Pamela Sklar - US grants

DESCRIPTION (provided by applicant): A strong genetic basis for bipolar disorder has been demonstrated by family and twin studies, yet classical genetic linkage analyses have yet to define relevant loci. Thus, multiple genes, each conferring a moderate increase in risk may underlie susceptibility to this disorder. We propose using large-scale association studies (of the transmission disequilibrium design) to identify alleles conferring increased risk for bipolar disease. This approach is complementary to linkage analyses and takes advantage of data from linkage analyses. We hypothesize that certain areas which have yielded linkage signals in three or more whole genome scans may harbor disease alleles of moderate individual impact, but of large potential population impact. Thus, we will focus on genes/SNPs from these areas. Additionally, in selecting further genes for our association studies, we will take into account biochemical and mRNA expression studies that are beyond the scope of this grant, but which will likely identify additional interesting genes to genotype. Thus, triangulating on candidate genes using knowledge obtained from linkage analysis, biochemical and expression studies is a promising approach to identifying risk alleles for bipolar disease. We have developed a robust, inexpensive genotyping method, have gained access to extensive, patient-parent trios, will benefit from the analytical and informatics expertise of the Whitehead Institute Center for Genome Research and are therefore poised to proceed with a rationally designed, large-scale association study of bipolar disease which will include analyses of upwards of 2,000,000 genotypes.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] This revised collaborative R01 application is designed to identify susceptibility genes for bipolar disorder (BD) by testing single nucleotide polymorphisms (SNPs) across chromosomal regions previously linked to BD. Our proposal is an ancillary study to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large treatment study involving approximately 5000 affected individuals. The sample will consist of consenting probands from STEP-BD (n = 1780), consenting family members, and a sample of unrelated controls. Because of its unprecedented size and longitudinal nature, STEP-BD provides a unique opportunity for the genetic dissection of BD. We will conduct the study in stages as follows: 1) perform a meta-analysis of available genome scans of BD to identify regions most likely to harbor susceptibility loci, 2) use pooled genotyping methods to test SNPs under these linkage peaks in a Screening Sample of 550 cases and 550 unrelated controls, 3) follow-up positive associations in a Family-Based Sample of 1361 nuclear families using family-based and haplotype analyses with a more focused and dense SNP map, and 4) perform secondary analyses to evaluate epitasis among associated loci and examine phenotypic subtypes. This proposal combines the advantages of systematic phenotyping and statistical power offered by the STEP-BD cohort together with innovative molecular and statistical genetic methods to permit rigorous evaluation of chromosomal regions most strongly implicated by prior linkage studies. The feasibility of this proposal has been further enhanced since the previous submission because NIMH will be separately funding the collection of DNA and phenotypic data from STEP-BD cases to establish a repository for the scientific community. Moreover, Dr. Nimgaonkar and Dr. Smoller (PIs for the current proposal) will be co-directing this effort on behalf of the STEP-BD study. [unreadable] [unreadable] Identification of liability genes would represent a major advance in understanding the pathophysiology of BD, and might guide the development of more effective and targeted treatments. An important dividend of this large study will be the expansion of the repository to include DNA data on relatives and on an independent sample of controls, thus facilitating future genetic studies. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Prepulse inhibition of startle (PPI) is a neurophysiological trait that is impaired in schizophrenia patients and varies among inbred mouse strains. We have studied chromosome substitution mouse strains (consomic strains) derived from C57BL/6J and A/J mice to identify chromosomes that harbor PPI quantitative trait loci (QTLs), and have obtained evidence for one or more PPI genes on mouse chromosome 16. Since our original application, we have rapidly completed intercross mapping, allowing us to identify two significant PPI QTLs on chromosome 16 (LODs = 3.9 and 4.6) that are 3.5 cM and 5.5 cM in size. We propose to identify the mouse chromosome 16 PPI genes using a multi-faceted approach that incorporates inbred strain haplotype mapping and mRNA expression profiling. We will first refine the chromosome 16 QTLs using haplotype mapping across multiple inbred mouse strains known to vary in PPI. In parallel, we will perform backcrosses of mice segregating each chromosome 16 QTL and test recombinant inbred strains for PPI to assist in refining the loci. We will then perform mRNA expression studies of relevant brain regions in the C57BL/6J and chromosome 16 substitution strains to identify differentially expressed genes as candidate PPI genes. These data will be translated into the human studies ongoing in our lab to determine whether the orthologs of the candidate mouse PPI genes are involved in human PPI or schizophrenia risk. We will carry out this aim by constructing human haplotype maps of candidate PPI genes identified by mapping and profiling, and then testing for association with schizophrenia and PPI in our patient samples. This proposal is a pilot study to identify genes involved in PPI and perhaps schizophrenia, and is also a proof-of-principle that this multi-faceted approach could be widely applicable to the study of complex human traits. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Schizophrenia is a common psychotic disorder with peak incidence in early adulthood that often leads to lifelong morbidity. Several candidate genes for schizophrenia have been replicated in independent samples;each accounts for only a small increase in risk for an individual, and taken together they account for only a small percentage of the overall population risk of schizophrenia. Thus, identification of additional risk genes is crucial. In this revised application, we propose to identify the genetic variation located in chromosomal region 5q31-35 that leads to increased susceptibility to schizophrenia. Linkage to this region has been detected in multiple populations and thus identification of a candidate gene for association with schizophrenia is likely to identify a general risk factor. Prior to detailed haplotype mapping, a three-pronged approach to narrow the locus will be taken that includes detailed genealogy, joint linkage analysis with other investigators, and fine mapping in families with many affected members. Within the narrowed region, we will then commence screening association studies initially focusing on strong biological candidate genes in the 5q locus. Individual SNPs and haplotypes will be tested for association with schizophrenia in a sample of Portuguese schizophrenia patients (n=631 affecteds). Nominally positive results will be followed up in a large replication sample that is a collaboration between four academic centers (n=3,545 DNAs). Further testing of the linked region will occur in the Azorean samples by an interval-based approach with novel sliding window statistical analyses. In order to determine the interactions between the chromosome 5 locus and other loci, haplotype maps will be created for genes previously implicated in schizophrenia. Individual haplotypes in these genes will be tested for association in the screening sample and for gene-gene interactions with any gene identified on chromosome 5q. In depth phenotypic investigation by latent class analysis will be coupled with the haplotype analyses to identify subgroups of schizophrenia. We expect these studies to be significant in that they will identify a common risk factor for schizophrenia and help elucidate its role in schizophrenia risk.

DESCRIPTION (provided by applicant): Bipolar disorder (BPD) is a major public health priority, responsible for a vast burden of disability, personal suffering, and economic cost. Genetic susceptibility is the strongest known risk factor for BPD, and the identification of specific susceptibility genes would have enormous implications for advancing our understanding of the biology of BPD and revealing novel targets for treatment. The limited success to date of genetic studies of BPD has been due to its complex genetic architecture that likely includes many contributing loci of modest effect. Advances in population genetics and genotyping technologies have recently made the genetic dissection of complex disorders like BPD a feasible project. Genomewide association studies (GWAS) have already identified susceptibility variants underlying a range of other common medical disorders. However, it has become clear that much larger samples than are currently available will be needed to achieve such successes for BPD. This application is a response by an international consortium of investigators to RFA-MH-08-130: "Genomic Parsing of Bipolar Disorder and Schizophrenia: Studies of Large Cohorts in the U.S. and Across the Globe." The proposed International Cohort Collection for Bipolar Disorder (ICCBD) will address the need for large-scale DNA and data resources by establishing a uniquely large collection of samples and data from individuals with BPD. The specific aims of this application are 1) to ascertain and collect a large cohort of BPD cases (N = 9000) and unaffected controls (N = 9000) over five years at two U.S. sites (Boston and Los Angeles) using novel high-throughput phenotyping methods;and 2) 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 and Sweden. Separately funded genotyping and genetic analyses of these resources will fully characterize common polymorphisms and copy number variants in the full sample to detect novel risk variants and attempt replication of the most compelling prior findings. This resource, augmented by existing samples, will provide an unprecedented platform for the discovery of the genetic determinants of BPD. Bipolar disorder (BPD) is a major public health priority, responsible for a vast burden of disability, personal suffering, and economic cost. Genetic susceptibility is the strongest known risk factor for BPD, and the identification of specific susceptibility genes would have enormous implications for advancing our understanding of the biology of BPD and revealing novel targets for treatment. The limited success to date of genetic studies of BPD has been due to its complex genetic architecture that likely includes many contributing loci of modest effect. The proposed International Cohort Collection for Bipolar Disorder (ICCBD) will address the need for large-scale DNA and data resources by establishing a uniquely large collection of samples and data from individuals with BPD.