This application is to identify heritable, quantitative traits (endophenotypes) that are related to bipolar disorder (BP) and then to use these endophenotypes for linkage and association analyses to identify quantitative trait loci (QTL) in a series of well characterized extended pedigrees. It is hypothesized that the endophenotypes may be more powerfully genetically mapped than the clinical BP phenotype. The first step is to measure selected neuroanatomical, neurocognitive, temperament, and activity related features previously shown or hypothesized to be associated with BP. These features will be measured using high resolution structural magnetic resonance imaging (MRI) brain scans, and widely used scales for neurocognition, temperament, and seasonal/circadian variation in activity. The investigative team has considerable experience in using these assessment tools. Aggregation of each of these features will be assessed in about 400 members of 11 previously investigated extended pedigrees from the genetically isolated populations of Antioquia, Colombia and Costa Rica. These pedigrees were ascertained based on their including multiple individuals affected with severe BP (BP-I). Therefore, these pedigrees should be enriched for the presence of BP-associated alleles for the various endophenotypic features. Any of the endophenotypes that demonstrate familial aggregation will be used for genomewide QTL linkage and association analysis of the complete pedigrees using high-resolution genomewide genotypes (for single nucleotide polymorphisms, SNPs) that we will obtain in this project. The study will take advantage of the well-characterized pedigrees and extensive genealogical and clinical characterization already undertaken by members of the collaborative team on these pedigrees. The genetic homogeneity of the two study populations should enhance the probability that this project will identify QTL associated with BP. Future studies will use the QTL to identify sequence variants that may shed light on the pathophysiology of BP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH075007-03
Application #
7596842
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Lehner, Thomas
Project Start
2007-06-20
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
3
Fiscal Year
2009
Total Cost
$505,275
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hibar, D P; Westlye, L T; Doan, N T et al. (2018) Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry 23:932-942
Peterson, Christine B; Service, Susan K; Jasinska, Anna J et al. (2016) Characterization of Expression Quantitative Trait Loci in Pedigrees from Colombia and Costa Rica Ascertained for Bipolar Disorder. PLoS Genet 12:e1006046
Pagani, Lucia; St Clair, Patricia A; Teshiba, Terri M et al. (2016) Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder. Proc Natl Acad Sci U S A 113:E754-61
Hibar, D P; Westlye, L T; van Erp, T G M et al. (2016) Subcortical volumetric abnormalities in bipolar disorder. Mol Psychiatry 21:1710-1716
Fears, Scott C; Schür, Remmelt; Sjouwerman, Rachel et al. (2015) Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder. Brain 138:2087-102
Fears, Scott C; Service, Susan K; Kremeyer, Barbara et al. (2014) Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees. JAMA Psychiatry 71:375-87
Zhang, Zhongyang; Lange, Kenneth; Sabatti, Chiara (2012) Reconstructing DNA copy number by joint segmentation of multiple sequences. BMC Bioinformatics 13:205
Reich, David; Patterson, Nick; Campbell, Desmond et al. (2012) Reconstructing Native American population history. Nature 488:370-4
Congdon, Eliza; Poldrack, Russell A; Freimer, Nelson B (2010) Neurocognitive phenotypes and genetic dissection of disorders of brain and behavior. Neuron 68:218-30
Kremeyer, B; Garcia, J; Muller, H et al. (2010) Genome-wide linkage scan of bipolar disorder in a Colombian population isolate replicates Loci on chromosomes 7p21-22, 1p31, 16p12 and 21q21-22 and identifies a novel locus on chromosome 12q. Hum Hered 70:255-68

Showing the most recent 10 out of 12 publications