A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation

Bonfante, Betty; Faux, Pierre; Navarro, Nicolas; Mendoza‐Revilla, Javier; Dubied, Morgane; Montillot, Charlotte; Winchester, Emma Wentworth; Poloni, Lauriane; Varón‐González, Ceferino; Jones, Philip G.; Xiong, Zhenzhen; Fuentes-Guajardo, Macarena; Palmal, Sagnik; Chacón-Duque, Juan Camilo; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Jaramillo, Claudia; Arias, William; Barquera, Rodrigo; Everardo-Martínez, Paola; Sánchez-Quinto, Mirsha; Gómez-Valdés, Jorge; Villamil‐Ramírez, Hugo; Cerqueira, Caio César Silva de; Hünemeier, Tábita; Ramallo, Virgínia; Liu, Fan; Weinberg, Seth M.; Shaffer, John R.; Stergiakouli, Evie; Howe, Laurence J; Hysi, Pirro G.; Spector, Timothy D.; González‐José, Rolando; Schüler‐Faccini, Lavínia; Bortolini, Maria-Cátira; Acuña-Alonzo, Víctor; Canizales‐Quinteros, Samuel; Gallo, Carla; Poletti, Giovanni; Bedoya, Gabriel; Rothhammer, Francisco; Thauvin‐Robinet, Christel; Faivre, Laurence; Costedoat, Caroline; Balding, David J.; Cox, Timothy C.; Kayser, Manfred; Duplomb, Laurence; Yalcin, Binnaz; Cotney, Justin; Adhikari, Kaustubh; Ruiz-Linares, Andrés

doi:10.1126/sciadv.abc6160

Cited by 42 publications

(56 citation statements)

References 86 publications

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“…Compared to 2D landmarks, 3D landmarks are more robust against shifting, rotation, and scaling. Compared with the studies using micro‐CT images, 3D surface images may capture additional information from facial soft tissue thickness 7 …”

Section: Discussionmentioning

confidence: 99%

“…Compared with the studies using micro‐CT images, 3D surface images may capture additional information from facial soft tissue thickness. 7 …”

Section: Discussionmentioning

confidence: 99%

“…Several independent genome‐wide association studies (GWASs) on human facial morphology highlighted DNA variants in or closed to TBX15 and PAX1 with genome‐wide significant association with human facial phenotypes. 1 , 2 , 3 , 4 , 5 , 6 , 7 In particular, Xiong et al found DNA variants near TBX15 and PAX1 significantly associated with human face length and nose width, respectively. 1 Adhikari et al reported SNPs in TBX15 to be significantly associated with two human ear traits, folding of the antihelix and antitragus size.…”

Section: Introductionmentioning

confidence: 99%

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The effects of Tbx15 and Pax1 on facial and other physical morphology in mice

Xiong

et al. 2021

FASEB BioAdvances

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DNA variants in or close to the human TBX15 and PAX1 genes have been repeatedly associated with facial morphology in independent genome‐wide association studies, while their functional roles in determining facial morphology remain to be understood. We generated Tbx15 knockout (Tbx15−/−) and Pax1 knockout (Pax1−/−) mice by applying the one‐step CRISPR/Cas9 method. A total of 75 adult mice were used for subsequent phenotype analysis, including 38 Tbx15 mice (10 homozygous Tbx15−/−, 18 heterozygous Tbx15+/−, 10 wild‐type Tbx15+/+ WT littermates) and 37 Pax1 mice (12 homozygous Pax1−/−, 15 heterozygous Pax1+/−, 10 Pax1+/+ WT littermates). Facial and other physical morphological phenotypes were obtained from three‐dimensional (3D) images acquired with the HandySCAN BLACK scanner. Compared to WT littermates, the Tbx15−/− mutant mice had significantly shorter faces (p = 1.08E‐8, R2 = 0.61) and their ears were in a significantly lower position (p = 3.54E‐8, R2 = 0.62) manifesting a “droopy ear” characteristic. Besides these face alternations, Tbx15−/− mutant mice displayed significantly lower weight as well as shorter body and limb length. Pax1−/− mutant mice showed significantly longer noses (p = 1.14E‐5, R2 = 0.46) relative to WT littermates, but otherwise displayed less obvious morphological alterations than Tbx15−/− mutant mice did. We provide the first direct functional evidence that two well‐known and replicated human face genes, Tbx15 and Pax1, impact facial and other body morphology in mice. The general agreement between our findings in knock‐out mice with those from previous GWASs suggests that the functional evidence we established here in mice may also be relevant in humans.

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Section: Discussionmentioning

confidence: 99%

“…Compared with the studies using micro‐CT images, 3D surface images may capture additional information from facial soft tissue thickness. 7 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of Tbx15 and Pax1 on facial and other physical morphology in mice

Xiong

et al. 2021

FASEB BioAdvances

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“…In addition, the reconstructed rare haplotype variant may be known to be associated with a rare phenotype [e.g. a Denisovan haplotype was recently discovered to be associated with the lip thickness ( Bonfante et al, 2021 )], in which case the phenotypes (e.g. the facial appearance) of the human subject can be inferred.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Haplotype-based membership inference from summary genomic data

Tang

2021

Bioinformatics

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Motivation The availability of human genomic data, together with the enhanced capacity to process them, is leading to transformative technological advances in biomedical science and engineering. However, the public dissemination of such data has been difficult due to privacy concerns. Specifically, it has been shown that the presence of a human subject in a case group can be inferred from the shared summary statistics of the group, e.g. the allele frequencies, or even the presence/absence of genetic variants (e.g. shared by the Beacon project) in the group. These methods rely on the availability of the target’s genome, i.e. the DNA profile of a target human subject, and thus are often referred to as the membership inference method. Results In this article, we demonstrate the haplotypes, i.e. the sequence of single nucleotide variations (SNVs) showing strong genetic linkages in human genome databases, may be inferred from the summary of genomic data without using a target’s genome. Furthermore, novel haplotypes that did not appear in the database may be reconstructed solely from the allele frequencies from genomic datasets. These reconstructed haplotypes can be used for a haplotype-based membership inference algorithm to identify target subjects in a case group with greater power than existing methods based on SNVs. Availability and implementation The implementation of the membership inference algorithms is available at https://github.com/diybu/Haplotype-based-membership-inferences.

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“…A handful of rare variants have been identified in genes, however most are found in non-coding portions of the genome. We and others have shown that such variants are systematically enriched in sequences that obtain active chromatin states during early human craniofacial development, particularly those annotated as strong enhancers (Bonfante et al, 2021;Liu et al, 2021;Wilderman et al, 2018). Strong enhancers only active in developing craniofacial tissues were enriched for craniofacial related transcription factor (TF) binding sites and generally localized near genes implicated in craniofacial abnormalities.…”

Section: Introductionmentioning

confidence: 97%

Integrative analysis of transcriptomics in human craniofacial development reveals novel candidate disease genes

Yankee

Wilderman

Winchester

et al. 2022

Preprint

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Craniofacial disorders are among the most common of all congenital defects. A majority of craniofacial development occurs early in pregnancy and to fully understand how craniofacial defects arise, it is essential to observe gene expression during this critical time period. To address this we performed bulk and single-cell RNA-seq on human craniofacial tissue from embryonic development 4 to 8 weeks post conception. This data comprises the most comprehensive profiling of the transcriptome in the early developing human face to date. We identified 239 genes that were specifically expressed in craniofacial tissues relative to dozens of other human tissues and stages. We found that craniofacial specific enhancers are enriched within 400kb of these genes establishing putative regulatory interactions. To further understand how genes are organized in this program we constructed coexpression networks. Strong disease candidates are likely genes that are coexpressed with many other genes, serving as regulatory hubs within these networks. We leveraged large functional genomics databases including GTEx and GnomAD to reveal hub genes that are specifically expressed in craniofacial tissue and genes which are resistant to mutation in the normal healthy population. Our unbiased method revealed dozens of novel disease candidate genes that warrant further study.

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A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation

Cited by 42 publications

References 86 publications

The effects of Tbx15 and Pax1 on facial and other physical morphology in mice

The effects of Tbx15 and Pax1 on facial and other physical morphology in mice

Haplotype-based membership inference from summary genomic data

Integrative analysis of transcriptomics in human craniofacial development reveals novel candidate disease genes

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