A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 populations, resulting in numerous publications in the past. We have recently published results of a genome-wide association study (GWAS) of refractive error in the AREDS, KORA, Framingham Eye Study (FES), the MESA study and the OGP-Talana study in Sardinia, with confirmation of the discoveries from these data in several other GWAS. During this year we have analyzed Exome SNP array genotyping in all of the Family Myopia Study families, the AREDS cohort and an additional 4000 unrelated individuals. We are analyzing these data using multiple approaches to detect rare variants that contribute to refractive error traits. Dr. Bailey-Wilson is also one of the leaders of CREAM, an international consortium on meta-analysis of refractive error related traits and is co-Chair of CREAM Analysis Working Group 2 and is Chair of the Biometrics Working Group. The collaborative analyses performed by CREAM will increase power to detect common alleles with small effects on refractive error as a quantitative trait and its related clinical disorders, myopia, hyperopia and astigmatism. Previously, we performed analyses on our AREDS, KORA and FES GWAS data for meta-analyses of refractive error by the CREAM consortium and were co-authors on multiple papers presenting these results. Dr. Bailey-Wilson is co-leading the CREAM study of astigmatism with Dr. Jeremy Guggenheim and our first astigmatism meta-analysis was published this year in 2015. We have also completed analyses of myopia on the AREDS data for several published (1-4) and ongoing CREAM meta-analyses and are also leading a second astigmatism meta-analysis. We have begun a new project with CREAM, whereby our group is recalling all genotypes jointly across studies in CREAM that used the same Illumina Exome-chip genotyping platforms. This is expected to improve the quality of all the genotype calls for rare variants and will make a major contribution to all of the planned CREAM meta-analyses of exome-chip data. Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic and Dr. Terri Beaty of Johns Hopkins Bloomberg School of Public Health on studies of oral clefts. We have performed a study attempting to identify gene-gene interactions within the WNT pathway for nonsyndromic oral clefts (with or without cleft palate) using Asian and European trio data. This project used some methods newly developed by our group as part of another Annual Report and was published in 2015 (Li et al., 2015). We are currently analyzing whole-exome and whole-genome sequence data of selected members of our multiplex pedigrees and a manuscript is under development. Dr. Bailey-Wilson is working with Drs. Forbes Porter of NICHD/NIH and Elaine Tierney of Kennedy Krieger Institute on a genetic study of autism. Evidence for excess hypocholesterolemia in autistic individuals has been observed in some multiplex families 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. Whole exome sequence data for all of the families is now being analyzed. Since the data were sequenced over a long time period, we are recalling all the data together and analyses will be ongoing over the next year. We are also collaborating with Drs. Sue Swedo and Audrey Thurm of NIMH/NIH to analyze WES of their very well phenotyped parent-child trios and families where at least one child is affected with autism. All of these data have now been sequenced and analyses are underway. Dr. Simpson, a former fellow in the Section and now an Assistant Professor at University of Tennessee Health Sciences Center will be taking over the lead on this project. 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 analyses have been completed in these families. Dr. Bailey-Wilson was awarded WES sequencing of these families through a competitive application to the National Intramural Sequencing Center (NISC) and WES analyses have been completed in all of our families. Analyses of these data are ongoing, using methods available in Golden Helix SVS and other family-based methods. Dr. Bailey-Wilson is also collaborating with Dr. Larry Brody and Dr. Alexander Wilson of NHGRI on analyses of GWAS data on metabolic traits in the Trinity Study of healthy young adults. This work is ongoing; several papers are in preparation or under review. A paper presenting evidence of genetic variants that influence circulating methyl malonic acid concentration in blood was published this year (5). Dr. Claire Simpson, a Staff Scientist at the time, has continued her collaboration with Dr. Steve Brant of Johns Hopkins School of Medicine. They are analyzing GWAS data on 500 African American Crohn's Disease patients. Dr. Simpson was a coauthor this year on a paper characterizing genetic loci that affect risk of IBD in African-Americans (6). Dr. Simpson has moved this project to University of Tennessee and this project will be discontinued in SGS in the future. Independently of Dr. Bailey-Wilson, Dr. Emily Holzinger, a fellow in SGS co-authored a paper on gene-gene interactions influencing body mass index (7) and Dr. Bashira Charles, a fellow in SGS at the time coauthored a paper on hypertension in African-Americans (8).
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