Novel Genetic Determinants of Dental Maturation in Children.

Dental occlusion requires harmonious development of teeth, jaws, and other elements of the craniofacial complex, which are regulated by environmental and genetic factors. We performed the first genome-wide association study (GWAS) on dental development (DD) using the Demirjian radiographic method. Radiographic assessments from participants of the Generation R Study (primary study population, N1 = 2,793; mean age of 9.8 y) were correlated with ~30 million genetic variants while adjusting for age, sex, and genomic principal components (proxy for population stratification). Variants associated with DD at genome-wide significant level (P < 5 × 10-8) mapped to 16q12.2 (IRX5) (lead variant rs3922616, B = 0.16; P = 2.2 × 10-8). We used Fisher's combined probability tests weighted by sample size to perform a meta-analysis (N = 14,805) combining radiographic DD at a mean age of 9.8 y from Generation R with data from a previous GWAS (N2 = 12,012) on number of teeth (NT) in infants used as proxy of DD at a mean age of 9.8 y (including the ALSPAC and NFBC1966). This GWAS meta-analysis revealed 3 novel loci mapping to 7p15.3 (IGF2BP3: P = 3.2 × 10-8), 14q13.3 (PAX9: P = 1.9 × 10-8), and 16q12.2 (IRX5: P = 1.2 × 10-9) and validated 8 previously reported NT loci. A polygenic allele score constructed from these 11 loci was associated with radiographic DD in an independent Generation R set of children (N = 703; B = 0.05, P = 0.004). Furthermore, profiling of the identified genes across an atlas of murine and human stem cells observed expression in the cells involved in the formation of bone and/or dental tissues (>0.3 frequency per kilobase of transcript per million mapped reads), likely reflecting functional specialization. Our findings provide biological insight into the polygenic architecture of the pediatric dental maturation process.

Genome-wide Scan of Dental Fear and Anxiety Nominates Novel Genes.

Dental care-related fear and anxiety (DFA) is prevalent, affects oral health care utilization, and is related to poor oral health and decreased quality of life. In addition to learned and cultural factors, genetics is hypothesized to contribute to DFA. Therefore, we performed a genome-wide association study to identify genetic variants contributing to DFA. Adult and adolescent participants were from 4 cohorts (3 from the US-based Center for Oral Health Research in Appalachia, n = 1,144, 1,164, and 535, and the UK-based Avon Longitudinal Study of Parents and Children [ALSPAC], n = 2,078). Two self-report instruments were used to assess DFA: the Dental Fear Survey (US cohorts) and Corah's Dental Anxiety Scale (ALSPAC). Genome-wide scans were performed for the DFA total scores and subscale scores (avoidance, physiological arousal, fear of dental treatment-specific stimuli), adjusting for age, sex, educational attainment, recruitment site, and genetic ancestry. Results across cohorts were combined using meta-analysis. Heritability estimates for DFA total and subscale scores were similar across cohorts and ranged from 23% to 59%. The meta-analysis revealed 3 significant (P < 5E-8) associations between genetic loci and 2 DFA subscales: physiological arousal and avoidance. Nearby genes included NTSR1 (P = 3.05E-8), DMRTA1 (P = 4.40E-8), and FAM84A (P = 7.72E-9). Of these, NTSR1, which was associated with the avoidance subscale, mediates neurotensin function, and its deficiency may lead to altered fear memory in mice. Gene enrichment analyses indicated that loci associated with the DFA total score and physiological arousal subscale score were enriched for genes associated with severe and persistent mental health (e.g., schizophrenia) and neurocognitive (e.g., autism) disorders. Heritability analysis indicated that DFA is partly explained by genetic factors, and our association results suggested shared genetic underpinnings with other psychological conditions.

Heritability of Caries Scores, Trajectories, and Disease Subtypes.

Previous studies report that dental caries is partially heritable, but there is uncertainty in the magnitude of genetic effects and little understanding of how genetic factors might influence caries progression or caries subtypes. This study aimed to estimate the relative importance of genetic and environmental factors in the etiology of different caries outcomes using a twin-based design. Analysis included up to 41,678 twins in the Swedish Twin Register aged 7 to 97 y, and dental data were obtained from preexisting dental records. The outcome measures were 1) summary indices of caries experience, 2) parameters representing trajectory in caries progression derived from longitudinal modeling, and 3) caries scores in groups of biologically similar tooth surfaces derived from hierarchical clustering of tooth surfaces (termed caries clusters). Additive genetic factors explained between 49.1% and 62.7% of variation in caries scores and between 50.0% and 60.5% of variation in caries trajectories. Seven caries clusters were identified, which had estimates of heritability lying between 41.9% and 54.3%. Shared environmental factors were important for only some of these clusters and explained 16% of variation in fissure caries in molar teeth but little variation in other clusters of caries presentation. The genetic factors influencing these clusters were only partially overlapping, suggesting that different biological processes are important in different groups of tooth surfaces and that innate liability to some patterns of caries presentation may partially explain why groups of tooth surfaces form clusters within the mouth. These results provide 1) improved quantification of genetic factors in the etiology of caries and 2) new data about the role of genetics in terms of longitudinal changes in caries status and specific patterns of disease presentation, and they may help lay the foundations for personalized interventions in the future.

Ten years on: Is dental general anaesthesia in childhood a risk factor for caries and anxiety?

Objectives To identify whether dental general anaesthesia (DGA) status is informative in assessing risk of caries or dental anxiety by (a) describing long-term oral health and dental anxiety for people who underwent DGA in childhood and (b) testing whether DGA status in childhood is associated with incident future dental caries or anxiety independently of preconceived risk factors.Design Analysis of prospectively obtained data.Setting An established population based cohort in the UK, the Avon Longitudinal Study of Parents and Children.Participants and methods In total 1,695 participants with dental data in childhood and adolescence were included in analysis. DGA status by age 7 and oral health measures at age 17 were identified from questionnaire data.Main outcome measures Filled or extracted permanent teeth at age 17, Corah Dental Anxiety Scale.Results One hundred and twenty-eight (7.6%) participants underwent DGA in childhood. Individuals who underwent DGA had higher measures of filled or extracted permanent teeth in adolescence (0.36 more affected teeth in fully-adjusted model [95% confidence interval: 0.27, 0.55; P <0.001]).Conclusions DGA in childhood predicts burden of treated caries in adolescence, independently of other risk factors. DGA status may be a clinically useful adjunct in identifying young people at high risk of further disease.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.

Lack of association between DRD2 and OPRM1 genotypes and adiposity.

BACKGROUND: Dopaminergic and opioid systems are both involved in food intake and appetite control. The dopamine D2 receptor gene (DRD2) and the µ-opioid receptor gene (OPRM1) therefore represent plausible candidates for association with obesity. OBJECTIVE: Previous studies of these variants have yielded inconsistent findings, which are likely due to insufficient statistical power. The aim of the current study was to determine whether, in a large population-based sample, there are associations between adiposity and (i) the A1 (T) allele of the Taq1A polymorphism (rs1800497) in DRD2 and (ii) the G allele of the A118G polymorphism (rs1799971) in OPRM1. STUDY POPULATION: Annual clinic-based measures of body mass index (BMI) and waist circumference were taken from children (N=3720) at 5 measurement time points from ages 7 through to 11 years. BMI was also recorded in their mothers (N=2460) at comparable time points and at pre-pregnancy. All participants were genotyped. Our study was powered (at 80%) to detect per-allele effects on BMI of 0.21 kg m(-2). RESULTS: Our results indicate a lack of association between DRD2 and OPRM1 genotypes and adiposity. Combining the data across mothers and children found per-allele effects on BMI of 0.02 kg m(-2) (95% confidence interval (CI): -0.17, 0.20), P=0.9 for rs1800497 and -0.08 kg m(-2) (95% CI: -0.29, 0.22), P=0.4 for rs1799971. As a positive control, we also examined the effect of FTO genotype over the same time period and confirmed the expected relationship between variability at this locus and higher adiposity. CONCLUSION: Our findings question existing evidence suggesting associations at DRD2 and OPRM1 loci and adiposity. They also highlight the caution required when employing candidate gene approaches to further our understanding of the neurobiology of eating and obesity.

Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs.

AIMS/HYPOTHESIS: Evaluation of the association of 31 common single nucleotide polymorphisms (SNPs) with fasting glucose, fasting insulin, HOMA-beta cell function (HOMA-ß), HOMA-insulin resistance (HOMA-IR) and type 2 diabetes in the Indian population. METHODS: We genotyped 3,089 sib pairs recruited in the Indian Migration Study from four cities in India (Lucknow, Nagpur, Hyderabad and Bangalore) for 31 SNPs in 24 genes previously associated with type 2 diabetes in European populations. We conducted within-sib-pair analysis for type 2 diabetes and its related quantitative traits. RESULTS: The risk-allele frequencies of all the SNPs were comparable with those reported in western populations. We demonstrated significant associations of CXCR4 (rs932206), CDKAL1 (rs7756992) and TCF7L2 (rs7903146, rs12255372) with fasting glucose, with ß values of 0.007 (p = 0.05), 0.01 (p = 0.01), 0.007 (p = 0.05), 0.01 (p = 0.003) and 0.08 (p = 0.01), respectively. Variants in NOTCH2 (rs10923931), TCF-2 (also known as HNF1B) (rs757210), ADAM30 (rs2641348) and CDKN2A/B (rs10811661) significantly predicted fasting insulin, with ß values of -0.06 (p = 0.04), 0.05 (p = 0.05), -0.08 (p = 0.01) and -0.08 (p = 0.02), respectively. For HOMA-IR, we detected associations with TCF-2, ADAM30 and CDKN2A/B, with ß values of 0.05 (p = 0.04), -0.07 (p = 0.03) and -0.08 (p = 0.02), respectively. We also found significant associations of ADAM30 (ß = -0.05; p = 0.01) and CDKN2A/B (ß = -0.05; p = 0.03) with HOMA-ß. THADA variant (rs7578597) was associated with type 2 diabetes (OR 1.5; 95% CI 1.04, 2.22; p = 0.03). CONCLUSIONS/INTERPRETATION: We validated the association of seven established loci with intermediate traits related to type 2 diabetes in an Indian population using a design resistant to population stratification.

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier.

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.

C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.

CONTEXT: The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed. OBJECTIVE: Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique. PARTICIPANTS AND METHODS: The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them. RESULTS: Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in log CRP of 1.03 kg m(-2) (95% confidence interval (95% CI): 1.00, 1.07), P<0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in log CRP of -0.24 kg m(-2) (95% CI: -0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006). CONCLUSIONS: Taken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components.

Age- and puberty-dependent association between IQ score in early childhood and depressive symptoms in adolescence.

BACKGROUND: Lower cognitive functioning in early childhood has been proposed as a risk factor for depression in later life but its association with depressive symptoms during adolescence has rarely been investigated. Our study examines the relationship between total intelligence quotient (IQ) score at age 8 years, and depressive symptoms at 11, 13, 14 and 17 years. METHOD: Study participants were 5250 children and adolescents from the Avon Longitudinal Study of Parents and their Children (ALSPAC), UK, for whom longitudinal data on depressive symptoms were available. IQ was assessed with the Wechsler Intelligence Scale for Children III, and self-reported depressive symptoms were measured with the Short Mood and Feelings Questionnaire (SMFQ). RESULTS: Multi-level analysis on continuous SMFQ scores showed that IQ at age 8 years was inversely associated with depressive symptoms at age 11 years, but the association changed direction by age 13 and 14 years (age-IQ interaction, p<0.0001; age squared-IQ interaction, p<0.0001) when a higher IQ score was associated with a higher risk of depressive symptoms. This change in IQ effect was also found in relation to pubertal stage (pubertal stage-IQ interaction, 0.00049