Ongoing Research Projects

The International Multi-Centre ADHD Genetics (IMAGE) Project

  • Principal Investigator (PI): Stephen V. Faraone
  • Samples: 4061 subjects comprising 958 parent-child trios and small nuclear families with at least one child or adolescent proband affected by Attention-Deficit/Hyperactivity Disorder (ADHD).
  • Description: The Principal Investigator successfully applied for and was chosen to participate in the Genetic Association Information Network (GAIN) initiative supported by the Foundation for the National Institutes of Health for a genome-wide association scan of the IMAGE sample. The GAIN program will fund a 600,000 tag SNP genome-wide association scan of 958 parent-child trios from the project. As of this writing, the scan has been completed, and the data are currently being cleaned by NCBI. Several candidate genes have also been evaluated for association with ADHD in the IMAGE sample.

Pharmacogenomics of ADHD: Evaluation of the Safety, Tolerability, and Efficacy Response to Daytrana™ (methylphenidate transdermal system) as Determined by a Multivariate Genomic Analysis in Children Aged 6-12 with Attention Deficit Hyperactivity Disorder (ADHD)

  • PI: Stephen V. Faraone
  • Samples: 2,000 subjects with ADHD whose symptoms are being treated with medications provided by Shire Pharmaceuticals, and 2,000 control subjects obtained by Dr. Faraone.
  • Description: This project is ongoing, with comparisons planned to detect risk genes for ADHD (by comparing allele frequencies in controls and affected cases) and genes that influence treatment response, including efficacy and adverse events. All individuals will be evaluated at over 500,000 SNPs on the latest Affymetrix platform, and candidate genes emerging from this initial screen will be supplemented by additional haplotype-tagging and functional SNPs in their vicinity by additional genotyping on the SNPlex protocol.

Validating Novel Familial Phenotypes of Drug Abuse

  • PI: Stephen V. Faraone
  • Samples: 1299 parents with a substance use disorder (SUD) and 94 of their offspring, and 1444 control parents and 1774 of their offspring, who were recruited into six contemporaneous studies of four psychiatric conditions including ADHD, panic disorder, major depression, and bipolar disorder.
  • Description: The overall goal of this proposal is to use a multigenerational perspective and an extensive assessment of multiple domains of functioning to systematically and precisely develop familial SUD phenotypes that can be informative to genetic studies. Within the context of families ascertained from a referred ADHD youth, we are determining what clinical and functional phenotypic features are more common among subjects with SUDs than those without SUDs, and whether these features are stable over time. We next examine whether these phenotypes are transmitted through families and if the strength of this transmission is related to SUDs. We also are investigating the familial association between SUDs and comorbid mood and antisocial disorders. The specificity of these findings is being assessed by replicating these analyses in families ascertained by youth with bipolar disorder. Throughout this research, we are testing the effect of gender on the expression and familiality of these novel phenotypes.

Searching for ADHD Susceptibility Genes

  • PI: Stephen V. Faraone
  • Samples: 1,000 families from the IMAGE study, 300 controls from the Massachusetts General Hospital, and 200 controls from the NIMH Genetic Data Repository.
  • Description: The goal of this study is to confirm and extend the haplotype association results for ADHD we previously observed with the HTR1B, SLC6A3 and SNAP25 genes using family-based and case-control samples. We are also extending our project to test the hypothesis that additional genes are associated with ADHD. For each of these genes we are: 1. Selecting htSNPs that characterize the haplotype structure of each gene as well as SNPs reported to be associated with ADHD in previous studies; 2. Genotyping these htSNPs in our ADHD samples. 3. Performing family-based and haplotype-based analyses that are resistant to population stratification biases; and 4. Performing exploratory studies of ADHD phenotypes, gene-gene interaction and gene- environment interaction.

Translational Studies of Cycling in Bipolar Disorder

  • PI: Stephen V. Faraone
  • Samples: 153 trios of probands with pediatric-onset bipolar disorder and both of their parents, as well as an additional 152 independent cases and 140 controls.
  • Description: In this project, we are studying distinct features of the bipolar disorder phenotype (e.g., cycling and switching) in an animal model of the condition, and extending these results by testing novel candidate genes for association with the illness in a phenotypically enriched, and presumably more homogeneous, sample of patients with pediatric onset of bipolar disorder.

Re-Establishing DRD2 as a Risk Gene for Schizophrenia: Haplotype Mapping and Family Based Association Analysis

  • PI: Stephen J. Glatt
  • Samples: 1214 affected subjects and 1194 unaffected first-degree relatives of affected subjects from 616 Han Chinese families from Taiwan.
  • Description: The goal of this study is to conduct the largest known family-based association analysis of all functional and haplotype-tagging polymorphisms in the DRD2 gene in schizophrenia to determine if the evidence for significant association we previously observed in case-control studies (Glatt et al., 2003; Glatt and J├Ânsson, 2006) can be replicated. Once associated variants are identified, they will be evaluated in a battery of functional genomic paradigms to determine how these DNA sequence variations translate into deleterious consequences of relevance to schizophrenia.

Biomarkers of Autism at 12 Months: From Brain Overgrowth to Genes

  • PI: Stephen J. Glatt
  • Samples: 270 12-month-old children, divided equally among children at risk for an autistic spectrum disorder, children at risk for other developmental disorders, and typically developing children.
  • Description: The goal of this study is to identify gene expression-based biomarkers for autism in peripheral blood samples from children at risk for the disorder. At 12 months of age, children visiting their pediatrician for a well-baby checkup will be screened for early behavioral signs of autism or other developmental disorders. These children, along with a comparison cohort of typically developing children, will be evaluated on a battery of behavioral, neuroimaging, and genetic tests, including gene expression profiling. Longitudinal analyses will be performed on serial samples of blood from these children at 12 months, at 24 months when clinical diagnoses will be more concrete, and at 36 months after at-risk children have received 12 months of intensive behavioral intervention.

Expanding Rapid Ascertainment Networks of Schizophrenia Families in Taiwan

  • PI: Stephen J. Glatt
  • Samples: 15,000 individuals from 5,000 Han Chinese families in Taiwan who are affecetd with schizophrenia.
  • Description: The goal of this study is to quickly ascertain parent-child trios with at least one offspring who is affected with schizophrenia. The DNA collected from all family members will be genotyped for genome-wide association analysis, wherein we aim to detect both common and rare variants that increase susceptibility to the illness. Aside from single nucleotide polymorphisms, we will also evaluate the contribution of copy-number variations to disease liability. Analyses will also be performed to determine if gene-gene and gene-environment interactions are operating to increase risk for the disorder in the sample.

Genetic Studies of Schizophrenia, Bipolar Disorder, and Psychosis in the Portuguese Island Collection

  • PIs: Carlos N. Pato and Frank A. Middleton
  • Samples: 130 families with multiple cases of schizophrenia, 25 families with multiple cases of bipolar disorder, an additional 330 non-familial cases of schizophrenia, 250 unrelated matched control subjects who have been screened for all major psychiatric disorders.
  • Description: Drs. Pato and Middleton have been conducting an ongoing study of the Portuguese population with special emphasis on the Azorean and Madeiran island populations. These populations have contributed to a national repository of DNA from families informative for genetic linkage studies of schizophrenia and bipolar disorder, and together comprise the Portuguese Island Collection (PIC). Genome-wide linkage studies have been completed in this sample using schizophrenia, bipolar disorder, or psychosis as affected phenotypes (Sklar et al., 2004; Pato et al., 2005). In addition, the schizophrenia samples have been analyzed for association with several candidate genes (including several GABAA subunit genes, NRG1, NRGN, TP53, and CX50) and a portion of the sample (50 unrelated schizophrenia cases and 50 controls) recently have been assayed at over 500,000 SNPs, analyses of which are ongoing.

Identifying Novel Candidate Genes for Alzheimer's Disease (AD)

  • PI: Louis A. Profenno
  • Samples: A dataset of 500,000 SNP genotypes in 1400 Alzheimer's disease cases and controls.
  • Description: A dataset of 500,000 SNP genotypes in 1400 Alzheimer's disease cases and controls will be mined by set association analysis to reveal novel candidate risk pathways for AD. Results will be followed up by additional genotyping and statistical genetic analysis to pinpoint novel candidate genes in AD.

Pathways of Gene Expression in Spontaneous and Environmentally-Induced Rat Models of ADHD

  • Co-PIs: Stephen V. Faraone and Frank A. Middleton
  • Samples: Brain areas obtained from Sprague Dawley rats, PCB-treated Sprague Dawley rats, SHR and WKY rats
  • Description: This study investigates whether the SHR model of ADHD and the PCB-induced model of ADHD produced similar changes in brain circuits involved in ADHD. Gene expression analysis, using micro array, was performed in six brain regions (the anterior cingulate cortex, ventral striatum, dorsal striatum, hippocampus, midbrain and vermis), which abundantly express the IMAGE genes. Results show that a small subset of IMAGE genes show robust differences in expression in some brain regions of both SHR and PCB-treated SD rats compared to SD controls (r-squared=0.70). Some of the IMAGE genes have been confirmed by real time quantitative PCR (p< 0.005) using RNA samples from individual rats. Collectively, the data provide strong evidence that both genes and environment can lead to the same effects on the brain circuits involved in ADHD.

Cigarette Smoke Alters Expression of ADHD Candidate Genes in Mice Brains

  • Co-PIs: Stephen V. Faraone and Frank A. Middleton
  • Samples: Brain areas obtained from control and cigarette smoke-exposed mice, both male and female.
  • Description: This study is designed to evaluate molecular mechanisms which can explain alterations in brain leading to ADHD-like behaviors in animals exposed to prenatal cigarette smoke. Gene expression analysis performed on three brain regions (the ventral mesencephalon, ventral striatum and vermis) which abundantly express the IMAGE genes showed robust differences in expression of a small subset of IMAGE genes in the brains of young adult male and female mice following prenatal cigarette smoke exposure. Changes were observed in the expression of genes directly involved in chromatin remodeling and epigenetic regulation. We now seek to determine if exposure to cigarette smoke prenatally has an influence on the methylation status of genes which may partly help to explain the gene expression profile observed in this study.

Genetics of Schizophrenia in Oceanic Palau

  • PI: Marina Myles-Worsley
  • Samples: In this isolated population of only 20,000 individuals, we have identified 175 (250) cases of narrowly (broadly) defined schizophrenia representing 59 separate families. Most of these families can be connected through marriage, but the population is not inbred. We have DNA samples for over 1,000 individuals and diagnostic/genealogical data for over 3,000 individuals. A WGA study of a carefully selected sample of 500 Palauan individuals—250 cases, 150 mothers, and 100 controls—is underway.
  • Description: The principal objective of the study is to identify genetic variation that underlies liability to schizophrenia and other psychotic disorders (Scz) in Palau, Micronesia by conducting a genome-wide study of linkage and association. We will genotype 500 individuals for 250,000 SNPs and search for variation conforming to the conventional hypothesis—that risk to Scz is determined by genetic variation carried by affected individuals. We will test a novel hypothesis—that initial liability to Scz is generated during fetal development by environmental stressors, so that the placental environment cannot adequately buffer the developing fetus. A rich set of maternal/fetal risk factors will be collected and used in gene X environment analyses. Statistical analyses will target identification of extended haplotypes, which will be facilitated by extended linkage disequilibrium that is characteristic of this isolated population.