Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein on analyses of existing family data from the Beaver Dam Eye Study. A private census of the town and township of Beaver Dam, Wisconsin was performed and all individuals between the ages of 43-84 were asked to enroll, given extensive eye examinations and asked to fill out a questionnaire that measures environmental risk factor exposures. We have previously analyzed STRP genome-wide scan (GWS) data on the entire Beaver Dam cohort of families for glaucoma, IOP, refractive error, myopia, hyperopia, and various forms of cataracts. We published 2 manuscripts in Archives of Ophthalmology this year detailing our linkage results for myopia/hyperopia and IOP/glaucoma, a letter to the editor is in press that highlights a possible combined glaucoma/high IOP risk locus, and a commentary on our glaucoma work was highlighted in JAMA (Pasquale et al, 2007). Genotyping for a SNP linkage panel was just completed at CIDR and will be released shortly. This will give us increased power for linkage with multiple traits including: refraction, myopia, nuclear sclerosis, etc. Dense SNPs for finemapping of Chromosome 19 for IOP and 2 smaller glaucoma-associated regions on chromosomes 5 and 6 will be genotyped and analyzed in the next fiscal year.? ? A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 5 populations. Analyses of refractive error in the Ashkenazi Jewish and Amish families have revealed evidence of a QTL on chromosome 1. A set of about 1500 SNPs were genotyped in our Ashkenazi and Amish families to follow up the linkage of refractive error on chromosome 1; these data analyses are ongoing. New families have been genotyped for a genome wide scan and a paper presenting confirmation of our previous chromosome 22 linkage results for myopia in these new Ashkenazi families has been published. Two papers describing our myopia and refractive error linkage results in a set of African-American families and a set of Caucasian familes are in preparation. ? ? Dr. Bailey-Wilson and several members of her group have received permission to analyze genetic data from the Framingham Eye Study and Offspring Study cohorts. The sample consists of about 1100 nuclear families whose members have been phenotyped extensively and genotyped for 116,000 SNPs and 600 microsatellite marker loci. Genomewide linkage and association analyses of traits related to myopia and hyperopia have begun in this fiscal year and next year we will begin similar analyses of the glaucoma related traits (IOP, Cup-to Disc, Glaucoma).? ? Dr. Bailey-Wilson is advising Dr. Arash Etemadi on familial aggregation and segregation analyses of family data from the Tehran Eye Study. A paper was published this year showing strong patterns of aggregation of myopia in this population, consistent with other populations around the world. Segregation analyses are ongoing.? ? Drs. Wojciechowski and Bailey-Wilson have started a new collaboration with Drs. Chris Murphy, Donald Mutti and Edwin Stone on a study of myopia in English springer spaniel dogs, a model organism for human myopia. Dr. Stones laboratory will perform genotyping using a recently developed SNP chip for dogs, and we will perform the analyses.? ? Dr. Bailey-Wilson is a member of a collaborative study of Attention Deficit Hyperactivity Disorder, collaborating with Drs. Max Muenke and Dr. Mauricio Arcos-Burgos of NHGRI and University of Antioquia, Columbia. Dr. Bailey-Wilsons role is to help with study design and to serve as advising statistical geneticist on the project. Genome-wide scan genotyping and linkage analysis has been completed on the first set of families followed by finemapping. We have previously shown evidence of linkage of ADHD to 4q132, 5q333, 11q22, and 17p11. Association studies have been performed to follow up our linkage results, and significant associations have been replicated in additional samples. Papers are in preparation.? ? Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic, Dr. Diego Wyszynski of Boston University and Dr. Terri Beaty of Johns Hopkins School of Public Health on a linkage study of oral clefts. Data collection is ongoing in the Syrian Arab Republic. New Syrian families have been genotyped for genome-wide scan markers and analyses of these data are ongoing.? ? Dr. Bailey-Wilson is working with Drs. Forbes Porter of NIH and Elaine Tierney of Kennedy Krieger on a genetic study of autism. Evidence for linkage of autistic individuals with hypocholesterolemia has been found. Confirmation in additional data is underway.? ? Another set of projects led by Dr. Priya Duggal, a senior postdoctoral trainee in the Section, encompass the human genetic predisposition to infectious diseases including Visceral leishmaniasis, Amebiasis and HIV/AIDS.? ? Dr. Duggal collaborates with Dr. Mary Wilson of the University of Iowa and ? Dr. Selma Jeronimo of Natal, Brazil on the study of Visceral leishmaniasis (VL).? VL is a potentially fatal disease caused by the protozoan Leishmania chagasi that is carried by the sandfly. We have completed a genome wide linkage scan for the DTH immune response, and the manuscript (Jeronimo et al is in press at JID). We are currently choosing a panel of 7600 SNPs to finemap the regions in and around our linkage peaks. ? ? Dr. Duggal collaborates with Dr. William Petri of the University of Virginia and Dr. Rashidul Haque at the ICDDR,B, Dhaka, Bangladesh on the host susceptibility to Amebiasis. Amebiasis is a large contributor to diarrheal disease in the developing world, and is caused by infection of the intestine by the parasite Entamoeba histolytica. This past year we published a manuscript on IFN-g and malnutrition and stunting in our cohort of children (Haque et al. AJTMH 2007). In addition, we identified an association with HLA class II alleles and cryptosporidium, another cause of diarrheal disease in these children (Kirkpatrick et al., in press JID) and another is under review. We have genotyped tagging SNPs in 90 candidate genes for 450 children in this study. Of the 20 genes already analyzed, we have identified a strong association with a functional coding SNP in the Leptin Receptor gene.? ? Dr. Duggal also aims to understand genetic host susceptibility to HIV/AIDS, using a cohort of 3000 injection drug users in Baltimore, Maryland that participate in the AIDS Link to Intravenous Experience (ALIVE). Part of the APOBEC compex is the CUL5 factor; we have identified a cluster of haplotypes driven by 3 SNPs that influences progression to AIDS, and also has a strong influence on CD4 cell counts. There is also a strong additive interaction with our previous finding in APOBEC3G. A paper was published earlier this year in PLOS genetics (An et al, 2007).? ? Another project, led by Dr. Elizabeth Gillanders, a postdoctoral fellow in the section, is a collaborative study of Neural Tube Defects (NTDs) with Dr. Larry Brody of NHGRI. NTDs are one of the most common birth defects with a prevalence of about 1/1000 live births. NTSs are known to have a large genetic component and to often be preventable by folic acid therapy. We analyzed a 1536 SNPs in 83 candidate genes selected from the folate/vitamin B12 pathway, genes involved in transport of folate or vitamin B12 and genes implicated in NTD risk from mouse models (transcription or developmental genes) in about 300 NTD cases and their parents and in about 300 Irish unaffected controls. We have performed case-control and family-based tests of association. Additional analyses are ongoing.
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