Projects

Please click on the title below to learn more about the project.

• Influence of Psychosis on Brain-Behavior Endophenotypes for Bipolar Disorder
• Genetics of Brain Structure and Function
• Genetics of Brain Structure and Function: Genome Wide Association
• Genetics of Bipolar Disorder in Latino Populations
• Neuropsychological and Neuroimaging Abnormalities in Siblings Pairs Discordant for Bipolar Disorder
• Neuropsychological Predictors of Functional Outcome in Bipolar Disorder
• Neuropsychological Correlates of Bipolar Disorder
• Affective & Neurobiological Predictors of Adolescent-Onset Alcohol Use Disorders

Bipolar I disorder (BPI) is a major public health burden whose biology is largely unknown. Although it is well established that BPI is heritable, the molecular genetic basis for this illness remains elusive. In face of evidence that genes predisposing to BPI may be transmitted without expression of the clinical phenotype, interest has arisen in developing endophenotypes for the illness, indicators of processes mediating between genotype and phenotype. Given the high rates of psychosis in BPI and that history of psychosis may alter brain structure and function, we believe that elucidating neurocognitive and neuroimaging endophenotypes for the disorder must account for the potential impact of hallucinations and delusions on these markers. The aims in this study will (1) develop candidate neurocognitive and neuroimaging endophenotypes for BPI, (2) examine the association of history of psychosis on these brain-behavior markers in BPI patients, and (3) determine if markers are sensitive to liability for psychosis in healthy siblings. The ultimate promise of this research is to develop endophenotypic markers that will characterize the biological mechanisms of BPI and facilitate the discovery of genes that predispose the illness. To this end, we will perform anatomic and functional neuroimaging and conduct neuropsychological examinations on 130 euthymic patients with BPI (65 with history of psychosis), 130 of their unaffected same-sex siblings and 65 unrelated comparison subjects. Through the development of brain-behavior markers sensitive to genetic liability for bipolar disorder, the proposed research should significantly aid the discovery of genes that predispose the illness and facilitate the identification of the biological determinants of bipolar disorder. This, in turn, should lead to improved characterization and treatment of bipolar disorder. This study is funded by a R01 from the National Institutes of Mental Health (Glahn, DC PI).

The goal of this project is to identify quantitative trait loci associated with variation in brain structure and function.  The ultimate promise of this research is the discovery of genes that predispose to brain disorders and mental illnesses.  We believe that the analysis of genetic influences on brain structure and function in randomly sampled extended pedigrees will provide significant clues regarding the genes that are involved in both normal and pathological brain function. The focus of the project is on the genetic dissection of quantitative endophenotypes that more directly index the underlying biological basis of brain function than do discrete disease states themselves. Our specific aims are to: 1) perform high quality brain magnetic resonance imaging and neuropsychological examinations on 1,000 Mexican Americans who are members of approximately 30 large extended families, 2) assess the quantitative genetic architecture of brain-related phenotypes by estimating their heritabilities and their genetic correlations, 3) classify specific brain morphological variables and quantitative leukocyte-derived gene expression measures as endophenotypes related to brain function, 4) localize QTLs influencing variation in the quantitative brain-related phenotypes by performing linkage-based genome scanning using the variance component method, 5) refine the position of localized QTLs and identify positional candidate loci using an objective prioritization strategy that jointly utilizes in silico bioinformatics, genetic, and transcriptional data, and 6) identify the most likely functional variations within the two best positional candidate genes.  This ongoing study is funded with coordinated R01s from the National Institutes of Mental Health to Dr. John Blangero and Dr. Glahn.

The goal of this project is to identify genes that influence variation in brain structure and function using high-density genome-wide association (GWA) analysis. The ultimate promise of this research is the discovery of genes that predispose to brain disorders and mental illnesses. Our focus is on the genetic analysis of variation in brain structure and function in randomly sampled extended pedigrees to provide significant clues regarding the specific genes that are involved in both normal and pathological brain function. In 2006, we began collecting brain-related endophenotypes on related Mexican American individuals for linkage-based analyses (MH078111 & MH078143). However, given the number of recent successes using GWA, we believe that shifting our design to exploit the availability of high density SNPs will dramatically speed gene discovery by substantially reducing the genomic region of interest nominated in our linkage-based study. Using alternative funding, we have begun this process of high-density genotyping. Because of power issues due to multiple testing inherent in GWA, it is necessary to expand our original sample to obtain sufficient power for gene identification. By adding 500 new individuals from the same large pedigrees and completing the high-density genotyping in the original sample (n=1,000), we will have 80% power to detect relatively small genetic effects on brain-related endophenotypes. Our specific aims for this independent R01 are to: 1) extend our existing study by performing high quality brain magnetic resonance imaging and neuropsychological examinations on an additional 500 Mexican Americans who are members of 30 previously studied extended families, 2) perform GWA analysis to prioritize potential genes involved in brain structure/function, using 1 million SNPs genotyped on all 1,500 individuals, 3) increase our genome-wide transcriptional profile data by performing identical assays on the additional 500 samples to identify genes whose lymphocyte-derived expression levels correlate with measures of brain structure/function in the total sample, 4) identify the most likely functional variations within the five best empirically nominated candidate genes by resequencing 192 founder individuals, and 5) confirm the strongest association in an independent data set. Combining these new samples with those currently being collected represents the most cost effective and rapid approach for the discovery of genes associated with brain-related traits. This ongoing study is funded by a R01 from the National Institutes of Mental Health (Glahn, DC PI)

Bipolar Disorder, type 1 (BPI) is a severe mental illness that appears to be caused in part by multiple susceptibility genes, each of small effect. Detection of BPI susceptibility genes will thus likely require investigation of a very large sample of pedigrees with multiple affected cases and a focus on more genetically homogeneous populations. We will collect, over 4 years, diagnostic information and DNA samples from 385 families of Latino descent, each with a minimum of 2 siblings affected with BPI to detect BPI susceptibility loci in this population. We have formed a collaboration of 7 sites throughout the Southwest United States, Mexico, and Central America to accomplish this task. Each site has access to a large Latino population and extensive experience in diagnosis of BPI in Latinos. A uniform approach will be used to diagnose subjects, consisting of blinded interviews with the Diagnostic Interview for Genetic Studies, collection of pertinent medical records and laboratory tests, and interview with a close relative of each subject. A best estimate consensus process will be used to assign final diagnoses and clinical information for each subject will be entered and stored in a centralized database. Blood samples will be obtained from all family members with a diagnosis of BPI or other, as well as from both parents and 2 other siblings. Cell cultures will be created and DNA extracted at the NIMH designated Center for Genetic Studies. In year five, a complete genome screen at an approximate density of 10 cM will be performed at CIDR. Linkage analysis based on identification of multipoint allele sharing in BPI subjects will be performed at the Southwest Foundation for Biomedical Research (SFBR). Secondary analyses will also be performed, including covariate and quantitative trait analysis, in a set of extended pedigrees containing an additional 750 subjects. Endophenotypes defined by neurocognitive and structural MRI tests related to BPI will be validated in these pedigrees and genes which contribute to these biologic variables will also be mapped through covariate quantitative trait analyses. This ongoing study is funded by a R01 from the National Institutes of Mental Health (Escamilla MA, PI)

Twin, family and adoption studies have demonstrated that bipolar disorder (BPD) is substantially heritable.  Yet, despite considerable evidence that risk for BPD is inherited, the molecular genetic basis for this illness remains elusive.  The search for the genetic loci involved in BPD has likely been hampered by the complexity of this syndrome, heterogeneity of phenotypic expression, and comorbidity with other disorders that may distort symptom presentation (e.g. substance abuse).  BPD seems to involve more than one gene, each of which probably has a moderate to small effect on phenotypic expression.  Given evidence that genes predisposing to BPD may be transmitted without expression of the clinical phenotype, interest has arisen in developing indicators of processes mediating between genotype and phenotype.  Such allied phenotypes or endophenotypes may directly index the underlying pathology, or liability to disease, and hence can be measured in both affected and unaffected individuals.  Endophenotypic markers are often quantitative, allowing for powerful linkage analysis strategies which are not readily available for qualitative phenotypic markers such as diagnostic category.  The aim of the proposed study is to determine if neuropsychological and structural MRI abnormalities identified in BPD patients are present in their unaffected siblings, raising the potential that these measures could be use as endophenotypes for BPD.  Specifically, we aim to (1) apply neuropsychological tests of attention, executive functions, working and declarative memory to 20 sibling pairs discordant for BPD and 20 matched healthy subjects and (2) aquire high quality structural MRI images in this same sample to better define the prefrontal, and medial temporal/limbic abnormalities associated with BPD. This study is funded by a young investigator award from National Alliance for Research on Schizophrenia and Depression (NARSAD) (Glahn, DC PI).

Many individuals with bipolar disorder suffer from neuropsychological impairments, particularly in the domains of attention, executive functioning, and verbal declarative memory. Neuropsychological deficits have been documented in depressive, manic and euthymic phases of the illness. While the relationship between cognitive impairments and clinical course is not fully established, it appears that deficits in some cognitive domains appear to worsen with clinical severity or duration of illness while impairments in other areas appear to be stable. Indeed, worse clinical course, particularly increased numbers of manic episodes, is associated with more severe verbal declarative memory impairments. In contrast, executive dysfunction is less consistently linked to clinical factors and appears to be a relatively independent of duration of illness, affective symptomatology or hospitalizations. One consequence of impaired cognitive processing in individuals with bipolar disorder appears to be lower levels of employment, reduced psychosocial functioning, and generally poorer functional outcome. However, the relationship between cognition and functional outcome in bipolar disorder is not well studied. The goal of this project is to determine if neuropsychological measures can meaningfully predict functional outcome in clinically stable patients with bipolar disorder. Of particular interest is weather those areas of cognition that worse with illness severity are better predictors of functional outcome than domains less influenced by symptomatology. To examine this relationship, we will perform neuropsychological and psychosocial assessments on 65 individuals with bipolar disorder and on 65 demographically matched healthy comparison subjects. In order to isolate those cognitive abilities that worsen with clinical course, detailed clinical histories will be examined and neurocognitive assessments will be conducted twice, one year apart. This study is part of a Bipolar Treatment center that is being reviewed by the National Institutes of Mental Health (Bowden CL, PI)

Although there is no doubt that the severe alterations in mood state that characterize bipolar disorder affect the ability to think, concentrate, reason, and remember, the nature and extent of such changes is less clear.  Patients with bipolar disorder suffer from neuropsychological impairments, particularly in the domains of attention, executive functioning and declarative memory.  Impaired cognitive processing has been linked to lower levels of employment and the reduced psychosocial functioning found in these patients.  Neuropsychological deficits have been documented in depressive, manic and euthymic phases of the illness, suggesting that disruption of cognitive functioning may be a trait marker for bipolar disorder.  This claim has been strengthened by recent reports that healthy siblings of individuals affected with bipolar disorder show subtle executive and declarative memory deficits, implying that genetic liability for bipolar disorder may be associated with neurocognitive dysfunction.  However, questions remain concerning the extent to which mood state impairs neuropsychological functioning in bipolar disorder.  Here, we propose to conduct serial neuropsychological assessments on a patients with bipolar disorder (n=30) and healthy comparison subjects (n=30) to document the relationship between changing mood states and neurocognitive performance. This study is funded by the National Institutes of Mental Health center entitled “Bipolar Illness Intervention in Hispanic Communities.”  Data collection is complete and analysis is ongoing.

Despite decades of research linking depression and alcohol use disorders (AUD), our understanding of their shared etiologies remains understudied, especially the importance of their emergence during adolescence, a period of increased susceptibility for AUD. This application describes a study of affective and neurobiological risk factors for the onset of AUD during adolescence. The aims of the study are to: 1) Identify the main effects and interactions among premorbid affective, neurobiological, genetic, and environmental factors as they relate to the risk to develop AUD; 2) Determine which combinations of these factors predict the eventual development of AUD during adolescence; and 3) Examine the consequences of AUD on adolescent brain development. The design is aimed at disentangling how these risk factors are involved in the development of AUD moderated by preexisting risk for depression. This will be accomplished by selecting two samples of adolescents, aged 12 to 14 years at the time of initial assessment, who have either high or low familial loading for depression and following them annually over a three year period into late adolescence. Measures will include: the assessment of mood and negative affect; functional imaging of neural circuitry subserving affective behaviors; genetic polymorphisms involved in serotonin neurotransmission; exposure to acute/chronic stressors; and dimensional assessments of alcohol use as well as disorders. The short-term goals of this work are to understand the etiologic links between depression and AUD and ultimately their emergence during adolescence. The long-term goals are to identify pathways and mechanisms involved in the development of AUD in ways that will inform early intervention and prevention strategies. This ongoing study is funded by a R01 from the National Institute on Alcohol Abuse and Alcoholism (Williamson DE, PI).