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1.  X- linked markers in DMD associated with oral clefts 
As part of an international consortium, case-parent trios were collected for a genome wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP) and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes, environmental factors, and differs markedly by gender. Family based association tests (FBAT) were used on 14,486 SNPs spanning the X chromosome, stratified by type of cleft and racial group. Significant results even after multiple comparisons correction were obtained for the Duchene’s muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P trios (both CL and CLP combined). When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asians. Although conventional sliding window haplotype analysis showed no increase in significance, analysis selected combinations of the 25 most significant SNPs in DMD identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within DMD.
PMCID: PMC3600648  PMID: 23489894
oral clefts; case-parent trios; X-linked; family-based association; DMD
2.  A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk 
BMC Genetics  2014;15:24.
Copy number variants (CNVs) may play an important part in the development of common birth defects such as oral clefts, and individual patients with multiple birth defects (including clefts) have been shown to carry small and large chromosomal deletions. In this paper we investigate de novo deletions defined as DNA segments missing in an oral cleft proband but present in both unaffected parents. We compare de novo deletion frequencies in children of European ancestry with an isolated, non-syndromic oral cleft to frequencies in children of European ancestry from randomly sampled trios.
We identified a genome-wide significant 62 kilo base (kb) non-coding region on chromosome 7p14.1 where de novo deletions occur more frequently among oral cleft cases than controls. We also observed wider de novo deletions among cleft lip and palate (CLP) cases than seen among cleft palate (CP) and cleft lip (CL) cases.
This study presents a region where de novo deletions appear to be involved in the etiology of oral clefts, although the underlying biological mechanisms are still unknown. Larger de novo deletions are more likely to interfere with normal craniofacial development and may result in more severe clefts. Study protocol and sample DNA source can severely affect estimates of de novo deletion frequencies. Follow-up studies are needed to further validate these findings and to potentially identify additional structural variants underlying oral clefts.
PMCID: PMC3929298  PMID: 24528994
Oral clefts; DNA copy numbers; de novo deletions; Case-parent trios
3.  Heritability of Face Shape in Twins: A Preliminary Study using 3D Stereophotogrammetry and Geometric Morphometrics 
Dentistry 3000  2013;1(1):14.
Previous research suggests that aspects of facial surface morphology are heritable. Traditionally, heritability studies have used a limited set of linear distances to quantify facial morphology and often employ statistical methods poorly designed to deal with biological shape. In this preliminary report, we use a combination of 3D photogrammetry and landmark-based morphometrics to explore which aspects of face shape show the strongest evidence of heritability in a sample of twins.
3D surface images were obtained from 21 twin pairs (10 monozygotic, 11 same-sex dizygotic). Thirteen 3D landmarks were collected from each facial surface and their coordinates subjected to geometric morphometric analysis. This involved superimposing the individual landmark configurations and then subjecting the resulting shape coordinates to a principal components analysis. The resulting PC scores were then used to calculate rough narrow-sense heritability estimates.
Three principal components displayed evidence of moderate to high heritability and were associated with variation in the breadth of orbital and nasal structures, upper lip height and projection, and the vertical and forward projection of the root of the nose due to variation in the position of nasion.
Aspects of facial shape, primarily related to variation in length and breadth of central midfacial structures, were shown to demonstrate evidence of strong heritability. An improved understanding of which facial features are under strong genetic control is an important step in the identification of specific genes that underlie normal facial variation.
PMCID: PMC3911821  PMID: 24501696
3D stereophotogrammetry; face shape; geometric morphometrics; heritability; twins
4.  Search for Genetic Modifiers of IRF6 and Genotype-Phenotype Correlations in Van der Woude and Popliteal Pterygium Syndromes 
Van der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1-2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype-phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA-binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van der Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van der Woude syndrome.
PMCID: PMC3898350  PMID: 23949966
Modifier gene; Van der Woude; popliteal pterygium; cleft; lip pit
5.  Genome-Wide Association Study of Periodontal Health Measured by Probing Depth in Adults Ages 18−49 years 
G3: Genes|Genomes|Genetics  2013;4(2):307-314.
The etiology of chronic periodontitis clearly includes a heritable component. Our purpose was to perform a small exploratory genome-wide association study in adults ages 18–49 years to nominate genes associated with periodontal disease−related phenotypes for future consideration. Full-mouth periodontal pocket depth probing was performed on participants (N = 673), with affected status defined as two or more sextants with probing depths of 5.5 mm or greater. Two variations of this phenotype that differed in how missing teeth were treated were used in analysis. More than 1.2 million genetic markers across the genome were genotyped or imputed and tested for genetic association. We identified ten suggestive loci (p-value ≤ 1E-5), including genes/loci that have been previously implicated in chronic periodontitis: LAMA2, HAS2, CDH2, ESR1, and the genomic region on chromosome 14q21-22 between SOS2 and NIN. Moreover, we nominated novel loci not previously implicated in chronic periodontitis or related pathways, including the regions 3p22 near OSBPL10 (a lipid receptor implicated in hyperlipidemia), 4p15 near HSP90AB2P (a heat shock pseudogene), 11p15 near GVINP1 (a GTPase pseudogene), 14q31 near SEL1L (an intracellular transporter), and 18q12 in FHOD3 (an actin cytoskeleton regulator). Replication of these results in additional samples is needed. This is one of the first research efforts to identify genetic polymorphisms associated with chronic periodontitis-related phenotypes by the genome-wide association study approach. Though small, efforts such this are needed in order to nominate novel genes and generate new hypotheses for exploration and testing in future studies.
PMCID: PMC3931564  PMID: 24347629
GWAS; chronic periodontitis
6.  Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome wide association on chromosome 1p22 
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology reflecting the action of multiple genetic and/or environmental factors. Genome wide association studies have successfully identified five novel loci associated with NSCL/P including a locus on 1p22.1 near the ABCA4 gene. Since neither expression analysis nor mutation screening support a role for ABCA4 in NSCL/P, we investigated the adjacent gene ARHGAP29.
Mutation screening for ARHGAP29 protein coding exons was conducted in 180 individuals with NSCL/P and controls from the US and the Philippines. Nine exons with variants in ARHGAP29 were then screened in an independent set of 872 cases and 802 controls. Arhgap29 expression was evaluated using in situ hybridization in murine embryos.
Sequencing of ARHGAP29 revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant. Arhgap29 showed craniofacial expression and was reduced in a mouse deficient for Irf6, a gene previously shown to have a critical role in craniofacial development.
The combination of genome wide association, rare coding sequence variants, craniofacial specific expression and interactions with IRF6 support a role for ARHGAP29 in NSCL/P and as the etiologic gene at the 1p22 GWAS locus for NSCL/P. This work suggests a novel pathway in which the IRF6 gene regulatory network interacts with the Rho pathway via ARHGAP29.
PMCID: PMC3501616  PMID: 23008150
ARHGAP29; cleft lip and palate; candidate gene; complex traits; Rho signaling
7.  Association of maternal CNVs in GSTT1/GSTT2 with smoking, preterm delivery, and low birth weight 
Frontiers in Genetics  2013;4:196.
Preterm delivery (PTD) is an adverse birth outcome associated with increased infant mortality and negative lifelong health consequences. PTD may be the result of interactions between genetics and maternal/fetal environmental factors including smoking exposure (SMK). A common deletion in the GSTT1 gene was previously reported to affect birth outcomes in smokers. In this study, we dissect the associations among SMK, birth outcomes, and copy number variations (CNVs) in the GSTT1/GSTT2 region. A preterm birth case-control dataset of 1937 mothers was part of the GENEVA preterm birth study, which included genome-wide genotyping used to identify CNVs. We examined the association of SMK with birth outcomes, detected CNVs within the GSTT1/GSTT2 region using PennCNV, and examined associations of the identified CNVs with preterm birth and with birth weight (BW) in full term birth controls, including interactions with SMK. Finally, we tested the association of CNVs in GSTT1/GSTT2 with SMK. We confirmed the association of smoking with low BW and PTD. We identified 2 CNVs in GSTT2 (GSTT2a and GSTT2b), 1 CNV in GSTTP1 and 2 CNVs in GSTT1 (GSTT1a and GSTT1b). The GSTT2a deletion was associated with reduced BW (−284 g, p = 2.50E-7) in smokers, and was more common in smokers [odds ratio(OR) = 1.30, p = 0.04]. We found that the size of the reported common deletion CNV in GSTT1 was larger than previously shown. The GSTTP1 and GSTT1b null genotypes were in high linkage disequilibrium (LD) (D′ = 0.89) and less common in smokers (OR = 0.68, p = 0.019 and OR = 0.73, p = 0.055, respectively). These two deletions were in partial LD with GSTT2a and GSTT2b duplications. All 5 CNVs seem to be associated with increased risk of preterm birth before 35 completed weeks. CNVs in the GSTTT1/GSTT2 region appear associated with low BW and PTD outcomes, but LD complicated these CNVs in GSTT1/GSTT2. In genetic association studies of BW, multiple CNVs in this region need to be investigated instead of a single polymorphism.
PMCID: PMC3809558  PMID: 24194744
prematurity; preterm birth; copy number variation; GSTT1; GSTT2; birth weight
8.  Multi-Dimensional Prioritization of Dental Caries Candidate Genes and Its Enriched Dense Network Modules 
PLoS ONE  2013;8(10):e76666.
A number of genetic studies have suggested numerous susceptibility genes for dental caries over the past decade with few definite conclusions. The rapid accumulation of relevant information, along with the complex architecture of the disease, provides a challenging but also unique opportunity to review and integrate the heterogeneous data for follow-up validation and exploration. In this study, we collected and curated candidate genes from four major categories: association studies, linkage scans, gene expression analyses, and literature mining. Candidate genes were prioritized according to the magnitude of evidence related to dental caries. We then searched for dense modules enriched with the prioritized candidate genes through their protein-protein interactions (PPIs). We identified 23 modules comprising of 53 genes. Functional analyses of these 53 genes revealed three major clusters: cytokine network relevant genes, matrix metalloproteinases (MMPs) family, and transforming growth factor-beta (TGF-β) family, all of which have been previously implicated to play important roles in tooth development and carious lesions. Through our extensive data collection and an integrative application of gene prioritization and PPI network analyses, we built a dental caries-specific sub-network for the first time. Our study provided insights into the molecular mechanisms underlying dental caries. The framework we proposed in this work can be applied to other complex diseases.
PMCID: PMC3795720  PMID: 24146904
9.  The Evolution of Human Genetic Studies of Cleft Lip and Cleft Palate 
Orofacial clefts (OFCs)—primarily cleft lip and cleft palate—are among the most common birth defects in all populations worldwide, and have notable population, ethnicity, and gender differences in birth prevalence. Interest in these birth defects goes back centuries, as does formal scientific interest; scientists often used OFCs as examples or evidence during paradigm shifts in human genetics, and have also used virtually every new method of human genetic analysis to deepen our understanding of OFC. This review traces the evolution of human genetic investigations of OFC, highlights the specific insights gained about OFC through the years, and culminates in a review of recent key OFC genetic findings resulting from the powerful tools of the genomics era. Notably, OFC represents a major success for genome-wide approaches, and the field is poised for further breakthroughs in the near future.
PMCID: PMC3760163  PMID: 22703175
genetics; paradigm; history; phenomics; phenotypes
10.  Candidate gene linkage approach to Identify DNA variants that predispose to preterm birth 
Pediatric research  2012;73(2):135-141.
To identify genetic variants contributing to preterm birth using a linkage candidate gene approach.
We studied 99 single nucleotide polymorphisms for 33 genes in 257 families with preterm births segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.
Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (p=0.0012) and CYP2E1 (p=0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (p=0.003), IGFBP3 (p=0.006), DHCR7 (p=0.009), and TRAF2 (p=0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants.
These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of preterm birth.
PMCID: PMC3740714  PMID: 23168575
Genetic epidemiology  2012;36(3):253-262.
A major concern for all copy number variation (CNV) detection algorithms is their reliability and repeatability. However, it is difficult to evaluate the reliability of CNV calling strategies due to the lack of gold standard data that would tell us which CNVs are real. We propose that if CNVs are called in duplicate samples, or inherited from parent to child, then these can be considered validated CNVs. We used two large family-based Genome-Wide Association Study (GWAS) datasets from the GENEVA consortium to look at concordance rates of CNV calls between duplicate samples, parent-child pairs, and unrelated pairs. Our goal was to make recommendations for ways to filter and use CNV calls in GWAS datasets that do not include family data. We used PennCNV as our primary CNV-calling algorithm, and tested CNV calls using different datasets and marker sets, and with various filters on CNVs and samples. Using the Illumina core HumanHap550 SNP (single nucleotide polymorphism) set, we saw duplicate concordance rates of approximately 55% and parent-child transmission rates of approximately 28% in our datasets. GC model adjustment and sample quality filtering had little effect on these reliability measures. Stratification on CNV size and DNA sample type did have some effect. Overall, our results show that it is probably not possible to find a CNV calling strategy (including filtering and algorithm) that will give us a set of “reliable” CNV calls using current chip technologies. But if we understand the error process, we can still use CNV calls appropriately in genetic association studies.
PMCID: PMC3696390  PMID: 22714937
evaluation; CNV calling strategies; family-based GWAS
12.  No Observed Association for Mitochondrial SNPs with Preterm Delivery and Related Outcomes 
Pediatric research  2012;72(5):539-544.
Preterm delivery (PTD) is the leading cause of neonatal morbidity and mortality. Epidemiologic studies indicate recurrence of PTD is maternally inherited creating a strong possibility that mitochondrial variants contribute to its etiology. This study examines the association between mitochondrial genotypes with PTD and related outcomes.
This study combined, through meta-analysis, two case-control, genome-wide association studies (GWAS); one from the Danish National Birth Cohort (DNBC) Study and one from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. The outcomes of PTD (≤36 weeks), very PTD (≤32 weeks) and preterm prelabor rupture of membranes (PPROM) were examined. 135 individual SNP associations were tested using the combined genome from mothers and neonates (case vs. control) in each population and then pooled via meta-analysis.
After meta-analysis there were four SNPs for the outcome of PTD below p≤0.10, and two below p≤0.05. For the additional outcomes of very PTD and PPROM there were three and four SNPs respectively below p≤0.10.
Given the number of tests no single SNP reached study wide significance (p=0.0006). Our study does not support the hypothesis that mitochondrial genetics contributes to the maternal transmission of PTD and related outcomes.
PMCID: PMC3694399  PMID: 22902432
13.  Genetic and environmental factors associated with dental caries in children: The Iowa Fluoride Study 
Caries research  2012;46(3):177-184.
Dental caries remains the most common chronic childhood disease. Despite strong evidence of genetic components, there have been few studies of candidate genes and caries. In this analysis we tried to assess genetic and environmental factors contributing to childhood caries in the Iowa Fluoride Study. Environmental factors (age, sex, race, tooth-brushing frequencies and water fluoride level) and three dental caries scores (d2fs-total, d2fs-pit/fissure, and d2fs-smooth surface) were assessed in 575 unrelated children (mean age=5.2 years). Regression analyses were applied to assess environmental correlates. The Family Based Association Test was used to test genetic associations for 23 SNP markers in 7 caries candidate genes on 333 Caucasian parent-child trios. We evaluated the associations between caries status and the level of both single SNPs and multiple SNPs (haplotype) respectively. Permutation procedure was performed for correction of inflated type-I errors due to multiple testing. Age, tooth-brushing frequencies and water fluoride level were significantly correlated to at least one carious score. Caries on pit and fissure surfaces was substantially higher than on smooth surfaces (61% vs. 39%). SNPs in three genes (DSPP, KLK4, and AQP5) showed consistent associations with protection against caries. Of note, KLK4 and AQP5 were also highlighted by subsequent haplotype analysis. Our results support the concept that genes can modify the susceptibility of caries in children. Replication analysis in independent cohorts is highly needed in order to verify the validity of our findings.
PMCID: PMC3580152  PMID: 22508493
dental caries; genetics; children; candidate gene; association analysis
14.  Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts 
We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin effects on risk of orofacial clefting using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a p-value <10−5 for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor parent of origin effects play major roles in the etiology of orofacial clefting in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or parent of origin effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus the most promising SNPs identified by this study may still be worth further investigation.
PMCID: PMC3617127  PMID: 22419666
GWAS; CL/P; CP; maternal genes; parent-of-origin; family-based study; association study
15.  Rapid Testing of SNPs and Gene–Environment Interactions in Case–Parent Trio Data Based on Exact Analytic Parameter Estimation 
Biometrics  2011;68(3):766-773.
Case–parent trio studies concerned with children affected by a disease and their parents aim to detect single nucleotide polymorphisms (SNPs) showing a preferential transmission of alleles from the parents to their affected offspring. A popular statistical test for detecting such SNPs associated with disease in this study design is the genotypic transmission/disequilibrium test (gTDT) based on a conditional logistic regression model, which usually needs to be fitted by an iterative procedure. In this article, we derive exact closed-form solutions for the parameter estimates of the conditional logistic regression models when testing for an additive, a dominant, or a recessive effect of a SNP, and show that such analytic parameter estimates also exist when considering gene–environment interactions with binary environmental variables. Because the genetic model underlying the association between a SNP and a disease is typically unknown, it might further be beneficial to use the maximum over the gTDT statistics for the possible effects of a SNP as test statistic. We therefore propose a procedure enabling a fast computation of the test statistic and the permutation-based p-value of this MAX gTDT. All these methods are applied to whole-genome scans of the case–parent trios from the International Cleft Consortium. These applications show our procedures dramatically reduce the required computing time compared to the conventional iterative methods allowing, for example, the analysis of hundreds of thousands of SNPs in a few minutes instead of several hours.
PMCID: PMC3387527  PMID: 22150644
Conditional logistic regression; Family-based design; Genome-wide association studies; Genotypic transmission/disequilibrium test; International Cleft Consortium; MAX test
16.  The FaceBase Consortium: A comprehensive program to facilitate craniofacial research 
Developmental biology  2011;355(2):175-182.
The FaceBase Consortium consists of ten interlinked research and technology projects whose goal is to generate craniofacial research data and technology for use by the research community through a central data management and integrated bioinformatics hub. Funded by the National Institute of Dental and Craniofacial Research (NIDCR) and currently focused on studying the development of the middle region of the face, the Consortium will produce comprehensive datasets of global gene expression patterns, regulatory elements and sequencing; will generate anatomical and molecular atlases; will provide human normative facial data and other phenotypes; conduct follow up studies of a completed genome-wide association study; generate independent data on the genetics of craniofacial development, build repositories of animal models and of human samples and data for community access and analysis; and will develop software tools and animal models for analyzing and functionally testing and integrating these data. The FaceBase website ( will serve as a web home for these efforts, providing interactive tools for exploring these datasets, together with discussion forums and other services to support and foster collaboration within the craniofacial research community.
PMCID: PMC3440302  PMID: 21458441
Craniofacial development; Cleft lip and palate; Human genetics; Animal models; Database; Morphometrics
17.  Evidence for gene-environment interaction in a genome wide study of isolated, non-syndromic cleft palate 
Genetic epidemiology  2011;35(6):469-478.
Non-syndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G×E) interaction simultaneously, plus a separate 1 df test for G×E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome wide significance when considered alone, markers in several genes attained or approached genome wide significance when G×E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G×E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G×E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as non-syndromic CP.
PMCID: PMC3180858  PMID: 21618603
18.  Gene-Environment Interplay in Common Complex Diseases: Forging an Integrative Model—Recommendations From an NIH Workshop 
Genetic epidemiology  2011;10.1002/gepi.20571.
Although it is recognized that many common complex diseases are a result of multiple genetic and environmental risk factors, studies of gene-environment interaction remain a challenge and have had limited success to date. Given the current state-of-the-science, NIH sought input on ways to accelerate investigations of gene-environment interplay in health and disease by inviting experts from a variety of disciplines to give advice about the future direction of gene-environment interaction studies. Participants of the NIH Gene-Environment Interplay Workshop agreed that there is a need for continued emphasis on studies of the interplay between genetic and environmental factors in disease and that studies need to be designed around a multifaceted approach to reflect differences in diseases, exposure attributes, and pertinent stages of human development. The participants indicated that both targeted and agnostic approaches have strengths and weaknesses for evaluating main effects of genetic and environmental factors and their interactions. The unique perspectives represented at the workshop allowed the exploration of diverse study designs and analytical strategies, and conveyed the need for an interdisciplinary approach including data sharing, and data harmonization to fully explore gene-environment interactions. Further, participants also emphasized the continued need for high-quality measures of environmental exposures and new genomic technologies in ongoing and new studies.
PMCID: PMC3228883  PMID: 21308768
gene-environment interaction; epidemiology; study design; genetics; environment
19.  Effects of Smoking and Genotype on the PSR Index of Periodontal Disease in Adults Aged 18–49 
Studies have found both genetic and environmental influences on chronic periodontitis. The purpose of this study was to examine the relationships among previously identified genetic variants, smoking status, and two periodontal disease-related phenotypes (PSR1 and PSR2) in 625 Caucasian adults (aged 18–49 years). The PSR Index was used to classify participants as affected or unaffected under the PSR1 and PSR2 phenotype definitions. Using logistic regression, we found that the form of the relationship varied by single nucleotide polymorphism (SNP): For rs10457525 and rs12630931, the effects of smoking and genotype on risk were additive; whereas for rs10457526 and rs733048, smoking was not independently associated with affected status once genotype was taken into consideration. In contrast, smoking moderated the relationships of rs3870371 and rs733048 with affected status such that former and never smokers with select genotypes were at increased genetic risk. Thus, for several groups, knowledge of genotype may refine the risk prediction over that which can be determined by knowledge of smoking status alone. Future studies should replicate these findings. These findings provide the foundation for the exploration of novel pathways by which periodontitis may occur.
PMCID: PMC3447590  PMID: 23066400
adult; chronic periodontitis; genetics; genomics; smoking
20.  Phenotype harmonization and cross-study collaboration in GWAS consortia: the GENEVA experience 
Genetic epidemiology  2011;35(3):159-173.
Genome-wide association study (GWAS) consortia and collaborations formed to detect genetic loci for common phenotypes or investigate gene-environment (G*E) interactions are increasingly common. While these consortia effectively increase sample size, phenotype heterogeneity across studies represents a major obstacle that limits successful identification of these associations. Investigators are faced with the challenge of how to harmonize previously collected phenotype data obtained using different data collection instruments which cover topics in varying degrees of detail and over diverse time frames. This process has not been described in detail. We describe here some of the strategies and pitfalls associated with combining phenotype data from varying studies. Using the Gene Environment Association Studies (GENEVA) multi-site GWAS consortium as an example, this paper provides an illustration to guide GWAS consortia through the process of phenotype harmonization and describes key issues that arise when sharing data across disparate studies. GENEVA is unusual in the diversity of disease endpoints and so the issues it faces as its participating studies share data will be informative for many collaborations. Phenotype harmonization requires identifying common phenotypes, determining the feasibility of cross-study analysis for each, preparing common definitions, and applying appropriate algorithms. Other issues to be considered include genotyping timeframes, coordination of parallel efforts by other collaborative groups, analytic approaches, and imputation of genotype data. GENEVA's harmonization efforts and policy of promoting data sharing and collaboration, not only within GENEVA but also with outside collaborations, can provide important guidance to ongoing and new consortia.
PMCID: PMC3055921  PMID: 21284036
phenotype; harmonization; genome-wide association studies; GENEVA; consortia
21.  Single-Nucleotide Polymorphisms in the KCNN3 Gene Associate With Preterm Birth 
Reproductive Sciences  2011;18(3):286-295.
The objectives were to determine whether single-nucleotide polymorphisms (SNPs) in KCNN3 (encodes the small conductance calcium-activated potassium channel subfamily N, member 3), associate with preterm birth (PTB). In all, 602 preterm families with at least 1 preterm (<37 weeks gestation) infant were studied: DNA from the infant and one or both parents were genotyped for 16 SNPs in KCNN3. A region of interest within KCNN3 was sequenced in 512 Caucasian non-Hispanic mothers (412 with preterm deliveries;100 who delivered at term). Family-based association testing was used for genotyping analysis; Fisher exact test was used for sequencing analysis. Six SNPs (rs1218585, rs4845396, rs12058931, rs1218568, rs6426985, and rs4845394) were associated with PTB (all Ps < .05). These variations were all located within the intronic region between exons 1 and 2. Maternal sequencing revealed an association of 3 SNPs with spontaneous PTB; rs1218585 (P = .007), rs1218584 (P = .05), and a novel SNP at chromosome1:153099353 (P = .02). Polymorphisms in KCNN3 are associated with PTB and investigation into the functional significance of these allelic changes is warranted.
PMCID: PMC3053422  PMID: 21266667
KCNN3; SK3; preterm birth; ion channel
22.  Revisiting the Recurrence Risk of Nonsyndromic Cleft Lip with or without Cleft Palate 
Sub-epithelial defects (i.e. discontinuities) of the superior orbicularis oris (OO) muscle appear to be a part of the phenotypic spectrum of cleft lip with or without cleft palate (CL±P). Analysis of the OO phenotype as a clinical tool is hypothesized to improve familial recurrence risk estimates of CL±P. Study subjects (n=3912) were drawn from 835 families. Occurrences of CL±P were compared in families with and without members with an OO defect. Empiric recurrence risks were calculated for CL±P and OO defects among first degree relatives (FDRs). Risks were compared to published data and/or to other outcomes of this study using chi square or Fisher's exact tests. In our cohort, the occurrence of CL±P was significantly increased in families with OO defects versus those without (p < 0.01, OR = 1.74). The total FDR recurrence of isolated OO defects in this cohort is 16.4%; the sibling recurrence is 17.2%. The chance for one or more FDRs of a CL±P proband to have an OO defect is 11.4%; or 14.7% for a sibling. Conversely, the chance for any FDR of an individual with an OO defect to have CL±P is 7.3%; or for a sibling, 3.3%; similar to published recurrence risk estimates of nonsyndromic (NS) CL±P. This study supports sub-epithelial OO muscle defects as being part of the CL±P spectrum and suggests a modification to recurrence risk estimates of CL±P by utilizing OO defect information.
PMCID: PMC2965308  PMID: 20949506
cleft lip and palate; recurrence risk; orbicularis oris; genetic counseling; phenotypic spectrum
23.  Vitamin D Receptor (VDR) and Group-Specific Component (GC, Vitamin D–Binding Protein) Polymorphisms in Myopia 
The protective effect of time outdoors in lowering the risk of myopia onset suggests that vitamin D metabolism may be altered in myopia. This study provides evidence that genetic variants within the vitamin D receptor gene VDR may be associated with myopia in white subjects with milder levels of myopia. Replication is needed, as well as establishing whether there is any biological relevance of these variations to myopia.
Epidemiologic evidence indicates that time outdoors reduces the risk of myopia, suggesting a possible role for vitamin D. This case–control study was conducted to determine whether single-nucleotide polymorphisms (SNPs) within VDR at 12q13.11 and GC at 4q12-13 are associated with myopia.
The primary analysis was conducted on 81 white adult control subjects between 18 and 50 years of age with a spherical equivalent refractive error between +0.50 and +2.00 D in both eyes and less than 1.50 D of astigmatism. Affected myopic subjects were 289 unrelated white adults at least 18 years of age with at least −0.75 D myopia in both principal meridians of both eyes.
One SNP within VDR was significantly associated with myopia in the multivariate analysis of the primary sample (rs2853559: odds ratio = 1.99, P = 0.003). In a subsample of less severely myopic white subjects between −0.75 and −4.00 D, three SNPs within VDR were significantly associated in a multivariate model after adjustment for multiple comparisons (rs2239182: odds ratio = 2.17, P = 0.007; rs3819545: odds ratio = 2.34, P = 0.003; rs2853559: odds ratio = 2.14, P = 0.0035), accounting for 12% of model variance over age alone.
Polymorphisms within VDR appear to be associated with low to moderate amounts of myopia in white subjects. Future studies should determine whether this finding can be replicated and should explore the biological significance of these variations with respect to myopia.
PMCID: PMC3109057  PMID: 21357399
24.  The PhenX Toolkit: Get the Most From Your Measures 
American Journal of Epidemiology  2011;174(3):253-260.
The potential for genome-wide association studies to relate phenotypes to specific genetic variation is greatly increased when data can be combined or compared across multiple studies. To facilitate replication and validation across studies, RTI International (Research Triangle Park, North Carolina) and the National Human Genome Research Institute (Bethesda, Maryland) are collaborating on the consensus measures for Phenotypes and eXposures (PhenX) project. The goal of PhenX is to identify 15 high-priority, well-established, and broadly applicable measures for each of 21 research domains. PhenX measures are selected by working groups of domain experts using a consensus process that includes input from the scientific community. The selected measures are then made freely available to the scientific community via the PhenX Toolkit. Thus, the PhenX Toolkit provides the research community with a core set of high-quality, well-established, low-burden measures intended for use in large-scale genomic studies. PhenX measures will have the most impact when included at the experimental design stage. The PhenX Toolkit also includes links to standards and resources in an effort to facilitate data harmonization to legacy data. Broad acceptance and use of PhenX measures will promote cross-study comparisons to increase statistical power for identifying and replicating variants associated with complex diseases and with gene-gene and gene-environment interactions.
PMCID: PMC3141081  PMID: 21749974
environmental exposure; epidemiologic methods; genetic research; genetics; genome-wide association study; meta-analysis as topic; phenotype; research design
25.  Women Are More Susceptible to Caries but Individuals Born with Clefts Are Not 
The identification of individuals at a higher risk of developing caries is of great interest. Isolated forms of cleft lip and palate are among the most common craniofacial congenital anomalies in humans. Historically, several reports suggest that individuals born with clefts have a higher risk for caries. Caries continues to be the most common infectious noncontagious disease worldwide and a great burden to any health system. The identification of individuals of higher susceptibility to caries is of great interest. In this paper, we assessed caries experience of 1,593 individuals from three distinct populations. The study included individuals born with clefts, their unaffected relatives, and unrelated unaffected controls that were recruited from areas with similar cultural pressures and limited access to dental care. DMFT/dmft scores were obtained, and caries experience rates were compared among the three groups in each geographic area. Individuals born with clefts did not present higher caries experience in comparison to their unaffected relatives or unrelated unaffected controls. Women tend to present higher caries rates in comparison to men. Our work provides strong evidence that individuals born with clefts are not at higher risk to caries; however, women tend to have more severe caries experience.
PMCID: PMC3124302  PMID: 21747859

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