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1.  Genetics of Cleft Lip and Cleft Palate 
Orofacial clefts are common birth defects and can occur as isolated, nonsyndromic events or as part of Mendelian syndromes. There is substantial phenotypic diversity in individuals with these birth defects and their family members: from subclinical phenotypes to associated syndromic features that is mirrored by the many genes that contribute to the etiology of these disorders. Identification of these genes and loci has been the result of decades of research using multiple genetic approaches. Significant progress has been made recently due to advances in sequencing and genotyping technologies, primarily through the use of whole exome sequencing and genome-wide association studies. Future progress will hinge on identifying functional variants, investigation of pathway and other interactions, and inclusion of phenotypic and ethnic diversity in studies.
PMCID: PMC3925974  PMID: 24124047
Cleft lip; cleft palate; genetics; syndromes; nonsyndromic
2.  Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries 
Caries research  2014;48(4):330-338.
Dental caries continues to be the most common chronic disease in children today. Despite the substantial involvement of genetics in the process of caries development, the specific genes contributing to dental caries remain largely unknown.
We performed separate genome-wide association studies of smooth and pit-and-fissure tooth surface caries experience in the primary dentitions of self-reported white children in two samples from Iowa and rural Appalachia. In total, 1006 children (ages 3-12 years) were included for smooth surface analysis, and 979 children (ages 4-14 years) for pit-and-fissure surface analysis. Associations were tested for more than 1.2 million single nucleotide polymorphisms, either genotyped or imputed.
We detected genome-wide significant signals in KPNA4 (p-value = 2.0E-9), and suggestive signals in ITGAL (p-value = 2.1E-7) and PLUNC family genes (p-value = 2.0E-6), thus nominating these novel loci as putative caries susceptibility genes. We also replicated associations observed in previous studies for MPPED2 (p-value = 6.9E-6), AJAP1 (p-value = 1.6E-6) and RPS6KA2 (p-value = 7.3E-6). Replication of these associations in additional samples, as well as experimental studies to determine the biological functions of associated genetic variants, are warranted. Ultimately, efforts such as this may lead to a better understand of caries etiology, and could eventually facilitate the development of new interventions and preventive measures.
PMCID: PMC4043868  PMID: 24556642
genome-wide association study; primary dentition; susceptibility gene; smooth surface; pit-and-fissure surface
3.  Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course 
Human Molecular Genetics  2013;22(17):3597-3607.
Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10−8) near FTO (P = 3.72 × 10−23), TMEM18 (P = 3.24 × 10−17), MC4R (P = 4.41 × 10−17), TNNI3K (P = 4.32 × 10−11), SEC16B (P = 6.24 × 10−9), GNPDA2 (P = 1.11 × 10−8) and POMC (P = 4.94 × 10−8) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10−5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18–90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.
PMCID: PMC3736869  PMID: 23669352
4.  Role of TRAV Locus in Low Caries Experience 
Human genetics  2013;132(9):1015-1025.
Caries is the most common chronic, multifactorial disease in the world today; and little is still known about the genetic factors influencing susceptibility. Our previous genome- wide linkage scan has identified five loci related to caries susceptibility: 5q13.3, 13q31.1, 14q11.2, 14q 24.3, and Xq27. In the present study, we fine mapped the 14q11.2 locus in order to identify genetic contributors to caries susceptibility. Four hundred seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. An additional 387 DNA samples from unrelated individuals were used to determine allele frequencies. For replication purposes, a total of 1,446 independent subjects from four different populations were analyzed based on their caries experience (low versus high). Forty-eight markers in 14q11.2 were genotyped using TaqMan chemistry. Transmission disequilibrium test was used to detect overtransmission of alleles in the Filipino families, and chi-square, Fisher’s exact and logistic regression were used to test for association between low caries experience and variant alleles in the replication data sets. We finally assessed the mRNA expression of TRAV4 in the saliva of 143 study subjects. In the Filipino families, statistically significant associations were found between low caries experience and markers in TRAV4. We were able to replicate these results in the populations studied that were characteristically from underserved areas. Direct sequencing of 22 subjects carrying the associated alleles detect one missense mutation (Y30R) that is predicted to be probably damaging. Finally, we observed higher expression in children and teenagers with low caries experience, correlating with specific alleles in TRAV4. Our results suggest TRAV4 may have a role in protecting against caries.
PMCID: PMC3744616  PMID: 23657505
5.  Exploratory genotype–phenotype correlations of facial form and asymmetry in unaffected relatives of children with non-syndromic cleft lip and/or palate 
Journal of anatomy  2014;224(6):688-709.
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.
PMCID: PMC4025896  PMID: 24738728
facial asymmetry; genotype-phenotype correlations; morphometrics; NSCL/P; 3D morphology
6.  Demographic, socioeconomic, and behavioral factors affecting patterns of tooth decay in the permanent dentition: Principal components and factor analyses 
Dental caries of the permanent dentition is a multi-factorial disease resulting from the complex interplay of endogenous and environmental risk factors. The disease is not easily quantified due to the innumerable possible combinations of carious lesions across individual tooth surfaces of the permanent dentition. Global measures of decay, such as the DMFS index (which was developed for surveillance applications), may not be optimal for studying the epidemiology of dental caries because they ignore the distinct patterns of decay across the dentition. We hypothesize that specific risk factors may manifest their effects on specific tooth surfaces leading to patterns of decay that can be identified and studied. In this study we utilized two statistical methods of extracting patterns of decay from surface-level caries data in order to create novel phenotypes with which to study the risk factors affecting dental caries.
Intra-oral dental examinations were performed on 1,068 participants aged 18 to 75 years to assess dental caries. The 128 tooth surfaces of the permanent dentition were scored as carious or not and used as input for principal components analysis (PCA) and factor analysis (FA), two methods of identifying underlying patterns without a priori knowledge of the patterns. Demographic (age, sex, birth year, race/ethnicity, and educational attainment), anthropometric (height, body mass index, waist circumference), endogenous (saliva flow), and environmental (tooth brushing frequency, home water source, and home water fluoride) risk factors were tested for association with the caries patterns identified by PCA and FA, as well as DMFS, for comparison. The ten strongest patterns (i.e., those that explain the most variation in the data set) extracted by PCA and FA were considered.
The three strongest patterns identified by PCA reflected (i) global extent of decay (i.e., comparable to DMFS index), (ii) pit and fissure surface caries, and (iii) smooth surface caries, respectively. The two strongest patterns identified by FA corresponded to (i) pit and fissure surface caries and (ii) maxillary incisor caries. Age and birth year were significantly associated with several patterns of decay, including global decay/DMFS index. Sex, race, educational attainment, and tooth brushing were each associated with specific patterns of decay, but not with global decay/DMFS index.
Taken together, these results support the notion that caries experience is separable into patterns attributable to distinct risk factors. This study demonstrates the utility of such novel caries patterns as new outcomes for exploring the complex, multifactorial nature of dental caries.
PMCID: PMC3568445  PMID: 23106439
dental caries; permanent dentition; pit and fissure surfaces; smooth surfaces; tooth surfaces; principal components analysis; factor analysis; tooth brushing
7.  Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay 
BMC Medical Genetics  2014;15:81.
Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans.
We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice.
Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience.
The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy.
PMCID: PMC4112727  PMID: 25023176
Dental caries; Deafness; Dental development; Ear development; Linkage disequilibrium; Genetics; Polymorphisms
8.  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
9.  Vaginal and Oral Microbes, Host Genotype and Preterm Birth 
Medical hypotheses  2009;73(6):963-975.
Preterm birth (PTB) is a leading cause of infant mortality and morbidity in the U.S. and across the globe. Infection and associated inflammation are important initiators for PTB pathways; an estimated 40% of PTBs are attributed to amniochorionic-decidual or systemic inflammation. Historically, intrauterine infections have been implicated in PTB; recent evidence suggests that infections remote from the fetal site may also be causative. There is strong epidemiological evidence that bacterial vaginosis and periodontitis -- two syndromes characterized by perturbations in the normal vaginal and oral bacterial microflora respectively-- are linked to infection-associated PTB. Oral and vaginal environments are similar in their bacterial microbiology; identical bacterial species have been independently isolated in periodontitis and bacterial vaginosis. Periodontitis and bacterial vaginosis also share many behavioral and sociodemographic risk factors suggesting a possible common pathophysiology. Genetic polymorphisms in host inflammatory responses to infection are shared between bacterial vaginosis, periodontitis and PTB, suggesting common mechanisms through which host genotype modify the effect of abnormal bacterial colonization on preterm birth. We review the state of knowledge regarding the risk of PTB attributable to perturbations in bacterial flora in oral and vaginal sites and the role of host genetics in modifying the risk of infection-related PTB. We posit that bacterial species that are common in perturbed vaginal and oral sites are associated with PTB through their interaction with the host immune system.
PMCID: PMC4026093  PMID: 19942083
Prematurity; infection; genotype
To assess association between nonsyndromic (NS) cleft lip with or without cleft palate (CL(P)) and SNPs within the CRISPLD2 gene (cysteine-rich secretory protein LCCL domain containing 2).
Four SNPs within the CRISPLD2 gene domain (rs1546124, rs8061351, rs2326398, rs4783099) were genotyped to test for association via family-based association methods.
5,826 individuals from 1,331 families in which one or more family member is affected with CL(P).
Evidence of association was seen for SNP rs1546124 in USA (p=0.02) and Brazilian (p=0.04) Caucasian cohorts. We also found association of SNP rs1546124 with cleft palate alone (CP) in South Americans (Guatemala and ECLAMC) and combined Hispanics (Guatemala, ECLAMC and Texas Hispanics) (p=0.03 for both comparisons), and with both cleft lip with cleft palate (CLP; p=0.04) and CL(P) (p=0.02) in North Americans. Strong evidence of association was found for SNP rs2326398 with CP in Asian populations (p=0.003) and with CL(P) in Hispanics (p=0.03), and also with bilateral CL(P) in the Brazilians (p=0.004). In the Brazilians, SNP rs8061351 showed association with cleft subgroups incomplete CL(P) (p=0.004), and unilateral incomplete CL(P) (p=0.003). Prediction of SNP functionality revealed that the C allele in the C471T silent mutation (overrepresented in cases with CL(P) presents two putative exonic splicing enhancer motifs and creates a binding site AP-2 alpha, a transcription factor involved in craniofacial development.
Our results support the hypothesis that variants in the CRISPLD2 gene may be involved in the etiology of NS CL(P).
PMCID: PMC3000893  PMID: 20815724
CRISPLD2 gene; cleft lip; cleft palate; subphenotypes
11.  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
12.  Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking 
Stephens, Sarah H. | Hartz, Sarah M. | Hoft, Nicole R. | Saccone, Nancy L. | Corley, Robin C. | Hewitt, John K. | Hopfer, Christian J. | Breslau, Naomi | Coon, Hilary | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Han, Younghun | Hansel, Nadia N. | Jiang, Chenhui | Korhonen, Tellervo | Lind, Penelope A. | Liu, Jason | Lyytikäinen, Leo-Pekka | Michel, Martha | Shaffer, John R. | Short, Susan E. | Sun, Juzhong | Teumer, Alexander | Thompson, John R. | Vogelzangs, Nicole | Vink, Jacqueline M. | Wenzlaff, Angela | Wheeler, William | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri H. | Benjamin, Daniel J. | Bergen, Andrew W. | Broms, Ulla | Cesarini, David | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gillespie, Nathan A. | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Heikkilä, Kauko | Hickie, Ian B. | Hottenga, Jouke Jan | Jousilahti, Pekka | Kaakinen, Marika | Kähönen, Mika | Koellinger, Philipp D. | Kittner, Stephen | Konte, Bettina | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Murray, Tanda | Nauck, Matthias | North, Kari E. | Paré, Peter D. | Pergadia, Michele | Ruczinski, Ingo | Salomaa, Veikko | Viikari, Jorma | Willemsen, Gonneke | Barnes, Kathleen C. | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Edenberg, Howard J. | Francks, Clyde | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Johannesson, Magnus | Kendler, Kenneth S. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Marazita, Mary L. | Marchini, Jonathan | Mitchell, Braxton D. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Schwartz, Ann G. | Shete, Sanjay | Spitz, Margaret | Swan, Gary E. | Völzke, Henry | Veijola, Juha | Wei, Qingyi | Amos, Chris | Cannon, Dale S. | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J. | Ehringer, Marissa A.
Genetic epidemiology  2013;37(8):846-859.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
PMCID: PMC3947535  PMID: 24186853
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
13.  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
14.  Evidence of Gene−Environment Interaction for Two Genes on Chromosome 4 and Environmental Tobacco Smoke in Controlling the Risk of Nonsyndromic Cleft Palate 
PLoS ONE  2014;9(2):e88088.
Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10−6
PMCID: PMC3916361  PMID: 24516586
Human Heredity  2009;68(3):151-170.
Non-syndromic orofacial clefts, i.e. cleft lip (CL) and cleft palate (CP), are among the most common birth defects. The goal of this study was to identify genomic regions and genes for CL with or without CP (CL/P).
We performed linkage analyses of a 10 cM genome scan in 820 multiplex CL/P families (6,565 individuals). Significant linkage results were followed by association analyses of 1,476 SNPs in candidate genes and regions, utilizing a weighted false discovery rate (wFDR) approach to control for multiple testing and incorporate the genome scan results.
Significant (multipoint HLOD ≥3.2) or genome-wide-significant (HLOD ≥4.02) linkage results were found for regions 1q32, 2p13, 3q27-28, 9q21, 12p11, 14q21-24 and 16q24. SNPs in IRF6 (1q32) and in or near FOXE1 (9q21) reached formal genome-wide wFDR-adjusted significance. Further, results were phenotype dependent in that the IRF6 region results were most significant for families in which affected individuals have CL alone, and the FOXE1 region results were most significant in families in which some or all of the affected individuals have CL with CP.
These results highlight the importance of careful phenotypic delineation in large samples of families for genetic analyses of complex, heterogeneous traits such as CL/P.
PMCID: PMC2709160  PMID: 19521098
Cleft lip; Cleft palate; Linkage; Association; wFDR; IRF6; FOXE1; Genetics
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
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
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
Human heredity  2009;68(3):151-170.
Non-syndromic orofacial clefts, i.e. cleft lip (CL) and cleft palate (CP), are among the most common birth defects. The goal of this study was to identify genomic regions and genes for CL with or without CP (CL/P).
We performed linkage analyses of a 10 cM genome scan in 820 multiplex CL/P families (6,565 individuals). Significant linkage results were followed by association analyses of 1,476 SNPs in candidate genes and regions, utilizing a weighted false discovery rate (wFDR) approach to control for multiple testing and incorporate the genome scan results.
Significant (multipoint HLOD≥3.2) or genome-wide-significant (HLOD≥4.02) linkage results were found for regions 1q32, 2p13, 3q27-28, 9q21, 12p11, 14q21-24 and 16q24. SNPs in IRF6 (1q32) and in or near FOXE1 (9q21) reached formal genome-wide wFDR-adjusted significance. Further, results were phenotype dependent in that the IRF6 region results were most significant for families in which affected individuals have CL alone, and the FOXE1 region results were most significant in families in which some or all of the affected individuals have CL with CP.
These results highlight the importance of careful phenotypic delineation in large samples of families for genetic analyses of complex, heterogeneous traits such as CL/P.
PMCID: PMC2709160  PMID: 19521098
cleft lip; cleft palate; linkage; association; wFDR; IRF6; FOXE1; genetics
BMC Medical Genetics  2013;14:116.
Our previous genome-wide linkage scan mapped five loci for caries experience. The purpose of this study was to fine map one of these loci, the locus 13q31.1, in order to identify genetic contributors to caries.
Seventy-two pedigrees from the Philippines were studied. Caries experience was recorded and DNA was extracted from blood samples obtained from all subjects. Sixty-one single nucleotide polymorphisms (SNPs) in 13q31.1 were genotyped. Association between caries experience and alleles was tested. We also studied 1,481 DNA samples obtained from saliva of subjects from the USA, 918 children from Brazil, and 275 children from Turkey, in order to follow up the results found in the Filipino families. We used the AliBaba2.1 software to determine if the nucleotide changes of the associated SNPs changed the prediction of the presence of transcription-binding site sequences and we also analyzed the gene expression of the genes selected based on binding predictions. Mutation analysis was also performed in 33 Filipino individuals of a segment of 13q31.1 that is highly conserved in mammals.
Statistically significant association with high caries experience was found for 11 markers in 13q31.1 in the Filipino families. Haplotype analysis also confirmed these results. In the populations used for follow-up purposes, associations were found between high caries experience and a subset of these markers. Regarding the prediction of the transcription-binding site, the base change of the SNP rs17074565 was found to change the predicted-binding of genes that could be involved in the pathogenesis of caries. When the sequence has the allele C of rs17074565, the potential transcription factors binding the sequence are GR and GATA1. When the subject carries the G allele of rs17074565, the potential transcription factor predicted to bind to the sequence is GATA3. The expression of GR in whole saliva was higher in individuals with low caries experience when compared to individuals with high caries experience (p = 0.046). No mutations were found in the highly conserved sequence.
Genetic factors contributing to caries experience may exist in 13q31.1. The rs17074565 is located in an intergenic region and is predicted to disrupt the binding sites of two different transcription factors that might be involved with caries experience. GR expression in saliva may be a biomarker for caries risk and should be further explored.
PMCID: PMC3907033  PMID: 24192446
Caries; Genetics; Polymorphism; Oral health
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
To investigate genetic etiologies of preterm birth (PTB) in Argentina through evaluation of single-nucleotide polymorphisms (SNP) in candidate genes and population genetic admixture.
Study Design
Genotyping was performed in 389 families. Maternal, paternal, and fetal effects were studied separately. Mitochondrial DNA (mtDNA) was sequenced in 50 males and 50 females. Y-chromosome anthropological markers were evaluated in 50 males.
Fetal association with PTB was found in the progesterone receptor (PGR, rs1942836; p= 0.004). Maternal association with PTB was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; p= 0.01). Gestational age associated with PTB in PGR rs1942836 at 32 –36 weeks (p= 0.0004). MtDNA sequencing determined 88 individuals had Amerindian consistent haplogroups. Two individuals had Amerindian Y-chromosome consistent haplotypes.
This study replicates single locus fetal associations with PTB in PGR, maternal association in KCNN3, and demonstrates possible effects for divergent racial admixture on PTB.
PMCID: PMC3719965  PMID: 23018797
Prematurity; genetic admixture
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
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
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

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