Combined genome-wide association study of 136 quantitative ear morphology traits in multiple populations reveal 8 novel loci.

Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we quantitatively assessed 136 ear morphology traits using deep learning analysis of digital face images in 14,921 individuals from five different cohorts in Europe, Asia, and Latin America. Through GWAS meta-analysis and C-GWASs, a recently introduced method to effectively combine GWASs of many traits, we identified 16 genetic loci involved in various ear phenotypes, eight of which have not been previously associated with human ear features. Our findings suggest that ear morphology shares genetic determinants with other surface ectoderm-derived traits such as facial variation, mono eyebrow, and male pattern baldness. Our results enhance the genetic understanding of human ear morphology and shed light on the shared genetic contributors of different surface ectoderm-derived phenotypes. Additionally, gene editing experiments in mice have demonstrated that knocking out the newly ear-associated gene (Intu) and a previously ear-associated gene (Tbx15) causes deviating mouse ear morphology.

Impact of orthodontic-induced facial morphology changes on aesthetic evaluation: a retrospective study.

BACKGROUND: The profound influence of orthodontic treatments on facial aesthetics has been a topic of increasing interest. This study delves into the intricate interplay between orthodontic treatments, facial feature alterations, and aesthetic perceptions. METHODS: A total of 73 patients who had undergone orthodontic treatment were included in this study. Facial photographs were taken before and after treatment. Ten orthodontists provided facial aesthetic ratings (FAR) for each patient's frontal, profile, and overall views. 48 facial landmarks were manually placed by the orthodontists and normalized using Generalized Procrustes analysis (GPA). Two types of phenotypes were derived from facial landmarks. Global facial phenotypes were then extracted using principal component analysis (PCA). Additionally, 37 clinical features related to aesthetics and orthodontics were extracted. The association between facial features and changes in FAR after orthodontic treatment was determined using these two types of phenotypes. RESULTS: The FAR exhibited a high correlation among orthodontic experts, particularly in the profile view. The FAR increased after orthodontic treatment, especially in profile views. Extraction of premolars and orthognathic surgery were found to result in higher FAR change. For global facial phenotypes, the most noticeable changes in the frontal and profile views associated with FAR occurred in the lip area, characterized by inward retraction of the lips and slight chin protrusion in the profile view, as well as a decrease in lip height in the frontal view. The changes observed in the profile view were statistically more significant than those in the frontal view. These facial changes were consistent with the changes from orthodontic treatment. For clinical features, two profile features, namely pg.sm.hori and pg.n.ls, were found to be associated with FAR following orthodontic treatment. The highest FAR scores were achieved when pg.sm.hori was at 80° and pg.n.ls was at 8°. On the other hand, frontal clinical features had a subtle effect on FAR during orthodontic treatment. CONCLUSIONS: This study demonstrated that orthodontic treatment improves facial aesthetics, particularly at lip aera in the profile view. Profile clinical features, such as pg.sm.hori and pg.n.ls, are essential in orthodontic treatment which could increase facial aesthetics.

Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans.

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10(-10)) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10(-8)). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10(-11)) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure.

The massive assimilation of indigenous East Asian populations in the origin of Muslim Hui people inferred from paternal Y chromosome.

OBJECTIVES: The Hui people are the adherents of Muslim faith and distributing throughout China. There are two contrasting hypotheses about the origin and diversification of the Hui people, namely, the demic diffusion involving the mass movement of people or simple cultural diffusion. MATERIALS AND METHODS: We collected 621 unrelated male individuals from 23 Hui populations all over China. We comprehensively genotyped more than 100 informative Y-chromosomal single nucleotide polymorphisms and 17 Y-chromosomal short tandem repeats (STRs) on those samples. RESULTS: Co-analyzed with published worldwide populations, our results suggest the origin of Hui people has involved massive assimilation of indigenous East Asians with about 70% in total of the paternal ancestry could be traced back to East Asia and the left 30% to various regions in West Eurasia. DISCUSSION: The genetic structure of the extant Hui populations was primarily shaped by the indigenous East Asian populations as they contribute the majority part of the paternal lineages of Hui people. The West Eurasian admixture was probably a sex-biased male-driven process since we have not found such a high proportion of West Eurasian gene flow on autosomal STRs and maternal mtDNA.

EDARV370A associated facial characteristics in Uyghur population revealing further pleiotropic effects.

An adaptive variant of human Ectodysplasin receptor, EDARV370A, had undergone strong positive selection in East Asia. In mice and humans, EDARV370A was found to affect ectodermal-derived characteristics, including hair thickness, hair shape, active sweat gland density and teeth formation. Facial characteristics are also largely ectodermal derived. In this study, taking advantage of an admixed population of East Asian and European ancestry-the Uyghur, we aim to test whether EDARV370A is affecting facial characteristics and to investigate its pleiotropic nature and genetic model. In a sample of 1027 Uyghurs, we discover that EDARV370A is significantly associated with several facial characteristics, in particular shape of earlobe (P = 3.64 × 10 (-6) ) and type of chin (P = 9.23 × 10 (-5) ), with successful replication in other East Asian populations. Additionally, in this Uyghur population, we replicate previous association findings of incisors shoveling (P = 1.02 × 10 (-7) ), double incisors shoveling (P = 1.86 × 10 (-12) ) and hair straightness (P = 3.99 × 10 (-16) ), providing strong evidence supporting an additive model for the EDARV370A associations. Partial least square path model confirms EDARV370A systematically affect these weakly related ectodermal-derived characteristics, suggesting the pleiotropic effect of EDARV370A mainly plays roles in early embryo development. This study extends our knowledge about the pleiotropic nature of EDARV370A and provides potential clues to its adaptation fitness in human evolution.

Genome-wide scans reveal variants at EDAR predominantly affecting hair straightness in Han Chinese and Uyghur populations.

Hair straightness/curliness is one of the most conspicuous features of human variation and is particularly diverse among populations. A recent genome-wide scan found common variants in the Trichohyalin (TCHH) gene that are associated with hair straightness in Europeans, but different genes might affect this phenotype in other populations. By sampling 2899 Han Chinese, we performed the first genome-wide scan of hair straightness in East Asians, and found EDAR (rs3827760) as the predominant gene (P = 4.67 × 10-16), accounting for 3.66 % of the total variance. The candidate gene approach did not find further significant associations, suggesting that hair straightness may be affected by a large number of genes with subtle effects. Notably, genetic variants associated with hair straightness in Europeans are generally low in frequency in Han Chinese, and vice versa. To evaluate the relative contribution of these variants, we performed a second genome-wide scan in 709 samples from the Uyghur, an admixed population with both eastern and western Eurasian ancestries. In Uyghurs, both EDAR (rs3827760: P = 1.92 × 10-12) and TCHH (rs11803731: P = 1.46 × 10-3) are associated with hair straightness, but EDAR (OR 0.415) has a greater effect than TCHH (OR 0.575). We found no significant interaction between EDAR and TCHH (P = 0.645), suggesting that these two genes affect hair straightness through different mechanisms. Furthermore, haplotype analysis indicates that TCHH is not subject to selection. While EDAR is under strong selection in East Asia, it does not appear to be subject to selection after the admixture in Uyghurs. These suggest that hair straightness is unlikely a trait under selection.

Inferring population structure and demographic history using Y-STR data from worldwide populations.

The Y chromosome is one of the best genetic materials to explore the evolutionary history of human populations. Global analyses of Y chromosomal short tandem repeats (STRs) data can reveal very interesting world population structures and histories. However, previous Y-STR works tended to focus on small geographical ranges or only included limited sample sizes. In this study, we have investigated population structure and demographic history using 17 Y chromosomal STRs data of 979 males from 44 worldwide populations. The largest genetic distances have been observed between pairs of African and non-African populations. American populations with the lowest genetic diversities also showed large genetic distances and coancestry coefficients with other populations, whereas Eurasian populations displayed close genetic affinities. African populations tend to have the oldest time to the most recent common ancestors (TMRCAs), the largest effective population sizes and the earliest expansion times, whereas the American, Siberian, Melanesian, and isolated Atayal populations have the most recent TMRCAs and expansion times, and the smallest effective population sizes. This clear geographic pattern is well consistent with serial founder model for the origin of populations outside Africa. The Y-STR dataset presented here provides the most detailed view of worldwide population structure and human male demographic history, and additionally will be of great benefit to future forensic applications and population genetic studies.

A multi-ancestry GWAS meta-analysis of facial features and its application in predicting archaic human features.

Facial morphology, a complex trait influenced by genetics, holds great significance in evolutionary research. However, due to limited fossil evidence, the facial characteristics of Neanderthals and Denisovans have remained largely unknown. In this study, we conducted a large-scale multi-ethnic meta-analysis of Genome-Wide Association Study (GWAS), including 9674 East Asians and 10,115 Europeans, quantitatively assessing 78 facial traits using 3D facial images. We identified 71 genomic loci associated with facial features, including 21 novel loci. We developed a facial polygenic score (FPS) that enables the prediction of facial features based on genetic information. Interestingly, the distribution of FPSs among populations from diverse continental groups exhibited significant correlations with observed facial features. Furthermore, we applied the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA, and aligned predictions with the fossil records. Our results suggested that Neanderthals and Denisovans likely shared similar facial features, such as a wider but shorter nose and a wider endocanthion distance. The decreased mouth width was characterized specifically in Denisovan. The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.

[Effects of mouth opening breathing for different reasons on maxillofacial development in children].

Objective:To explore the effects of mouth opening breathing for different reasons on children's maxillofacial development. Methods:One hundred and fifty-one children were selected as the research objects of this experiment. They were divided into 49 cases of adenoid hypertrophy group（group A）, 52 cases of tonsillar hypertrophy group（group B） and 50 cases of adenoid with tonsillar hypertrophy group（Group C）. Healthy children in the same period were selected as the control group, a total of 45 cases. The reflex nasopharyngeal measurement parameters, facial development indexes and cephalometric parameters of group A, group B, group C and control group were analyzed, and the incidence of Angle ClassⅡand Angle Class Ⅲ in group A, group B and group C were studied. Results:Compared with the control group, the reflex nasopharyngeal measurement parameters in group A, group B and group C was significantly different（P<0.05）, and the cephalometric parameters changed with variation in groups（P<0.05）. The incidence of Angle Class Ⅱ facial pattern in group A and group C was higher, but the incidence of Angle Class Ⅲ facial pattern in group B and group C was higher（P<0.05）. Conclusion:Adenoid hypertrophy leads to mandibular retraction; tonsil hypertrophy leads to anterior mandibular arch; adenoid hypertrophy and tonsil hypertrophy are easy to lead to clockwise rotation of the mandible. In clinical practice, to avoid children's uncoordinated maxillofacial development, we should correct the maxillofacial situation of children as soon as possible.

Genetic evidence for facial variation being a composite phenotype of cranial variation and facial soft tissue thickness.

Facial and cranial variation represent a multidimensional set of highly correlated and heritable phenotypes. Little is known about the genetic basis explaining this correlation. We develop a software package ALoSFL for simultaneous localization of facial and cranial landmarks from head computed tomography (CT) images, apply it in the analysis of head CT images of 777 Han Chinese women, and obtain a set of phenotypes representing variation in face, skull and facial soft tissue thickness (FSTT). Association analysis of 301 single nucleotide polymorphisms (SNPs) from 191 distinct genomic loci previously associated with facial variation reveals an unexpected larger number of loci showing significant associations (P < 1e-3) with cranial phenotypes than expected under the null (O/E = 3.39), suggesting facial and cranial phenotypes share a substantial proportion of genetic components. Adding FSTT to a SNP-only model shows a large impact in explaining facial variance. A gene ontology analysis reveals that bone morphogenesis and osteoblast differentiation likely underlie our cranial-significant findings. Overall, this study simultaneously investigates the genetic effects on both facial and cranial variation of the same sample, supporting that facial variation is a composite phenotype of cranial variation and FSTT.

Genetic variants underlying differences in facial morphology in East Asian and European populations.

Facial morphology-a conspicuous feature of human appearance-is highly heritable. Previous studies on the genetic basis of facial morphology were performed mainly in European-ancestry cohorts (EUR). Applying a data-driven phenotyping and multivariate genome-wide scanning protocol to a large collection of three-dimensional facial images of individuals with East Asian ancestry (EAS), we identified 244 variants in 166 loci (62 new) associated with typical-range facial variation. A newly proposed polygenic shape analysis indicates that the effects of the variants on facial shape in EAS can be generalized to EUR. Based on this, we further identified 13 variants related to differences between facial shape in EUR and EAS populations. Evolutionary analyses suggest that the difference in nose shape between EUR and EAS populations is caused by a directional selection, due mainly to a local adaptation in Europeans. Our results illustrate the underlying genetic basis for facial differences across populations.

A genome-wide association study of facial morphology identifies novel genetic loci in Han Chinese.

The human face is a heritable surface with many complex sensory organs. In recent years, many genetic loci associated with facial features have been reported in different populations, yet there is a lack of studies on the Han Chinese population. Here, we report a genome-wide association study of 3D normal human faces of 2,659 Han Chinese with autosegment phenotypes of facial morphology. We identify single-nucleotide polymorphisms (SNPs) encompassing four genomic regions showing significant associations with different facial regions, including SNPs in DENND1B associated with the chin, SNPs among PISRT1 associated with eyes, SNPs between DCHS2 and SFRP2 associated with the nose, and SNPs in VPS13B associated with the nose. We replicate 24 SNPs from previously reported genetic loci in different populations, whose candidate genes are DCHS2, SUPT3H, HOXD1, SOX9, PAX3, and EDAR. These results provide a more comprehensive understanding of the genetic basis of variation in human facial morphology.

Three-dimensional evaluation of maxillary sinus and maxilla for adolescent patients with unilateral cleft lip and palate using cone-beam computed tomography.

BACKGROUND AND OBJECTIVE: Maxillary sinus disease is frequently observed in patients with unilateral cleft lip and palate (UCLP). The anatomical variations of maxillary sinus and maxilla may play a role in the high incidence of sinusitis. The aims of this study were to evaluate and compare the three-dimensional (3D) structural features of maxillary sinus and maxilla in UCLP adolescent patients between the defect and non-defect sides, and investigate the morphological relationship between the maxillary sinus and maxilla on the defect side by using cone-beam computed tomography (CBCT). METHODS: CBCT images were acquired from 42 UCLP adolescent patients. Maxillary sinus and maxilla on the defect and non-defect sides were segmented respectively and assessed three dimensionally, and the comparison was performed by paired t-test. A multiple linear regression was conducted to investigate the morphological relationship between the maxillary sinus and maxilla on the defect side. RESULTS: No statistically significant difference was observed in any parameter of the maxillary sinus between the defect and non-defect sides (P > 0.05). Significant differences were observed in the length, anterior width, anterior height, and volume of the maxilla between the defect side and non-defect sides (P < 0.05). The parameters of maxillary sinus were significant related to the posterior width and height of maxilla on the defect side. CONCLUSION: Adolescent patients with UCLP present similar 3D structural features of the maxillary sinus on both sides. Significant differences of the maxilla between the defect and non-defect sides were displayed in the area adjacent to the defect but not showed in the posterior portion of maxilla. Certain structures of the posterior portion of maxilla contribute to the variability of maxillary sinus.

Indoor PM2.5 exposure affects skin aging manifestation in a Chinese population.

Traffic-related air pollution is known to be associated with skin aging manifestations. We previously found that the use of fossil fuels was associated with skin aging, but no direct link between indoor air pollutants and skin aging manifestations has ever been shown. Here we directly measured the indoor PM2.5 exposure in 30 households in Taizhou, China. Based on the directly measured PM2.5 exposure and questionnaire data of indoor pollution sources, we built a regression model to predict the PM2.5 exposure in larger datasets including an initial examination group (N = 874) and a second examination group (N = 1003). We then estimated the association between the PM2.5 exposure and skin aging manifestations by linear regression. In the initial examination group, we showed that the indoor PM2.5 exposure levels were positively associated with skin aging manifestation, including score of pigment spots on forehead (12.5% more spots per increase of IQR, P-value 0.0371), and wrinkle on upper lip (7.7% more wrinkle on upper lip per increase of IQR, P-value 0.0218). The results were replicated in the second examination group as well as in the pooled dataset. Our study provided evidence that the indoor PM2.5 exposure is associated with skin aging manifestation in a Chinese population.

Genetic structure of Qiangic populations residing in the western Sichuan corridor.

The Qiangic languages in western Sichuan (WSC) are believed to be the oldest branch of the Sino-Tibetan linguistic family, and therefore, all Sino-Tibetan populations might have originated in WSC. However, very few genetic investigations have been done on Qiangic populations and no genetic evidences for the origin of Sino-Tibetan populations have been provided. By using the informative Y chromosome and mitochondrial DNA (mtDNA) markers, we analyzed the genetic structure of Qiangic populations. Our results revealed a predominantly Northern Asian-specific component in Qiangic populations, especially in maternal lineages. The Qiangic populations are an admixture of the northward migrations of East Asian initial settlers with Y chromosome haplogroup D (D1-M15 and the later originated D3a-P47) in the late Paleolithic age, and the southward Di-Qiang people with dominant haplogroup O3a2c1*-M134 and O3a2c1a-M117 in the Neolithic Age.