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 Ashkenazi Jewish and Amish families this year (1, 2) using data from the Family Myopia Study. Another paper presenting results from our African-American families is in preparation. The results of these studies have served as justification for our successful application for whole genome sequencing in the most informative Amish and African-American families paid for through competition for central NHGRI funding at the NISC lab. The samples are at the sequencing lab and we expect to analyze these data in the upcoming year. 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 with two prior publications. We have also completed analyses of myopia on the AREDS data for several published and ongoing CREAM meta-analyses. This year, two papers built on our publication 4 from 2018 (Tedja et al., 2018). This paper implicates light-induced signaling as a driver of refractive error development. The new papers published this year looked at overlap of top myopia associations with MMD and at whether polygenic risk scores for myopia showed any correlation with risk of acute open angle glaucoma (3, 4). Dr. Bailey-Wilson and her postdoctoral fellow, Dr. Anthony Musolf, are co-leading analyses of exome chip data in the CREAM consortim. 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. We have completed performing quality control analyses of these data and are now performing the analyses of the CREAM exome chip data to attempt to detect moderately-rare genetic variants that contribute to the development of refractive errors. We expect multiple publications to result from this work in the next year. 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. Multiple papers have been published previously and this year, one paper that developed new methods and then applied them to our data was published (see HG000153-21). We recently successfully competed for central NHGRI funding for whole genome sequencing at the NISC lab for our most informative families and expect to analyze these data in the upcoming year. 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 published online awaiting print publication (5). 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 677CT variant of MTHFR is the major genetic modifier of biomarkers of folate status in this sample of young, healthy Irish students (6). This study was a motivating force for the development of the COMPASS-GWAS statistical methodology described in annual report HG000153-21. 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 This year we have been analyzing the whole exome sequence data. Quality control, alignment and variant calling have been performed and risk analysis will be performed during the next year.

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15
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2019
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National Human Genome Research Institute
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Shah, Rupal L; Li, Qing; Zhao, Wanting et al. (2018) A genome-wide association study of corneal astigmatism: The CREAM Consortium. Mol Vis 24:127-142
Chen, Ying; Gilbert, Melissa A; Grochowski, Christopher M et al. (2018) A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1. PLoS Genet 14:e1007532
Musolf, Anthony M; Simpson, Claire L; Long, Kyle A et al. (2018) Myopia in Chinese families shows linkage to 10q26.13. Mol Vis 24:29-42
Fu, Jack; Beaty, Terri H; Scott, Alan F et al. (2017) Whole exome association of rare deletions in multiplex oral cleft families. Genet Epidemiol 41:61-69
Afshari, Natalie A; Igo Jr, Robert P; Morris, Nathan J et al. (2017) Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy. Nat Commun 8:14898
Holzinger, Emily R; Verma, Shefali S; Moore, Carrie B et al. (2017) Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. BioData Min 10:25
Xie, Hongbo M; Werner, Petra; Stambolian, Dwight et al. (2017) Rare copy number variants in patients with congenital conotruncal heart defects. Birth Defects Res 109:271-295
Lewis, D D; Shaffer, J R; Feingold, E et al. (2017) Genetic Association ofMMP10,MMP14, andMMP16with Dental Caries. Int J Dent 2017:8465125
Velkova, Aneliya; Diaz, Jennifer E L; Pangilinan, Faith et al. (2017) The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation. Hum Mol Genet 26:4975-4988
Holzinger, Emily R; Li, Qing; Parker, Margaret M et al. (2017) Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families. Mol Genet Genomic Med 5:570-579

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