Genetic Epidemiology of Complex Traits

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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. 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 myopia risk loci on in our Ashkenazi Jewish, Chinese, African-American and Amish families in previous years using data from the Family Myopia Study. We are currently analyzing whole genome sequence data in our most informative Amish and African-American families and currently sequencing more families. Ongoing analyses of these data will continue in collaboration with Dr. Claire Simpson at UTHSC, a former trainee in the Statistical Genetics Section, upon Dr. Bailey-Wilsons retirement and transition to Scientist Emeritus. 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 co-led the CREAM study of astigmatism with Dr. Jeremy Guggenheim with two prior publications. We have also completed analyses of myopia, hyperopia and refractive error on the AREDS data for several published and ongoing CREAM meta-analyses. Our recent GWAS studies implicate light-induced signaling as a driver of refractive error development and also presented genes that were implicated as risk factors common to both myopia and hyperopia. Dr. Bailey-Wilson and her postdoctoral fellow, Dr. Anthony Musolf, are co-leading analyses of exome chip data in the CREAM consortium. Previously, we recalled all genotypes jointly across studies in CREAM that used the same Illumina Exome-chip genotyping platforms. Despite multiple legal problems surrounding genomic data sharing for the EU studies, we were able to complete these gene-based association analyses by combining a subset of the studies into a single mega-analysis discovery sample plus several other replication studies that were analyzed separately using our scripts. This work has detected multiple novel significant genes that contribute to the development of refractive errors. A publication of the refractive error results is under review and future analyses will address other related traits, including myopia, hyperopia and astigmatism. These future studies will be conducted in collaboration with Dr. Deyana Lewis at Morehouse College of Medicine. This year we have also published two other CREAM analyses, including analysis of exome sequence data in the UK Biobank and an association analysis contrasting genes associated with eye size versus those associated with myopia risk (1-2). 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. Dr. Albacha-Hejazi continues our study enrolling families from the Syrian Arab Republic who have multiple family members affected with non-syndromic oral clefts. Previously, we have studied gene-gene interactions within the WNT pathway for nonsyndromic oral clefts using Asian and European trio data and analyzed whole-exome and whole-genome sequence data of selected members of our multiplex pedigrees along with multiplex families from other members of our familial oral clefts consortium, publishing these results. We are currently analyzing WGS data from some families and are sequencing additional families this year. Future work will be in collaboration with Dr. Claire Simpson at UTHSC and Dr. Albacha-Hejazi. Dr. Bailey-Wilson and her postdoc, Dr. Anthony Musolf, are 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. Our WES analyses revealed strong linkage evidence of the existence of susceptibility loci in two different chromosomal regions (different genes in different families) and was published 2019. We are currently working closely with Dr. Heiss to follow-up the candidate genes discovered in this study and are analyzing WGS data. Future work will be done in collaboration with Dr. Anthony Musolf who will transition to a Special Volunteer position with Dr. Heiss at NINDS. 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. We previously published multiple applied association studies of various metabolic traits in this sample of young, healthy Irish students. We applIed our new machine learning methods to several traits from this dataset to determine if there is evidence for epistatic interactions in any of these traits. Future work will be in collaboration with Dr. Cheryl Cropp who is transitioning to a Special Volunteer position with Dr. Brody. Dr. Bailey-Wilson and her postdoc, Dr. Candace Middlebrooks, and her post-Bacc IRTA, Jordan Connors, 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 (SCD) 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 funded whole genome sequencing of SCD patients from multiple families in order to carry out this investigation. Both Dr. Bonham and Dr. Bailey-Wilson used their research funds to sequence additional members of this study. Previously, we analyzed WGS data on 121 sickle cell patients, (53 who had leg ulcers and 68 who did not have leg ulcers) to identify genetic variation that may contribute to increased risk for leg ulcers but did not obtain genome-wide significant results. This year we analyzed new WGS data on additional SCD patients and detected significant results. These results were presented at the recent European Society of Human Genetics meeting and a manuscript is in preparation. Dr. Bailey-Wilson is also collaborating with Drs. Tierney and Porter on a study of autism. One new paper has been published presenting results of our lipid analyses (3). Dr. Musolf has been collaborating with Dr. Cristina Justice on association analyses of craniosynostosis. This year they published a paper presenting results of their sequence analysis of regions showing association with various subtypes of this disorder (4). Dr. Bailey-Wilson also guided statistical analyses of data for a study of Niemann-Pick disease modifier loci this year, in collaboration with Dr. Porter at NICHD and paper was published (5).