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.

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

Statistics in Medicine, 2005

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

Investigative Ophthalmology & Visual Science, 2007

Investigative Ophthalmology & Visual Science, 2007

International Journal of Epidemiology, 2005

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.

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

Statistics in Medicine, 2005

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

Investigative Ophthalmology & Visual Science, 2007

Investigative Ophthalmology & Visual Science, 2007

International Journal of Epidemiology, 2005

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.