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 also 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. We have published evidence of a myopia risk locus on chromosome 10q in our Chinese families this year (1) using data from the Family Myopia Study, which is the first such study of linkage of non-pathogenic myopia in an Asian population. We also published results from another case-control genome-wide association study that used the AREDS data as controls (2). 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 second astigmatism meta-analysis was published this year (3). We have also completed analyses of myopia on the AREDS data for several published and ongoing CREAM meta-analyses leading to discovery this year of additional common risk alleles of small effect (4). This new work implicates light-induced signaling as a driver of refractive error development. In 2017, we completed a new project with CREAM, whereby our group recalled 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. We are currently performing quality control analyses of these data and were selected by the members of CREAM to lead the analyses of the CREAM exome chip data to attempt to detect moderately-rare genetic variants that contribute to the development of refractive errors. 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 along with similar data from multiplex families from other members of our familial oral clefts consortium. One paper presenting results of some of these analyses, examining the effects of copy number polymorphisms on oral cleft risk in these highly multiplex families was published this year (5) and another that identified candidate risk rare variants in a large Syrian family was also published this year (6). Another paper was recently accepted for publication. Dr. Bailey-Wilson is collaborating with Dr. Claire Simpson, University of Tennessee Health Sciences Center, Dr. Forbes Porter of NICHD/NIH and Dr. Elaine Tierney of Kennedy Krieger Institute on a genetic study of autism. Dr. Simpson, one of my former trainees, has taken over as the leader of this project. Whole exome sequence data for all of the families is now being analyzed. 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 will be preparing manuscripts reporting on results from 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 were completed, using methods available in Golden Helix SVS and other family-based methods. Strong linkage evidence of the existence of susceptibility loci in two different chromosomal regions (different genes in different families) was found and a manuscript presenting these results, first-authored by Dr. Anthony Musolf, a fellow in SGS, is under review. 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 have been published and others are in preparation. This year we published work showing that the FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation (7). Dr. Bailey-Wilson and her postdoctoral fellow, Dr. Candace Middlebrooks, in collaboration with Vence Bonham (NHGRI) and his group, continued to study genetic risk factors for the wide range of clinical manifestations related to sickle cell disease that are not observed in all affected individuals. One of the many complications that may result is leg ulcers, observed in approximately 2-18% of U.S. sickle cell patients. Dr. Middlebrooks was awarded a 2017 NIMHD William G. Coleman, Jr., Ph.D. Minority Health and Health Disparities Research Innovation Award that will fund whole exome sequencing of patients from multiple families in order to carry out this investigation. Sample preparation was recently completed and we just received the sequence data. Quality control, alignment and variant calling, followed by risk analysis will be performed during the next year. Independently of Dr. Bailey-Wilson, Dr. Deyana Lewis, a fellow in SGS co-authored a paper arising from her PhD dissertation work (8).
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