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.

Accelerating the Search for Autism Genes Using Extremely Discordant Sib Pairs
This study seeks to identify autism susceptibility genes by means of the Extremely Discordant Sibling Pair method. This is a continuation of a pilot study funded by The Medical Foundation. The goal is to collect 40-50 extremely discordant sibling pairs to do a genetic linkage study to find autism susceptibility genes.

Nicotine Dependence
Risk and Recovery Over Generations - This is a multi-site Transdisciplinaary Tobacco Use Research Center, the major goal of which is to identify familial, early childhod and lifetime psychiatric 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.

A Genetic Linkage Study of Gilles de la Tourette Syndrome
This study aims to identify the genes responsible for Gilles de la Tourette syndrome, using an affected sib-pair linkage study design. This investigation is being conducted in association with the Tourette syndrome Association (TSA) and is part of an international consortium. Researchers from 6 countries are collaborating in their efforts to clarify the role of genes in the occurrence of TS within families. This study seeks to extend the consortium's earlier findings in which two candidate areas were identified that may affect the likelihood of developing TS.

Etiologic Studies of Age-Related Macular Degeneration
The purpose of this study is to determine the genetic susceptibility to development of age-related macular degeneration, primarily via the use of affected sibling pair linkage analysis.

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.