Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.

Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10-8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

Effects of Objective 3-Dimensional Measures of Facial Shape and Symmetry on Perceptions of Facial Attractiveness.

PURPOSE: Meeting patient desires for enhanced facial esthetics requires that providers have standardized and objective methods to measure esthetics. The authors evaluated the effects of objective 3-dimensional (3D) facial shape and asymmetry measurements derived from 3D facial images on perceptions of facial attractiveness. MATERIALS AND METHODS: The 3D facial images of 313 adults in Iowa were digitized with 32 landmarks, and objective 3D facial measurements capturing symmetric and asymmetric components of shape variation, centroid size, and fluctuating asymmetry were obtained from the 3D coordinate data using geo-morphometric analyses. Frontal and profile images of study participants were rated for facial attractiveness by 10 volunteers (5 women and 5 men) on a 5-point Likert scale and a visual analog scale. Multivariate regression was used to identify the effects of the objective 3D facial measurements on attractiveness ratings. RESULTS: Several objective 3D facial measurements had marked effects on attractiveness ratings. Shorter facial heights with protrusive chins, midface retrusion, faces with protrusive noses and thin lips, flat mandibular planes with deep labiomental folds, any cants of the lip commissures and floor of the nose, larger faces overall, and increased fluctuating asymmetry were rated as significantly (P < .001) less attractive. CONCLUSION: Perceptions of facial attractiveness can be explained by specific 3D measurements of facial shapes and fluctuating asymmetry, which have important implications for clinical practice and research.

Exploratory genotype-phenotype correlations of facial form and asymmetry in unaffected relatives of children with non-syndromic cleft lip and/or palate.

Family relatives of children with nonsyndromic cleft lip with or without cleft palate (NSCL/P) who presumably carry a genetic risk yet do not manifest overt oral clefts, often present with distinct facial morphology of unknown genetic etiology. This study investigates distinct facial morphology among unaffected relatives and examines whether candidate genes previously associated with overt NSCL/P and left-right body patterning are correlated with such facial morphology. Cases were unaffected relatives of individuals with NSCL/P (n = 188) and controls (n = 194) were individuals without family history of NSCL/P. Cases and controls were genotyped for 20 SNPs across 13 candidate genes for NSCL/P (PAX7, ABCA4-ARHGAP29, IRF6, MSX1, PITX2, 8q24, FOXE1, TGFB3 and MAFB) and left-right body patterning (LEFTY1, LEFTY2, ISL1 and SNAI1). Facial shape and asymmetry phenotypes were obtained via principal component analyses and Procrustes analysis of variance from 32 coordinate landmarks, digitized on 3D facial images. Case-control comparisons of phenotypes obtained were performed via multivariate regression adjusting for age and gender. Phenotypes that differed significantly (P < 0.05) between cases and controls were regressed on the SNPs one at a time. Cases had significantly (P < 0.05) more profile concavity with upper face retrusion, upturned noses with obtuse nasolabial angles, more protrusive chins, increased lower facial heights, thinner and more retrusive lips and more protrusive foreheads. Furthermore, cases showed significantly more directional asymmetry compared to controls. Several of these phenotypes were significantly associated with genetic variants (P < 0.05). Facial height and width were associated with SNAI1. Midface antero-posterior (AP) projection was associated with LEFTY1. The AP position of the chin was related to SNAI1, IRF6, MSX1 and MAFB. The AP position of the forehead and the width of the mouth were associated with ABCA4-ARHGAP29 and MAFB. Lastly, facial asymmetry was related to LEFTY1, LEFTY2 and SNAI1. This study demonstrates that, genes underlying lip and palate formation and left-right patterning also contribute to facial features characteristic of the NSCL/P spectrum.

Maternal Perception of Infant Sleep and Bonding in Opioid Use Disorder.

OBJECTIVE: Infant sleep problems are common in early infancy and can negatively influence maternal-infant bonding. As opioid-exposed neonates are at increased risk of sleep difficulties, we examined the association between maternal perception of infant sleep difficulties and maternal-infant bonding among dyads affected by maternal opioid use disorder (OUD), from birth through 6 months. METHODS: We enrolled 100 birthing people (participants) between 6 months and 2 years postpartum who had received medications for OUD during their pregnancy. Participants answered questions regarding maternal and infant characteristics, as well as the Postpartum Bonding Questionnaire (PBQ), on which higher scores indicate decreased maternal-infant bonding. Unadjusted and adjusted linear regression models were used to examine the association between infant sleep and bonding. RESULTS: Of 100 study participants, 91 completed the PBQ. Of these, 55% reported difficulties with their infant's sleep during the first 6 months postpartum. Although bonding scores were overall strong, those who reported infant sleep difficulties scored on average 10.40 points higher on the PBQ (ß = 10.40; 95% confidence interval, 5.94-14.85) than participants who did not report sleep difficulties, indicating the negative association between infant sleep problems and bonding. This effect remained after adjusting for relevant maternal-infant characteristics (ß = 6.86; 95% confidence interval, 2.49-11.24). CONCLUSIONS: In this study among postpartum individuals with OUD, maternal perception of infant sleep problems was associated with reduced maternal-infant bonding. This relationship between infant sleep and bonding offers a target for supporting dyads affected by OUD.

Assessment of US Federal Funding of Incarceration-Related Research, 1985 to 2022.

Importance: The US leads the world in the raw number of incarcerated persons as well as the rate of incarceration, with detrimental effects on individual-, family-, community-, and population-level health; as such, federal research has a critical role in documenting and addressing the health-related impacts of the US criminal legal system. How often incarceration-related research is funded at the National Institutes of Health (NIH), National Science Foundation (NSF), and US Department of Justice (DOJ) levels has a direct association with the public attention given to mass incarceration as well as the efficacy of strategies to mitigate negative effects and poor health related to incarceration. Objective: To understand how many incarceration-related projects have been funded at the NIH, NSF, and DOJ. Design, Setting, and Participants: This cross-sectional study used public historical project archives to search for relevant incarceration-related keywords (eg, incarceration, prison, parole) since January 1, 1985 (NIH and NSF), and since January 1, 2008 (DOJ). Quotations and Boolean operator logic were used. All searches and counts were conducted and double verified by 2 coauthors between December 12 and 17, 2022. Main Outcomes and Measures: Number and prevalence of funded projects related to incarceration and prison keywords. Results: The term incarceration resulted in 3540 of 3 234 159 total project awards (0.11%) and prisoner-related terms resulted in 11 455 total project awards (0.35%) across the 3 federal agencies since 1985. Nearly a tenth of all projects funded at NIH since 1985 related to education (256 584 [9.62%]) compared with only 3373 projects (0.13%) that related to criminal legal or criminal justice or correctional system and 18 projects (0.0007%) that related to incarcerated parents. Only 1857 (0.07%) of all NIH-funded projects have been funded related to racism since 1985. Conclusions and Relevance: This cross-sectional study found that a very low number of projects about incarceration have historically been funded at the NIH, DOJ, and NSF. These findings reflect a dearth of federally funded studies investigating the effects of mass incarceration or intervention strategies to mitigate adverse effects. Given the consequences of the criminal legal system, it is undoubtedly time for researchers, and our nation, to invest more resources into studying whether this system should be maintained, the intergenerational effects of mass incarceration, and strategies to best mitigate its impact on public health.

Association between perinatal depression and risk of attention deficit hyperactivity disorder among children: a retrospective cohort study.

PURPOSE: Perinatal depression has previously been identified as a risk factor for attention deficit hyperactivity disorder (ADHD) in the offspring. Population-based studies utilizing diagnosis data are needed to better understand the relationship between these two variables. The objective of this study was to examine the association between perinatal depression and the risk of ADHD among children born during a 5 or-more-year follow-up period. METHODS: The sample was drawn from a population-based cohort of privately insured mother-child pairs within the state of Iowa. Hazard ratios for risk of ADHD by exposure to perinatal depression were estimated using adjusted Cox proportional-hazard models. RESULTS: Among the 5,635 mother-child pairs, 484 mothers were diagnosed with depression during the perinatal period, and 269 children were diagnosed with ADHD. After adjustment for confounders, children born to mothers with perinatal depression were over three times more likely to be diagnosed with ADHD (HR 3.16 (95% CI 2.35, 4.23)). CONCLUSIONS: Children born to mothers with perinatal depression were found to be at increased risk of ADHD. This finding suggests that ADHD and its adverse sequelae could be mitigated by increasing maternal depression intervention efforts as well as ADHD screening and treatment efforts targeted to this vulnerable population.

Meta-Analysis Of Antenatal Depression And Adverse Birth Outcomes In US Populations, 2010-20.

Untreated depression presents a distinct set of risks for pregnancy complications. Past studies have connected antenatal depression with adverse birth outcomes. The purpose of this study was to conduct an updated systematic review and meta-analysis examining the relationship between depression during pregnancy and associated adverse birth outcomes in US populations during the period 2010-20. As a trend, disparities in adverse pregnancy outcomes and maternal morbidities for Black pregnant people compared with those for White pregnant people continue to rise. Addressing mental health conditions during pregnancy has the potential to ameliorate a large and excessive burden on adverse birth outcomes among childbearing people and their offspring. Policy solutions to encourage, mandate, and reimburse universal depression screening during pregnancy are warranted.

Gestational vitamin D and offspring risk of multiple sclerosis: a systematic review and meta-analysis.

PURPOSE: Our objective was to systematically review and meta-analyze studies that assessed the association between gestational vitamin D levels and risk of multiple sclerosis (MS) in offspring. METHODS: Embase and Pubmed databases were searched from inception to May 2018. Original, observational studies that investigated both clinically defined MS (in offspring) and vitamin D levels in utero or shortly after birth were included. Two reviewers independently abstracted data and assessed the quality of studies using the Newcastle-Ottawa Quality Assessment Scale. Summary effect estimates and 95% confidence intervals were calculated with random effects models using inverse variance weighting. Determinants of heterogeneity were evaluated. RESULTS: Four case-control studies of moderate to low risk of bias were included. Summary effect estimates of the effect of higher levels of gestational vitamin D on risk of offspring MS demonstrated a significant protective effect in random effects (OR: 0.63, 95% CI: 0.47, 0.84) models and in a stratified analysis based on study quality. Factors identified as determinants of heterogeneity were the definitions of vitamin D deficiency, the characteristics of study participants, and the quality of the study. CONCLUSIONS: Sufficient levels of vitamin D during pregnancy may be protective against offspring's development of multiple sclerosis later in life.

Disparities in Donor Human Milk Supplementation Among Well Newborns.

BACKGROUND: Donor human milk supplementation for healthy newborns has increased. Racial-ethnic disparities in supplementation have been described in the neonatal intensive care unit but not in the well newborn setting. RESEARCH AIM: The aim of this study was to identify maternal characteristics associated with donor human milk versus formula supplementation in the well newborn unit. METHODS: This retrospective cohort study includes dyads of well newborns and their mothers (N = 678) who breastfed and supplemented with formula (n = 372) or donor human milk (n = 306) during the birth hospitalization at a single hospital in the midwestern United States. Maternal characteristics and infant feeding type were extracted from medical records. Chi-square and logistic regression were used to examine associations between maternal characteristics and feeding type. RESULTS: Nonwhite women were less likely to use donor human milk. Compared to non-Hispanic white women, the largest disparity was with Hispanic (adjusted odds ratio [OR] = 0.28, 95% CI [0.12, 0.65]), then non-Hispanic black (adjusted OR = 0.32, 95% CI [0.13, 0.76]) and Asian women (adjusted OR = 0.34, 95% CI [0.16, 0.74]). Lower donor human milk use was associated with primary language other than English and public versus private insurance. CONCLUSION: The goal of improving public health through breastfeeding promotion may be inhibited without targeting donor human milk programs to these groups. Identifying the drivers of these disparities is necessary to inform person-centered interventions that address the needs of women with diverse backgrounds.

First trimester prenatal screening biomarkers and gestational diabetes mellitus: A systematic review and meta-analysis.

Biomarkers commonly assessed in prenatal screening have been associated with a number of adverse perinatal and birth outcomes. However, it is not clear whether first trimester measurements of prenatal screening biomarkers are associated with subsequent risk of gestational diabetes mellitus (GDM). We aimed to systematically review and statistically summarize studies assessing the relationship between first trimester prenatal screening biomarker levels and GDM development. We comprehensively searched PubMed/MEDLINE, EMBASE, CINAHL, and Scopus (from inception through January 2018) and manually searched the reference lists of all relevant articles. We included original, published, observational studies examining the association of first trimester pregnancy associated plasma protein-A (PAPP-A) and/or free ß-human chorionic gonadotropin (free ß-hCG) levels with GDM diagnosis. Mean differences were calculated comparing PAPP-A and free ß-hCG multiples of median (MoM) levels between women who developed GDM and those who did not and were subsequently pooled using two-sided random-effects models. Our meta-analysis of 13 studies on PAPP-A and nine studies on free ß-hCG indicated that first trimester MoM levels for both biomarkers were lower in women who later developed GDM compared to women who remained normoglycemic throughout pregnancy (MD -0.17; 95% CI -0.24, -0.10; MD -0.04; 95% CI -0.07-0.01). There was no evidence for between-study heterogeneity among studies on free ß-hCG (I2 = 0%). A high level of between-study heterogeneity was detected among the studies reporting on PAPP-A (I2 = 90%), but was reduced after stratifying by geographic location, biomarker assay method, and timing of GDM diagnosis. Our meta-analysis indicates that women who are diagnosed with GDM have lower first trimester levels of both PAPP-A and free ß-hCG than women who remain normoglycemic throughout pregnancy. Further assessment of the predictive capacity of these biomarkers within large, diverse populations is needed.

Using the 3D Facial Norms Database to investigate craniofacial sexual dimorphism in healthy children, adolescents, and adults.

BACKGROUND: Although craniofacial sex differences have been extensively studied in humans, relatively little is known about when various dimorphic features manifest during postnatal life. Using cross-sectional data derived from the 3D Facial Norms data repository, we tested for sexual dimorphism of craniofacial soft-tissue morphology at different ages. METHODS: One thousand five hundred fifty-five individuals, pre-screened for craniofacial conditions, between 3 and 25 years of age were placed in to one of six age-defined categories: early childhood, late childhood, puberty, adolescence, young adult, and adult. At each age group, sex differences were tested by ANCOVA for 29 traditional soft-tissue anthropometric measurements collected from 3D facial scans. Additionally, sex differences in shape were tested using a geometric morphometric analysis of 24 3D facial landmarks. RESULTS: Significant (p < 0.05) sex differences were observed in every age group for measurements covering multiple aspects of the craniofacial complex. The magnitude of the dimorphism generally increased with age, with large spikes in the nasal, cranial, and facial measurements observed after puberty. Significant facial shape differences (p < 0.05) were also seen at each age, with some dimorphic features already present in young children (eye fissure inclination) and others emerging only after puberty (mandibular position). CONCLUSIONS: Several craniofacial soft-tissue sex differences were already present in the youngest age group studied, indicating that these differences emerged prior to 3 years of age. The results paint a complex and heterogeneous picture, with different groups of traits exhibiting distinct patterns of dimorphism during ontogeny. The definitive adult male and female facial shape was present following puberty, but arose from numerous distinct changes taking place at earlier stages.