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1.  Association of a Body Mass Index Genetic Risk Score with Growth throughout Childhood and Adolescence 
PLoS ONE  2013;8(11):e79547.
While the number of established genetic variants associated with adult body mass index (BMI) is growing, the relationships between these variants and growth during childhood are yet to be fully characterised. We examined the association between validated adult BMI associated single nucleotide polymorphisms (SNPs) and growth trajectories across childhood. We investigated the timing of onset of the genetic effect and whether it was sex specific.
Children from the ALSPAC and Raine birth cohorts were used for analysis (n = 9,328). Genotype data from 32 adult BMI associated SNPs were investigated individually and as an allelic score. Linear mixed effects models with smoothing splines were used for longitudinal modelling of the growth parameters and measures of adiposity peak and rebound were derived.
The allelic score was associated with BMI growth throughout childhood, explaining 0.58% of the total variance in BMI in females and 0.44% in males. The allelic score was associated with higher BMI at the adiposity peak (females  =  0.0163 kg/m2 per allele, males  =  0.0123 kg/m2 per allele) and earlier age (-0.0362 years per allele in males and females) and higher BMI (0.0332 kg/m2 per allele in females and 0.0364 kg/m2 per allele in males) at the adiposity rebound. No gene:sex interactions were detected for BMI growth.
This study suggests that known adult genetic determinants of BMI have observable effects on growth from early childhood, and is consistent with the hypothesis that genetic determinants of adult susceptibility to obesity act from early childhood and develop over the life course.
PMCID: PMC3823612  PMID: 24244521
2.  Modelling BMI Trajectories in Children for Genetic Association Studies 
PLoS ONE  2013;8(1):e53897.
The timing of associations between common genetic variants and changes in growth patterns over childhood may provide insight into the development of obesity in later life. To address this question, it is important to define appropriate statistical models to allow for the detection of genetic effects influencing longitudinal childhood growth.
Methods and Results
Children from The Western Australian Pregnancy Cohort (Raine; n = 1,506) Study were genotyped at 17 genetic loci shown to be associated with childhood obesity (FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, SEC16B, LYPLAL1, TFAP2B, MTCH2, BCDIN3D, NRXN3, SH2B1, MRSA) and an obesity-risk-allele-score was calculated as the total number of ‘risk alleles’ possessed by each individual. To determine the statistical method that fits these data and has the ability to detect genetic differences in BMI growth profile, four methods were investigated: linear mixed effects model, linear mixed effects model with skew-t random errors, semi-parametric linear mixed models and a non-linear mixed effects model. Of the four methods, the semi-parametric linear mixed model method was the most efficient for modelling childhood growth to detect modest genetic effects in this cohort. Using this method, three of the 17 loci were significantly associated with BMI intercept or trajectory in females and four in males. Additionally, the obesity-risk-allele score was associated with increased average BMI (female: β = 0.0049, P = 0.0181; male: β = 0.0071, P = 0.0001) and rate of growth (female: β = 0.0012, P = 0.0006; male: β = 0.0008, P = 0.0068) throughout childhood.
Using statistical models appropriate to detect genetic variants, variations in adult obesity genes were associated with childhood growth. There were also differences between males and females. This study provides evidence of genetic effects that may identify individuals early in life that are more likely to rapidly increase their BMI through childhood, which provides some insight into the biology of childhood growth.
PMCID: PMC3547961  PMID: 23349760
3.  Toward a roadmap in global biobanking for health 
European Journal of Human Genetics  2012;20(11):1105-1111.
Biobanks can have a pivotal role in elucidating disease etiology, translation, and advancing public health. However, meeting these challenges hinges on a critical shift in the way science is conducted and requires biobank harmonization. There is growing recognition that a common strategy is imperative to develop biobanking globally and effectively. To help guide this strategy, we articulate key principles, goals, and priorities underpinning a roadmap for global biobanking to accelerate health science, patient care, and public health. The need to manage and share very large amounts of data has driven innovations on many fronts. Although technological solutions are allowing biobanks to reach new levels of integration, increasingly powerful data-collection tools, analytical techniques, and the results they generate raise new ethical and legal issues and challenges, necessitating a reconsideration of previous policies, practices, and ethical norms. These manifold advances and the investments that support them are also fueling opportunities for biobanks to ultimately become integral parts of health-care systems in many countries. International harmonization to increase interoperability and sustainability are two strategic priorities for biobanking. Tackling these issues requires an environment favorably inclined toward scientific funding and equipped to address socio-ethical challenges. Cooperation and collaboration must extend beyond systems to enable the exchange of data and samples to strategic alliances between many organizations, including governmental bodies, funding agencies, public and private science enterprises, and other stakeholders, including patients. A common vision is required and we articulate the essential basis of such a vision herein.
PMCID: PMC3477856  PMID: 22713808
4.  A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm 
Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5α reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), androgen receptor (AR) and estrogen receptor 2 (ESR2)) related to sex hormone production and action in 1711 men, 640 of whom had an AAA. One genotype was also assessed in an independent cohort of 782 men, of whom 513 had large AAAs. Associations were assessed adjusting for other risk factors for AAA. One SNP in CYP19A1 was strongly associated with aortic diameter. Subjects who had the rare homozygote genotype (TT) for CYP19A1g.49412370C>T (SNP ID rs1961177), had an increased aortic diameter (coefficient 5.058, SE 1.394, P=0.0003, under a recessive model). This SNP was not associated with aortic diameter in an independent cohort, which included patients with larger AAAs. Our findings do not support an important role of genetic polymorphisms in genes determining sex hormones in aortic dilatation in men. The association of one SNP in CYPA9A1 with small but not large AAA may suggest differences between AAA formation and progression. This SNP warrants further investigation in another large population, including patients with small AAAs.
PMCID: PMC3062004  PMID: 21119710
aorta; aneurysm; sex hormones
5.  Association of an allele on chromosome 9 and abdominal aortic aneurysm 
Atherosclerosis  2010;212(2):539-542.
Abdominal aortic aneurysm (AAA) has been recognized as a multi-factorial disease with both genetic and environmental risk factors. A locus residing within non-coding DNA on chromosome 9p21.3 has recently been associated with AAA. To further investigate the significance of this site for AAA, we performed an association study on a large group of 3,371 men aged 65-83 years of whom 513 had an AAA.
All men were assessed for other risk factors in a uniform way and an ultrasound of the abdominal aorta was performed.
Our findings validated the strong association of the chromosome 9p21.3 SNPs rs10757278 and rs1333049 with AAA and demonstrated the upregulation of LINE-1 elements at the site of AAA.
This study confirms a reproducible association between risk alleles on chromosome 9p21.3 and AAA. We also provide preliminary evidence for an association of LINE-1 elements with AAA which will require further investigation.
PMCID: PMC2952706  PMID: 20605023
Abdominal aortic aneurysm; risk locus; retrotransposons
6.  Apolipoprotein E genotype is associated with serum C-reactive protein but not abdominal aortic aneurysm 
Atherosclerosis  2009;209(2):487-491.
Apolipoprotein E (ApoE) genotype has been associated with systemic inflammation and athero-thrombosis however the association with abdominal aortic aneurysm (AAA) has not been previously examined. We assessed the association between ApoE genotype with AAA presence and growth, and serum C-reactive protein (CRP).
Serum concentrations of CRP (in 1358 men) and 6 single nucleotide polymorphisms (SNPs) for ApoE (in 1711 men) were examined in subjects from the Health In Men Study. 640 men with small AAAs were followed by ultrasound surveillance for a mean of 4.1 years.
There was no association between ApoE genotype and AAA presence. Men heterozygote for the ApoE p.Arg176Cys polymorphism had slower AAA growth, odds ratio for AAA progression ≥ median 0.41, 95% confidence intervals 0.21-0.80, p=0.01. Men heterozygote for the ApoE g.50093756A>G polymorphism had slightly more rapid AAA growth, odds ratio for AAA progression ≥ median 1.48, 95% confidence intervals 1.02-2.14, p=0.04. None of the ApoE SNPs were associated with AAA growth however taking into account multiple testing. Two SNPs in ApoE were associated with serum CRP under a co-dominant model, ApoE p.Cys130Arg (SNP ID rs429358), p=0.00003 and ApoE g.50114786A>G (SNP ID rs4420638), p=0.00013. Adjusting for other risk factors plus serum creatinine the ε4 allele was associated with lower serum CRP under a dominant model, coefficient 0.089, p=0.002.
We found no consistent association between ApoE genotype and AAA. We confirmed an association between ApoE genotype and serum CRP.
PMCID: PMC2846218  PMID: 19818961
Apolipoprotein E; abdominal aortic aneurysm; genotype
7.  Association of PPARγ Allelic Variation, osteoprotegerin and abdominal aortic aneurysm 
Clinical endocrinology  2009;72(1):128-132.
We have previously demonstrated high concentrations of the glycoprotein osteoprotegerin (OPG) in biopsies of abdominal aortic aneurysm (AAA) and demonstrated that ligation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) downregulates OPG in vitro and within a mouse model. The aims of this study were to assess the associations between circulating concentrations of OPG, polymorphisms of the gene encoding PPARγ (PPARG), AAA presence and growth.
Design, patients and measurements
Two genetic polymorphisms in PPARG were assessed in 4227 men, 699 of whom had an AAA. For 631 men, who had AAAs, maximum aortic diameter was monitored by yearly ultrasound for a median of 5 years. Plasma OPG was measured in 838 men, 318 of whom had an AAA.
Plasma concentrations of OPG were independently associated with AAA (adjusted odds ratio 1.38, 95% CI 1.10–1.72). The PPARG c.1347C>T polymorphism was associated with plasma concentrations of OPG (beta 0.12, p<0.01). The PPARG c.34G>C polymorphism was weakly associated with AAA (adjusted odds ratio 1.28, 95% CI 1.01–1.61). PPARG c.1347C>T was associated with increased AAA growth (recessive model, p=0.03).
Circulating concentrations of OPG are associated with AAA and with one PPARG polymorphism. PPARG polymorphisms are weakly associated with AAA presence and growth. Confirmation of these findings is required in other cohorts.
PMCID: PMC2802661  PMID: 19438902
Abdominal aortic aneurysm; peroxisome proliferator-activated receptor-gamma; genetic polymorphism; osteoprotegerin
8.  The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI 
BMC Medical Genetics  2010;11:140.
Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the KCNJ11, PPARG, TCF7L2, IGF2BP2, CDKAL1, SLC30A8 and HHEX gene loci, with fasting glucose level; and of an obesity-associated variant in the FTO gene, with body mass index (BMI).
The study analysed data from the Busselton Health Study (n = 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models.
In cross-sectional analyses, we observed associations of the T allele at the IGF2BP2 single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (p = 0.045), and the A allele at the FTO SNP rs9939609 with raised BMI (p = 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood.
There was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time.
PMCID: PMC2958899  PMID: 20929593
9.  Polymorphisms of the MMP-9 gene and abdominal aortic aneurysm 
The British journal of surgery  2008;95(10):1239-1244.
Increased matrix metalloproteinase-9 (MMP-9) activity has been implicated in the formation of abdominal aortic aneurysms (AAAs). The aim of the present study was to explore the association between potentially functional variants of the MMP-9 gene and AAA.
The −1562C>T and −1811A>T variants of the MMP-9 gene were genotyped in 678 men with AAAs (>30mm in diameter) and 659 controls (aortic diameter 19−22mm) recruited from a population-based trial of screening for AAAs. The levels of MMP-9 were measured in a random subset of 300 cases and 84 controls. The association between genetic variants (including haplotypes) and AAA was assessed using multivariate logistic regression.
There was no association between the MMP-9 −1562C>T (OR 0.70 95%CI 0.27, 1.82) or −1811A>T (OR 0.71, 95%CI 0.28, 1.85) genotypes, or the most common haplotype (OR 0.81 95%CI 0.62, 1.05), and AAA. The serum MMP-9 concentration (ng/mL) was higher in cases than controls and in minor allele carriers in cases and controls although the differences were not statistically significant.
The results suggest that a genetic tendency to have higher levels of circulating MMP-9 is not associated with AAAs.
PMCID: PMC2597005  PMID: 18763261
10.  SimHap GUI: An intuitive graphical user interface for genetic association analysis 
BMC Bioinformatics  2008;9:557.
Researchers wishing to conduct genetic association analysis involving single nucleotide polymorphisms (SNPs) or haplotypes are often confronted with the lack of user-friendly graphical analysis tools, requiring sophisticated statistical and informatics expertise to perform relatively straightforward tasks. Tools, such as the SimHap package for the R statistics language, provide the necessary statistical operations to conduct sophisticated genetic analysis, but lacks a graphical user interface that allows anyone but a professional statistician to effectively utilise the tool.
We have developed SimHap GUI, a cross-platform integrated graphical analysis tool for conducting epidemiological, single SNP and haplotype-based association analysis. SimHap GUI features a novel workflow interface that guides the user through each logical step of the analysis process, making it accessible to both novice and advanced users. This tool provides a seamless interface to the SimHap R package, while providing enhanced functionality such as sophisticated data checking, automated data conversion, and real-time estimations of haplotype simulation progress.
SimHap GUI provides a novel, easy-to-use, cross-platform solution for conducting a range of genetic and non-genetic association analyses. This provides a free alternative to commercial statistics packages that is specifically designed for genetic association analysis.
PMCID: PMC2639440  PMID: 19109877
11.  Prenatal, perinatal, and heritable influences on cord blood immune responses 
Maternal and perinatal environmental exposures, as well as inherited factors, may influence neonatal immune responses.
To determine relations of maternal and perinatal exposures to antigen-specific cord blood lymphoproliferative responses.
In 427 newborns from a Boston pregnancy/birth cohort, lymphoproliferative responses in cord blood mononuclear cells to stimulation with cockroach (Bla g 2), house dust mite (Der f 1), ovalbumin, and mitogen phytohemagglutinin were measured as stimulation index (SI). We used the Wilcoxon rank sum and χ2 tests to evaluate predictors of ovalbumin SI as a continuous ranked or dichotomous outcome. We used t test and Spearman correlation for univariate testing and linear regression to evaluate predictors of natural log-transformed Bla g 2, Der f 1, and phytohemagglutinin SI. Logistic multivariate regression was applied to evaluate predictors of Bla g 2, Der f 1, and phytohemagglutinin SI dichotomized at 2 or at the median for phytohemagglutinin.
Maternal smoking during pregnancy, inadequate or excessive maternal weight gain during pregnancy, neonate black race/ethnicity (compared with white), and Apgar score less than 8 were each independently associated with increased cord blood mononuclear cell proliferative responses to stimulation with Bla g 2 and/or Der f 1. Maternal history of asthma was associated only with increased lymphoproliferative response to ovalbumin stimulation.
Distinct fetal and perinatal exposures and black race/ethnicity may be associated with increased cord blood lymphoproliferative responses. The implications of these findings for future development of allergy or asthma are, as yet, unknown.
PMCID: PMC1562525  PMID: 16597079
12.  Nuclear Factor Kappa B Activation in Human Cord Blood Mononuclear Cells 
Pediatric research  2004;56(2):212-218.
The immunologic signals participating in immune responses early in life have not been completely elucidated. Regarding the characterization of neonatal cells, little is known concerning the activity of transcription factor nuclear factor kappa B (NF-κB), which regulates inflammatory genes and cytokine production. The aim of this study was to characterize NF-κB activation in cord blood mononuclear cells (CBMC). We analyzed the potential association of NF-κB activity with lymphocyte proliferation and influences on cytokine secretion in the early immune system. To determine the contribution of a disease whereby inheritance may impact neonatal immunity, we assessed the influence of maternal allergic disease on NF-κB regulation and cytokine secretion. CBMC from healthy newborns were isolated and stimulated with mitogen (n = 28). Nuclear extracts were analyzed by electrophoretic mobility shift assay, cytokine secretion by ELISA. FISH analysis excluded relevant maternal contamination of CBMC. All samples showed a positive lymphoproliferative response, and NF-κB activity was both increased and decreased after mitogen stimulation. Increased NF-κB activation was significantly associated with decreased TNF-α secretion (median 6.1 versus 50.3 pg/mL) in unstimulated CBMC. Mitogen stimulation resulted in increased NF-κB activity with a trend to increased IL-13 production. Maternal allergic disease was associated with higher TNF-α (median 982 versus 173 pg/mL) and IL-13 secretion (median 1328 versus 1120 pg/mL) after mitogen stimulation. Together, NF-κB activity is differentially activated in cord blood and associated with a distinct cytokine pattern. Whether differential NF-κB activity in cord blood is related to the subsequent development of immune diseases requires further investigation.
PMCID: PMC1488728  PMID: 15181194
CBMC, cord blood mononuclear cells; EMSA, electrophoretic mobility shift assay; IFN-γ, interferon gamma; NF-κB, nuclear factor kappa B; PHA, phytohemagglutinin; SI, stimulation index; Th, T helper; TNF-α, tumor necrosis factor alpha
13.  Diminished Lipoxin Biosynthesis in Severe Asthma 
Rationale and Objectives: Severe asthma is characterized by increased airway inflammation that persists despite therapy with corticosteroids. It is not, however, merely an exaggeration of the eosinophilic inflammation that characterizes mild to moderate asthma; rather, severe asthma presents unique features. Although arachidonic acid metabolism is well appreciated to regulate airway inflammation and reactivity, alterations in the biosynthetic capacity for both pro- and antiinflammatory eicosanoids in severe asthma have not been determined.
Methods: Patients with severe asthma were identified according to National Heart, Lung, and Blood Institute Severe Asthma Research Program criteria. Samples of whole blood from individuals with severe or moderate asthma were assayed for biosynthesis of lipoxygenase-derived eicosanoids.
Measurements and Main Results: The counterregulatory mediator lipoxin A4 was detectable in low picogram amounts, using a novel fluorescence-based detection system. In activated whole blood, mean lipoxin A4 levels were decreased in severe compared with moderate asthma (0.4 [SD 0.4] ng/ml vs. 1.8 [SD 0.8] ng/ml, p = 0.001). In sharp contrast, mean levels of prophlogistic cysteinyl leukotrienes were increased in samples from severe compared with moderate asthma (112.5 [SD 53.7] pg/ml vs. 64.4 [SD 24.8] pg/ml, p = 0.03). Basal circulating levels of lipoxin A4 were also decreased in severe relative to moderate asthma. The marked imbalance in lipoxygenase-derived eicosanoid biosynthesis correlated with the degree of airflow obstruction.
Conclusions: Mechanisms underlying airway responses in severe asthma include underproduction of lipoxins. This is the first report of a defect in lipoxin biosynthesis in severe asthma, and suggests an alternative therapeutic strategy that emphasizes natural counterregulatory pathways in the airways.
PMCID: PMC2718403  PMID: 15961693
biosynthesis; chromatography, eicosanoids; high-pressure liquid; inflammation mediators
14.  JLIN: A java based linkage disequilibrium plotter 
BMC Bioinformatics  2006;7:60.
A great deal of effort and expense are being expended internationally in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Techniques such as Linkage Disequilibrium mapping are being increasingly used to examine and compare markers across increasingly large datasets. Visualisation techniques are becoming essential to analyse the ever-growing volume of data and results available with any given analysis.
JLIN (Java LINkage disequilibrium plotter) is a software package designed for customisable, intuitive visualisation of Linkage Disequilibrium (LD) across all common computing platforms. Customisation allows the user to choose particular visualisations, statistical measures and measurement ranges. JLIN also allows the user to export images of the LD visualisation in several common document formats.
JLIN allows the user to visually compare and contrast the results of a range of statistical measures on the input dataset(s). These measures include the commonly used D' and r2 statistics and empirical p-values. JLIN has a number of unique and novel features that improve on existing LD visualisation tools.
PMCID: PMC1402328  PMID: 16466584
15.  The effect of missing data on linkage disequilibrium mapping and haplotype association analysis in the GAW14 simulated datasets 
BMC Genetics  2005;6(Suppl 1):S151.
We used our newly developed linkage disequilibrium (LD) plotting software, JLIN, to plot linkage disequilibrium between pairs of single-nucleotide polymorphisms (SNPs) for three chromosomes of the Genetic Analysis Workshop 14 Aipotu simulated population to assess the effect of missing data on LD calculations. Our haplotype analysis program, SIMHAP, was used to assess the effect of missing data on haplotype-phenotype association. Genotype data was removed at random, at levels of 1%, 5%, and 10%, and the LD calculations and haplotype association results for these levels of missingness were compared to those for the complete dataset. It was concluded that ignoring individuals with missing data substantially affects the number of regions of LD detected which, in turn, could affect tagging SNPs chosen to generate haplotypes.
PMCID: PMC1866783  PMID: 16451612
16.  Genome-wide linkage and association mapping of disease genes with the GAW14 simulated datasets 
BMC Genetics  2005;6(Suppl 1):S41.
We combined the results of whole-genome linkage and association analyses to determine which markers were most strongly associated with Kofendrerd Personality Disorder. Using replicate 1 from the Genetic Analysis Workshop 14 Aipotu, Karangar, Danacaa, and New York City simulated populations, we determined that several markers showed significant linkage and association with disease status. We used both SNP and microsatellite markers to determine patterns and chromosomal regions of markers. Three consistently associated markers were C01R0050, C03R0280, and C10R0882. Using generalized linear mixed models, we modelled the effect of the three predefined phenotypic categories on disease status and concluded that the phenotypes defining the "anxiety-related" category best predicted the outcome.
PMCID: PMC1866743  PMID: 16451652
17.  Genome-wide linkage analysis of longitudinal phenotypes using σ2A random effects (SSARs) fitted by Gibbs sampling 
BMC Genetics  2003;4(Suppl 1):S12.
The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the familial aggregation and evidence for linkage to change in systolic blood pressure (SBP) over time. We used Gibbs sampling to derive sigma-squared-A-random-effects (SSARs) for the longitudinal phenotype, and then used these as a new phenotype in subsequent genome-wide linkage analyses.
Additive genetic effects (σ2A.time) were estimated to account for ~9.2% of the variance in the rate of change of SBP with age, while additive genetic effects (σ2A) were estimated to account for ~43.9% of the variance in SBP at the mean age. The linkage results suggested that one or more major loci regulating change in SBP over time may localize to chromosomes 2, 3, 4, 6, 10, 11, 17, and 19. The results also suggested that one or more major loci regulating level of SBP may localize to chromosomes 3, 8, and 14.
Our results support a genetic component to both SBP and change in SBP with age, and are consistent with a complex, multifactorial susceptibility to the development of hypertension. The use of SSARs derived from quantitative traits as input to a conventional linkage analysis appears to be valuable in the linkage analysis of genetically complex traits. We have now demonstrated in this paper the use of SSARs in the context of longitudinal family data.
PMCID: PMC1866446  PMID: 14975080
18.  Lack of reproducibility of linkage results in serially measured blood pressure data 
BMC Genetics  2003;4(Suppl 1):S37.
Using the longitudinal Framingham Heart Study data on blood pressure, we analyzed the reproducibility of linkage measures from serial cross-sectional surveys of a defined population by performing genome-wide model-free linkage analyses to systolic blood pressure (SBP) and history of hypertension (HTN) measured at five separate time points.
The heritability of SBP was relatively stable over time, ranging from 11.6 to 23.5% (coefficient of variation = 25.7%). However, the variability in linkage results was much greater. The average correlation in LOD scores at any pair of time points was 0.46 for HTN (NPL All LOD) and 0.17 for SBP (Variance Components LOD). No evidence of reproducible linkage results was found, with a mean κ of 0.02 for linkage to HTN and -0.03 for SBP linkage. At loci with potential evidence for linkage (LOD > 1.0 at one or more time points), the correlation was even lower. The coefficient of variation at loci with potential evidence of linkage was 126% for HTN and 135% for SBP. None of 15 chromosomal regions for HTN and only one of 28 regions for SBP with potential evidence for linkage had a LOD > 1.0 at more than two of the five time points.
These data suggest that, although heritability estimates at different time points are relatively robust, the reproducibility of linkage results in serial cross-sectional samples of a geographically defined population at successive time points is poor. This may explain in part the difficulty encountered in replicating linkage studies of complex phenotypes.
PMCID: PMC1866472  PMID: 14975105
19.  Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma 
Respiratory Research  2001;2(2):102-112.
Asthma is the most common chronic childhood disease in the developed nations, and is a complex disease that has high social and economic costs. Studies of the genetic etiology of asthma offer a way of improving our understanding of its pathogenesis, with the goal of improving preventive strategies, diagnostic tools, and therapies. Considerable effort and expense have been expended in attempts to detect specific polymorphisms in genetic loci contributing to asthma susceptibility. Concomitantly, the technology for detecting single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a method of investigating the genetic etiology of complex human diseases. This paper reviews both current and potential future contributions of SNPs to our understanding of asthma pathophysiology.
PMCID: PMC59575  PMID: 11686872
association studies; asthma; genetics; review; SNP
20.  Genome-wide association study of body mass index in 23,000 individuals with and without asthma 
Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics.
We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
Conclusions and Clinical Relevance
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
PMCID: PMC3608930  PMID: 23517042
Association; Asthma; BMI; Genetics; Genome-wide; Obesity
21.  Rationale, design and methods for a community-based study of clustering and cumulative effects of chronic disease processes and their effects on ageing: the Busselton healthy ageing study 
BMC Public Health  2013;13:936.
The global trend of increased life expectancy and increased prevalence of chronic and degenerative diseases will impact on health systems. To identify effective intervention and prevention strategies, greater understanding of the risk factors for and cumulative effects of chronic disease processes and their effects on function and quality of life is needed.
The Busselton Healthy Ageing Study aims to enhance understanding of ageing by relating the clustering and interactions of common chronic conditions in adults to function. Longitudinal (3–5 yearly) follow-up is planned.
Phase I (recruitment) is a cross-sectional community-based prospective cohort study involving up to 4,000 'Baby Boomers’ (born from 1946 to 1964) living in the Busselton Shire, Western Australia. The study protocol involves a detailed, self-administered health and risk factor questionnaire and a range of physical assessments including body composition and bone density measurements, cardiovascular profiling (blood pressure, ECG and brachial pulse wave velocity), retinal photography, tonometry, auto-refraction, spirometry and bronchodilator responsiveness, skin allergy prick tests, sleep apnoea screening, tympanometry and audiometry, grip strength, mobility, balance and leg extensor strength. Cognitive function and reserve, semantic memory, and pre-morbid intelligence are assessed. Participants provide a fasting blood sample for assessment of lipids, blood glucose, C-reactive protein and renal and liver function, and RNA, DNA and serum are stored. Clinically relevant results are provided to all participants. The prevalence of risk factors, symptoms and diagnosed illness will be calculated and the burden of illness will be estimated based on the observed relationships and clustering of symptoms and illness within individuals. Risk factors for combinations of illness will be compared with those for single illnesses and the relation of combinations of illness and symptoms to cognitive and physical function will be estimated.
This study will enable a thorough characterization of multiple disease processes and their risk factors within a community-based sample of individuals to determine their singular, interactive and cumulative effects on ageing. The project will provide novel cross-sectional data and establish a cohort that will be used for longitudinal analyses of the genetic, lifestyle and environmental factors that determine whether an individual ages well or with impairment.
PMCID: PMC3852572  PMID: 24099269
Busselton; Healthy ageing; Clusters of illness; Cross-sectional; Prevalence; Multi-morbidity
22.  Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits 
Diabetes  2012;61(8):2176-2186.
Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r2 > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post–oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.
PMCID: PMC3402303  PMID: 22698912
23.  Common variants at 6q22 and 17q21 are associated with intracranial volume 
Nature genetics  2012;44(5):539-544.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10−11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10−12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10−3 for 6q22 and p=1.2*10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.
PMCID: PMC3618290  PMID: 22504418
24.  Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study 
PLoS ONE  2013;8(4):e61253.
Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5–17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors.
To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia.
Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2–3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14).
Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52–95.28).
These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.
PMCID: PMC3634031  PMID: 23626673
25.  A comprehensive investigation of variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/R2), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome 
BMC Medical Genetics  2013;14:15.
Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals.
Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling.
Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134).
Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.
PMCID: PMC3598639  PMID: 23351195
Adiponectin; ADIPOQ; ADIPOR; Type 2 diabetes; Insulin resistance and Metabolic syndrome

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