard for the assessment of sleep, and provides valuable information for researchers and clinicians alike. However, 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. A protocol using ambulatory PSG and systematic desensitization is described that was developed to study sleep in individuals with autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). Using this procedure, PSG was successfully attained in 144 subjects (89.4%). Individuals with ASD were equally able to obtain successful PSG; however, they did take significantly longer to desensitize to the equipment than DD or TD subjects. Age, sex, IQ, and tactile sensitivity did not predict the duration of time required for successful desensitization. Clinicians and researchers might consider use of a similar protocol to facilitate future sleep investigations.
    No preview · Article · Nov 2015 · Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine
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    A Garrett · S Gupta · A L Reiss · J Waring · K Sudheimer · L Anker · N Sosa · J F Hallmayer · R O'Hara
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    ABSTRACT: Studies have shown that a functional polymorphism of the serotonin transporter gene (5-HTTLPR) impacts performance on memory-related tasks and the hippocampal structures that subserve these tasks. The short (s) allele of 5-HTTLPR has been linked to greater susceptibility for impaired memory and smaller hippocampal volume compared to the long allele (l). However, previous studies have not examined the associations between 5-HTTLPR allele and activation in subregions of the hippocampus. In this study, we used functional magnetic resonance imaging (fMRI) to measure activation in hippocampal and temporal lobe subregions in 36 elderly non-clinical participants performing a face-name encoding and recognition task. Although there were no significant differences in task performance between s allele carriers and l homozygotes, right CA1 and right parahippocampal activation during recognition errors was significantly greater in individuals bearing the s allele. In an exploratory analysis, we determined that these effects were more pronounced in s allele carriers with the apolipoprotein ɛ4 allele. Our results suggest that older individuals with the s allele inefficiently allocate neural resources while making errors in recognizing face-name associations, which could negatively impact memory performance during more challenging tasks.
    Full-text · Article · Sep 2015 · Translational Psychiatry
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    ABSTRACT: 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. 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). 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. 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.
    No preview · Article · Jul 2015 · Journal of child and adolescent psychopharmacology
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    Full-text · Article · Feb 2015
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    ABSTRACT: Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jan 2015 · The American Journal of Human Genetics
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    C O'Dushlaine · L Rossin · PH Lee · L Duncan · NN Parikshak · S Newhouse · S Ripke · BM Neale · SM Purcell · D Posthuma · [...] · N Craddock · KS Kendler · LA Weiss · NR Wray · Z Zhao · DH Geschwind · PF Sullivan · JW Smoller · PA Holmans · G Breen ·
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    ABSTRACT: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
    Full-text · Article · Jan 2015
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    ABSTRACT: 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.
    Full-text · Article · Dec 2014 · Molecular Systems Biology
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    ABSTRACT: Several genetic and environmental factors place youth offspring of parents with bipolar disorder (BD) at high risk for developing mood and anxiety disorders. Recent studies suggest that anxiety symptoms, even at subclinical levels, have been associated with an increased risk for developing BD. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the pathophysiology of both BD and anxiety disorders. We aimed to explore whether anxiety in BD offspring was associated with the BDNF Val66Met polymorphism. 64 BD offspring (mean age: 13.73 (S.D. 3.45) M = 30, F = 34) and 51 HC (mean age: 13.68 (S.D. 2.68) M = 23, F = 28) were compared on presence of the met allele and on scores from the Multidimensional Anxiety Scale for Children (MASC). To assess family function, we used the Family Adaptability and Cohesion Evaluation Scales (FACES-IV). The Baron & Kenny method was the statistical approach used to examine the moderating effects between variables. BD offspring showed higher levels of overall anxiety than did the HC group. BD offspring with the val/val genotype showed higher levels of anxiety than BD offspring with other genotypes. No significant levels of anxiety or its association with BDNF genotype were found in the HC group. BD offspring group showed significantly more family dysfunction when compared with the HC group and the family dysfunction moderated the association between the BDNF genotype and anxiety symptoms. This study demonstrated the potential interplay of three factors: BD offspring, anxiety symptoms and family dysfunction. Copyright © 2014 Elsevier Ltd. All rights reserved.
    No preview · Article · Nov 2014 · Journal of Psychiatric Research
  • Ruth O’Hara · Joachim Hallmayer

    No preview · Article · Oct 2014 · American Journal of Geriatric Psychiatry
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    ABSTRACT: A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and anomalous levels of cortisol secretion in this relation. Despite these associations, no study has assessed telomere length or its relation with HPA-axis activity in individuals at risk for depression, before the onset of disorder. In the present study, we assessed cortisol levels in response to a laboratory stressor and telomere length in 97 healthy young daughters of mothers either with recurrent episodes of depression (i.e., daughters at familial risk for depression) or with no history of psychopathology. We found that daughters of depressed mothers had shorter telomeres than did daughters of never-depressed mothers and, further, that shorter telomeres were associated with greater cortisol reactivity to stress. This study is the first to demonstrate that children at familial risk of developing MDD are characterized by accelerated biological aging, operationalized as shortened telomere length, before they had experienced an onset of depression; this may predispose them to develop not only MDD but also other age-related medical illnesses. It is critical, therefore, that we attempt to identify and distinguish genetic and environmental mechanisms that contribute to telomere shortening.Molecular Psychiatry advance online publication, 30 September 2014; doi:10.1038/mp.2014.119.
    Full-text · Article · Sep 2014 · Molecular Psychiatry
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    ABSTRACT: The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.
    No preview · Article · Aug 2014 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.
    Full-text · Article · Jul 2014 · Frontiers in Aging Neuroscience
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    ABSTRACT: Introduction: Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently. Methods: Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed. Results: Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74). Conclusions: Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.
    No preview · Article · Jul 2014 · Journal of Psychiatric Research
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    ABSTRACT: Background There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. Methods In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Results Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). Conclusions TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
    Full-text · Article · May 2014 · Molecular Autism
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    ABSTRACT: Background: Phelan-McDermid Syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of Autism Spectrum Disorders (ASDs). PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. Objectives: To investigate cellular and molecular phenotypes associated with PMDS in human neurons. Methods: We generated induced pluripotent stem cells (iPSCs) from individuals with PMDS and autism and used them to produce functional neurons. We then use elctrophysiology, biochemistry, and molecular biology to characterize the properties of iPSC-derived neurons. Results: We show that PMDS neurons have reduced Shank3 expression and major defects in excitatory but not inhibitory synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring Shank3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of excitatory synapses that lack Shank3 but contain PSD95 and NMDA receptors with fast deactivation kinetics. Conclusions: Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it.
    Full-text · Conference Paper · May 2014
  • N. T. Bott · J. Phillips · J. F. Hallmayer · S. Cleveland · A. Y. Hardan
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    ABSTRACT: Background: Autism is a highly heritable neurodevelopmental disorder. Previous studies have found sub-threshold social impairments in siblings of children with ASD, as well as in unaffected twins. Objectives: The primary aim of this investigation was to examine the intellectual and social cognitive functioning of monozygotic and dizygotic twins with ASD, with at least one affected twin. This was part of a larger study examining the behavioral and neural correlates of twins with ASD, their siblings, and neurotypical twin pairs. Methods: Monozygotic and dizygotic same-sex twins with ASD, and age-, gender- matched neurotypical twins between the ages of 6 and 14 years were included. Intellectual functioning was assessed using the Stanford-Binet Intelligence Scales (SB5). Social abilities were assessed using the Social Responsiveness Scale (SRS), the Theory of Mind (ToM) and Affect Recognition (AR) Social Perception subtests of the NEPSY-II, as well as a reading the mind in the eyes (Eyes) task, and a Theory of Mind (Smarties) task. Results: A total of 92 participants were included in this investigation: 24 monozygotic with ASD, 40 dizygotic, and 28 neurotypical twins (12 MZ, and 16 DZ). There was no significant difference in age or gender between groups. Difference scores (Δ= Most severe – least affected) on intellectual and social cognitive measures were compared between MZ and DZ neurotypical pairs. As expected, a significant difference was found on the Δ score between monozygotic and dizygotic ASD twin pairs on the SRS total T-score with a trend toward significance on FSIQ score. When comparing the most severe proband between monozygotic and dizygotic twins, there were no significant differences on intellectual abilities or social cognitive functioning measures. The least severely affected MZ probands performed significantly better than the most severely affected DZ probands on both affect recognition tasks (AR and Eyes). Conclusions: Findings from this study suggest that the most severe probands of MZ and DZ twin pairs do not differ significantly from one another on several clinical measures. Interestingly, the least severely affected MZ probands perform better on measures of affect recognition than the most severely affected DZ probands, raising the question of whether aspects of affect recognition are less heritable. This observation is intriguing, but final conclusions cannot be made in light of the small sample size. These preliminary findings warrant additional investigation to comprehensively examine all aspects of intellectual and social cognition in monozygotic and dizygotic twins with autism of all ages.
    No preview · Conference Paper · May 2014
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    ABSTRACT: Background: Using proton magnetic resonance spectroscopy (1H MRS) to examine a variety of brain metabolites in twins provides an opportunity to assess the contributions of genetic inheritance, disease state, as well as confounding factors while controlling for metabolite variability in the population. The present ongoing study looks to elucidate relationships between 1H MRS metabolite levels and clinical features across a cohort of same-sex twin pairs with autism and high variability in disease severity. Objectives: 1) To explore differences and similarities among different brain metabolites in MZ and DZ twins, where at least one sibling serves as a proband with autism, and 2) To evaluate the relationship between clinical features and reliably calculated metabolite levels. Methods: The study aims to recruit 120 same-sex twin pairs, 80 with at least one pair with autism, 40 monozygotic (MZ) and 40 dizygotic (DZ), and 40 typically developing twin pair controls, 20 MZ and 20 DZ. High- resolution MRI and 1H MRS imaging scans are being obtained from all participants. Behavior and cognition are also being assessed to provide specific covariates for neuroimaging variables. Results: In this preliminary examination, data from 45 twin pairs were analyzed (age range: 6-15 yrs; Mean 11.04 years ± SD 3.23). Correlations between clinical measures of social abilities and repetitive/restricted behaviors and differences in N Acetyl Aspartate/Creatine levels between twin pairs were examined and several associations were observed including relationships in caudate and putamen with measures of rigidity/restricted behaviors and social cognition, respectively. Among the present findings, our investigation has found lower levels of NAA correlated with symptoms such as repetitive behaviors (Left Putamen NAA/Cre vs total RBS-R score, 95% CI -0.001 : -0.03), sensory abnormalities (Left Caudate NAA/Cre vs SPQ total, 95% CI -0.001 : -0.03), affect recognition (Right Putamen NAA/Cre vs NEPSY AR raw score, 95% CI 0.02 : 0.41), and social responsiveness (Right Thalamus GCP+PCh/Cre vs SRS raw score, 95% CI 0.01 : 0.98). Conclusions: Findings from this preliminary analysis indicate a relationship in autism between brain metabolites and behavior. These observations appear to be consistent with previous reports. Further analyses including more twin pairs will help further current knowledge metabolite abnormalities and neuroanatomic pathways implicated in autism.
    No preview · Conference Paper · May 2014
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    ABSTRACT: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
    Full-text · Article · Apr 2014 · The American Journal of Human Genetics
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    ABSTRACT: RationaleA functional polymorphism of the serotonin transporter gene (5-HTTLPR) has previously been related to upper airway pathology, but its contribution to obstructive sleep apnea (OSA), a highly prevalent sleep disorder in older adults, remains unclear. Objectives We aimed to investigate the relationship between apnea-hypopnea index (AHI) and genetic variations in the promoter region of the 5-HTTLPR in older adults. MethodsDNA samples from 94 community-dwelling older adults (57% female, mean age 728) were genotyped for the 5-HTTLPR polymorphism. All participants were assessed in their homes with full ambulatory polysomnography in order to determine AHI and related parameters such as hypoxia, sleep fragmentation, and self-reported daytime sleepiness. ResultsThe 5-HTT l allele was significantly associated with AHI (p=0.019), with l allele carriers displaying a higher AHI than s allele homozygotes. A single allele change in 5-HTTLPR genotype from s to l resulted in an increase of AHI by 4.46 per hour of sleep (95% CI, 0.75-8.17). The l allele was also associated with increased time during sleep spent at oxygen saturation levels below 90% (p=0.014). Conclusions The observed significant association between the 5-HTTLPR l allele and severity of OSA in older adults suggests that the l allele may be important to consider when assessing for OSA in this age group. This association may also explain some of the observed variability among serotonergic pharmacological treatment studies for OSA, and 5-HTT genotype status may have to be taken into account in future therapeutic trials involving serotonergic agents. Copyright (c) 2013 John Wiley & Sons, Ltd.
    No preview · Article · Mar 2014 · International Journal of Geriatric Psychiatry

Publication Stats

12k Citations
1,480.71 Total Impact Points


  • 1994-2015
    • Stanford University
      • • Department of Psychiatry and Behavioral Sciences
      • • Division of Child and Adolescent Psychiatry
      • • Department of Computer Science
      • • Department of Medicine
      • • Department of Genetics
      Palo Alto, California, United States
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1994-2014
    • Stanford Medicine
      • • Department of Psychiatry and Behavioral Sciences
      • • Division of Child and Adolescent Psychiatry and Child Development
      Stanford, California, United States
  • 2011
    • University of California, San Diego
      • Department of Psychiatry
      San Diego, California, United States
  • 2010
    • University of Miami
      • Department of Psychiatry and Behavioral Sciences
      كورال غيبلز، فلوريدا, Florida, United States
  • 1996-2008
    • University of Western Australia
      • • Centre for Clinical Research in Neuropsychiatry
      • • School of Psychiatry and Clinical Neurosciences
      • • Centre for Water Research
      Perth, Western Australia, Australia
    • Edith Cowan University
      Joondalup, Western Australia, Australia
  • 2002
    • Palo Alto University
      Palo Alto, California, United States
  • 1998-2000
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 1997-2000
    • University of Bonn
      • Institute of Human Genetics
      Bonn, North Rhine-Westphalia, Germany
  • 1999
    • Hollywood Private Hospital
      Perth City, Western Australia, Australia
  • 1991-1995
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany