Katrina Scurrah - Academia.edu (original) (raw)

Papers by Katrina Scurrah

Human Genetics, Jan 5, 2007

To examine the familial correlations, heritability (h(2)) and common environmental components (c(... more To examine the familial correlations, heritability (h(2)) and common environmental components (c(2)) of myopia and ocular biometric traits (all treated as continuous outcomes) in families collected through the Genes in Myopia (GEM) family study in Australia. A total of 132 pedigrees (723 participants) were recruited for this study. All individuals completed a risk factor questionnaire and underwent a detailed eye examination including spherical equivalent (SphE) and ocular biometric measurements of axial length (AL), anterior chamber depth (ACD) and corneal curvature (CC). Familial correlations were calculated and h(2) and c(2) were estimated using a variance component model that assumes a multivariate t distribution within each pedigree. Two definitions of common environments (c(2)) were considered: nuclear family (current) shared environment (Model 1) and sib-ship (childhood) shared environment (Model 2). Population ascertainment adjustment was performed using the Blue Mountains eye study dataset. The trends observed for familial correlations suggested that SphE is influenced by both environmental and genetic factors whereas AL, ACD and CC are predominantly genetically determined. This was largely confirmed by variance components modelling. Heritability estimates (adjusted for age, sex and years of education) from the best fitting ACE model (Model 2, childhood shared environment) were 0.50 +/- 0.05 for SphE, 0.73 +/- 0.04 for AL, 0.78 +/- 0.04 for ACD and 0.16 +/- 0.06 for CC. Childhood environmental effects were significant with c(2) estimated to be 0.33 +/- 0.04 for SphE, 0.06 +/- 0.03 for AL, 0.22 +/- 0.04 for ACD and 0.10 +/- 0.05 for CC. Age was associated with SphE, total years of education was associated with AL and sex was associated with all traits studied. We used a novel and conservative approach to account for and estimate common environmental effects by specifying either nuclear family or sib-ship environment when estimating heritability estimates and showed that all traits examined (SphE, AL, ACD and CC) are heritable, thus reflecting a genetic component. These traits therefore all represent candidates for quantitative trait linkage analyses.

Hypertension, 2007

Systolic blood pressure is determined in large part by genes. Six independent studies have report... more 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 ␥-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; nϭ96) and lower (mean: 98 mm Hg; nϭ94) 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: Pϭ0.0001). 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 (Pϭ0.0001). 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. (Hypertension. 2007;50:672-678.)

Journal of Biometrics & Biostatistics, 2013

International journal of epidemiology, 2005

A longitudinal family study is an epidemiological design that involves repeated measurements over... more A longitudinal family study is an epidemiological design that involves repeated measurements over time in a sample that includes families. Such studies, that may also include relative pairs and unrelated individuals, allow closer investigation of not only the factors that cause a disease to arise, but also the genetic and environmental determinants that modulate the subsequent progression of that disease. Knowledge of such determinants may pay high dividends in terms of prognostic assessment and in the development of new treatments that may be tailored to the prognostic profile of individual patients. Unfortunately longitudinal family studies are difficult to analyse. They conflate the complex within-family correlation structure of a cross-sectional family study with the correlation over time that is intrinsic to longitudinal repeated measures. Here we describe an approach to analysis that is relatively straightforward to implement, yet is flexible in its application. It represents ...

Biometrical Journal, 2014

Methods to examine whether genetic and/or environmental sources can account for the residual vari... more Methods to examine whether genetic and/or environmental sources can account for the residual variation in ordinal family data usually assume proportional odds. However, standard software to fit the non-proportional odds model to ordinal family data is limited because the correlation structure of family data is more complex than for other types of clustered data. To perform these analyses we propose the non-proportional odds multivariate logistic regression model and take a simulation-based approach to model fitting using Markov chain Monte Carlo methods, such as partially collapsed Gibbs sampling and the Metropolis algorithm. We applied the proposed methodology to male pattern baldness data from the Victorian Family Heart Study.

BMC medical genomics, 2014

The role of copy number variation (CNV) has been poorly explored in essential hypertension in par... more The 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. Using 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. A 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). Our data suggests that CNVs ...

The Journal of Steroid Biochemistry and Molecular Biology, 2015

Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although ep... more Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene-gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint=0.45, p=0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6×10(-9) to 7.5×10(-7)). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.

Statistics in Medicine, 2005

A population-based study of a quantitative trait may be seriously compromised when the trait is s... more A population-based study of a quantitative trait may be seriously compromised when the trait is subject to the e ects of a treatment. For example, in a typical study of quantitative blood pressure (BP) 15 per cent or more of middle-aged subjects may take antihypertensive treatment. Without appropriate correction, this can lead to substantial shrinkage in the estimated e ect of aetiological determinants of scientiÿc interest and a marked reduction in statistical power. Correction relies upon imputation, in treated subjects, of the underlying BP from the observed BP having invoked one or more assumptions about the bioclinical setting. There is a range of di erent assumptions that may be made, and a number of di erent analytical models that may be used. In this paper, we motivate an approach based on a censored normal regression model and compare it with a range of other methods that are currently used or advocated. We compare these methods in simulated data sets and assess the estimation bias and the loss of power that ensue when treatment e ects are not appropriately addressed. We also apply the same methods to real data and demonstrate a pattern of behaviour that is consistent with that in the simulation studies. Although all approaches to analysis are necessarily approximations, we conclude that two of the adjustment methods appear to perform well across a range of realistic settings. These are:

Statistics in Medicine, 2005

The semi-parametric regression achieved via penalized spline smoothing can be expressed in a line... more The semi-parametric regression achieved via penalized spline smoothing can be expressed in a linear mixed models framework. This allows such models to be ÿtted using standard mixed models software routines with which many biostatisticians are familiar. Moreover, the analysis of complex correlated data structures that are a hallmark of biostatistics, and which are typically analysed using mixed models, can now incorporate directly smoothing of the relationship between an outcome and covariates. In this paper we provide an introduction to both linear mixed models and penalized spline smoothing, and describe the connection between the two. This is illustrated with three examples, the ÿrst using birth data from the U.K., the second relating mammographic density to age in a study of female twin-pairs and the third modelling the relationship between age and bronchial hyperresponsiveness in families. The models are ÿtted in R (a clone of S-plus) and using Markov chain Monte Carlo (MCMC) implemented in the package WinBUGS.

Physiological Genomics, 2010

Buffering of blood pressure during change of posture such as standing is controlled largely by th... more Buffering of blood pressure during change of posture such as standing is controlled largely by the baroreflex. In our population-based Victorian Family Heart Study (VFHS), we previously demonstrated that, on average, systolic blood pressure (SBP) changes very little on standing; however, interindividual variation is substantial and shows familial aggregation, with approximately 25% of the variance attributable to genetic factors. Our genomewide linkage analysis suggests a region on chromosome 12p that harbors two strong candidate genes, KCNJ8 and ABCC9, encoding the channel-forming inward rectifier subunit Kir6.1 and the ATP-sensitive binding cassette SUR2B, respectively. These are key components of smooth muscle ATP-sensitive potassium (K(ATP)) channels, important regulators of arterial tone and blood flow and central to autonomic baroreceptor control of changes in total peripheral resistance. We performed a comprehensive association analysis of 47 tag single nucleotide polymorphisms (SNPs) spanning the KCNJ8 and ABCC9 gene regions with postural change in SBP (DeltaSBP). To augment power, we took a selective genotyping approach in which we compared allele and genotype frequencies between 150 unrelated individuals with high (positive) DeltaSBP (> or = 7 mmHg) and 150 unrelated individuals with low (negative) DeltaSBP (< or = -7 mmHg) drawn from the offspring generation (18-30 yr) of the VFHS. Association analyses showed that no SNPs demonstrated statistically significant differences in genotype frequencies between groups, particularly after adjustments for multiple testing. We conclude that sequence variants in KCNJ8 and ABCC9 are unlikely to contribute to variation in DeltaSBP. Other genes in the identified chromosome 12p region warrant investigation.

Pediatric Rheumatology, 2013

Journal of Hypertension, 2008

We have demonstrated that familial genetic and shared environmental factors influence postural re... more We have demonstrated that familial genetic and shared environmental factors influence postural responses of blood pressure, such that some families show a fall and others show a rise in systolic pressure on standing. These differences might reflect programmed differences in the underlying responses in mean arterial pressure and pulse pressure that together determine systolic pressure. Using variance components modelling techniques, we assessed familial aggregation of postural changes in mean arterial pressure and pulse pressure in 767 adult families from the Victorian Family Heart Study. On average mean arterial pressure rose (P < 0.001) and pulse pressure fell (P < 0.001) on standing, but there were no significant correlations between the two. We found little evidence of genetic effects on changes in either mean arterial pressure or pulse pressure, although significant spouse correlations indicated that some shared environmental effects might be present. The majority of variation in postural responses of mean arterial pressure (69.5%) and pulse pressure (81.2%) was attributable to individual-specific factors. These findings were not altered by adjustments for height or body mass index. Total variance was greater for males than females for both change in mean arterial pressure (33.7 versus 30.2, P = 0.04) and change in pulse pressure (70.7 versus 56.8, P < 0.001), differences also attributable to individual rather than familial factors. These findings suggest that the postural autoregulatory responses in peripheral arterial resistance and cardiac output that determine mean arterial and pulse pressure are not programmed by familial factors.

Journal of Bone and Mineral Research, 2005

Using a classical twin design study, we estimated the genetic contribution to liability of wrist ... more 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.

Investigative Ophthalmology & Visual Science, 2007

PURPOSE. Myopia (short sightedness) is a complex trait influenced by as yet unidentified genetic ... more PURPOSE. Myopia (short sightedness) is a complex trait influenced by as yet unidentified genetic factors. To date, there have been four myopia susceptibility loci (MYP7 to -10) identified in twin studies, but these are yet to be independently verified. In an independent yet ethnically and phenotypically similar twin cohort, linkage to these chromosomal regions was sought. METHODS. Participants were 223 dizygotic twin pairs from the Australian Twin Registry who were assessed for evidence of linkage, by using polymorphic microsatellite markers spanning MYP7-10. Data were analyzed by using Haseman-Elston regression analysis.

Investigative Ophthalmology & Visual Science, 2007

PURPOSE. Myopia is a common disorder with a large public health impact. Although 12 myopia loci h... more PURPOSE. Myopia is a common disorder with a large public health impact. Although 12 myopia loci have been reported and heterogeneity for high myopia loci have been demonstrated, replication of high-myopia loci with a common myopia phenotype has not been successful. This study reports the successful replication of MYP12 in three large, multigenerational families with autosomal dominant (AD) common myopia (spherical equivalent [SphE] Յ Ϫ0.50 D). METHODS. These families contained 49 participants (35 affected). The average spherical equivalent was Ϫ2.76 D (range, Ϫ0.50 to Ϫ10.25 D), average axial length was 24.52 mm (range, 23.05-27.11 mm), and average keratometry was 43.21 D (range, 39.12-47.31 D). Only five individuals in the three families presented with myopia of SphE Յ Ϫ6.00 D. Glaucoma, keratoconus, lenticonus, and dislocated lens were not present in any study participants. A genomewide scan was performed using a mapping set with 400 markers at ϳ10 cM coverage. Merlin software was used for multipoint linkage analysis based on an AD model with a penetrance of 0.9 and disease allele frequency of 0.013. RESULTS. Significant linkage with a multipoint parametric LOD score of 3.428 (P ϭ 0.000035) and a multipoint nonparametric (Kong and Cox) LOD score of 2.37 (empiric P Ͻ 0.001) was obtained on 2q37.1, with a 1-LOD support interval that overlapped the previously reported MYP12 locus for high myopia. CONCLUSIONS. This study provided evidence that some highmyopia loci may contribute to all degrees of myopia and indicated the likely location of a myopia gene for the low/ moderate as well as the high form of myopia. (Invest Ophthalmol Vis Sci.

International Journal of Epidemiology, 2005

A longitudinal family study is an epidemiological design that involves repeated measurements over... more A longitudinal family study is an epidemiological design that involves repeated measurements over time in a sample that includes families. Such studies, that may also include relative pairs and unrelated individuals, allow closer investigation of not only the factors that cause a disease to arise, but also the genetic and environmental determinants that modulate the subsequent progression of that disease. Knowledge of such determinants may pay high dividends in terms of prognostic assessment and in the development of new treatments that may be tailored to the prognostic profile of individual patients. Unfortunately longitudinal family studies are difficult to analyse. They conflate the complex within-family correlation structure of a cross-sectional family study with the correlation over time that is intrinsic to longitudinal repeated measures.

Hypertension, 2011

The P2X4 receptor is involved in endothelium-dependent changes in large arterial tone in response... more 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 Tyr315ϾCys 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 mol/L of ATP; nϭ4 -8 cells; PϽ0.001). Concentration-response curves for ATP and the partial agonist BzATP demonstrate that the 315Cys-P2X4 mutant had an increased EC 50 value for both ligands. Mutation of Tyr315ϾCys 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 Tyr315ϾCys 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 (Pϭ0.023 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. (Hypertension. 2011;58:1086-1092.) • Online Data Supplement

Hypertension, 2007

Systolic blood pressure is determined in large part by genes. Six independent studies have report... more 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 ␥-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; nϭ96) and lower (mean: 98 mm Hg; nϭ94) 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: Pϭ0.0001). 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 (Pϭ0.0001). 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. (Hypertension. 2007;50:672-678.)

Hypertension, 2011

Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associa... more Variants in the gene encoding the γ-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.

Human Genetics, Jan 5, 2007

To examine the familial correlations, heritability (h(2)) and common environmental components (c(... more To examine the familial correlations, heritability (h(2)) and common environmental components (c(2)) of myopia and ocular biometric traits (all treated as continuous outcomes) in families collected through the Genes in Myopia (GEM) family study in Australia. A total of 132 pedigrees (723 participants) were recruited for this study. All individuals completed a risk factor questionnaire and underwent a detailed eye examination including spherical equivalent (SphE) and ocular biometric measurements of axial length (AL), anterior chamber depth (ACD) and corneal curvature (CC). Familial correlations were calculated and h(2) and c(2) were estimated using a variance component model that assumes a multivariate t distribution within each pedigree. Two definitions of common environments (c(2)) were considered: nuclear family (current) shared environment (Model 1) and sib-ship (childhood) shared environment (Model 2). Population ascertainment adjustment was performed using the Blue Mountains eye study dataset. The trends observed for familial correlations suggested that SphE is influenced by both environmental and genetic factors whereas AL, ACD and CC are predominantly genetically determined. This was largely confirmed by variance components modelling. Heritability estimates (adjusted for age, sex and years of education) from the best fitting ACE model (Model 2, childhood shared environment) were 0.50 +/- 0.05 for SphE, 0.73 +/- 0.04 for AL, 0.78 +/- 0.04 for ACD and 0.16 +/- 0.06 for CC. Childhood environmental effects were significant with c(2) estimated to be 0.33 +/- 0.04 for SphE, 0.06 +/- 0.03 for AL, 0.22 +/- 0.04 for ACD and 0.10 +/- 0.05 for CC. Age was associated with SphE, total years of education was associated with AL and sex was associated with all traits studied. We used a novel and conservative approach to account for and estimate common environmental effects by specifying either nuclear family or sib-ship environment when estimating heritability estimates and showed that all traits examined (SphE, AL, ACD and CC) are heritable, thus reflecting a genetic component. These traits therefore all represent candidates for quantitative trait linkage analyses.

Hypertension, 2007

Systolic blood pressure is determined in large part by genes. Six independent studies have report... more 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 ␥-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; nϭ96) and lower (mean: 98 mm Hg; nϭ94) 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: Pϭ0.0001). 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 (Pϭ0.0001). 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. (Hypertension. 2007;50:672-678.)

Journal of Biometrics & Biostatistics, 2013

International journal of epidemiology, 2005

A longitudinal family study is an epidemiological design that involves repeated measurements over... more A longitudinal family study is an epidemiological design that involves repeated measurements over time in a sample that includes families. Such studies, that may also include relative pairs and unrelated individuals, allow closer investigation of not only the factors that cause a disease to arise, but also the genetic and environmental determinants that modulate the subsequent progression of that disease. Knowledge of such determinants may pay high dividends in terms of prognostic assessment and in the development of new treatments that may be tailored to the prognostic profile of individual patients. Unfortunately longitudinal family studies are difficult to analyse. They conflate the complex within-family correlation structure of a cross-sectional family study with the correlation over time that is intrinsic to longitudinal repeated measures. Here we describe an approach to analysis that is relatively straightforward to implement, yet is flexible in its application. It represents ...

Biometrical Journal, 2014

Methods to examine whether genetic and/or environmental sources can account for the residual vari... more Methods to examine whether genetic and/or environmental sources can account for the residual variation in ordinal family data usually assume proportional odds. However, standard software to fit the non-proportional odds model to ordinal family data is limited because the correlation structure of family data is more complex than for other types of clustered data. To perform these analyses we propose the non-proportional odds multivariate logistic regression model and take a simulation-based approach to model fitting using Markov chain Monte Carlo methods, such as partially collapsed Gibbs sampling and the Metropolis algorithm. We applied the proposed methodology to male pattern baldness data from the Victorian Family Heart Study.

BMC medical genomics, 2014

The role of copy number variation (CNV) has been poorly explored in essential hypertension in par... more The 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. Using 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. A 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). Our data suggests that CNVs ...

The Journal of Steroid Biochemistry and Molecular Biology, 2015

Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although ep... more Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene-gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint=0.45, p=0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6×10(-9) to 7.5×10(-7)). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.

Statistics in Medicine, 2005

A population-based study of a quantitative trait may be seriously compromised when the trait is s... more A population-based study of a quantitative trait may be seriously compromised when the trait is subject to the e ects of a treatment. For example, in a typical study of quantitative blood pressure (BP) 15 per cent or more of middle-aged subjects may take antihypertensive treatment. Without appropriate correction, this can lead to substantial shrinkage in the estimated e ect of aetiological determinants of scientiÿc interest and a marked reduction in statistical power. Correction relies upon imputation, in treated subjects, of the underlying BP from the observed BP having invoked one or more assumptions about the bioclinical setting. There is a range of di erent assumptions that may be made, and a number of di erent analytical models that may be used. In this paper, we motivate an approach based on a censored normal regression model and compare it with a range of other methods that are currently used or advocated. We compare these methods in simulated data sets and assess the estimation bias and the loss of power that ensue when treatment e ects are not appropriately addressed. We also apply the same methods to real data and demonstrate a pattern of behaviour that is consistent with that in the simulation studies. Although all approaches to analysis are necessarily approximations, we conclude that two of the adjustment methods appear to perform well across a range of realistic settings. These are:

Statistics in Medicine, 2005

The semi-parametric regression achieved via penalized spline smoothing can be expressed in a line... more The semi-parametric regression achieved via penalized spline smoothing can be expressed in a linear mixed models framework. This allows such models to be ÿtted using standard mixed models software routines with which many biostatisticians are familiar. Moreover, the analysis of complex correlated data structures that are a hallmark of biostatistics, and which are typically analysed using mixed models, can now incorporate directly smoothing of the relationship between an outcome and covariates. In this paper we provide an introduction to both linear mixed models and penalized spline smoothing, and describe the connection between the two. This is illustrated with three examples, the ÿrst using birth data from the U.K., the second relating mammographic density to age in a study of female twin-pairs and the third modelling the relationship between age and bronchial hyperresponsiveness in families. The models are ÿtted in R (a clone of S-plus) and using Markov chain Monte Carlo (MCMC) implemented in the package WinBUGS.

Physiological Genomics, 2010

Buffering of blood pressure during change of posture such as standing is controlled largely by th... more Buffering of blood pressure during change of posture such as standing is controlled largely by the baroreflex. In our population-based Victorian Family Heart Study (VFHS), we previously demonstrated that, on average, systolic blood pressure (SBP) changes very little on standing; however, interindividual variation is substantial and shows familial aggregation, with approximately 25% of the variance attributable to genetic factors. Our genomewide linkage analysis suggests a region on chromosome 12p that harbors two strong candidate genes, KCNJ8 and ABCC9, encoding the channel-forming inward rectifier subunit Kir6.1 and the ATP-sensitive binding cassette SUR2B, respectively. These are key components of smooth muscle ATP-sensitive potassium (K(ATP)) channels, important regulators of arterial tone and blood flow and central to autonomic baroreceptor control of changes in total peripheral resistance. We performed a comprehensive association analysis of 47 tag single nucleotide polymorphisms (SNPs) spanning the KCNJ8 and ABCC9 gene regions with postural change in SBP (DeltaSBP). To augment power, we took a selective genotyping approach in which we compared allele and genotype frequencies between 150 unrelated individuals with high (positive) DeltaSBP (> or = 7 mmHg) and 150 unrelated individuals with low (negative) DeltaSBP (< or = -7 mmHg) drawn from the offspring generation (18-30 yr) of the VFHS. Association analyses showed that no SNPs demonstrated statistically significant differences in genotype frequencies between groups, particularly after adjustments for multiple testing. We conclude that sequence variants in KCNJ8 and ABCC9 are unlikely to contribute to variation in DeltaSBP. Other genes in the identified chromosome 12p region warrant investigation.

Pediatric Rheumatology, 2013

Journal of Hypertension, 2008

We have demonstrated that familial genetic and shared environmental factors influence postural re... more We have demonstrated that familial genetic and shared environmental factors influence postural responses of blood pressure, such that some families show a fall and others show a rise in systolic pressure on standing. These differences might reflect programmed differences in the underlying responses in mean arterial pressure and pulse pressure that together determine systolic pressure. Using variance components modelling techniques, we assessed familial aggregation of postural changes in mean arterial pressure and pulse pressure in 767 adult families from the Victorian Family Heart Study. On average mean arterial pressure rose (P < 0.001) and pulse pressure fell (P < 0.001) on standing, but there were no significant correlations between the two. We found little evidence of genetic effects on changes in either mean arterial pressure or pulse pressure, although significant spouse correlations indicated that some shared environmental effects might be present. The majority of variation in postural responses of mean arterial pressure (69.5%) and pulse pressure (81.2%) was attributable to individual-specific factors. These findings were not altered by adjustments for height or body mass index. Total variance was greater for males than females for both change in mean arterial pressure (33.7 versus 30.2, P = 0.04) and change in pulse pressure (70.7 versus 56.8, P < 0.001), differences also attributable to individual rather than familial factors. These findings suggest that the postural autoregulatory responses in peripheral arterial resistance and cardiac output that determine mean arterial and pulse pressure are not programmed by familial factors.

Journal of Bone and Mineral Research, 2005

Using a classical twin design study, we estimated the genetic contribution to liability of wrist ... more 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.

Investigative Ophthalmology & Visual Science, 2007

PURPOSE. Myopia (short sightedness) is a complex trait influenced by as yet unidentified genetic ... more PURPOSE. Myopia (short sightedness) is a complex trait influenced by as yet unidentified genetic factors. To date, there have been four myopia susceptibility loci (MYP7 to -10) identified in twin studies, but these are yet to be independently verified. In an independent yet ethnically and phenotypically similar twin cohort, linkage to these chromosomal regions was sought. METHODS. Participants were 223 dizygotic twin pairs from the Australian Twin Registry who were assessed for evidence of linkage, by using polymorphic microsatellite markers spanning MYP7-10. Data were analyzed by using Haseman-Elston regression analysis.

Investigative Ophthalmology & Visual Science, 2007

PURPOSE. Myopia is a common disorder with a large public health impact. Although 12 myopia loci h... more PURPOSE. Myopia is a common disorder with a large public health impact. Although 12 myopia loci have been reported and heterogeneity for high myopia loci have been demonstrated, replication of high-myopia loci with a common myopia phenotype has not been successful. This study reports the successful replication of MYP12 in three large, multigenerational families with autosomal dominant (AD) common myopia (spherical equivalent [SphE] Յ Ϫ0.50 D). METHODS. These families contained 49 participants (35 affected). The average spherical equivalent was Ϫ2.76 D (range, Ϫ0.50 to Ϫ10.25 D), average axial length was 24.52 mm (range, 23.05-27.11 mm), and average keratometry was 43.21 D (range, 39.12-47.31 D). Only five individuals in the three families presented with myopia of SphE Յ Ϫ6.00 D. Glaucoma, keratoconus, lenticonus, and dislocated lens were not present in any study participants. A genomewide scan was performed using a mapping set with 400 markers at ϳ10 cM coverage. Merlin software was used for multipoint linkage analysis based on an AD model with a penetrance of 0.9 and disease allele frequency of 0.013. RESULTS. Significant linkage with a multipoint parametric LOD score of 3.428 (P ϭ 0.000035) and a multipoint nonparametric (Kong and Cox) LOD score of 2.37 (empiric P Ͻ 0.001) was obtained on 2q37.1, with a 1-LOD support interval that overlapped the previously reported MYP12 locus for high myopia. CONCLUSIONS. This study provided evidence that some highmyopia loci may contribute to all degrees of myopia and indicated the likely location of a myopia gene for the low/ moderate as well as the high form of myopia. (Invest Ophthalmol Vis Sci.

International Journal of Epidemiology, 2005

A longitudinal family study is an epidemiological design that involves repeated measurements over... more A longitudinal family study is an epidemiological design that involves repeated measurements over time in a sample that includes families. Such studies, that may also include relative pairs and unrelated individuals, allow closer investigation of not only the factors that cause a disease to arise, but also the genetic and environmental determinants that modulate the subsequent progression of that disease. Knowledge of such determinants may pay high dividends in terms of prognostic assessment and in the development of new treatments that may be tailored to the prognostic profile of individual patients. Unfortunately longitudinal family studies are difficult to analyse. They conflate the complex within-family correlation structure of a cross-sectional family study with the correlation over time that is intrinsic to longitudinal repeated measures.

Hypertension, 2011

The P2X4 receptor is involved in endothelium-dependent changes in large arterial tone in response... more 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 Tyr315ϾCys 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 mol/L of ATP; nϭ4 -8 cells; PϽ0.001). Concentration-response curves for ATP and the partial agonist BzATP demonstrate that the 315Cys-P2X4 mutant had an increased EC 50 value for both ligands. Mutation of Tyr315ϾCys 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 Tyr315ϾCys 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 (Pϭ0.023 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. (Hypertension. 2011;58:1086-1092.) • Online Data Supplement

Hypertension, 2007

Systolic blood pressure is determined in large part by genes. Six independent studies have report... more 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 ␥-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; nϭ96) and lower (mean: 98 mm Hg; nϭ94) 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: Pϭ0.0001). 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 (Pϭ0.0001). 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. (Hypertension. 2007;50:672-678.)

Hypertension, 2011

Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associa... more Variants in the gene encoding the γ-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.