Browsing by Author "Wysocka, Joanna"

Now showing 1 - 7 of 7
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    3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies
    (Public Library of Science, 2021-05-13) Hoskens, Hanne; Liu, Dongjing; Naqvi, Sahin; Lee, Myoung Keun; Eller, Ryan J.; Indencleef, Karlijne; White, Julie D.; Li, Jiarui; Larmuseau, Maarten H. D.; Hens, Greet; Wysocka, Joanna; Walsh, Susan; Richmond, Stephen; Shriver, Mark D.; Shaffer, John R.; Peeters, Hilde; Weinberg, Seth M.; Claes, Peter; Biology, School of Science
    The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.
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    Decoding the Human Face: Progress and Challenges in Understanding the Genetics of Craniofacial Morp
    (Annual Reviews, 2022) Naqvi, Sahin; Hoskens, Hanne; Wilke, Franziska; Weinberg, Seth M.; Shaffer, John R.; Walsh, Susan; Shriver, Mark D.; Wysocka, Joanna; Claes, Peter; Biology, School of Science
    Variations in the form of the human face, which plays a role in our individual identities and societal interactions, have fascinated scientists and artists alike. Here, we review our current understanding of the genetics underlying variation in craniofacial morphology and disease-associated dysmorphology, synthesizing decades of progress on Mendelian syndromes in addition to more recent results from genome-wide association studies of human facial shape and disease risk. We also discuss the various approaches used to phenotype and quantify facial shape, which are of particular importance due to the complex, multipartite nature of the craniofacial form. We close by discussing how experimental studies have contributed and will further contribute to our understanding of human genetic variation and then proposing future directions and applications for the field.
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    Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations
    (Public Library of Science, 2021-08-19) Liu, Chenxing; Lee, Myoung Keun; Naqvi, Sahin; Hoskens, Hanne; Liu, Dongjing; White, Julie D.; Indencleef, Karlijne; Matthews, Harold; Eller, Ryan J.; Li, Jiarui; Mohammed, Jaaved; Swigut, Tomek; Richmond, Stephen; Manyama, Mange; Hallgrímsson, Benedikt; Spritz, Richard A.; Feingold, Eleanor; Marazita, Mary L.; Wysocka, Joanna; Walsh, Susan; Shriver, Mark D.; Claes, Peter; Weinberg, Seth M.; Shaffer, John R.; Biology, School of Science
    Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10-8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10-10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation.
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    Inappropriate p53 Activation During Development Induces Features of CHARGE Syndrome
    (Nature Publishing Group, 2014-10-09) Van Nostrand, Jeanine L.; Brady, Colleen A.; Jung, Heiyoun; Fuentes, Daniel R.; Kozak, Margaret M.; Johnson, Thomas M.; Lin, Chieh-Yu; Lin, Chien-Jung; Swiderski, Donald L.; Vogel, Hannes; Bernstein, Jonathan A.; Attié-Bitach, Tania; Chang, Ching-Pin; Wysocka, Joanna; Martin, Donna M.; Attardi, Laura D.; Department of Medicine, IU School of Medicine
    CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.
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    Insights into the genetic architecture of the human face
    (Springer Nature, 2021) White, Julie D.; Indencleef, Karlijne; Naqvi, Sahin; Eller, Ryan J.; Hoskens, Hanne; Roosenboom, Jasmien; Lee, Myoung Keun; Li, Jiarui; Mohammed, Jaaved; Richmond, Stephen; Quillen, Ellen E.; Norton, Heather L.; Feingold, Eleanor; Swigut, Tomek; Marazita, Mary L.; Peeters, Hilde; Hens, Greet; Shaffer, John R.; Wysocka, Joanna; Walsh, Susan; Weinberg, Seth M.; Shriver, Mark D.; Claes, Peter; Biology, School of Science
    The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.
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    Shared heritability of human face and brain shape
    (Springer Nature, 2021) Naqvi, Sahin; Sleyp, Yoeri; Hoskens, Hanne; Indencleef, Karlijne; Spence, Jeffrey P.; Bruffaerts, Rose; Radwan, Ahmed; Eller, Ryan J.; Richmond, Stephen; Shriver, Mark D.; Shaffer, John R.; Weinberg, Seth M.; Walsh, Susan; Thompson, James; Pritchard, Jonathan K.; Sunaert, Stefan; Peeters, Hilde; Wysocka, Joanna; Claes, Peter; Biology, School of Science
    Evidence from model organisms and clinical genetics suggests coordination between the developing brain and face, but the role of this link in common genetic variation remains unknown. We performed a multivariate genome-wide association study of cortical surface morphology in 19,644 individuals of European ancestry, identifying 472 genomic loci influencing brain shape, of which 76 are also linked to face shape. Shared loci include transcription factors involved in craniofacial development, as well as members of signaling pathways implicated in brain-face cross-talk. Brain shape heritability is equivalently enriched near regulatory regions active in either forebrain organoids or facial progenitors. However, we do not detect significant overlap between shared brain-face genome-wide association study signals and variants affecting behavioral-cognitive traits. These results suggest that early in embryogenesis, the face and brain mutually shape each other through both structural effects and paracrine signaling, but this interplay may not impact later brain development associated with cognitive function.
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    The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation
    (Frontiers Media, 2021-02-22) Indencleef, Karlijne; Hoskens, Hanne; Lee, Myoung Keun; White, Julie D.; Liu, Chenxing; Eller, Ryan J.; Naqvi, Sahin; Wehby, George L.; Moreno Uribe, Lina M.; Hecht, Jacqueline T.; Long, Ross E., Jr.; Christensen, Kaare; Deleyiannis, Frederic W.; Walsh, Susan; Shriver, Mark D.; Richmond, Stephen; Wysocka, Joanna; Peeters, Hilde; Shaffer, John R.; Marazita, Mary L.; Hens, Greet; Weinberg, Seth M.; Claes, Peter; Biology, School of Science
    Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10–3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10–8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10–10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.