Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein and Sudha Iyengar on analyses of existing family data from the Beaver Dam Eye Study (BDES). 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. Linkage analyses using a new SNP linkage panel with multiple traits including: refraction, myopia, nuclear sclerosis, etc are underway. Dense SNPs for finemapping of Chromosome 19 for IOP and 2 smaller glaucoma-associated regions on chromosomes 5 and 6 are currently underway. A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 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 analyses confirmed our previous linkage of a QTL for refractive error on 1p34-p36. During follow-up of our previous chromosome 22 linkage results for myopia, we have used association and sequencing methods to narrow the region to 3 candidate loci. We are carefully examining these candidates to determine which is the susceptibility locus and are currently performing additional extensive deep sequencing of this region. We found significant evidence of linkage of refractive error to chromosome 7q in the African-American pedigrees and are analyzing a finemapping panel of SNPs to follow-up this region. This year we published evidence of association of matrix metalloproteinase gene polymorphisms with refractive error in our Amish and Ashkenazi family data (4). Drs. Stambolian, Bailey-Wilson and Thomas Meitinger (Germany) are collaborating to perform a GWAS of refractive error in the AREDS and KORA population cohorts and genotyping is underway. Dr. Bailey-Wilson is also leading an international consortium on meta-analysis of refractive error and related traits which will increase power to detect common alleles with small effects on this eye trait and its related disorders, myopia and hyperopia. 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 over 500,000 SNPs and 600 microsatellite marker loci. Genomewide linkage and association analyses of traits related to myopia and hyperopia, refractive error and glaucoma related traits (IOP, Cup-to Disc, Glaucoma) are ongoing. 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-Wilson's 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. One candidate gene has been identified and a paper reporting evidence that a variant in the iatrophilin 3 gene contributes to risk of ADHD and predicts effectively of stimulant medication was published this year (1). 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 and more genotyping will be performed when enrollment of a total of 50 families informative for linkage is completed. We have also applied for funding of whole-exome sequencing of selected members of these unique pedigrees and will pursue this avenue of research if funds become available. 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 and additional family data are being collected. Special funding from the Office of the Director was sought and awarded to perform whole-exome sequencing of autistic patients with extreme cholesterol values and a sibling with either autism or autism spectrum disorder (ASD) to search for rare variants of large effect in this subset of patients with familial autism/ASD. This study is ongoing and we are seeking funding to extend our study to autistic patients with extreme hypocholesterolemia but who do not have siblings affected with ASD. Dr. Bailey-Wilson is collaborating with Dr. John Heiss on a study of Chiari Syndrome in Russia. This rare neurological syndrome is observed at increased frequency in several large families from a founder region there. Linkage and family-based association analyses are underway in these families. Dr. Bailey-Wilson also serves in an advisory role on study design and interpretation of results for the Familial Intracranial Aneurysm (IA) consortium. This consortium is using both linkage and genome-wide association methods to detect genetic predisposition to this type of familial strokes. Results of a 6000 SNP genome-wide linkage study previously yielded evidence for linkage of IA on chromosome 4q and chromosome 12p. Significant evidence for a gene x smoking interaction was detected on chromosome 7p. These results suggest it is unlikely that there is a single common variant with a strong effect in the majority of the IA families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms. Linkage analysis using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, showed evidence for linkage on chromosomes 11 and 6, which supports the concept of shared genetic risk for these different types of aneurysm. We are now pursuing a genome-wide association study to attempt to identify common alleles of small effect that may contribute to risk of this disorder. This year we have published results showing a relationship between smoking and replicated sequence variants in intracranial aneurysm (2). Dr. Bailey-Wilson also collaborates with Dr. Joan Marini of NICHD on studies of mutation age in a rare disorder, Lethal Recessive Type VIII Osteogenesis Imperfecta, in West Africans and African Americans. A manuscript is under review reporting these results. Dr. Bailey-Wilson also served in an advisory capacity to Dr. Ching-Yu Cheng, a Special Volunteer in the Statistical Genetics Section, on a study of primary angle-closure glaucoma, resulting in a publication on structure-function correlations using scanning laser polarimetry in this disorder (3).