Katrina J. Scurrah

Risk of Wrist Fracture in Women Is Heritable and Is Influenced by Genes That Are Largely Independent of Those Influencing BMD

Using a classical twin design study, we estimated the genetic contribution to liability of wrist fracture in women to be statistically and clinically significant. BMD is highly heritable, but statistical models showed very little overlap of shared genes between the two traits.

Variance components analysis for pedigree-based censored survival data using generalized linear mixed models (GLMMs) and Gibbs sampling in BUGS

Complex human diseases are an increasingly important focus of genetic research. Many of the determinants of these diseases are unknown and there is often a strong residual covariance between relatives even when all known genetic and environmental factors have been taken into account. This must be modeled correctly whether scientific interest is focused on fixed effects, as in an association analysis, or on the covariance structure itself. Analysis is straightforward for multivariate normally distributed traits, but difficulties arise with other types of trait. Generalized linear mixed models (GLMMs) offer a potentially unifying approach to analysis for many classes of phenotype including right censored survival times. This includes age‐at‐onset and age‐at‐death data and a variety of other censored traits. Markov chain Monte Carlo (MCMC) methods, including Gibbs sampling, provide a convenient framework within which such GLMMs may be fitted. In this paper, we use BUGS (“Bayesian inference using Gibbs sampling”: a readily available, generic Gibbs sampler) to fit GLMMs for right‐censored survival times in nuclear and extended families. We discuss parameter interpretation and statistical inference, and show how to circumvent a number of important theoretical and practical problems. Using simulated data, we show that model parameters are consistent. We further illustrate our methods using data from an ongoing cohort study. Finally, we propose that the random effects associated with a genetic component of variance (e.g., σ2A) in a GLMM may be regarded as an adjusted “phenotype” and used as input to a conventional model‐based or model‐free linkage analysis. This provides a simple way to conduct a linkage analysis for a trait reflected in a right‐censored survival time while comprehensively adjusting for observed confounders at the level of the individual and latent environmental effects shared across families. Genet. Epidemiol. 19:127–148, 2000.

Etiology of molar incisor hypomineralization – A systematic review

OBJECTIVES Molar incisor hypomineralization (MIH) is a common developmental dental defect of permanent teeth, which can increase the risk of dental caries, infection and hospitalization. The etiology is currently unclear although prenatal or early childhood health factors are suspected. The aim of this systematic review was to assess the strength of evidence linking etiological factors with MIH. METHODS A systematic search was conducted using the Medline and Embase electronic databases for studies investigating environmental etiological factors of MIH. Two reviewers assessed the eligibility of studies. The level of evidence and bias was determined for all eligible studies according to Australian National Health and Medical Research Council guidelines for systematic reviews of etiology and the Newcastle-Ottawa Scale. RESULTS From a total of 2254 studies identified through electronic and hand searching, 28 were eligible for inclusion. Twenty-five of these investigated MIH and three investigated a related condition in primary teeth, hypomineralized second primary molars (HSPM), and these were analysed separately. A limited number of studies reported significant associations between MIH and pre- and perinatal factors such as maternal illness and medication use in pregnancy, prematurity and birth complications. Early childhood illness was implicated as an etiological factor in MIH in several studies, in particular fever, asthma and pneumonia. The studies investigating HSPM revealed an association with maternal alcohol consumption, infantile fever and ethnicity. However, the validity of these findings is impaired by study design, lack of adjustment for confounders, lack of detail and consistency of exposures investigated and poor reporting. CONCLUSIONS Childhood illness is likely to be associated with MIH. Further prospective studies of the etiology of MIH/HSPM are needed.

Effect of Birth Parameters on Retinal Vascular Caliber The Twins Eye Study in Tasmania

Recent studies reported an association between smaller birth size and narrower retinal vascular caliber, but it remains unclear whether this association is attributed to confounding by shared environment or genetic factors. At a mean age of 9.3 years, 266 twins (49 monozygotic and 84 dizygotic pairs) in the Twins Eye Study in Tasmania underwent an ophthalmic examination including retinal photography. Retinal vascular caliber was measured using a validated protocol. The majority of these twins were also in the Tasmanian Infant Health Study, which prospectively collected data on birth parameters and antenatal maternal factors. We conducted the main analysis using linear mixed models, accounting for birth set clustering. Both the within-pair (−9.73; 95% CI: −14.68 to −4.77 &mgr;m per 5-cm decrease in birth length) and between-pair associations (−7.15; 95% CI: −11.54 to −3.01) with retinal arteriolar caliber were significant and of similar magnitude (difference in effect, P=0.61), after adjusting for age, sex, maternal smoking, mean arterial blood pressure, and other confounders. These associations remained within dizygotic and monozygotic pairs. Analyses of head circumference and retinal arteriolar caliber were similar to those of birth length (within-pair regression coefficient: −2.41; 95% CI: −5.09 to 0.28; between-pair regression coefficient: −2.60; 95% CI: −5.00 to −0.19). For birth weight, only a between-pair association was evident (−7.28; 95% CI: −13.07 to −1.48). This study demonstrates a consistent association between smaller birth size and narrower retinal arterioles in twins. The independent effect of shorter birth length on retinal arteriolar caliber supports a role for twin-specific supply line factors affecting fetal growth on vascular structure.

Selective Genotyping Reveals Association Between the Epithelial Sodium Channel γ-Subunit and Systolic Blood Pressure

Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G, the gene encoding the γ-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we sampled unrelated subjects within the upper (mean: 166 mm Hg; n=96) and lower (mean: 98 mm Hg; n=94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms (rs13331086, rs11074553, and rs4299163) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: P=0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10 000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects (P=0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population.

A Loss-of-Function Polymorphism in the Human P2X4 Receptor Is Associated With Increased Pulse Pressure

The P2X4 receptor is involved in endothelium-dependent changes in large arterial tone in response to shear stress and is, therefore, potentially relevant to arterial compliance and pulse pressure. Four identified nonsynonymous polymorphisms in P2RX4 were reproduced in recombinantly expressed human P2X4. Electrophysiological studies showed that one of these, the Tyr315>Cys mutation (rs28360472), significantly reduced the peak amplitude of the ATP-induced inward current to 10.9% of wild-type P2X4 receptors in transfected HEK-293 cells (10 &mgr;mol/L of ATP; n=4–8 cells; P<0.001). Concentration-response curves for ATP and the partial agonist BzATP demonstrate that the 315Cys-P2X4 mutant had an increased EC50 value for both ligands. Mutation of Tyr315>Cys likely disrupts the agonist binding site of P2X4 receptors, a finding supported by molecular modeling based on the zebrafish P2X4 receptor crystal structure. We tested inheritance of rs28360472 encoding the Tyr315>Cys mutation in P2RX4 against pulse pressure in 2874 subjects from the Victorian Family Heart Study. The minor allele frequency was 0.014 (1.4%). In a variance components analysis we found significant association with pulse pressure (P=0.023 for total association) where 1 minor allele increased pulse pressure by 2.84 mm Hg (95% CI: 0.41–5.27). This increase in pulse pressure associated with inheritance of 315Cys-P2X4 receptors might reflect reduced large arterial compliance as a result of impaired endothelium-dependent vasodilation in large arteries.

Evidence for two independent functional variants for androgenetic alopecia around the androgen receptor gene

Please cite this paper as: Evidence for two independent functional variants for androgenetic alopecia around the androgen receptor gene. Experimental Dermatology 2010; 19: 1026–1028.

The Epithelial Sodium Channel γ-Subunit Gene and Blood Pressure: Family Based Association, Renal Gene Expression, and Physiological Analyses

Variants in the gene encoding the &ggr;-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index–adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.

Measurement of absolute copy number variation reveals association with essential hypertension

BackgroundThe role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR.MethodsUsing a “power of extreme” approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random.ResultsA deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013).ConclusionsOur data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.

Longitudinal variance components models for systolic blood pressure, fitted using Gibbs sampling

This paper describes an analysis of systolic blood pressure (SBP) in the Genetic Analysis Workshop 13 (GAW13) simulated data. The main aim was to assess evidence for both general and specific genetic effects on the baseline blood pressure and on the rate of change (slope) of blood pressure with time. Generalized linear mixed models were fitted using Gibbs sampling in WinBUGS, and the additive polygenic random effects estimated using these models were then used as continuous phenotypes in a variance components linkage analysis. The first-stage analysis provided evidence for general genetic effects on both the baseline and slope of blood pressure, and the linkage analysis found evidence of several genes, again for both baseline and slope.