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1.  Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders 
European Journal of Human Genetics  2011;19(10):1082-1089.
Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.
doi:10.1038/ejhg.2011.75
PMCID: PMC3190264  PMID: 21522181
autism; genome-wide association analysis; pathway analysis; family-based association test; gene ontology
2.  Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism 
Molecular Autism  2014;5:17.
Background
While most neuropathologic studies focus on regions involved in behavioral abnormalities in autism, it is also important to identify whether areas that appear functionally normal are devoid of pathologic alterations. In this study we analyzed the posteroinferior occipitotemporal gyrus, an extrastriate area not considered to be affected in autism. This area borders the fusiform gyrus, which is known to exhibit functional and cellular abnormalities in autism.
Findings
No studies have implicated posteroinferior occipitotemporal gyrus dysfunction in autism, leading us to hypothesize that neuropathology would not occur in this area. We indeed observed no significant differences in pyramidal neuron number or size in layers III, V, and VI in seven pairs of autism and controls.
Conclusions
These findings are consistent with the hypothesis that neuropathology is unique to areas involved in stereotypies and social and emotional behaviors, and support the specificity of the localization of pathology in the fusiform gyrus.
doi:10.1186/2040-2392-5-17
PMCID: PMC3938306  PMID: 24564936
Autism; Fusiform gyrus; Neuropathology; Posteroinferior occipitotemporal gyrus; Stereology
3.  Network- and Attribute-Based Classifiers Can Prioritize Genes and Pathways for Autism Spectrum Disorders and for Intellectual Disability 
Autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders with significant combined prevalence (~1%) and high heritability. Dozens of individually rare genes and loci associated with high-risk for ASD have been identified, which overlap extensively with genes for intellectual disability (ID). However, studies indicate that there may be hundreds of genes that remain to be identified. The advent of inexpensive massively parallel nucleotide sequencing can reveal the genetic underpinnings of heritable complex diseases, including ASD and ID. However, whole exome sequencing (WES) and whole genome sequencing (WGS) provides an embarrassment of riches, where many candidate variants emerge. It has been argued that genetic variation for ASD and ID will cluster in genes involved in distinct pathways and protein complexes. For this reason, computational methods that prioritize candidate genes based on additional functional information such as protein-protein interactions or association with specific canonical or empirical pathways, or other attributes, can be useful. In this study we applied several supervised learning approaches to prioritize ASD or ID disease gene candidates based on curated lists of known ASD and ID disease genes. We implemented two network-based classifiers and one attribute-based classifier to show that we can rank and classify known, and predict new, genes for these neurodevelopmental disorders. We also show that ID and ASD share common pathways that perturb an overlapping synaptic regulatory subnetwork. We also show that features relating to neuronal phenotypes in mouse knockouts can help in classifying neurodevelopmental genes. Our methods can be applied broadly to other diseases helping in prioritizing newly identified genetic variation that emerge from disease gene discovery based on WES and WGS.
doi:10.1002/ajmg.c.31330
PMCID: PMC3505691  PMID: 22499558
High-throughput sequencing; massively parallel sequencing; gene discovery; networks; pathways; neurodevelopmental disorders; classifiers; support vector machine
5.  Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia 
Progress in neurobiology  2010;93(1):13-24.
Multiple lines of evidence in schizophrenia, from brain imaging, studies in postmortem brains, and genetic association studies, have implicated oligodendrocyte and myelin dysfunction in this disease. Recent studies suggest that oligodendrocyte and myelin dysfunction leads to changes in synaptic formation and function, which could lead to cognitive dysfunction, a core symptom of schizophrenia. Furthermore, there is accumulating data linking oligodendrocyte and myelin dysfunction with dopamine and glutamate abnormalities, both of which are found in schizophrenia. These findings implicate oligodendrocyte and myelin dysfunction as a primary change in schizophrenia, not only as secondary consequences of the illness or treatment. Strategies targeting oligodendrocyte and myelin abnormalities could therefore provide therapeutic opportunities for patients suffering from schizophrenia.
doi:10.1016/j.pneurobio.2010.09.004
PMCID: PMC3622281  PMID: 20950668
myelin; gene expression; genetic association; brain imaging; oligodendrocyte; synaptic plasticity; dopamine; glutamate
6.  Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution 
Nature genetics  2013;45(4):415-421e2.
Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ~500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms.
doi:10.1038/ng.2568
PMCID: PMC3709584  PMID: 23435085
7.  Epigenetic Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD 
Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of “environmental regulation” that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively.
doi:10.3389/fpsyt.2013.00118
PMCID: PMC3784793  PMID: 24098286
PTSD; veterans; epigenetics; methylation; promoter; glucocorticoid receptor; FK506 binding protein 5; psychotherapy
8.  SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders 
Molecular Autism  2013;4:17.
Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome appears to be one of the more penetrant causes of ASD. In this companion review, we show that in samples ascertained for ASD, SHANK3 haploinsufficiency is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. We note that SHANK3 haploinsufficiency remains underdiagnosed in ASD and developmental delay, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise.
doi:10.1186/2040-2392-4-17
PMCID: PMC3695795  PMID: 23758743
9.  Network Topologies and Convergent Aetiologies Arising from Deletions and Duplications Observed in Individuals with Autism 
PLoS Genetics  2013;9(6):e1003523.
Autism Spectrum Disorders (ASD) are highly heritable and characterised by impairments in social interaction and communication, and restricted and repetitive behaviours. Considering four sets of de novo copy number variants (CNVs) identified in 181 individuals with autism and exploiting mouse functional genomics and known protein-protein interactions, we identified a large and significantly interconnected interaction network. This network contains 187 genes affected by CNVs drawn from 45% of the patients we considered and 22 genes previously implicated in ASD, of which 192 form a single interconnected cluster. On average, those patients with copy number changed genes from this network possess changes in 3 network genes, suggesting that epistasis mediated through the network is extensive. Correspondingly, genes that are highly connected within the network, and thus whose copy number change is predicted by the network to be more phenotypically consequential, are significantly enriched among patients that possess only a single ASD-associated network copy number changed gene (p = 0.002). Strikingly, deleted or disrupted genes from the network are significantly enriched in GO-annotated positive regulators (2.3-fold enrichment, corrected p = 2×10−5), whereas duplicated genes are significantly enriched in GO-annotated negative regulators (2.2-fold enrichment, corrected p = 0.005). The direction of copy change is highly informative in the context of the network, providing the means through which perturbations arising from distinct deletions or duplications can yield a common outcome. These findings reveal an extensive ASD-associated molecular network, whose topology indicates ASD-relevant mutational deleteriousness and that mechanistically details how convergent aetiologies can result extensively from CNVs affecting pathways causally implicated in ASD.
Author Summary
Autism Spectrum Disorders (ASD) are characterised by impairments in social interaction and communication, and restricted and repetitive behaviours. ASD are highly heritable and many different stretches of DNA have been found to be duplicated or deleted in individuals with ASD. We found that an unusually high number of genes affected by these DNA deletions/duplications are associated with the functioning of synaptic transmission between nerve cells. The proteins made by many of these genes are known to interact with each other and, together with proteins from other deleted/duplicated genes, form a large interlinked biological network. This network was affected by almost 50% of the deletions/duplications in the ASD patients considered. Many individual ASD patients had deletions or duplications of multiple genes within this network, but for those patients with just a single gene from the network changed, that single gene appeared to play an important role. Furthermore, the network predicts that the effects arising from the genes in the deletions are similar to the effects arising from the genes in the duplications. Thus, the way that this ASD-associated network is wired together contributes to the understanding of the impact of these DNA deletions and duplications.
doi:10.1371/journal.pgen.1003523
PMCID: PMC3675007  PMID: 23754953
10.  DSM-5: the debate continues 
Molecular Autism  2013;4:11.
We are fortunate to have invited commentaries from the laboratories of Dr Cathy Lord and Dr Fred Volkmar offering their perspectives on the new Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for the autism spectrum. Both commentaries note how DSM-5 collapses the earlier diagnostic categories of the pervasive developmental disorders into a single category of autism spectrum disorder. In addition, DSM-5 collapses social and communication domains into a single combined domain. The commentaries go on to discuss the positive aspects of these changes and raise some areas of potential concern. We support the evidence-based changes to autism diagnosis found in DSM-5, and look forward to further studies on the autism phenotype as this has implications for diagnosis and treatment. As our mechanistic understanding of autism improves, diagnoses based on behavioral parameters will continue to provide opportunities for interventions targeting the behaviors, while etiological diagnoses will provide opportunities for interventions tailored to etiology.
doi:10.1186/2040-2392-4-11
PMCID: PMC3672020  PMID: 23676181
11.  Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay 
Molecular Autism  2013;4:9.
Background
Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions. Therapeutic approaches that reverse deficits in SHANK3-haploinsufficiency may therefore be broadly beneficial in ASD and in developmental delay.
Findings
We observed that daily intraperitoneal injections of human insulin-like growth factor 1 (IGF-1) over a 2-week period reversed deficits in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling, long-term potentiation (LTP), and motor performance that we had previously reported in Shank3-deficient mice. Positive effects were observed with an IGF-1 peptide derivative as well.
Conclusions
We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology. Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD.
doi:10.1186/2040-2392-4-9
PMCID: PMC3649942  PMID: 23621888
Pharmacotherapy; Personalized medicine; Individualized medicine; 22q13 deletion syndrome; Phelan-McDermid syndrome
12.  A macromolecular complex involving the amyloid precursor protein (APP) and the cytosolic adapter FE65 is a negative regulator of axon branching 
Several studies suggest a role for the amyloid precursor protein (APP) in neurite outgrowth and synaptogenesis, but the downstream interactions that mediate the function of APP during neuron development are unknown. By introducing interaction-deficient FE65 into cultured hippocampal neurons using adenovirus, we show that a complex including APP, FE65 and an additional protein is involved in neurite outgrowth at early stages of neuronal development. Both FE65 that is unable to interact with APP (PID2 mutants) or a WW mutant increased axon branching. Although the FE65 mutants did not affect total neurite output, both mutants decreased axon segment length, consistent with an overall slowing of axonal growth cones. FE65 mutants did not alter the localization of either APP or FE65 in axonal growth cones, suggesting that the effects on neurite outgrowth are achieved by alterations in local complex formation within the axonal growth cone.
doi:10.1016/j.mcn.2007.02.003
PMCID: PMC3622246  PMID: 17383198
Alzheimer’s disease; APP; FE65; Mena; Neurite outgrowth; Branching
13.  AnnTools: a comprehensive and versatile annotation toolkit for genomic variants 
Bioinformatics  2012;28(5):724-725.
Summary: AnnTools is a versatile bioinformatics application designed for comprehensive annotation of a full spectrum of human genome variation: novel and known single-nucleotide substitutions (SNP/SNV), short insertions/deletions (INDEL) and structural variants/copy number variation (SV/CNV). The variants are interpreted by interrogating data compiled from 15 constantly updated sources. In addition to detailed functional characterization of the coding variants, AnnTools searches for overlaps with regulatory elements, disease/trait associated loci, known segmental duplications and artifact prone regions, thereby offering an integrated and comprehensive analysis of genomic data. The tool conveniently accepts user-provided tracks for custom annotation and offers flexibility in input data formats. The output is generated in the universal Variant Call Format. High annotation speed makes AnnTools suitable for high-throughput sequencing facilities, while a low-memory footprint and modest CPU requirements allow it to operate on a personal computer. The application is freely available for public use; the package includes installation scripts and a set of helper tools.
Availability: http://anntools.sourceforge.net/
Contact: vladimir.makarov@mssm.edu; chris.yoon@mssm.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts032
PMCID: PMC3289923  PMID: 22257670
14.  Reduced Excitatory Neurotransmission and Mild Autism-Relevant Phenotypes in Adolescent Shank3 Null Mutant Mice 
The Journal of Neuroscience  2012;32(19):6525-6541.
Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms.
doi:10.1523/JNEUROSCI.6107-11.2012
PMCID: PMC3362928  PMID: 22573675
SH3 and multiple ankyrin repeat domains 3; SHANK3; PROSAP2; Phelan-McDermid Syndrome; autism; mouse models; three-chambered social approach task; ultrasonic; vocalizations
15.  Loss of function studies in mice and genetic association link receptor protein tyrosine phosphatase α to schizophrenia 
Biological psychiatry  2011;70(7):626-635.
Background
Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness.
Methods
We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (2 independent cohorts; total of 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases)
Results
We find that Ptpra−/− mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to metamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in post mortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in post mortem dorsolateral prefrontal cortex of subjects with SZ.
Conclusion
The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.
doi:10.1016/j.biopsych.2011.06.016
PMCID: PMC3176920  PMID: 21831360
schizophrenia; tyrosine phosphatase; myelination; mouse model; RPTPα; PTPRA
16.  Mutation Screening of the PTEN Gene in Patients With Autism Spectrum Disorders and Macrocephaly 
American Journal of Medical Genetics  2007;144B(4):484-491.
Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Lhermitte–Duclos disease. In addition, PTENmutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as ≥2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte–Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.
doi:10.1002/ajmg.b.30493
PMCID: PMC3381648  PMID: 17427195
Cowden syndrome; Bannayan–Riley–Ruvalcaba syndrome; polydactyly; sequence analysis; multiplex ligation-dependent probe amplification
17.  In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism 
Brain research  2010;1380:198-205.
Attentional dysfunction is one of the most consistent findings in individuals with autism spectrum disorders (ASD). However, the significance of such findings for the pathophysiology of autism is unclear. In this study, we investigated cellular neurochemistry with proton magnetic resonance spectroscopy imaging (1H-MRS) in brain regions associated with networks subserving alerting, orienting, and executive control of attention in patients with ASD. Concentrations of cerebral N-acetyl-aspartate (NAA), creatinine + phosphocreatinine, choline-containing compounds, myo-inositol (Ins) and glutamate + glutamine (Glx) were determined by 3 T 1H-MRS examinations in 14 high-functioning medication-free adults with a diagnosis of ASD and 14 age- and IQ-matched healthy controls (HC) in the anterior cingulate cortex (ACC), thalamus, temporoparietal junction (TPJ), and areas near or along the intraparietal sulcus (IPS). Compared to HC group, the ASD group showed significantly lower Glx concentrations in right ACC and reduced Ins in left TPJ. This study provides evidence of abnormalities in neurotransmission related to networks subserving executive control and alerting of attention, functions which have been previously implicated in ASD pathogenesis.
doi:10.1016/j.brainres.2010.12.057
PMCID: PMC3073642  PMID: 21185269
autism; spectroscopy; glutamate; anterior cingulate cortex; intraparietal sulcus; myo-inositol
18.  APOE Genotype Results in Differential Effects on the Peripheral Clearance of Amyloid-β42 in APOE Knock-in and Knock-out Mice 
Journal of Alzheimer's Disease  2010;21(2):403-409.
The ε4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer’s disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-β (Aβ) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE−/− mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic Aβ42 in APOE ε2, ε3, and ε4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does influence the rate at which the mice are able to clear Aβ42 from their bloodstream. Both APOE ε4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Aβ42 over time compared to APOE ε2/APOE knock-out rE2 and APOE ε3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Aβ42 is significantly altered by APOE genotype. Given that APOE ε4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Aβ which may impact on clearance from the brain.
doi:10.3233/JAD-2010-100141
PMCID: PMC3292909  PMID: 20555142
Alzheimer’s disease; amyloid-β; APOE genotype; peripheral sink hypothesis
19.  Optimizing the phenotyping of rodent ASD models: enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features 
Molecular Autism  2012;3:1.
Background
There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitutes useful phenotypes in ASD models.
Methods
To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes.
Findings
We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1) Changes in brain and neuronal morphology; (2) electrophysiological changes; (3) neurological changes; and (4) higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms.
Conclusions
The results indicated that mutations in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD.
doi:10.1186/2040-2392-3-1
PMCID: PMC3337792  PMID: 22348382
Systems biology; mouse behavior; autism; autism spectrum disorders; genetically modified mice; forward genetics; reverse genetics
20.  PCDH11X variation is not associated with late-onset Alzheimer disease susceptibility 
Psychiatric genetics  2010;20(6):321-324.
SUMMARY
A recent genome-wide association study and follow-up shows significant association with the protocadherin 11 X-linked (PCDH11X) gene. Carrasquillo et al. (2009) show statistical association with four PCDH11X polymorphisms (rs5984894, rs2573905, rs5941047, rs4568761) in five of seven cohorts. The combined analysis of 2,356 cases and 2,384 controls showed the strongest association with a p-value of 2.2 × 10-7 with an allele specific odds ratio of 1.30 (95% CI, 1.18–1.43) at the rs5984894 polymorphism. We tested for association at these four SNPs in two independent datasets and then performed a joint analysis. Though we had adequate power to detect effects sizes with the reported odds ratios, we did not detect association between LOAD and the PCDH11X polymorphisms in our dataset of 889 cases and 850 controls, indicating that the PCDH11X association, if not a false positive, is not as strong or generalized as previously hypothesized.
doi:10.1097/YPG.0b013e32833b635d
PMCID: PMC2964434  PMID: 20523261
Alzheimer disease; genetic association study; PCDH11X
21.  Meta-Analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes 
Archives of neurology  2010;67(12):1473-1484.
Objectives
To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.
Design
Association study of AD and CLU, PICALM, CR1 and APOE genotypes.
Setting
Academic research institutions in the United States, Canada, and Israel.
Participants
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Results
Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.
Conclusions
We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.
doi:10.1001/archneurol.2010.201
PMCID: PMC3048805  PMID: 20697030
22.  Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease 
Naj, Adam C | Jun, Gyungah | Beecham, Gary W | Wang, Li-San | Vardarajan, Badri Narayan | Buros, Jacqueline | Gallins, Paul J | Buxbaum, Joseph D | Jarvik, Gail P | Crane, Paul K | Larson, Eric B | Bird, Thomas D | Boeve, Bradley F | Graff-Radford, Neill R | De Jager, Philip L | Evans, Denis | Schneider, Julie A | Carrasquillo, Minerva M | Ertekin-Taner, Nilufer | Younkin, Steven G | Cruchaga, Carlos | Kauwe, John SK | Nowotny, Petra | Kramer, Patricia | Hardy, John | Huentelman, Matthew J | Myers, Amanda J | Barmada, Michael M | Demirci, F. Yesim | Baldwin, Clinton T | Green, Robert C | Rogaeva, Ekaterina | St George-Hyslop, Peter | Arnold, Steven E | Barber, Robert | Beach, Thomas | Bigio, Eileen H | Bowen, James D | Boxer, Adam | Burke, James R | Cairns, Nigel J | Carlson, Chris S | Carney, Regina M | Carroll, Steven L | Chui, Helena C | Clark, David G | Corneveaux, Jason | Cotman, Carl W | Cummings, Jeffrey L | DeCarli, Charles | DeKosky, Steven T | Diaz-Arrastia, Ramon | Dick, Malcolm | Dickson, Dennis W | Ellis, William G | Faber, Kelley M | Fallon, Kenneth B | Farlow, Martin R | Ferris, Steven | Frosch, Matthew P | Galasko, Douglas R | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H | Ghetti, Bernardino | Gilbert, John R | Gilman, Sid | Giordani, Bruno | Glass, Jonathan D | Growdon, John H | Hamilton, Ronald L | Harrell, Lindy E | Head, Elizabeth | Honig, Lawrence S | Hulette, Christine M | Hyman, Bradley T | Jicha, Gregory A | Jin, Lee-Way | Johnson, Nancy | Karlawish, Jason | Karydas, Anna | Kaye, Jeffrey A | Kim, Ronald | Koo, Edward H | Kowall, Neil W | Lah, James J | Levey, Allan I | Lieberman, Andrew P | Lopez, Oscar L | Mack, Wendy J | Marson, Daniel C | Martiniuk, Frank | Mash, Deborah C | Masliah, Eliezer | McCormick, Wayne C | McCurry, Susan M | McDavid, Andrew N | McKee, Ann C | Mesulam, Marsel | Miller, Bruce L | Miller, Carol A | Miller, Joshua W | Parisi, Joseph E | Perl, Daniel P | Peskind, Elaine | Petersen, Ronald C | Poon, Wayne W | Quinn, Joseph F | Rajbhandary, Ruchita A | Raskind, Murray | Reisberg, Barry | Ringman, John M | Roberson, Erik D | Rosenberg, Roger N | Sano, Mary | Schneider, Lon S | Seeley, William | Shelanski, Michael L | Slifer, Michael A | Smith, Charles D | Sonnen, Joshua A | Spina, Salvatore | Stern, Robert A | Tanzi, Rudolph E | Trojanowski, John Q | Troncoso, Juan C | Deerlin, Vivianna M Van | Vinters, Harry V | Vonsattel, Jean Paul | Weintraub, Sandra | Welsh-Bohmer, Kathleen A | Williamson, Jennifer | Woltjer, Randall L | Cantwell, Laura B | Dombroski, Beth A | Beekly, Duane | Lunetta, Kathryn L | Martin, Eden R | Kamboh, M. Ilyas | Saykin, Andrew J | Reiman, Eric M | Bennett, David A | Morris, John C | Montine, Thomas J | Goate, Alison M | Blacker, Deborah | Tsuang, Debby W | Hakonarson, Hakon | Kukull, Walter A | Foroud, Tatiana M | Haines, Jonathan L | Mayeux, Richard | Pericak-Vance, Margaret A | Farrer, Lindsay A | Schellenberg, Gerard D
Nature genetics  2011;43(5):436-441.
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study (GWAS) of late-onset Alzheimer disease (LOAD) using a 3 stage design consisting of a discovery stage (Stage 1) and two replication stages (Stages 2 and 3). Both joint and meta-analysis analysis approaches were used. We obtained genome-wide significant results at MS4A4A [rs4938933; Stages 1+2, meta-analysis (PM) = 1.7 × 10−9, joint analysis (PJ) = 1.7 × 10−9; Stages 1–3, PM = 8.2 × 10−12], CD2AP (rs9349407; Stages 1–3, PM = 8.6 × 10−9), EPHA1 (rs11767557; Stages 1–3 PM = 6.0 × 10−10), and CD33 (rs3865444; Stages 1–3, PM = 1.6 × 10−9). We confirmed that CR1 (rs6701713; PM = 4.6×10−10, PJ = 5.2×10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9×10−8), BIN1 (rs7561528; PM = 4.0×10−14; PJ = 5.2×10−14), and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0×10−10) but not EXOC3L2 are LOAD risk loci1–3.
doi:10.1038/ng.801
PMCID: PMC3090745  PMID: 21460841
23.  PERIPHERAL MYELIN PROTEIN-22 IS EXPRESSED IN CNS MYELIN 
Translational neuroscience  2010;1(4):282-285.
Myelin abnormalities exist in schizophrenia leading to the hypothesis that oligodendrocyte dysfunction plays a role in the pathophysiology of the disease. The expression of the mRNA for the peripheral myelin protein-22 (PMP-22) is decreased in schizophrenia and recent genetic evidence suggests a link between PMP-22 and schizophrenia. While PMP-22 mRNA is found in both rodent and human brain it has been generally thought that no protein expression occurs. Here we show that PMP-22 protein is present in myelin isolated from adult mouse and human brain. These results suggest that PMP-22 protein likely plays a role in the maintenance and function of central nervous system (CNS) myelin and provide an explanation for why altered PMP-22 expression may be pathophysiologically relevant in a CNS disorder such as schizophrenia.
doi:10.2478/v10134-010-0038-3
PMCID: PMC3093192  PMID: 21572910
Myelin; Peripheral myelin protein-22; Schizophrenia
24.  Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders 
Neuron  2013;77(2):235-242.
SUMMARY
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASD), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a two-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudo-autosomal regions on the X-chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together these results provide compelling evidence that rare autosomal and X-chromosome complete gene knockouts are important inherited risk factors for ASD.
doi:10.1016/j.neuron.2012.12.029
PMCID: PMC3613849  PMID: 23352160
25.  Genetic Markers for PTSD Risk and Resilience Among Survivors of the World Trade Center Attacks 
Disease markers  2011;30(2-3):101-110.
We have previously reported the differential expression of 17 probe sets in survivors of the 9/11 attacks with current posttraumatic stress disorder (PTSD) compared to similarly exposed survivors with no lifetime PTSD. The current study presents an expanded analysis of these subjects, including genotype at FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity. It includes data from additional subjects who developed PTSD following 9/11 but then recovered, distinguishing expression profiles associated with risk for developing PTSD, resilience, and symptom recovery. 40 Caucasians (20 with and 20 without PTSD, matched for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the 9/11 attacks from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained and genome-wide gene expression was analyzed. 25 probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal axis, signal transduction, or in brain and immune cell function. STAT5B, a direct inhibitor of GR, and nuclear factor I/A, both showed reduced expression in PTSD. Comparison of lifetime versus current PTSD identified overlapping genes with altered expression suggesting enduring markers, while some markers present only in current PTSD may reflect state measures. As a follow-up, direct comparisons of expression in current PTSD, lifetime-only PTSD, and control groups identified FKBP5 and MHC Class II as state markers, and also identified several trait markers. An analysis of indirect effects revealed that homozygosity for any of 4 PTSD risk-related polymorphisms at FKBP5 predicted FKBP5 expression, which mediated indirect effects of genotype on plasma cortisol and PTSD severity.
doi:10.3233/DMA-2011-0764
PMCID: PMC3825240  PMID: 21508514
Stress disorders; post-traumatic; gene expression; genotype; FKBP5 protein; human; cortisol; September 11 terrorist attacks; childhood trauma

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