Genetic Epidemiology of Complex Traits

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

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 myopia risk loci on in our Ashkenazi Jewish, Chinese and Amish families in previous years using data from the Family Myopia Study. Another paper presenting results from our African-American families was published this year 1. We are currently analyzing whole genome sequence data in our most informative Amish and African-American families and successfully competed for funding to sequence more families. 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. Two new papers published this year examined genes that were implicated as risk factors common to both myopia and hyperopia 2 and summarized results across association and linkage studies of RE 3. 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. 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. 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. 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 recently successfully competed for central NHGRI funding for whole genome sequencing at the NHGRI NISC lab for all members of our most informative families. We are currently analyzing these WGS data and analyses will sequence additional families next year. 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. Dr. Bailey-Wilson was awarded WES sequencing of these families through a competitive application to the National Intramural Sequencing Center (NISC) and 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 plan to start analyses of WGS data soon. 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 are currently applying 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. Dr. Bailey-Wilson and her postdoc, 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 (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. This year 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. Although not genome-wide significant, our top hits include a variant on chromosome 21 near the TIAM1 gene (P-val = 1.01E-4) and on chromosome 20 near the ZFP64 gene (P-val = 1.08E-4), both of which have been associated with Amyotrophic Lateral Sclerosis (ALS). Considering that both of the top variants are on different chromosomes but are associated with the same disease, this may have some implication for a common disease mechanism between SCD-associated leg ulcers and ALS. The results from this study will remain inconclusive until additional study participants are analyzed. We plan to analyze new WGS data on additional SCD patients in the coming year and to combine the results with other SCD datasets. Dr. Bailey-Wilson is also collaborating with Drs. Angela Delaney and Janet Hall of NIEHS on studies of genetic contributions to risk of hypothalamic amenorrhea. Dr. Bailey-Wilson has advised on study design, statistical analyses, and interpretation of results. One new paper has been published presenting evidence for genetic contributions to risk of this disorder 4.