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Searching for ADHD Susceptibility
Genes – Sklar,
Smoller,
Doyle
This project, a collaboration with
Dr. Stephen Faraone, PhD (SUNY Syracuse) and the MGH
Pediatric Psychopharmacology Program (Joseph Biederman,
MD and colleagues), focuses on identifying genes influencing
attention deficit hyperactivity disorder (ADHD) using
sib-pair and family based association studies in candidate
genes and regions of susceptibility to ADHD.
Genetic Study of Temperament
in Children at Risk for Depression and ADHD –
Smoller
This study, a collaboration with investigators
in the MGH Pediatric Psychopharmacology Unit, is designed
to identify genes and gene-environment interactions
that may influence the development of mood disorders
and ADHD by examining the genetic basis of temperamental
profiles as heritable risk factors and assessing candidate
genes implicated in biological and animal model studies
of mood disorders, ADHD and behavioral disinhibition
in conjunction with environmental risk factors.
Genetics of Executive
functions in ADHD and non-ADHD families –
Doyle
This project aims to use family-based
association studies and an affected sibling pair linkage
design to identify genes that confer susceptibility
to executive function deficits in individuals with ADHD.
PAM as a Candidate Gene
for Autism – Ramesh,
Santangelo
PAM (Protein Associated with Myc),
which interacts with the Tuberous Sclerosis Complex
(TSC) protein tuberin and whose lower organism orthologues
function as synaptic growth regulators, is being examined
as a participant in generating the autism phenotype
seen in some TSC patients. The possible associations
between tuberin, hamartin and PAM in autism spectrum
disorders is also being examined.
Genetic Determinants of
Behavioral Inhibition and Anxious Temperament
– Smoller
Behavioral inhibition (BI), a heritable
temperamental profile characterized by avoidant or shy
behavior in unfamiliar situations, is a familial and
developmental risk factor for anxiety disorders. The
major goal of this project is to identify genetic determinants
of BI and, thereby, for anxiety and mood disorders using
family-based association analysis and linkage disequilibrium
studies of candidate loci derived from mouse models
of anxious temperament.
Genetic Determinants of
Bipolar Disorder – Sklar,
Smoller
Multiple strategies are being pursued
to identify susceptibility loci for bipolar disorder.
These include analysis of biological candidate genes
under linkage peaks and family-based association, as
well as linkage disequilibrium mapping under linkage
peaks in the Systematic Treatment Enhancement Program
for Bipolar Disorder (STEP-BD), a large treatment study
of bipolar disorder involving approximately 5,000 affected
individuals. The latter is a multi-site collaborative
study with the primary sites at MGH (PI:Smoller), Broad
Institute (PI:Sklar) and the University of Pittsburgh.
A whole genome scan using 500,000 individual markers
in 2,500 cases and 2,500 controls is underway.
Genetic Determinants of
Bipolar Disorder and Schizophrenia in an Isolated Population:
the Portuguese Islands of the Azores and Madeira –
Sklar
We are pursuing traditional linkage
analysis and genome scanning as well as linkage disequilibrium
analysis of candidate regions to investigate the genetic
basis of schizophrenia and bipolar disorder in the populations
of Portuguese descent of the Azores, a nine-island archipelago
located in the mid-Atlantic, and Madeira, off the coast
of western Africa.
Genetics of Vulnerability
to Schizophrenia Progression – Petryshen,
Purcell,
Sklar
This study will investigate candidate
genes for association with clinical, cognitive, neuroimaging,
electrophysiological, and hormonal biomarkers of schizophrenia
disease progression and disturbances in neural circuitry
observed in schizophrenia patients. The study is a component
of the Boston Center for Intervention Development and
Applied Research (CIDAR) that also includes investigators
Drs. Robert McCarley (PI), Martha Shenton, Larry Seidman,
Jill Goldstein, and Wilson Woo from the Boston VA Healthcare
System, Brigham and Women’s Hospital, Beth Israel
Deaconess Medical Center, and McLean Hospital.
Genetic analysis of Cerebral
Amyloid Angiopathy – Rosand
Cerebral amyloid angiopathy occurs
both as a rare familial disease and a common sporadic
condition. Accumulating evidence suggests that susceptibility
even to the sporadic form is due to genetic factors.
Our group seeks to identify these factors.
Developmental Genome Anatomy
Project (DGAP) – Gusella
The goal of DGAP,
a collaboration with investigators at Brigham and Women’s
Hospital and the Children’s Hospital, is to pursue
functional genomics in humans by capitalizing on balanced
chromosomal rearrangements in subjects with developmental
abnormalities to identify genes and conserved sequences
critical to development that are disrupted or dysregulated.
Genetic analysis of Hereditary
Spastic Paraparesis – MacDonald
Hereditary spastic paraparesis (HSP)
comprises a clinically and genetically heterogeneous
group of diseases that features lower extremity spasticity,
with axonal degeneration of corticospinal neurons. We
continue to augment a collection of HSP families for
genetic linkage studies to identify new HSP loci, and
to perform mutation scanning on the 8 cloned HSP loci
to support gene structure function studies.
Genetic modifiers of Huntington’s
disease – Gusella,
MacDonald
Together with Richard Myers, PhD of
Boston University and an international consortium of
HD clinical investigators (HD-MAPS: Modifiers of Age-at-onset
in Paired Sibs), we are using genetic linkage and association
strategies to identify genetic factors that modify the
age-at-onset in Huntington’s disease.
DNA repair genes as candidate
modifiers of the age of onset of Huntington’s
disease – Wheeler
DNA repair genes are candidate modifiers
of HD pathogenesis, based on findings in mouse models
of HD, and the fact that DNA repair defects cause other
neurodegenerative diseases. This project tests candidate
DNA repair genes as modifiers of the age-at-onset of
HD using genetic association studies.
Modifiers of Huntington’s
disease phenotypes in the mouse – Wheeler
In this project we aim to identify
genetic loci that modify CAG repeat instability and
early phenotypes in HD knock-in mice. Phenotypes are
compared between congenic strains of HD knock-in mice
on different genetic backgrounds. Genetic mapping strategies
are then carried out to localize the chromosomal region
responsible for “faster” or “slower”
phenotypes, with the long-term aim of identifying the
modifier genes involved.
Genetic determinants of
intracerebral hemorrhage in patients on anticoagulation
– Rosand
Anticoagulants are a widely used class
of medications that have been proven to reduce the risk
of stroke due to blood clots. Patients who take these
medications, however, become at increased risk for hemorrhagic
stroke. Our group seeks to identify the genetic determinants
of this risk. Our ultimate goal is to use this information
to identify which individuals carry a risk for hemorrhagic
stroke may outweigh the benefit they will receive from
taking these medications.
Genetic determinants of
cerebral small vessel disease – Rosand
Radiographic white matter disease
(WMD) is the most common manifestation of cerebrovascular
disease in the elderly. Its presence strongly predicts
risk of symptomatic stroke, age-related cognitive and
gait decline as well as late-life depression. Effective
prevention of WMD progression therefore holds the promise
of transforming the human aging process and reducing
age-related disability for future generations. Studies
have consistently demonstrated a strong genetic effect
on the amount of WMD. Current efforts are directed at
identifying those gene variants that may effect one’s
probability of developing WMD.
Gene Discovery in Mitral
Valve Prolapse – Slaugenhaupt
In collaboration with Dr. Robert Levine
in the MGH Echocardiography Laboratory, the Slaugenhaupt
lab has established linkage of MVP to two independent
loci: MMVP2 on chromosome 11 and MMVP3 on chromosome
13. Studies are currently underway to identify the genes
involved in the pathogenesis of this common disorder.
Genetic Association Study
of Mood Disorders and Genetic Association Study of Depression
with and without Anger Attacks – Perlis,
Smoller
These studies are focused on examining
genes related to depression and bipolar disorder in
clinically characterized patients with mood disorders
and healthy controls, including those with depression
with anger attacks, a depressive subtype identified
in a series of studies at MGH that has been associated
a distinct biological and treatment response profile.
Identification of genes
in neurofibromatosis-associated tumors –
Gusella
In collaboration with members of the
MGH Departments of Neurology, Neurosurgery and Pathology,
the Gusella lab is using a combination of array comparative
genome hybridization, high density SNP arrays and gene
expression array analysis to identify chromosomal changes
and specific genes and pathways involved in initiation
and progression of neurofibromatosis 1 and 2-associated
tumors, including neurofibromas, MPNSTs, schwannomas
and, particularly, meningiomas.
Identification of genes
causing Neuronal Ceroid Lipofuscinosis –
MacDonald,
Sims
Six NCL genes have been cloned, CLN1,
CLN2, CLN3, CLN5, CLN6 and CLN8, but these do not explain
all cases of this neurodegerative disorder. We continue
to collect new NCL families for identification of novel
mutations in known NCL genes and to find new NCL loci
using linkage analysis.
Genetic modifiers in CLN3
(JNCL) and CLN6 (vLINCL) – Cotman,
MacDonald
We are seeking genetic modifiers
of JNCL and vLINCL, through study of genetic background
influence on phenotypes in genetically accurate murine
models.
Mapping Genes for Neurocognitive
Endophenotypes – Santangelo
Funded by NIMH, this study will attempt
to map the chromosomal locations of genes underlying
some of the neurocognitive traits known to be associated
with schizophrenia, including impaired sensory gating,
sustained focused attention, and spatial working memory.
The neurocognitive endophenotypes are being measured
in a homogeneous, genetically isolated population in
eastern Nepal consisting of over 2800 sampled individuals
belonging to a single six-generation extended pedigree.
Quantitative trait linkage mapping techniques will be
applied.
Prepulse Inhibition, a
Schizophrenia Endophenotype – Petryshen,
Sklar
Our objective is to identify genes
involved in prepulse inhibition of startle via QTL mapping
in consomic mouse strains by combining traditional QTL
mapping with haplotype mapping and gene expression analyses.
Impaired PPI in schizophrenia suggests that gating deficits
may underlie the disease etiology, and thus are an endophenotype
(risk factor) for the disorder.
Identifying genes for
social behavior – Sklar
The immediate objective of our investigation
is to identify the exact location of an X-linked gene
(or genes) that has a major influence upon the brain's
ability to interpret social information from faces.
Insufficient dosage of one or more X-linked genes influences
neural processing in women with Turner syndrome, who
lack a second sex chromosome (45,X). This locus has
been mapped and we aim to find functionally variable
forms of one or more specific genes in this region (expressed
in the brain), which distinguish 45,X women who are
severely impaired in social cognitive skills from those
with more mild deficits.
A Genetic Linkage Study
of Gilles de la Tourette Syndrome – Santangelo
This study aims to identify the genes
responsible for Gilles de la Tourette syndrome, using
an affected sib-pair linkage study design as part of
an international consortium in association with the
Tourette Syndrome Association. We seek to extend the
consortium's earlier findings in which two candidate
areas were identified that may affect the likelihood
of developing TS.
Genetic analysis of Obsessive-Compulsive
Disorder and Tourette’s Disorder –
Pauls,
Stewart
Obsessive-Compulsive Disorder (OCD)
and Tourette’s Disorder are common and debilitating
related neurodevelopmental disorders. Using family-based
association strategies, we are to define genes that
predispose to OCD with and without comorbid Tourette’s
Disorder.
Genetic analysis of Parkinson
disease – Gusella
Using linkage analysis and association
strategies in collaboration with Richard Myers, PhD
and the multi-center GenePD study, the Gusella group
is attempting to define genes that predispose to Parkinson
disease as well as modifier genes that alter age at
neurologic onset.
Genome-wide association
study of QT interval duration – Newton-Cheh
In collaboration with investigators
at the Framingham Heart Study, the Rotterdam Study and
the Cardiovascular Health Study, Dr. Newton-Cheh is
identifying genetic variants in known and novel genes
that influence QT interval duration in the general population
and testing these variants for their influence on sudden
cardiac death and drug-induced arrhythmia.
Genome-wide association
study of blood pressure: GLOBAL BPGEN –
Newton-Cheh
In a multinational collaboration with
investigators from Canada, Estonia, Finland, France,
Germany, Italy, Sweden, the United Kingdom and the United
States, the GLOBAL BPGEN consortium, in which Dr. Newton-Cheh
participates actively, seeks to identify genetic variants
in known and novel genes that influence blood pressure
in the general population.
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