Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

Revisiting the effects of state earned income tax credits on infant health: a quasi-experimental study using contiguous border counties approach.

BACKGROUND: To examine the effects of refundable state earned income tax credits (EITC) on infant health. METHODS: We use the restricted-access U.S. birth certificate data with county codes from 1989 to 2018. Birth outcomes include birth weight, low birth weight, gestational weeks, preterm birth, and the fetal growth rate. The analytical sample includes single mothers with high school education or less. Two specifications of two-way fixed effects models are employed. The first specification accounts for shared time trends across all states/counties. The second specification estimates effects based on EITC changes within contiguous counties across state borders which accounts for contemporaneous events specific to each contiguous county pair. Models are estimated pooling and stratifying by parity subgroups. RESULTS: Under the first specification, refundable state EITC is associated with improved birth outcomes. Pooling all parity, a 10%-point increase in refundable EITC is associated with an 8-gram increase in birth weight (95% CI: 2.9,14.6). The effect increases by parity. In contrast, the estimates from the second model are much smaller and statistically non-significant, both pooling and stratifying by parity. CONCLUSIONS: Comparing contiguous counties across state borders, there is no evidence that refundable state EITC affects birth outcomes. However, the estimates still do not rule out moderate to large benefits for third or higher born infants.

Changes in birth outcomes and utilization of prenatal care during the COVID-19 pandemic in 2020: a secondary analysis of vital statistics in Colombia.

BACKGROUND: Birth outcomes could have been affected by the COVID-19 pandemic through changes in access to prenatal services and other pathways. The aim of this study was to examine the effects of the COVID-19 pandemic on fetal death, birth weight, gestational age, number of prenatal visits, and caesarean delivery in 2020 in Colombia. METHODS: We conducted a secondary analysis of data on 3,140,010 pregnancies and 2,993,534 live births from population-based birth certificate and fetal death certificate records in Colombia between 2016 and 2020. Outcomes were compared separately for each month during 2020 with the same month in 2019 and pre-pandemic trends were examined in regression models controlling for maternal age, educational level, marital status, type of health insurance, place of residence (urban/rural), municipality of birth, and the number of pregnancies the mother has had before last pregnancy. RESULTS: We found some evidence for a decline in miscarriage risk in some months after the pandemic start, while there was an apparent lagging increase in stillbirth risk, although not statistically significant after correction for multiple comparisons. Birth weight increased during the onset of the pandemic, a change that does not appear to be driven by pre-pandemic trends. Specifically, mean birth weight was higher in 2020 than 2019 for births in April through December by about 12 to 21 g (p < 0.01). There was also a lower risk of gestational age at/below 37 weeks in 2020 for two months following the pandemic (April, June), but a higher risk in October. Finally, there was a decline in prenatal visits in 2020 especially in June-October, but no evidence of a change in C-section delivery. CONCLUSIONS: The study findings suggest mixed early effects of the pandemic on perinatal outcomes and prenatal care utilization in Colombia. While there was a significant decline in prenatal visits, other factors may have had counter effects on perinatal health including an increase in birth weight on average.

Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.

Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

Effects of Repealing the ACA Individual Mandate Penalty on Insurance Coverage and Marketplace Enrollment: Evidence From State Mandates in Massachusetts and New Jersey.

BACKGROUND: Congress eliminated the individual mandate penalty of the Affordable Care Act (ACA) effective January 1, 2019. OBJECTIVE: To examine the effects of repealing the ACA mandate penalty on private health insurance coverage and marketplace enrollment by leveraging state-based mandates in Massachusetts and New Jersey. RESEARCH DESIGN: We employ synthetic control and difference-in-differences methods to compare insurance and enrollment changes separately in Massachusetts and New Jersey, which had insurance mandates effective in 2019, to other states without such mandates. SUBJECTS: Adults aged 18-64 years with income of 150-300% and above 300% of the Federal Poverty Level who participated in the 2016-2019 American Community Survey (ACS) and adults aged 18-64 enrolled in insurance marketplaces based on state-level data from the 2016-2021 Marketplace Open Enrollment Period Public Use Files (MOEP-PUF). MEASURES: Any insurance, individually purchased coverage, and employer-sponsored coverage from the ACS and marketplace enrollment from the MOEP-PUF. RESULTS: Changes in any coverage, individually purchased coverage, and employer-sponsored coverage rates are relatively small (generally in the range of 1-2 percentage points) and statistically nonsignificant in both Massachusetts and New Jersey compared with states without mandates. Furthermore, there is no discernable difference by eligibility for marketplace subsidies based on income level in the ACS data. Similarly, estimates for changes in marketplace enrollment are also small overall and statistically nonsignificant. CONCLUSION: Private insurance coverage rates and marketplace enrollment for adults 18-64 do not appear to have changed thus far owing to the 2019 repeal of the ACA individual mandate penalty.

Academic outcomes of children with orofacial clefts: A review of the literature and recommendations for future research.

This paper summarizes the main findings of population-based studies of the academic outcomes of children with isolated orofacial clefts compared to peers, general samples, or siblings, published over the past decade. Most of the reviewed papers report that children with orofacial clefts, particularly children with cleft palate only or in some studies children with cleft lip and palate, may have on average lower achievement on certain outcomes like test scores when comparing to non-siblings. However, there are important differences across studies including designs, populations, outcome measures, and findings. The paper also offers recommendations for future research priorities including controlling for confounding, examining mechanisms and potential heterogeneity across family sociodemographic and contextual factors, and understanding outcomes in less developed settings.

The effects of state facial surgery mandates on timeliness of primary cleft repair surgery in the United States.

OBJECTIVE: This study examines the effects of state facial surgery mandates on the timeliness of primary cleft repair surgery for privately insured children with oral clefts in the United States. MATERIALS AND METHODS: Using IBM Health MarketScan® Database from 2001 to 2017, we estimate regression models separately for age at cleft lip repair and cleft palate repair by having a mandate while considering child-level factors and other state differences. The sample includes 1,451 children who had primary cleft lip repair by age 12 months, and 1,402 children who had primary cleft palate repair by age 18 months. RESULTS: A mandate was associated with earlier cleft lip repair by 13 days (95% CI, -21.5 to -4.7 days) when controlling for state differences, regardless if the child had other birth defects. For children needing cleft palate repair, a mandate was associated with earlier surgery by 87 days (95% CI, -136.1 to -38.4 days) only when no other birth defects were present. CONCLUSIONS: State facial surgery mandates were associated with earlier cleft lip repair for children with or without other birth defects, and earlier cleft palate repair for children without other birth defects (besides oral clefts). Findings suggest benefits to privately insured children with oral clefts from state mandates to cover needed services.

Effects of the ACA Medicaid expansions on access and health by nurse practitioner scope of practice laws.

BACKGROUND: The Affordable Care Act (ACA) Medicaid expansions increased demand for care whereas the Scope of Practice (SOP) laws for nurse procatitioners affect the supply of primary care providers. It is important to udnerstand the interaction of the demand and supply side policies on measures of access to care and health status. PURPOSE: To examine whether effects of the Affordable Care Act (ACA) Medicaid expansions on access to care and health status are moderated by state scope of practice (SOP) laws for nurse practitioners. METHODS: Using data from the 2011 to 2019 Behavioral Risk Factor Surveillance System, the study used a difference-in-differences design that compared outcome changes between expansion and non-expansion states and evaluated whether these changes differed by state SOP laws. DISCUSSION: Following Medicaid expansion, forgoing a needed doctor's visit due to cost declined more in expansion states with full SOP laws than states with reduced SOP laws by 3.0 percentage-points in years 1 to 3 after the expansion (p < .05). Furthermore, completing a routine checkup with a doctor increased more in expansion states with full SOP laws by 3.2 percentage-points in 4 to 6 years (p < .05). CONCLUSION: The ACA Medicaid expansions were associated with larger gains in certain access measures in states with full SOP laws.

Genome-Wide Association Study (GWAS) of dental caries in diverse populations.

BACKGROUND: Dental caries is one of the most common chronic diseases and is influenced by a complex interplay of genetic and environmental factors. Most previous genetic studies of caries have focused on identifying genes that contribute to dental caries in specific ethnic groups, usually of European descent. METHODS: The aim of this study is to conduct a genome-wide association study (GWAS) to identify associations affecting susceptibility to caries in a large multiethnic population from Argentina, the Philippines, Guatemala, Hungary, and the USA, originally recruited for studies of orofacial clefts (POFC, N = 3686). Ages of the participants ranged from 2 to 12 years for analysis of the primary dentition, and 18-60 years for analysis of the permanent dentition. For each participant, dental caries was assessed by counts of decayed and filled teeth (dft/DFT) and genetic variants (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Caries was analyzed separately for the primary and permanent dentitions, with age, gender, and presence/absence of any type of OFC treated as covariates. Efficient Mixed-Model Association eXpedited (EMMAX) was used to test genetic association, while simultaneously accounting for relatedness and stratification. RESULTS: We identified several suggestive loci (5 × 10-8 < P < 5 × 10-6) within or near genes with plausible biological roles for dental caries, including a cluster of taste receptor genes (TAS2R38, TAS2R3, TAS2R4, TASR25) on chromosome 7 for the permanent dentition analysis, and DLX3 and DLX4 on chromosome 17 for the primary dentition analysis. Genome-wide significant results were seen with SNPs in the primary dentition only; however, none of the identified genes near these variants have known roles in cariogenesis. CONCLUSION: The results of this study warrant further investigation and may lead to a better understanding of cariogenesis in diverse populations, and help to improve dental caries prediction, prevention, and/or treatment in future.

A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals.

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.

Effects of the Recent Medicaid Expansions on Dental Preventive Services and Treatments.

BACKGROUND: Low-income adults in the United States have historically had poor access to dental services largely due to limited dental coverage. OBJECTIVE: We examined the effects of recent Medicaid income-eligibility expansions under the Affordable Care Act on dental visits separately for preventive care and treatments. RESEARCH DESIGN: We used restricted data from the 2011 to 2016 Medical Expenditure Panel Survey with state geocodes. The main analytical sample included nearly 21,000 individuals who were newly eligible for Medicaid. We employed a quasi-experimental difference-in-differences design to identify the impact of the state Medicaid expansions effective in 2014 on dental services use by the level of state Medicaid dental benefit for the newly eligible. RESULTS: Expanding Medicaid in 2014 with extensive or limited dental coverage increased preventive dental visits and use of major dental treatments by over 5 percentage-points in 2014 and 2015. The increase in preventive visits continued in 2016 in expanding states with extensive coverage, while increase in major dental treatments continued in 2016 in expanding states with limited coverage. There is some but less consistent evidence of an increase in dental treatment with emergency-only coverage. CONCLUSIONS: Medicaid expansions with dental coverage beyond emergency-only services have increased access of the newly eligible low-income adults to dental treatments and preventive services, with extensive coverage showing continuing increase in preventive services use 3 years after the expansion. With limited coverage, there is some evidence of individuals needing to stretch treatments over a longer period. Providing comprehensive dental coverage can address unmet dental needs and improve oral health among low-income adults.

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.

Children's Oral Health and Academic Performance: Evidence of a Persisting Relationship Over the Last Decade in the United States.

OBJECTIVE: To assess the association between children's oral health and academic performance using the most recent US national data, a decade after the last assessment using similar previous data. STUDY DESIGN: Data from the 2016-2017 National Survey of Children's Health for 45 711 children aged 6-17 years were analyzed. Children's oral health measures were indicators of specific oral health problems and parent-rated oral health. Academic performance measures included problems at school and missing school days. Regression models were employed adjusting for relevant demographic, socioeconomic, and health characteristics and state effects. Analyses also were conducted stratifying by child's age, sex, household income, and type of health insurance. RESULTS: We found significant associations across all the evaluated academic outcomes and oral health measures. Children with oral health problems were more likely to have problems at school (OR 1.56, 95% CI 1.32-1.85), miss at least 1 school day (OR 1.54, 95% CI 1.28-1.85), and miss more than 3 or 6 school days (OR 1.39, 95% CI 1.20-1.61 and OR 1.39, 95% CI 1.14-1.69; respectively). These associations were generally larger when using the child's oral health rating. Poor oral health was consistently related to worse academic performance across age, sex, household income, and health insurance type subgroups. CONCLUSIONS: Children's oral health status continues to be strongly linked to their academic outcomes. This evidence highlights the need for broad population-wide policies and integrated approaches to reduce academic deficits and promote children's health and development, of which oral health is an important component.

The Impacts of the ACA Medicaid Expansions on Cancer Screening Use by Primary Care Provider Supply.

BACKGROUND: Recent studies of the impacts of the Affordable Care Act (ACA) Medicaid expansions on cancer screening use have mostly found insignificant effects. We posit that these findings mask meaningful heterogeneity in impacts depending on availability of primary care providers. OBJECTIVE: This study examined the impacts of the ACA Medicaid expansions on cancer screening use separately by state-level supply of primary care providers. RESEARCH DESIGN: We used data from the 2012 and 2016 Behavioral Risk Factor Surveillance System surveys to measure use of mammograms, Pap smear tests, blood stool tests, and sigmoidoscopy/colonoscopy for age groups recommended receiving these tests. The main analytical sample included 24,878-31,890 individuals with household income below 138% Federal Poverty Line. We used a difference-in-differences design comparing pre-post expansion changes in cancer screening use between expanding and nonexpanding states separately for 2 state groups defined by the median proportion of the state population residing in primary health professional shortage areas: low primary care provider supply (above median) and high supply (below median). RESULTS: Medicaid expansions were associated with significant increases in mammograms (11.4 percentage-points), Pap smear tests (6.9 percentage-points), and sigmoidoscopy/colonoscopy use (8.3 percentage-points) in states with high supply of primary care providers. In contrast, effects were small and insignificant in low supply states. CONCLUSIONS: ACA Medicaid expansions were associated with increased cancer screening use only in states with high supply of primary care providers. Improving access for Medicaid beneficiaries in provider shortage areas may require coupling coverage expansions with supply-side interventions to increase provider availability.

The Effects of the Patient Protection and Affordable Care Act on Children's Health Coverage.

BACKGROUND: Prior research of the impacts of the Patient Protection and Affordable Care Act (PPACA) on children's health coverage has been largely descriptive and focused on the Medicaid expansions. OBJECTIVE: This study examined the causal impacts of the PPACA Medicaid expansions and of the PPACA as a whole on children's health coverage through 2016. RESEARCH DESIGN: We utilized quasiexperimental difference in differences designs to estimate the Medicaid expansion and overall PPACA effects. The first model compared coverage changes between Medicaid expanding and nonexpanding states by household income level. The second model identified the overall PPACA effects by estimating coverage changes across differences in pre-PPACA area-level uninsured rates in expanding states for which the identifying assumptions were valid. We used data from the American Community Survey for years 2011 through 2016 for 3,630,988 children aged 0-18 years living in the 50 states and District of Columbia. RESULTS: The PPACA Medicaid expansions led to gains in public coverage for children at ≤405% federal poverty line especially in 2015-2016. Gains were largest for children at 138%-255% federal poverty line (~4 percentage-point increase in 2016). These gains however were mostly due to switching from private to public coverage (ie, crowd-out effects). As a whole however, the PPACA reduced children's uninsured rate in Medicaid-expanding states by about 3 percentage-points in 2016. CONCLUSIONS: The PPACA resulted in a meaningful decline in children's uninsured rate in Medicaid-expanding states. PPACA provisions targeting private coverage take-up offset crowd-out effects of the Medicaid expansions resulting in lower children's uninsured rates.

The Impact of the ACA Medicaid Expansions on Dental Visits by Dental Coverage Generosity and Dentist Supply.

BACKGROUND: Low-income adults in the United States have historically had limited access to dental coverage and poor dental health outcomes. OBJECTIVE: We examined the effects of the Affordable Care Act Medicaid expansions on dental visits among low-income adults focusing on the generosity of dental coverage and heterogeneity in effects by dentist supply. RESEARCH DESIGN: We used data from 2012, 2014, and 2016 Behavioral Risk Factor Surveillance System surveys. The main analytical sample included nearly 117,000 individuals <138% federal poverty level. We employed a quasi-experimental difference-in-differences design to identify the impact of the state Medicaid expansions on having a dental visit in the past 12 months by the generosity of dental coverage and dentist supply. RESULTS: Medicaid expansions were associated with a nearly 6 percentage-point increase in the likelihood of any dental visits in 2016 (over 10% increase from preexpansion rate) for individuals in Medicaid expanding states with extensive dental benefits. This increase, however, was concentrated in states with high dentist supply with no evidence of improvement in utilization in states with limited dental coverage or low dentist supply. CONCLUSIONS: Expanding Medicaid with generous dental coverage improved dental care use only in areas with high dentist supply with no evidence of benefits with low dentist supply or less generous coverage. Improving access to dental care may require both generous coverage and supply-side interventions to increase dentist availability.

Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.

Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01-1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value = .001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.

Effects of Contextual Economic Factors on Childhood Obesity.

OBJECTIVES: To examine the association between changes in contextual economic factors on childhood obesity in the US. METHODS: We combined data from 2003, 2007, and 2011/2012 National Surveys of Children's Health for 129,781 children aged 10-17 with 27 state-level variables capturing general economic conditions, labor supply, and the monetary or time costs of calorie intake, physical activity, and cigarette smoking. We employed regression models controlling for demographic factors and state and year fixed effects. We also examined heterogeneity in economic effects by household income. RESULTS: Obesity risk increased with workforce proportion in blue-collar occupations, urban sprawl, female labor force participation, and number of convenience stores but declined with median household income, smoking ban in restaurants, and full service restaurants per capita. Most effects were specific to low income households, except for density of supercenters/warehouse clubs which was significantly associated with higher overweight/obesity risk only in higher income households. CONCLUSIONS FOR PRACTICE: Changes in state-level economic factors related to labor supply and monetary or time cost of calorie intake may affect childhood obesity especially for children in low-income households. Policymakers should consider these effects when designing programs aimed at reducing childhood obesity.