Gene Regulation and Linkage Analysis in Bipolar Disorder (BPD) and Schizophrenia (SZ)
(Smoller, PI; with Dost Ongur and Bruce Cohen, McLean Hospital)
This study aims to investigate the association between single nucleotide polymorphisms (SNPs) and BPD or SZ diagnoses. These SNPs have been selected based upon their role in brain function. For example, research in recent years has focused on genetic polymorphisms in several genes with roles in brain development, synaptic neurotransmission, and neuronal-glial interactions as being possibly related to the development of these illnesses. This study will provide a resource for unbiased whole genome association analyses in the future.
Genetic Studies of Temperament
(Smoller, PI; with Hirshfeld-Becker, Henin, Kagan, Rosenbaum and Schwartz)
Behavioral Inhibition: This project aims to understand whether specific genes are implicated in the temperamental phenotype of behavioral inhibition (BI). Behavioral inhibition involves a stable tendency to exhibit withdrawal and excessive arousal to challenge or novelty. This temperament is of interest to geneticists because it is observed as early as infancy, is associated with biological traits (e.g. EEG asymmetry, amygdala reactivity) and is a familial and developmental risk factor for anxiety and mood disorders.
Behavioral Disinhibition: This project seeks to identify genes that influence the temperamental phenotype of behavioral disinhibition (BD). Children who are behaviorally disinhibited tend to spontaneously approach novel situations. Like BI, BD appears to be a stable temperamental tendency - suggesting a genetic influence on the trait - and is believed to be an intermediate phenotype for ADHD, bipolar disorder, and mood disorders.
Ongoing studies of these two cohorts (BI and BD) attempt to elucidate whether specific genes are implicated in brain structure, brain function, and behavior. We construct rich phenotypic definitions through the integration of multiple methods, including behavioral assessments of children and their families and brain imaging data (e.g. MRI). To then identify which genes are related to these definitions, we employ family-based association analysis and linkage disequilibrium studies of candidate loci derived from mouse models of anxious temperament.
Genome-Wide Association Study of Treatment-Resistant Depression (TRD)/i2b2
(Smoller/Perlis, PI's)
The ultimate goal of this project is to develop a clinically viable diagnostic tool that can be utilized to stratify risk for TRD. This project is being done in collaboration with i2b2 (Informatics for Integrating Biology and the Bedside). i2b2 technology is being used to identify subgroups of individuals with TRD in terms of natural history and health care utilization for major depressive disorder. The subgroups we're studying are 1) individuals with Treatment-Resistant Depression (TRD) treated in a health care system and 2) individuals with major depressive disorder (MDD) responsive to standard antidepressants (selective serotonin reuptake inhibitors, or SSRIs). We will also conduct a genomewide association study of these two groups of individuals to determine if genetic variation is associated with risk for treatment-resistant depression.
Genomic Superstruct Project
(Smoller, PI; with Randy Buckner (MGH))
The Superstruct Project is working to enhance understanding of basic properties of brain organization - i.e. what function different regions of the brain perform. It utilizes a novel imaging technique called fcMRI, or functional connectivity magnetic resonance imaging. Typically developing participants will be imaged and a saliva sample will be collected for genetic analysis. We expect to observe differences in imaging, and we will correlate these differences with genetic variants. Because this project draws - or 'superstructs' - on previous work done on autism, particular attention will be paid to genes associated with autism.
International Cohort Collection for Bipolar Disorder (ICCBD)
(Smoller/Sklar, PIs)
This study has two primary purposes. The first aim is to collect a large group of individuals with and without Bipolar Disorder (BPD) at two U.S. sites (USC, under the direction of Carlos Pato, and MGH) using high-throughput phenotyping methods. The second aim is to construct a harmonized data resource for genetic studies combining phenotypic data from the U.S. case-control sample with a parallel European case-control sample of individuals from the UK (Nick Craddock, PI), and Sweden (Mikael Landen, PI).
Using Genetics to Dissect Schizophrenia, Bipolar Disorder, and Depression
(Smoller, PI)
The aims of this study are to create a composite phenotypic database from large studies of schizophrenia (the CATIE study), bipolar disorder (the STEP-BD study), depression (the STAR*D study), and controls. Key phenotypic variables will be derived for genetic analyses. The team will then perform analyses to determine whether phenotypic effects of these genes (a) support nosologic distinctions among psychotic and mood disorders and (b) influence clinical features (psychosis, suicidality) and functional outcomes independent of diagnosis.
David Pauls, Ph.D.
A Genetic Linkage Study of Gilles de la Tourette Syndrome.
The goal of this project is to localize and characterize susceptibility genes for Gilles de la Tourette syndrome (GTS) and related conditions. Thirteen sites from the Unites States, Canada, the United Kingdom, the Netherlands, Germany and South Africa are participating in the collection of large multigenerational families, affected sib-pair families and triads of patients and their parents for use in genetic linkage and association studies.
A Genetic Study of the Gilles de la Tourette Syndrome and Obsessive Compulsive Disorder.
The goal of this family/genetic study of Gilles de la Tourette syndrome (GTS), obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) is to further understand the relationship between these disorders. Data collected includes structured interviews, neuropsychological data and self-report measures. These data will be analyzed to determine the familial relationship between these various conditions.
A Prospective Longitudinal Study of Children at Risk for GTS, OCD and Related Conditions.
The goal of this study is to identify non-genetic risk and protective factors important for the expression of GTS, OCD and related behaviors. Children at genetic risk for GTS and/or OCD and their families are followed prospectively to determine which non-genetic factors may play in a role in the expression of these behaviors. Once susceptibility genes for these conditions are identified, it will be possible to examine the interaction of these risk alleles and non-genetic factors identified over time.
A Genetic Linkage Study of Specific Reading Disability.
The goal of this project is to localize and characterize susceptibility loci for reading related processes known to be important for the acquisition of reading skills. It is a part of a Program Project entitled "Genotypic and Phenotypic Heterogeneity in Dyslexia" in which both genetic and neurobiological mechanisms involved in the development of dyslexia are being studied.
A Family Study of High Functioning Autism and Asperger's Syndrome.
The goal of this project is to examine the familial relationship between high functioning autism and Asperger's syndrome. This project is part of a Program Project entitled the "Neurobiology and Genetics of Autism and Related Conditions" of which Dr. Fred Volkmar of the child Study Center at Yale University is the Principal Investigator. The overall goal of the Program Project is to examine the neurobiology and genetics of autism and related conditions. In addition to examining the familial relationship between these two syndromes, other studies are using neuroimaging and molecular genetic methods to elucidate the underlying etiology of these severe childhood onset disorders.
A Genetic Study of High Functioning Autism and Asperger's Syndrome in Finland.
The goal of this project is to identify the chromosomal location of genes responsible for high functioning autism and Asperger's Syndrome using a population genetic mapping approach in the genetically isolated population of northern Finland. This work is being done in collaboration with Professor Irma Moilanen of the Department of Child Psychiatry at the University of Oulu, Oulu, Finland.
Tracey Petryshen, Ph.D.
Genetics of Vulnerability to Schizophrenia Progression
This project is investigating the genetic etiology neural circuit dysfunction in schizophrenia by performing a genetic association study of cognitive, neuroimaging, electrophysiological, and hormonal phenotypes that are abnormal in patients and that progressively deteriorate over the course of disease. The project is a component of an NIMH-funded P50 Center for Intervention Development and Applied Research (CIDAR) program project grant that also involves PNGU faculty Dr. Shaun Purcell and Dr. Pamela Sklar, and investigators from the Boston VA Healthcare System, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, and McLean Hospital.
Role of the Bipolar Disorder Risk Gene Ankyrin 3 in Behavioral Regulation
This project aims to gain a better understanding of the function of the ankyrin 3 gene in the pathophysiology of bipolar disorder. Ank3 was identified as a bipolar disorder risk gene in a meta-analysis of large-scale patient genome-wide association studies led by PNGU investigators Drs. Pamela Sklar and Shaun Purcell. The Petryshen lab is utilizing mouse in vivo brain RNA interference, knockout mice, and neuromolecular approaches as a first step in characterizing the role of Ank3 in modulating behaviors that target features of bipolar disorder.
Mouse Genetics of Prepulse Inhibition
Prepulse inhibition (PPI) is a neural information processing system that is impaired in many psychiatric disorders including schizophrenia and bipolar disorder during mania, and that is related to higher order cognition. This study is utilizing mouse genetic mapping and molecular approaches to identify genes regulating PPI that may also contribute to psychiatric and cognitive disorders. We have identified a PPI locus on mouse chr16 that corresponds to a human locus linked to neurocognitive traits impaired in ADHD that was identified by PNGU faculty member Dr. Alysa Doyle. We are integrating data from the mouse PPI and human neurocognition studies to identify the gene in this locus which we hypothesize regulates information processing and cognition in both mouse and human.
New Therapeutics for Treatment of Mood and Psychotic Disorders
We are examining novel molecules for therapeutic potential in mouse behavioral models of major psychiatric illness. Chemical compounds identified in cell-based screens by colleagues in the CHGR and the Stanley Center for Psychiatric Research at the Broad Institute are being tested for efficacy in attenuating behaviors reminiscent of bipolar mania, depression, and schizophrenia in wild-type mice and mouse genetic models. In parallel, the mechanism of drug action underlying behavioral modulation is being investigated using biochemical and molecular analysis of mouse brain.
Susan L. Santangelo, Sc.D.
Mapping Genes for Neurocognitive Endophenotypes
This study will attempt to map the chromosomal locations of genes underlying neurocognitive traits known to be associated with schizophrenia, such as impaired sensory gating, sustained focused attention, and working memory. The study sample is a homogeneous, genetically isolated population in eastern Nepal, consisting of over 2800 individuals in a single, six-generation extended pedigree.
Candidate Gene Pilot Study" in 'Nicotine Dependence: Risk and Recovery Over Generations'
This is a multi-site Transdisciplinary Tobacco Use Research Center, the major goal of which is to identify familial, early childhood and lifetime psychiatric risk factors that determine trajectories of progression from smoking initiation to dependence; lifetime smoking patterns; the natural course of cessation; and response to treatment, combining a treatment/prevention imperative, a genetic epidemiologic approach, and a lifespan developmental perspective. The pilot study will attempt to discover polymorphisms in specific candidate genes that are strongly associated with various smoking and nicotine dependence phenotypes.
PAM as a Candidate Gene for Autism
The objective of this pilot study is to test the hypothesis that PAM, a brain specific protein involved in Tuberous Sclerosis Complex might play a role in autism by investigating whether any of the 20+ identified htSNPs in PAM is associated with autism.
A genetic linkage study of GTS
The purpose of this study is to identify genes conferring susceptibility for Gilles de la Tourette Syndrome, primarily via the use of genetic linkage analysis and association analysis.
A Genome-Wide Association Study of Autism
This study will apply the Affymetrix 5.0 technology to scan approximately 1200 families from both the AGRE repository and locally collected samples with 500,000 SNP markers in order to identify common variants and copy number repeats associated with autism and autism spectrum disorders.
Phenotypic and Genetic Factors in Autism Spectrum Disorders
The overarching goal of this proposal is the foundation of a comprehensive program of research aimed at elucidating the underlying mechanisms involved in autism. We will develop a standard core phenotype assessment battery with which to establish a shared, continually evolving data repository to enable specific etiological studies (e.g. genotype-phenotype correlation, gene-environment interactions, cognitive neuroscience investigations, and metabolic biomarkers and endophenotypes), as well as translational research to address treatment and quality of life issues, establish best clinical practice and training standards, and accelerate understanding of and support for individuals with autism spectrum disorders and their families. This study aims to enroll and collect comprehensive behavioral phenotype data on approximately 115 families with a child with an autism spectrum disorder (ASD) in the first year.
Genes that Deregulate mTOR Signaling as Candidates for Autism Spectrum Disorders
This study will test the hypothesis that aberrant hyperactivation of mTOR in neurons, a common causal pathway for learning and other cognitive deficits associated with tuberous sclerosis complex and neurofibromatosis, also increases risk for autism spectrum disorders (ASD). Specifically, inherited variations in five genes that influence mTOR signaling, TSC1, TSC2, NF1, BDNF, Pam, and PTEN will be associated with risk for ASD. These hypotheses will be investigated via family-based association studies using single-nucleotide polymorphisms (SNPs) and haplotype analyses spanning the entire TSC1, TSC2, NF1, BDNF, Pam and PTEN genes in more than 1155 parent-offspring trios affected with ASD. If one or more of these genes is found to be associated with ASD, it would not only break new ground for understanding the pathogenesis of ASD, but would also indicate an effective therapeutic strategy, since rapamycin and its analogs are effective in blocking mTOR signaling.
Association of Distal-less Homeobox (DLX) Genes and Autism: Independent and Interactive Effects of Single SNPs and Haplotypes"
This mentor-based fellowship will support a pre-doctoral candidate in epidemiology to investigate whether one or more of the six genes in the distal-less homeobox (Dlx) gene family contributes to the etiology of autism either independently or through complex interaction between Dlx genes located on different chromosomes.
Maternal Dietary Factors and Risk of Autism Spectrum Disorders
This mentor-based fellowship will support a pre-doctoral candidate in epidemiology to investigate the role of maternal dietary factors in increasing risk for autism spectrum disorders.
Fetal Antecedents to Sex Differences in Depression: A Translational Approach Co-Investigator
Genes & Hormonal Fetal Antecedents to Sex Differences in the Brain in Depression
PI, Project 1
The major goal of this project is to test hypotheses regarding sex differences in the onset and manifestation of major depressive disorder via the analyses of functional and structural magnetic imaging data and hormonal evaluations regarding fetal antecedents to sex differences in brain abnormalities and neuroendocrine dysfunction in this disorder.
Maternal Risk Factors for Autism Spectrum Disorders in Children of the Nurses' Health Study II
The goal of this project is to identify maternal dietary factors, other environmental factors, such
as heavy metal exposure, and genetic factors that may influence the risk for autism spectrum disorders inchildren of a large longitudinal study of a cohort of nurses.
Investigation of genes involved in synaptic plasticity in Iranian families with ASD
The goal of this study is to determine if one or more genes related to new protein synthesis in
synaptic plasticity contribute to the etiology of autism spectrum disorders (ASD).
Epidemiology of Autism in Iran
The purpose of this three-year study is to implement a pilot prevalence study of autism in Tehran that will prepare the groundwork for future nationwide studies of environmental and genetic risk factors for autism in Iran. In a region of the world where reliable prevalence figures have yet to be established, this study will yield a population-based prevalence estimate of autism among children in Iran.
