A Genome‐Wide Linkage Scan for Quantitative Trait Loci Influencing the Craniofacial Complex in Humans (Homo sapiens sapiens)

The genetic architecture of the craniofacial complex has been the subject of intense scrutiny because of the high frequency of congenital malformations. Numerous animal models have been used to document the early development of the craniofacial complex, but few studies have focused directly on the genetic underpinnings of normal variation in the human craniofacial complex. This study examines 80 quantitative traits derived from lateral cephalographs of 981 participants in the Fels Longitudinal Study, Wright State University, Dayton, Ohio. Quantitative genetic analyses were conducted using the Sequential Oligogenic Linkage Analysis Routines analytic platform, a maximum‐likelihood variance components method that incorporates all familial information for parameter estimation. Heritability estimates were significant and of moderate to high magnitude for all craniofacial traits. Additionally, significant quantitative trait loci (QTL) were identified for 10 traits from the three developmental components (basicranium, splanchnocranium, and neurocranium) of the craniofacial complex. These QTL were found on chromosomes 3, 6, 11, 12, and 14. This study of the genetic architecture of the craniofacial complex elucidates fundamental information of the genetic architecture of the craniofacial complex in humans. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Genetic influences on dentognathic morphology in the Jirel population of Nepal

Patterns of genetic variation and covariation impact the evolution of the craniofacial complex and contribute to clinically significant malocclusions in modern human populations. Previous quantitative genetic studies have estimated the heritabilities and genetic correlations of skeletal and dental traits in humans and nonhuman primates, but none have estimated these quantitative genetic parameters across the dentognathic complex. A large and powerful pedigree from the Jirel population of Nepal was leveraged to estimate heritabilities and genetic correlations in 62 maxillary and mandibular arch dimensions, incisor and canine lengths, and post-canine tooth crown areas (N ≥ 739). Quantitative genetic parameter estimation was performed using maximum likelihood-based variance decomposition. Residual heritability estimates were significant for all traits, ranging from 0.269 to 0.898. Genetic correlations were positive for all trait pairs. Principal components analyses of the phenotypic and genetic correlation matrices indicate an overall size effect across all measurements on the first principal component. Additional principal components demonstrate positive relationships between post-canine tooth crown areas and arch lengths and negative relationships between post-canine tooth crown areas and arch widths, and between arch lengths and arch widths. Based on these findings, morphological variation in the human dentognathic complex may be constrained by genetic relationships between dental dimensions and arch lengths, with weaker genetic correlations between these traits and arch widths allowing for variation in arch shape. The patterns identified are expected to have impacted the evolution of the dentognathic complex and its genetic architecture as well as the prevalence of dental crowding in modern human populations.     

Morphological Integration of the Orbital Region in a Human Ontogenetic Sample

Most studies on craniofacial morphology have focused on adult individuals, but patterns of variation are the outcome of genetic and epigenetic variables that interact throughout ontogeny. Among cranial regions, the orbits exhibit morphological variation and occupy an intermediate position between neurocranial and facial structures. The main objective of this work was to analyze postnatal ontogenetic variation and covariation in the morphology of the orbital region in a cross‐sectional series of humans from 0 to 31 years old. Landmarks and semilandmarks were digitized on the orbital rim, as well as in neighboring neural and facial structures. Data were analyzed using geometric morphometrics. Results indicated that orbital size increases during the first years of postnatal life, while the shape of the orbital aperture does not change significantly with age. In general, the pattern and magnitude of shape covariation do not vary markedly during postnatal life although some subtle shifts were documented. Additionally, the shape of the orbital aperture is more related to the anterior neurocranium than to zygomatic structures, even when the allometry is adjusted. Although we expected some influence from postnatal craniofacial growth and from some functional factors, such as mastication, on the development of the orbits, this assumption was not completely supported by our results. As a whole, our findings are in line with the prediction of an early influence of the eyes and extraocular tissues on orbital morphology, and could be interpreted in relation to processes promoting early neural development that coordinately affects orbital traits and the neurocranial skeleton. Anat Rec, 299:70–80, 2016. © 2015 Wiley Periodicals, Inc.     

Quantitative genetic study of head size related phenotypes in ethnically homogeneous Chuvasha pedigrees

BACKGROUND: It is well established that genetic factors contribute significantly to the determination of head size and shape traits variability. However, the controversies in views and findings with respect to the more specific aspects of this issue have not yet been resolved. AIM: The primary objective of the study was to examine the patterns of the intergenerational familial transmission of 12 head size related traits in a large ethnically homogeneous sample of Chuvasha pedigrees. SUBJECTS AND METHODS: The research was carried out on 1406 individuals belonging to 357 nuclear and more complex families. Univariate and bivariate family-based analyses were performed to establish the pattern of head traits inheritance. RESULTS: Maximum heritability estimates ranged from 0.52 to 0.72 for traits adjusted for significant covariates. No significant sex differences were observed with respect to the genetic determination of the studied traits. Bivariate analysis of horizontal and vertical head size components suggested the existence of common genetic and environmental factors that explained 33.0% and 23.2% of the total variance of the adjusted traits, respectively. CONCLUSIONS: A significant genetic component is involved in inter-individual variation and covariation of various studied craniofacial traits.     

Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross

Using eight inbred founder strains of the mouse Collaborative Cross (CC) project and their reciprocal F1 hybrids, we quantified variation in craniofacial morphology across mouse strains, explored genetic contributions to craniofacial variation that distinguish the founder strains, and tested whether specific or summary measures of craniofacial shape display stronger additive genetic contributions. This study thus provides critical information about phenotypic diversity among CC founder strains and about the genetic contributions to this phenotypic diversity, which is relevant to understanding the basis of variation in standard laboratory strains and natural populations. Craniofacial shape was quantified as a series of size‐adjusted linear dimensions (RDs) and by principal components (PC) analysis of morphological landmarks captured from computed tomography images from 62 of the 64 reciprocal crosses of the CC founder strains. We first identified aspects of skull morphology that vary between these phenotypically ‘normal’ founder strains and that are defining characteristics of these strains. We estimated the contributions of additive and various non‐additive genetic factors to phenotypic variation using diallel analyses of a subset of these strongly differing RDs and the first eight PCs of skull shape variation. We find little difference in the genetic contributions to RD measures and PC scores, suggesting fundamental similarities in the magnitude of genetic contributions to both specific and summary measures of craniofacial phenotypes. Our results indicate that there are stronger additive genetic effects associated with defining phenotypic characteristics of specific founder strains, suggesting these distinguishing measures are good candidates for use in genotype–phenotype association studies of CC mice. Our results add significantly to understanding of genotype–phenotype associations in the skull, which serve as a foundation for modeling the origins of medically and evolutionarily relevant variation.     

A Natural Animal Model System of Craniofacial Anomalies: The Blind Mexican Cavefish

Natural model systems evolving under extreme environmental pressures provide the opportunity to advance our knowledge of how the craniofacial complex evolves in nature. Unlike traditional models, natural systems are less inbred, and, therefore, better model the complex variation of the human population. Owing to the nature of certain craniofacial aberrations in blind Mexican cavefish, we suggest that this organism can provide new insights to a variety of craniofacial changes. Diverse cranial features have evolved in natural cave-dwelling Astyanax fish, which have thrived in the unforgiving darkness and nutrient-poor environment of the cave for countless generations. While the genetic and environmental underpinnings of various cranial anomalies have been investigated for decades, a comprehensive characterization of their molecular and developmental origins remains incomplete. Cavefish provide numerous advantages given the availability of genomic resources, developmental and molecular tools, and the presence of a normative surface-dwelling “ancestral” surrogate for comparative studies. By leveraging the frequency of abnormal and asymmetric cranial features in cavefish, we anticipate advances in our knowledge of the etiologies of irregular cranial features. Extreme adaptations in cavefish are expected to offer new insights into the complex and multifactorial nature of craniofacial disorders and facial asymmetry. Anat Rec, 2018. © 2018 American Association for Anatomy.     

Molecular genetic analysis and evolution of begomoviruses and betasatellites causing yellow mosaic disease of bhendi

In India, Bhendi yellow vein mosaic disease (BYVMD) is one of the most economically important diseases of bhendi/okra and is caused by a complex of monopartite begomovirus (Bhendi yellow vein mosaic virus—BYVMV) and betasatellite (Bhendi yellow vein betasatellite—BYVB). In this study, we have analyzed the role of possible evolutionary factors involved in the evolution of BYVMV and BYVB isolates. Evidence of inter-species and inter-strain recombination events was detected among the viral isolates, and majority of these recombinant isolates possess microsatellites in their genome. Recombination analysis suggests that cotton-infecting and bhendi-infecting begomoviruses probably share a recent common ancestor. In addition to genetic differentiation and gene flow, high degree of genetic variability was detected among the viral population. A strong purifying selection seems to be acting on the viral coding regions. The nucleotide substitution rate of V1 gene (for BYVMV) and βC1 gene (for BYVB) was estimated to be 7.55 × 10^?4 and 2.25 × 10^?3 nucleotide substitutions/site/year, respectively. The present study underlines that the evolution of BYVMD-associated viral components is driven by selection acting on the genetic variation generated by recombination and mutation.     

Landmark‐based software for anatomical measurements: A precision study

The aim of this study was to develop a software program, called Landmarker, which would aid studies of complex anatomical morphometry by simplifying the manual identification of landmarks in 3D images. We also tested its precision on routine magnetic resonance imaging (MRI) scans. To understand human biological variation, there is a need to identify morphological characteristics from the exterior and the interior of human anatomy. MRI, as opposed to other radiographic methods (mainly based on X‐ray techniques), supplies good soft tissue contrast, which allows for more complex assessments than what bony landmarks can provide. Because automation of this assessment is highly demanding, one of the primary goals for the new software was to enable more rapid identification of landmark sets in 3D image data. Repeat acquisition of head MRIs having a resolution of 0.94 × 0.94 × 1.20 mm³ were performed on 10 volunteers. Intra‐ and interoperator, as well as interacquisition variations of manual identification of exterior, craniofacial interior, and brain landmarks were studied. The average distances between landmarks were <1.8 mm, <2.3 mm, and <2.0 mm in the intra‐ and interoperator, and interacquisition evaluations, respectively. This study presents new software for time efficient identification of complex craniofacial landmarks in 3D MRI. To the best of our knowledge, no evaluation of software for rapid landmark‐based analysis of complex anatomies from 3D MR data has yet been presented. This software may also be useful for studies in other anatomical regions and for other types of image data. Clin. Anat. 22:456–462, 2009. © 2009 Wiley‐Liss, Inc.     

Fat distribution in relation to sex and socioeconomic status in children 4–19 years

Fat distribution was studied in an urban sample of boys and girls 4.5 to 19.5 years from the Basque province of Biscay by means of Principal Component Analysis (PCA) of five skinfolds. The PCA extracted four components, which explained 99.1% of the total variance. The first principal component revealed strong stability across age and sex, and was related to a pattern of central body fat distribution. The three other components, upper-lower trunk fat, lateral-medial trunk fat, and upper-lower extremity fat, showed poor stability due largely to the influence of age and, to a lesser degree, sex. In both sexes, individual scores of the four factors did not show multivariate differences by socioeconomic status when a MANOVA with age, age² and age³ as covariates was done. Nevertheless, the first factor scores were significantly higher only in the poorer socioeconomic group of girls. The results are explained in the context of either different lifestyles related to socioeconomic status, a protective effect against environmental stress on urban males, or greater plasticity of trunk fat relative to extremity fat in females. Am. J. Hum. Biol. 10:799–806, 1998. © 1998 Wiley-Liss, Inc.     

Family-based study of association between ENPP1 genetic variants and craniofacial morphology

Background: Human craniofacial morphology is characterized by considerable diversity among individuals. The ENPP1 gene is essential for bone physiology. However, the potential effects of its genetic variants on head size phenotypes have not yet been studied.

Aim: The aim of this research was to investigate the association of polymorphisms in the ENPP1 locus with normal variability of craniofacial phenotypes.

Subjects and methods: Fourteen SNPs and 13 haplotypes in the ENPP1 locus were tested for association with six head size traits in 1042 Western Eurasian individuals.

Results: The most significant and consistent association was observed between upper facial height and the polymorphisms located near the promoter region and upstream from ENPP1 gene (p = 0.00009), which remained significant after adjustment for multiple testing. Additionally, association signals were detected between head breadths and lower face height, and markers residing in or close to the promoter and 3^′ untranslated regions of the ENPP1 gene (p < 0.05).

Conclusions: The findings obtained in this study suggest that the upstream, promoter and 3^′ untranslated regions in the ENPP1 locus harbor genetic variants affecting different aspects of craniofacial morphology. Further research is required to validate the relevancy of the potentially functional ENPP1 regions to normal and pathologic craniofacial growth.     

Gene by environment QTL mapping through multiple trait analyses in blood pressure salt-sensitivity: identification of a novel QTL in rat chromosome 5

Background  

The genetic mechanisms underlying interindividual blood pressure variation reflect the complex interplay of both genetic and environmental variables. The current standard statistical methods for detecting genes involved in the regulation mechanisms of complex traits are based on univariate analysis. Few studies have focused on the search for and understanding of quantitative trait loci responsible for gene × environmental interactions or multiple trait analysis. Composite interval mapping has been extended to multiple traits and may be an interesting approach to such a problem.     

Genetic and environmental determinants of hepatocyte growth factor levels and their association with obesity and blood pressure

Background: Hepatocyte growth factor (HGF) is a member of the adipocytokine family; it is implicated in tissue repair, regeneration, and angiogenesis. Several studies have reported that the HGF plays important role in obesity and cardiovascular disease.

Aim: This study examines whether HGF and its phenotypic correlations with obesity and blood pressure (BP), in healthy individuals, are due to shared genetic or common environmental factors.

Subjects and methods: Body mass index (BMI), waist-to-hip ratio (WHR), BP, and HGF plasma concentrations were measured in a sample of 733 individuals belonging to 248 pedigrees.

Results: The most significant phenotypic correlations were found among HGF, WHR, and systolic BP (p < 0.001). Analysis of the familial aggregation revealed that parent–offspring and sibling correlations in HGF levels, adjusted for age, age², and sex, were statistically highly significant (p < 0.001). Variance decomposition analysis showed that when adjusted for potential covariates, 48.4% of the HGF variation was due to putative genetic factors. The genetic correlations between all pairs of studied traits (HGF, WHR, and SBP) were statistically significant (p < 0.02) and ranged between 0.23 ± 0.07 and 0.40 ± 0.07. However, correlation between WHR and BP becomes non-significant after adjustment for HGF.

Conclusions: The results provide evidence that putative genetic factors involved in regulation of HGF variation contribute also significantly to variation of the obesity and BP. It is possible that the familial resemblance for WHR and the SBP correlation in the studied sample is affected substantially by genetic factors regulating circulating HGF levels.     

Quantitative genetics of sexual dimorphism in body fat measurements

A variance decomposition analysis using maximum likelihood methods was employed to examine the genetic architecture of sexual dimorphism in anthropometric traits in a large pedigreed sample of Mexican American individuals from San Antonio, Texas. For this analysis the magnitude of sexual dimorphism was viewed as arising from a special case of genotype by environment interaction (G × E), that of genotype by sex (G × S). Evidence indicates a marked G × S interaction for 9 of the 12 traits examined and 1 of the 4 indices, findings which are interpreted as indicators of a strong genetic component to the degree of sexual dimorphism expressed in these traits. Such results have important implications for the use and interpretation of these traits in an epidemiological as well as an evolutionary context. © 1993 Wiley-Liss, Inc.     

Heritabilities of somatotype components in a population from rural Mozambique

There have been few genetic studies of normal variation in body size and composition conducted in Africa. In particular, the genetic determinants of somatotype remain to be established for an African population. (1) To estimate the heritabilities of aspects of somatotype and (2) to compare the quantitative genetic effects in an African population to those that have been assessed in European and American populations. The sample composed of 329 subjects (173 males and 156 females) aged 7–17 years, belonging to 132 families. The sibships in the sample ranged in size from two to seven individuals. All sampled individuals were residents of the Calanga region, an area located to the north of Maputo in Mozambique. Somatotype was assessed using the Heath‐Carter technique. Herit abilities were estimated using SAGE software. Moderate heritabilities were determined for each trait. Between 30 and 40% of the variation in each somatotype measure was attributable to genetic factors. The heritability of ectomorphy was 31%. Mesomorphy was similarly moderately heritable, with ∼30% of the variationattributable to genetic factors. The heritability of endomorph was higher in the Calanga population (h² = 0.40). Quantitative genetic analyses of somatotype variation among siblings indicate that genetic factors significantly influence endomorphy, mesomorhpy, and ectomorphy. However, environmental factors also have significant effects on the variation in physique present in the population of Calanga. Lack of proper nutrition, housing, medical assistance, and primary health care, together with very demanding and sex‐specific daily chores may contribute to the environmental effects on these traits. Am. J. Hum. Biol., 2008. © 2008 Wiley‐Liss, Inc.     

Bone mineralization‐dependent craniosynostosis and craniofacial shape abnormalities in the mouse model of infantile hypophosphatasia

Background: Inactivating mutations in tissue‐nonspecific alkaline phosphatase (TNAP) cause hypophosphatasia (HPP), which is commonly characterized by decreased bone mineralization. Infants and mice with HPP can also develop craniosynostosis and craniofacial shape abnormalities, although the mechanism by which TNAP deficiency causes these craniofacial defects is not yet known. Manifestations of HPP are heterogeneous in severity, and evidence from the literature suggests that much of this variability is mutation dependent. Here, we performed a comprehensive analysis of craniosynostosis and craniofacial shape variation in the Alpl^?/? mouse model of murine HPP as an initial step toward better understanding penetrance of the HPP craniofacial phenotype. Results: Despite similar deficiencies in alkaline phosphatase, Alpl^?/? mice develop craniosynostosis and a brachycephalic/acrocephalic craniofacial shape of variable penetrance. Only those Alpl^?/? mice with a severe bone hypomineralization defect develop craniosynostosis and an abnormal craniofacial shape. Conclusions: These results indicate that variability of the HPP phenotype is not entirely dependent upon the type of genetic mutation and level of residual alkaline phosphatase activity. Additionally, despite a severity continuum of the bone hypomineralization phenotype, craniofacial skeletal shape abnormalities and craniosynostosis occur only in the context of severely diminished bone mineralization in the Alpl^?/? mouse model of HPP. Developmental Dynamics 245:175–182, 2016. © 2015 Wiley Periodicals, Inc.     

Genetic Evaluation and Application of Posterior Cranial Fossa Traits as Endophenotypes for Chiari Type I Malformation

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease‐relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10^?3) and 22 (LOD = 3.45, p = 6 × 10^?5) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.     

Variation in Timing,Duration, Intensity,and Direction of Adolescent Growth in the Mandible,Maxilla, and Cranial Base: The Fels Longitudinal Study

There is considerable individual variation in the timing, duration, and intensity of growth that occurs in the craniofacial complex during childhood and adolescence. The purpose of this article is to describe the extent of this variation between traits and between individuals within the Fels Longitudinal Study (FLS). Polynomial multilevel models were used to estimate the ages of onset, peak velocity, and cessation of adolescent growth, the time between these ages, the amount of growth between these ages, and peak velocity. This was done at both the group and individual levels for standard cephalometric measurements of the lengths of the mandible, maxilla, and cranial base, the gonial angle, and the saddle angle. Data are from 293 untreated boys and girls age 4–24 years in the FLS. The timing of the adolescent growth spurt was, in general, not significantly different between the mandible and the maxilla, with each having an earlier age of onset, later age of peak velocity, and later age of cessation of growth as compared to the cranial base length. Compared to lengths, angles had in general later ages of onset, peak velocity, and cessation of growth. Accurate characterization of the ontogenetic trajectories of the traits in the craniofacial complex is critical for both clinicians seeking to optimize treatment timing and anatomists interested in examining heterochrony. Anat Rec, 297:1195–1207, 2014. © 2014 Wiley Periodicals, Inc.     

Common genetic influences on depression,alcohol, and substance use disorders in Mexican‐American families

Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community‐ascertained sample of Mexican‐American families. A total of 1,122 Mexican‐American individuals from 71 extended pedigrees participated in the study. All subjects received in‐person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty‐five percent of the sample met criteria for DSM‐IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h² = 0.393 (P = 3.7 × 10^?6). Heritability estimates were higher for recurrent depression (h² = 0.463, P = 4.0 × 10^?6) and early onset depression (h² = 0.485, P = 8.5 × 10^?5). While the genetic correlation between major depression and alcohol use disorders was significant (ρ_g = 0.58, P = 7 × 10^?3), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US‐born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican‐American population is similar to that reported in other populations. © 2011 Wiley‐Liss, Inc.     

The Genetic Architecture of Liver Enzyme Levels: GGT, ALT and AST

High levels of liver enzymes GGT, ALT and AST are predictive of disease and all-cause mortality and can reflect liver injury, fatty liver and/or oxidative stress. Variation in GGT, ALT and AST levels is heritable. Moderation of the heritability of these liver enzymes by age and sex has not often been explored, and it is not clear to what extent non-additive genetic and shared environmental factors may play a role. To examine the genetic architecture of GGT, ALT and AST, plasma levels were assessed in a large sample of twins, their siblings, parents and spouses (N = 8,371; age range 18–90). For GGT and ALT, but not for AST, genetic structural equation modeling showed evidence for quantitative sex differences in the genetic architecture. There was no evidence for qualitative sex differences, i.e. the same genes were expressed in males and females. Both additive and non-additive genetic factors were important for GGT in females (total heritability h² 60 %) and AST in both sexes (total h² 43 %). The heritability of GGT in males and ALT for both sexes was due to additive effects only (GGT males 30 %; ALT males 40 %, females 22 %). Evidence emerged for shared environmental factors influencing GGT in the male offspring generation (variance explained 28 %). Thus, the same genes influence liver enzyme levels across sex and age, but their relative contribution to the variation in GGT and ALT differs in males and females and for GGT across age. Given adequate sample sizes these results suggest that genome-wide association studies may result in the detection of new susceptibility loci for liver enzyme levels when pooling results over sex and age.     

Heredity,nutrition, and craniofacial differentiation in weanling rats: A multivariate analysis

The effects of paternal heredity, congenital variation, and preweaning nutrition on craniofacial growth were studied on weanling Wistar (W), Holtzman (H), and their reciprocal crosses, W/H and H/W, male rats. Between-group Mahalanobis D² distances were calculated from the measurements made on lateral and vertical X-rays. Preweaning nutrition evoked the largest cranial differences, and paternal heredity the lowest; the effect of congenital variation was intermediate between these extremes. It is concluded that “strain” differences actually are the result of the complex interplay among congenital and lactational factors that can modify the genetic effect due to strain. © 1994 Wiley-Liss, Inc.