Shared heritability of human face and brain shape

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 C.; Pritchard, Jonathan K.; Sunaert, Stefan; Peeters, Hilde; Wysocka, Joanna; Claes, Peter

doi:10.1038/s41588-021-00827-w

Cited by 78 publications

(91 citation statements)

References 124 publications

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“…The CPCs on UKB discovery set found 432, 350, and 273 independent genetic loci associated with N0, ND, and NF, respectively (Figure 1E). The multivariate SNP-heritabilities 15 for N0, ND, and NF are 0.09 (95%CI 0.04 - 0.13), 0.06 (95%CI 0.02 - 0.10), and 0.05 (95%CI 0.01 - 0.09). The discovered loci explained 59%, 60%, and 58% of the SNP-heritabilities for N0, ND, and NF.…”

Section: Resultsmentioning

confidence: 98%

“…Type 2 Diabetes 49 and puberty timing 50 were also included. Based on a method that tailored for unsigned multivariate statistics 15 , we evaluated the signal shared between two traits using their summary statistics. The amount of shared signals was the Spearman correlation of the average SNP p values within each approximately independent LD blocks.…”

Section: Resultsmentioning

confidence: 99%

“…As proposed in other multivariate GWAS efforts 15 , we calculated the average for each of the approximately independent LD blocks 56 . Spearman correlations were performed for each pair of the GWAS results.…”

Section: Methodsmentioning

confidence: 99%

“…We rescaled the χ 2 according the extended methods 15 and then used the stratified LDSC to examine the relative enrichment in the cell-type specific annotations.…”

Section: Methodsmentioning

confidence: 99%

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Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

Fan

Loughnan

et al. 2021

Preprint

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It is important to understand the molecular determinants for microstructures of human brain. However, past genome-wide association studies (GWAS) on microstructures of human brain have had limited results due to methodological constraints. Here, we adopt advanced imaging processing methods and multivariate GWAS on two large scale imaging genetic datasets (UK Biobank and Adolescent Brain Cognitive Development study) to identify and validate key genetic association signals. We discovered 503 unique genetic loci that explained more than 50% of the average heritability across imaging features sensitive to tissue compartments. The genome-wide signals are strongly overlapped with neuropsychiatric diseases, cognitive functions, risk tolerance, and immune responses. Our results implicate the shared molecular mechanisms between tissue microstructures of brain and neuropsychiatric outcomes with astrocyte involvement in the early developmental stage.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…We rescaled the χ 2 according the extended methods 15 and then used the stratified LDSC to examine the relative enrichment in the cell-type specific annotations.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

Fan

Loughnan

et al. 2021

Preprint

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“…Craniofacial development closely corresponds to brain development. 42 Thus, classic facial features of FASD such as short palpebral fissure, smooth philtrum, and thin upper lip have been linked to brain abnormalities and cognitive outcome in FASD and have been used to diagnose children at risk of developing neurobehavioral deflicts. 9,37,38 Low-moderate PAE has also shown adverse associations with children's brain cognitive development, resulting in psychological and behavioral problems.…”

Section: Strengthens and Limitationsmentioning

confidence: 99%

Association between prenatal alcohol exposure and children’s facial shape. A prospective population-based cohort study

Liu

Kayser

Kushner

et al. 2021

Preprint

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IMPORTANCEChildren exposed to a high level of prenatal alcohol exposure (PAE) are more likely to develop fetal alcohol spectrum disorder with adverse phenotypes on their faces. However, it is still poorly understood, which level of PAE is associated with facial manifestation and if such associations persist during childhood.OBJECTIVETo examine the association between PAE and children’s facial phenotype in a prospective multi-ethnic population-based study.DESIGN, SETTING, AND PARTICIPANTSThis study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. Children had a 3D facial image taken at ages 9 (n=3160) and 13 years (n=2492).EXPOSURESWe defined 6 levels of PAE based on the frequency and dose of alcohol consumption, and defined three tiers based on the timing of alcohol exposure of the unborn child.MAIN OUTCOMES AND MEASURESFor image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 endophenotypes representing facial morphology. These facial endophenotypes were used as dependent variables in a linear regression analysis to search for associations with PAE. Finally, to detect specific facial components associated with PAE, we mapped statistically significant endophenotypes back to the 3D facial shape. We generated heatmaps to display the facial changes associated with PAE. PAE prediction based on facial shape was also performed; the prediction accuracy was estimated by area under the receiver operating characteristic curve (AUC).RESULTSA significant association between PAE and facial shape was found in the 9-year-old children, at all levels of alcohol exposure: the higher the level of exposure, the stronger the association. Moreover, PAE before and during pregnancy was associated with facial shape. The most common detected facial phenotypes included turned-up nose tip, shortened nose, turned-out jaw and turned-in lower-eyelid-related regions. For the 13-year-old children, the associations were weaker and the AUCs lower than those of the 9-years-old children.CONCLUSIONS AND RELEVANCEPAE before and during pregnancy, even at low level, is associated with the facial shape of children, and these associations become weaker as children grow older.Key pointsQuestionsWhich level of prenatal alcohol exposure (PAE) is associated with children’s facial shape at different lifetimes?FindingsA 3D facial phenotype analysis of 9- (N=3160) and 13- (N=2492) year-old children was conducted. PAE before and during pregnancy, even at low level, associates with the children’s facial shape; the association becomes weaker as children grow older.MeaningThe results suggest avoiding drinking alcohol at least three months before and during pregnancy is the safest option for the child. More research is needed to investigate the consequences of PAE on children; the discovered facial phenotypes could be used as a biomarker for further investigations.

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Perspectives on the future of dysmorphology

Solomon

Adam

Fong

et al. 2022

American J of Med Genetics Pt A

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The field of clinical genetics and genomics continues to evolve. In the past few decades, milestones like the initial sequencing of the human genome, dramatic changes in sequencing technologies, and the introduction of artificial intelligence, have upended the field and offered fascinating new insights. Though difficult to predict the precise paths the field will follow, rapid change may continue to be inevitable. Within genetics, the practice of dysmorphology, as defined by pioneering geneticist David W. Smith in the 1960s as “the study of, or general subject of abnormal development of tissue form” has also been affected by technological advances as well as more general trends in biomedicine. To address possibilities, potential, and perils regarding the future of dysmorphology, a group of clinical geneticists, representing different career stages, areas of focus, and geographic regions, have contributed to this piece by providing insights about how the practice of dysmorphology will develop over the next several decades.

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Shared heritability of human face and brain shape

Cited by 78 publications

References 124 publications

Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

Association between prenatal alcohol exposure and children’s facial shape. A prospective population-based cohort study

Perspectives on the future of dysmorphology

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