David Pauls, Ph.D. - Director
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.
Pamela Sklar, M.D., Ph.D. - Associate Director
Genetics of Bipolar Disorder
We have completed the early phase of a large genome-wide association study that provided strong evidence that two previously unanticipated genes, both of which influence ion channel function, lead to bipolar disorder. The laboratory is currently performing detailed analyses of the genetics of these loci as well as investigating in vitro and in vivo effects of disease related variation. Ongoing patient collections are set to double our dataset of the next several years and it is anticipated that these studies will provide many new loci for future investigation.
Genetics of Schizophrenia
As part of an International Consortium, we have completed a large genome-wide association scan that has identified novel structural and single nucleotide loci for schizophrenia. In addition, the lab has discovered an overall burden of structural variation in schizophrenia patients. The laboratory is continuing to investigate the overall genetic architecture of this disorder by examining the role of rare variation, common variation and structural variation. This is completed by in vitro and in vivo studies of disease related variation. As with bipolar disorder, ongoing patient collections are set to double our dataset of the next several years and it is anticipated that these studies will provide many new loci for future.
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.
Jordan Smoller, M.D., Sc.D.
Genetic Dissection of Anxious Temperament
The major goal of this project is to identify genetic influences on behavioral inhibition a temperamental profile linked to anxiety and mood disorders. Methods include family-based association analysis and linkage disequilibrium studies of candidate loci derived from mouse models of anxious temperament.
Genetic Determinants of Behavioral Inhibition
The goal of this study is to identify genes that influence the temperamental phenotype of behavioral inhibition to the unfamiliar, a familial and developmental risk factor for anxiety disorders. Statistical modeling techniques are applied to data collected in a large sample of children assessed for BI and their families to optimize the definition of the behavioral inhibition phenotype for genetic studies. Family-based association methods are used to examine the role of specific genes focusing on genes that have been previously implicated in anxiety and temperament in experimental animal models and in studies of anxiety disorders.
Genetic Determinants of Bipolar Disorder
The goal of this project is to identify genes that influence bipolar disorder by locating positional candidate loci through genome scan meta-analyses and then performing deep haplotype and linkage disequilibrium mapping of linked regions in both case-control and family-based samples. The study is funded by grants from the National Institute of Mental Health to three centers: Massachusetts General Hospital (Principal Investigator: Dr. Smoller), the Broad Institute (Principal Investigator: Pamela Sklar, MD, PhD), and the University of Pittsburgh (Principal Investigator: Vishwajit Nimgaonkar, MD, PhD).
Genetic Association Study of Mood Disorders
The goal of this study is to identify susceptibility loci for bipolar disorder and major depression through case-control association analyses of candidate loci.
Genetic Study of Temperament in Children at Risk for Depression and ADHD
This study is designed to identify genes and gene-environment interactions that may influence the development of mood disorders, anxiety disorders, and attention-deficit hyperactivity disorder (ADHD) by examining the genetic basis of temperamental profiles that appear to be heritable risk factors for these disorders. The study utilizes family-based linkage disequilibrium methods combined with gene-environment analyses to identify factors influencing risk for these disorders.
Genome-Wide Association Study of Treatment-Resistant Depression
The goal of this study is to combine novel informatics and genomewide association analysis to identify genetic variants that predict treatment response in major depressive disorder.
International Cohort Collection for Bipolar Disorder
The purposes of this study are twofold. The first aim is to collect a large cohort of BPD cases (N = 9000) and unaffected controls (N = 9000) over five years at two U.S. sites 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, separately funded European case-control sample (10,000 cases and 10,000 controls) obtained from the UK (Nick Craddock, PI) and Sweden (Mikael Landen, PI). The study is sponsored by the National Institutes of Mental Health.
Using Genetics to Dissect Schizophrenia, Bipolar Disorder, and Depression
The aims of the study are to 1) create a composite phenotypic database from large cohorts [the CATIE study of schizophrenia (N = 770), the STEP-BD study of bipolar disorder (N = 2090), the STAR*D study of depression (N = 1953), and a large sample of screened controls (N = 2000)], and derive key phenotypic variables for genetic analyses; 2) genotype 768 SNPs in 15 genes selected for having the strongest prior probability of involvement in the mood- and psychosis-related phenotypes; 3) 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.
